Ross & Wilson Pharmacology

Allison Grant, BSc, PhD, FHEA

Lecturer, School of Health and Life Sciences, Glasgow Caledonian University,
Glasgow, UK

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Table of Contents

Cover image

Title page

Copyright

Preface

Acknowledgements

Dedication

1. The Story of Pharmacology

The origins of pharmacology

From bench to bedside

2. Pharmacokinetics:: How the Body Affects the Drug

Drug movement around the body

Drug disposition (ADME)

Half-life and steady state

Administration

Drug interactions

Pharmacokinetic special situations

3. Pharmacodynamics:: What the Drug Does to the Body

Introduction to Pharmacodynamics
 Principal Targets of Drug Action

Assessment of Drug Action

Adverse Drug Reactions

Drug Dependence

4. Drugs and Neurological Function

Introduction

The neurotransmitters of the nervous system

Histamine

Endorphins (Endogenous Opioids)

Glutamate

Antidepressants, mood stabilisers, and anxiolytics

Antipsychotic drugs

Anaesthetics

Anticonvulsants

5. Drugs and Endocrine Function

Introduction

Hypothalamic and Pituitary Hormones in Therapeutics

Drugs and Thyroid Function

Drugs and Pancreatic Function

Pharmacological Control of Reproductive Function

6. Analgesics and Anti-Inflammatory Drugs

The Physiology of Pain

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 Opioids

Inflammation and Anti-Inflammatory Drugs

7. Drugs and Cardiovascular Function

Introduction

Drugs and the Heart

Cardiac Arrhythmias

Drugs and Blood Vessels

Ischaemic Heart Disease

Haemostasis

8. Drugs and the Respiratory System

Introduction

Drugs and Pulmonary Defence Mechanisms

Obstructive Airways Disease

9. Renal and Genitourinary Drugs

Introduction to the Urinary System

Male Sexual Function

10. Drugs and the Gastrointestinal Tract

The Structure and Function of the Gastrointestinal System

Drugs and Gastric Function

Drugs and Disorders of Gastrointestinal Motility

Antiemetics
11. Antimicrobial Drugs

The Biology of Microbes

Antibacterial Drugs

AntiViral Drugs

Antifungal Drugs

Antiparasitical Drugs

12. Cytotoxic Drugs

Introduction

Drugs that Interfere with One or More Stages of the Cell Cycle

Cell Signalling Pathway Inhibitors

Hormone-Responsive Cancers

Monoclonal Antibody Therapies

Immunotherapy

Miscellaneous Chemotherapy Drugs

Index

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Copyright

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Preface

Records dating from ancient civilisations in Sumeria, Egypt, India, and China show the
origins of medicine and mankind’s attempts to understand and treat disease. Healing
practices in antiquity often relied on the intervention of gods, the wearing of talismans
to ward off disease, a strong belief in magic, and the use of ceremonial rituals to increase
the patient’s chance of recovery; however, the concept that external substances
swallowed, applied topically, or inhaled could influence outcomes was also very familiar
to the earliest physicians. These early medicines were derived from the natural world
and included plant, animal, and mineral extracts; most were useless, and many were
actively harmful.

Fast forward to the 21st century, and the use of drugs to prevent, cure, or manage
diseases has become a cornerstone of therapeutics. Very few human diseases or
disorders are managed without the use of drugs, and all healthcare professionals require
a thorough, evidence-based understanding of clinical pharmacology to prescribe safely,
to monitor the effectiveness of treatment, and to competently advise and inform patients
from a solid, evidence-based knowledge base. This text has been written with this role in
mind. It goes beyond the simple listing of drugs, their actions, and side-effects and
explains the science underpinning the mechanisms of action of drugs, but without being
bogged down with excessive detail. Understanding what a drug does to a living system
and how it exerts its biological effects explains the rationale behind its use in the disease
for which it is being used and the reason why it may have apparently unconnected side-
effects. Understanding how the human body responds to a drug introduced into its
living tissues is an essential prerequisite for safe prescribing and when monitoring
response to treatment. It ensures that the prescriber chooses the most appropriate
medicine and drug formulation and, as far as possible, anticipates problems arising
from inter-individual drug responses, interactions, and issues.
The ‘focus boxes’ used in several chapters are designed to encapsulate and present key
content, emphasising important concepts and topic areas. ‘Key points’ boxes and ‘key
definitions’ boxes have also been used to help navigation and to emphasise significant
terms.
The pharmacology described here is anchored firmly in its scientific basis, but with a
clear clinical slant. This textbook should be a useful resource for students and
practitioners in health-related professions and would also be an appropriate resource
for students in a range of life science programmes with an element of pharmacological
content. Together with its companion book, Ross and Wilson’s Pathophysiology, this
text is designed to provide a fundamental but thorough grounding in the areas of disease
and therapeutics. Both books have been written for you, the student; I hope this
textbook meets your needs and is of direct and measurable benefit to your studies and
your practice. I am happy to receive feedback, suggestions, and comments; academic
resources are always improved by collaboration and discussion!
Allison Grant
March 2024

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Acknowledgements

Without the (sometimes unseen but always appreciated) efforts of a range of people, this
textbook would never have made it all the way from a few undefined ideas rattling
around in my head to the finished product you now hold in your hands. I think of it as
‘my book’, because the time and effort required to prepare it has extended over 3 years,
greedily consuming evenings and weekends and at times crowding out everything else
going on in my life, though I am very conscious of and grateful for the support of family
and friends and the huge role played by the team at Elsevier, because it would never
have happened without them.

I thank Pauline Graham, formerly of Elsevier, who suggested and initiated the project
in the first place. My gratitude is also due to Anne Waugh, who knows what I owe to her
over the 20-plus years that we have been collaborators, co-authors, and friends. Thank
you, Anne, for your time in reviewing some of this content and for everything else you’ve
contributed to this project.
I thank all those at Elsevier who have had any part to play in the realisation of this
project. I have no direct contact with the experts who deal with page layout, typesetting,
or any of the other stages in converting my digital files, figure lists, and so on to the
finished pages, but I thank you very much. In particular, I owe a huge debt of gratitude
to Fariha Nadeem, who has been a constant, steady, and rock-solid support. I am also
very pleased to thank Marie Dean, who managed to translate my coloured scrawls and
scribbled instructions into the book’s clear and colourful artwork.
I’ve been in higher education for a good few years now and taught thousands of
students, and it is for you all that academics like me pick up our pens and write
academic textbooks. Thank you for the inspiration. Stay curious, stay interested, keep
reading, take nothing at face value, always look for the evidence base, always think ‘but
why…???’, keep asking questions, don’t expect me (or my academic colleagues) to have
all the answers, and be prepared to go out and find the answers for yourselves. We are
giving you the foundation, but you are the next generation and will be standing on our
shoulders.
 And finally, to my much-loved circle of family and friends, thank you for everything.
None of you helped me write any of this, so you can’t be blamed for any errors, but none
of this would have happened without you.
Allison Grant
March 2024

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Dedication

For my sun, moon, and stars, Seona, Struan, and Will: the adventures go on!!
1: The Story of Pharmacology

The origins of pharmacology

From bench to bedside

The Drug Development Process
Pre-clinical Development
Clinical Trials
Drug Names

The history of human drug use from its earliest origins, for which we only have
archaeological evidence, through the scientific revolution of the 18th and 19th centuries
up to today’s position as one of the key pillars of modern medicine, is one of the most
interesting stories in science. One current definition of pharmacology from the British
Pharmacological Society is ‘the science of drugs and their effects on living systems’. A
‘drug’ can be defined as any chemical substance, natural or synthetic, that affects some
aspect of the biology of a living system. This broad definition therefore encompasses not
just the clinically useful drugs that are the subject of textbooks like this one aimed at
students and practitioners in medical and healthcare professions, but also food
additives, environmental pollutants, dyes and other chemicals, and a wide range of
substances derived from the natural world, which includes some of the most toxic
chemicals known. The conventional use of the word ‘drug’ implies a substance used to
diagnose, treat, or prevent a medical condition as well as substances used recreationally,
and the term ‘clinical pharmacology’ came into use in the 1950s to refer to all aspects of
research, policy, safety, teaching, and use of drugs in humans.

The origins of pharmacology

Mankind has had a long and fascinating relationship with chemical substances that
affect some aspects of behaviour, feelings, or well-being. The earliest written record of

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the use of a drug is a scrap of Egyptian papyrus dating from 3500 BC describing alcohol
production, but archaeological evidence from even earlier periods indicates that
intoxicants were in use well before then.
The earliest recorded drugs were psychotropic agents used for recreational, ritual, and
medicinal purposes, and include alcohol, opium, and cannabis. Alcohol was being
fermented at least 10,000 years ago. Opium, the juice obtained from the seed head of
the opium poppy (Fig. 1.1), was cultivated, distributed, and sold widely throughout
large areas of the Middle East, Europe, and beyond. Its analgesic, euphoric, and sedative
properties were well understood, as was its lethality: it was used to ease the passage into
death and occasionally as a means to dispose of enemies. Archaeologists have found
little opium flasks in graves and other archaeological sites, in the shape of the opium
poppy seed head (Fig. 1.2), and analysis has shown that they contained opium and
sometimes other psychoactive substances. Hemp has been in use for production of
fibres for clothing and rope for thousands of years. The use of cannabis, derived from
hemp, also dates back to pre-history and was well-known in multiple cultures including
ancient China, the Middle East, Greece, and Rome.
FIG 1.1 The seed head of the opium poppy.Once the petals have
fallen off, exposing the seed head, opium is collected from vertical
cuts made in the seed head. From Garg A (2010) Implant dentistry,
2nd ed, Fig. 10.2. Philadelphia: Mosby.

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 FIG 1.2 Clay vessel from Crete in the shape of the opium poppy
seed head. From Karageorghis V, Kanta A, Stampolides NC, et al.
(2014). Kypriaka in Crete: from the bronze age to the end of the
archaic period. Zurich: A.G. Leventis Foundation.

The plant kingdom was mankind’s main source for medicinal and recreational drugs
for thousands of years, and there is evidence that in some cultures, manufacturing took
place on a large scale. In the late 2000s, a large kitchen dating from 2000 BC was found
in Ebla in Syria, close to the city palace. There was no evidence of food remains, but
there were traces of a range of plants used in medicine, including opium, chamomile
(used as an anti-inflammatory), and heliotrope (used to treat infections), indicating a
small-scale but well-established and well-organised drug preparation industry. In the
era before written records, knowledge of useful plants and how to prepare extracts must
have been part of a people’s oral tradition. Development of traditional medicines over
the centuries, with none of today’s understanding of chemistry, physiology, genetics, or
molecular biology, was largely a process governed by careful observation and trial and
error. That is not to dismiss natural remedies as ineffective or without an evidence base:
the use of opium as an analgesic and sedative in ancient cultures is proof of that. Many
substances found in the natural world are highly potent: extracts of foxglove (Digitalis
purpurea, Fig. 1.3) were used for centuries to treat dropsy. Dropsy is an obsolete term
for oedema, which usually collects in the lower limb. Although it can be due to several
conditions, one of the most common is heart failure, and the use of foxglove extract,
which contains digitalis, improved heart function and relieved the oedema. Digitalis is
still used today to treat heart failure and some arrhythmias.
FIG 1.3 Digitalis purpurea (foxglove) From Renneberg R (2023)

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 Biotechnology for beginners, 3rd ed, Fig. 7.30. Philadelphia:
Academic Press.

The scientific revolution of the 16th to 19th centuries brought rapid development
across the biological, physical, and chemical sciences, driven by the change in thinking
that is the scientific method––the process by which a researcher draws factual and
substantiated conclusions after careful experimentation and rigorous testing of a
hypothesis. Key to the emergence of pharmacology as a separate speciality were the
advances made in chemistry, particularly organic chemistry, and physiology. As the
early chemists learned how to extract, separate, synthesise, purify, and concentrate
substances of interest, it became possible to test accurately measured drug quantities in
biological systems. The first drug to be isolated from its crude extract was morphine,
purified from opium by Friedrich Setürner in 1804 (Fig. 1.4). As physiological
knowledge advanced, so did the understanding of what drugs were doing to the body
and how they acted, and drug use in medicine began very slowly to move away from
traditional, often arbitrary, frequently useless, and potentially lethal practices towards a
more evidence-based approach to therapeutics grounded in observation, measurement,
analysis, and pooled knowledge.
The development of analytical chemistry directly and indirectly produced whole new
classes of drugs, many of which remain in widespread use. For example, the synthetic
dye industry emerged in the mid-1850s and spawned a range of clinically important
drug groups. The first dye to be used medicinally was methylene blue, the same dye
used by Paul Ehrlich to demonstrate the presence of the blood–brain barrier (p. 12). In
1891, he was trying to stain the protozoa Plasmodium, which causes malaria, with
methylene blue to study it under the microscope. He observed that the dye inhibited the
activity of the protozoa and reasoned that it might be a useful agent to treat malaria in
humans; as a result, methylene blue was used for this purpose until the early 20th
century, when newer drugs superseded it. Phenothiazine antipsychotics such as
chlorpromazine, antihistamines such as promethazine, tricyclic antidepressants
such as amitriptyline, thiazide diuretics such as bendrofluazide, and sulphonamide
antibacterials such as sulphamethoxazole are all derived from the synthetic dye
industry.
 FIG 1.4 Friedrich Sertürner From Göttmann F (1999) Paderborn -
Geschichte der Stadt in ihrer Region. Band 2. Die frühe Neuzeit:
gesellschaftliche Stabilität und politischer Wandel. Berlin:
Schöningh.

In the first half of the 20th century, a plethora of new drugs appeared on the scene.
Generally, they were found by accident; drugs developed as a side-line of the dye
industry for example, or Alexander Fleming’s chance observation that Penicillium
moulds inhibited bacterial growth in his test plates, leading to the isolation of
penicillin (Fig. 1.5). More targeted drug development became possible as research
into the molecular basis of drug action rapidly advanced. Increasing knowledge of
receptor science, enzyme structure, and molecular and cell biology expanded our
understanding of how drugs interact with specific molecules to produce their biological
effects.

Biologics
In the last 40 years or so, biotechnology has generated a wide range of new therapeutics

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called biologics. Biologics are drugs whose active substance is made by a living
organism, including genetically engineered bacteria, and include antibodies, hormones,
immunomodulators, vaccines, cytokines, blood products, and growth factors.

Pharmacogenomics
Advances in genetics have shone a bright light onto the relationship between our genes
and disease, and on an individual’s response to drugs. This new field,
pharmacogenomics, is an important element in personalised medicine. It has been
estimated that between 30% and 60% of drug treatments are ineffective because of
genetically determined responses to the medication. Identifying important genetic
variations between individuals allows optimal therapeutic choices to be made based on
predicted drug responses and likely side-effects. This principle is illustrated in Fig. 1.6.
The group of patients shown in Fig. 1.6 all have the same disease, and all are being
treated with the same dose of the same drug. Within this group, the patients depicted in
green are predicted to respond well. The patients depicted in blue are predicted to
respond poorly, if at all, and for these patients a different dose or a different drug would
be a better choice. The patients depicted in red are predicted to experience significant
toxicity, and this drug should not be used in these patients.

FIG 1.5 A. Alexander Fleming. B. A culture plate showing a large

Penicillium mould on the left, surrounded by a clear area of agar into
which the bacteria covering most of the plate cannot grow. Fleming
concluded that the mould was producing a chemical toxic to the
bacteria. From Oria M and Raffin J (1971) Anatomie, physiologie,
hygiène, 3rd ed, Hatier.
 For instance, the gene that codes for the important drug-metabolising enzyme
CYP2D6 commonly harbours mutations that can affect how effective the final enzyme
product is. CYP2D6 metabolises a range of drugs including anti-arrhythmics,
antidepressants, and antipsychotics, and for the 25% of the population in whom
this enzyme is less active, their ability to metabolise these drugs is impaired and the risk
of potentially dangerous side-effects at normal doses is increased. Clearly, genetic
profiling information flagging up CYP2D6 deficiency in advance of prescribing would be
very useful. Another example is serious hypersensitivity to abacavir, an antiviral used
in HIV combination therapy. Around 5% of patients have a gene variant called HLA-
B∗5701, which increases the risk of a serious hypersensitivity reaction. Testing for this
mutation allows the clinical team to make an informed choice regarding the risk-benefit
ratio and has reduced the incidence of hypersensitivity reactions.

From bench to bedside

The science underpinning the action of drugs is the foundation on which safe clinical
pharmacology is based. It is useful to remember that the range of drugs used in
medicine represents the tip of an iceberg; the bulk of the iceberg represents the vast
amount of research time, money, and effort required to bring the drug into clinical use.
Much of that research is done at the lab bench, so-called basic science. Fig. 1.7 shows
the main stages of drug development.

The drug development process

The average journey time of a drug from the lab bench to reaching the market is over 12
years, at a cost of over £1.1 billion. Typically, from an initial pool of 10,000 candidates,
only one will be approved by the regulatory body, and only one in five drugs that reach
the market will actually recoup the costs involved in its development.
In modern pharmaceutical science, the development of a new drug follows
identification of a specific target. For example, if a lab-based research project in a
university or a research institute studying the pathology of an inflammatory disease
identifies a new enzyme that synthesises an inflammatory mediator, a drug that inhibits
that enzyme might be a useful anti-inflammatory agent. The structure of the enzyme can
be precisely determined, making it possible to design a range of compounds which could
be expected to inhibit enzyme activity. This is called rational drug design. In addition,
candidates from natural sources or compound libraries held by pharmaceutical
companies may also be screened. Tens or possibly hundreds of thousands of potential

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candidates can be tested to see if they inhibit the enzyme. Of these initial screens,
compounds with the most promising profiles are taken forward into more
comprehensive studies. These are called lead compounds. Most screened compounds do
not make it to this stage for one or more reasons; perhaps their molecular weight is too
high, they demonstrate toxicity in cell lines or animal studies, they may not be potent
enough, or they fail to show expected activity in animal studies.

Pre-clinical development
The small number of candidate compounds, typically 10–20, that make it through the
earlier stages are taken to pre-clinical development. This involves toxicity screening and
pharmacokinetic assessment (absorption, distribution, metabolism, and excretion) in
computer modelling, cell lines, and animal models. The test compounds will also
undergo chemical assessment looking at formulation options and any limitations to
large-scale synthesis. Drug candidates that perform satisfactorily in preclinical trials can
go forward to clinical trials in humans.

FIG 1.6 The advantages of predicting genetically determined drug

responses.All patients have the same disease, and all are being
treated with the same dose of the same drug. Green patients are good
responders and should do well on the treatment. Blue patients will
respond poorly or not at all, and this treatment is not the optimal
choice. Red patients will experience significant toxicity and the
 treatment should be avoided. Modified from Patrinos GP (2020)
Applied genomics and public health, Fig. 6.1. Philadelphia: Academic
Press.

FIG 1.7 The main stages in drug development. Reproduced from

Profile, 2015 (2015) Pharmaceutical Industry, PhRMA, Washington
DC.

Clinical trials
There are four main stages, and the candidate drug can be stopped at any stage if
thought appropriate. In phase 1 studies, the candidate drug is given in small doses to a
small group, usually 20 to 100, of healthy volunteers. The volunteers are monitored
carefully for any adverse effects. In phase 2 studies, the drug is given to larger groups
(100–500) of patients suffering from the condition(s) for which the candidate drug is
thought to be potentially useful. Most drugs that fail at clinical trial do so during phase 2
studies, because evidence emerges of unacceptable adverse effects or toxicity, or the
drug turns out to be inadequately potent. Phase 3 trials are much larger, double-blind,
randomised clinical trials in which the candidate drug is tested at different doses in
groups of thousands of patients against current treatments and/or placebo. Assuming
the phase 3 trials show the drug to be effective, non-toxic, and not associated with
unacceptable side-effects, the company can apply to the relevant national regulatory
board for approval to bring it to market. Phase 4 trials are the processes by which the
performance of drugs on the market are monitored and rare and/or chronic adverse

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effects picked up. They also include any special trials required to allow the drug to be
licensed in specific groups of patients, e.g. children.

Drug names
A drug may have three names: its chemical name, its generic name, and its proprietary
name.
The full chemical name is often long, unwieldy, and rarely appropriate for use in
clinical settings. The recommendation to take two tablets of N-(4-hydroxyphenyl)
acetamide for a headache would not mean much to most people; recommending two
paracetamol tablets on the other hand is a much clearer and more familiar
instruction.
The generic (non-proprietary) name of the active drug is the name approved by an
expert regulatory body and used internationally. Paracetamol is the generic name for
this drug assigned by the World Health Organisation and is the name used outside the
US; it is called acetaminophen in the US because that is the generic name given to it
by American regulatory bodies.
Proprietary names are assigned by a manufacturer to their own formulation of a drug.
Paracetamol can be sold under the brand names Tylenol, Panadol, Metacin, Calpol,
Crocin, Hedex, and others. It is important to realise that there is not always
bioequivalence between two brands of the same dose of the same drug, meaning that
depending on the formulation, preparations from different manufacturers may give
different rates and extent of absorption. Plasma levels 1 hour after taking 500 mg of
product A from one manufacturer may be very different to plasma levels 1 hour after
taking 500 mg of exactly the same drug but as proprietary product B from another
company. Changing from one brand to another can cause issues with drugs for which
even slight changes in plasma levels can cause adverse effects, e.g. anticoagulants and
anticonvulsants.

References
1. Dollery C.T. Clinical pharmacology-the first 75 years and a view of the future. Br J
Clin Pharmacol. 2006;61(6):650–665.
2. Wainwright M. Dyes in the development of drugs and pharmaceuticals. Dyes
Pigm. 2008;76(3):582–589.

Online resources
Adams J.U. Pharmacogenomics and personalized medicine Available
at:. https://www.nature.com/scitable/topicpage/pharmacogenomics-
and-personalized-medicine-643/, 2008.
Genomics Education Programme. What is pharmacogenomics? Available
at:. https://www.genomicseducation.hee.nhs.uk/blog/what-is-
pharmacogenomics/#tab-id-4, 2018.
Matyszak P. Happy plants and laughing weeds: how people of the ancient world
used – and abused – drugs Available
at:. https://www.historyextra.com/period/ancient-history/ancient-
drug-use-history-how-what-for-opium-hemp/, 2019.
Torjesen I. Drug development: the journey of a medicine from lab to shelf Available
at:. https://pharmaceutical-journal.com/article/feature/drug-
development-the-journey-of-a-medicine-from-lab-to-shelf, 2015.

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2: Pharmacokinetics:
How the Body Affects the Drug

Drug movement around the body

The Cell Membrane
Drug Transfer Across the Plasma Membrane
pH, Drug Ionisation, and Drug Transfer Across
Membranes
pH Partitioning and Ion Trapping
Drug Disposition (Adme)
Absorption
Distribution
Distribution into Tissues and Fluids
Sanctuary Compartments
Body Fat Partitioning
Plasma Protein Binding
Metabolism
Phase 1 Metabolism
Phase 2 Metabolism
Inducers and Inhibitors
First-Pass Metabolism
Excretion
Faecal Excretion

Renal Excretion
Half-Life and Steady State
Half-Life
Steady State and the Therapeutic Dose Range
Therapeutic Drug Monitoring
Administration
Drug Formulations

Oral Administration
Topical Administration
Intravenous Administration
Intramuscular Administration
Subcutaneous/Intradermal Administration
Inhalation
Intrathecal and Epidural Administration
Administration into Body Cavities
Drug Interactions
Pharmacokinetic Interactions
Absorption
Distribution
Excretion
Pharmacodynamic Interactions
Beneficial Interactions
Unwanted/Dangerous Interactions
Pharmacokinetic Special Situations
Older Age
Babies and Children
Pregnancy

Genetic Variability

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Pharmacokinetics is the umbrella term which describes how the tissues and organs of
the body deal with biologically active drugs, sometimes simply put as ‘what the body
does to the drug’. The body is very good at dealing with foreign or unwanted substances,
and an understanding of the physical and chemical principles governing these processes
is an important part of clinical pharmacology. For example, pharmacokinetic data
informs dosing regimens, predicts plasma levels (important to ensure that dose and
dose frequency are appropriate), and guides a prescriber when inter-individual
variability is likely to affect drug response. Discussion of the four key pharmacokinetic
processes––absorption, distribution, metabolism, and excretion, often referred to by the
mnemonic ADME––forms the core of this chapter, along with an explanation of
relevant key concepts such as half-life and steady state.

Drug movement around the body

In general, drugs do not remain at their site of administration but travel to distant
tissues; drug mobility is usually essential to achieving its therapeutic aim. The main
biological barrier to drug movement between and through body compartments is the cell
membrane.

The cell membrane

For drugs to move around the body, they must travel through sheets of body cells. For
example, a swallowed drug is absorbed into the tissues of the wall of the small intestine
and then across the walls of intestinal blood vessels into the bloodstream. To do this, the
drug molecules must travel through the layers of cells from the intestinal lumen to the
bloodstream, and to do so must travel through the plasma membranes enclosing each
cell. Fig. 2.1 shows the key features of the cell membrane. Cell membranes are semi-
fluid sheets of phospholipid. A phospholipid molecule has two regions: two hydrophobic
(water-repelling) lipid tails and a hydrophilic (water-attracting) head containing a
phosphate group. Because body fluids, including both intracellular and extracellular
fluids, are water-based, the phospholipid molecules align themselves into a bilayer, with
the hydrophobic tails oriented inwards and the hydrophilic heads pointing outwards.
Embedded in the membrane is a wide variety of proteins and carbohydrates, many of
which are important drug targets and discussed in more detail in Chapter 3. Protein
receptors allow the cell to respond to chemical signals such as hormones, growth factors,
cytokines, and other substances in the extracellular environment, and these receptors
are important targets for a very wide range of clinically important drugs. Additionally,
the membrane is punctured with pores, channels, and pumps, which permits it to
selectively transfer ions or molecules in or out of the cell.

FIG. 2.1 The cell membrane. From Waugh A and Grant A (2020)
Ross & Wilson anatomy and physiology in health and illness, 14th ed,
Fig. 3.2A. Oxford: Elsevier.

Drug transfer across the plasma membrane

Most drugs transfer passively across cell membranes by simple diffusion: that is, they
travel down a concentration gradient from an area of high concentration to an area of
low concentration (Fig. 2.2A). Advantages of simple diffusion are that energy is not
required, and the transfer process is not saturable. This means that there is no rate-
limiting step as there may be with carrier- or pump-driven transport mechanisms as
described below. Taking absorption from the small intestine into the bloodstream as an
example, drug levels in the intestine rise rapidly as a swallowed drug arrives from the
stomach. Drug molecules therefore diffuse rapidly into the tract wall and across the
walls of the blood vessels supplying it. Because the blood is constantly flowing, absorbed
drug is rapidly carried away, keeping drug levels in the blood lower than drug levels in
the tract lumen, and until most drug is absorbed from the intestine, there is a

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concentration gradient to ensure that drug diffusion and absorption continues.
However, not all drugs travel equally well across plasma membranes. The main factors
determining the efficiency of drug transfer through membranes are the lipid (fat)
solubility, molecular weight (MW), and electrical charge (degree of ionisation) of the
drug molecules.

FIG. 2.2 Transport mechanisms across the cell membrane.A.

Simple diffusion. B. Diffusion through ion channel. C. Facilitated
diffusion. D. Active transport. Modified from Hall JE and Hall ME
(2021) Guyton and Hall textbook of medical physiology, 14th ed, Fig.
4.2. Philadelphia: Elsevier Inc.

Fat Solubility
The plasma membrane is essentially a lipid sheet, and to transfer rapidly from one side
to the other, drug molecules must be fat-soluble. The more fat-soluble the drug, the
faster and more efficiently it can transfer. Water-soluble drugs are repelled by the
phospholipid bilayer and transfer slowly, and so travel less well through body tissues.
Most drugs used in clinical practice are highly fat-soluble.
Molecular Weight
The plasma membrane is thin but densely packed, and larger molecules travel through it
less easily than smaller molecules. Water molecules, despite being insoluble in fat, are so
small (MW 18) that they travel freely through plasma membranes. To facilitate efficient
movement around the body, drug molecules are generally small, with MWs less than
600, and drugs with a MW of 80,000 or more transfer very slowly, if at all.

Degree of Ionisation
The degree to which a drug molecule is ionised (electrically charged) affects its ability to
transfer across cell membranes because it affects its water solubility and therefore its
ability to pass through the lipid-rich cell membrane. The more highly ionised (charged)
the drug is, the more water-soluble it tends to be, and it is repelled by membrane lipids,
preventing its transfer. The degree of ionisation is affected by pH, as will be explored in
more detail later; this is an important concept because there are significant differences
in pH across different areas of the body.

Ion Channels
These channels allow ions to travel across the membrane to the other side (Fig. 2.2B).
They are found in all cell membranes, but are particularly important in nerve and
muscle cells, which rely on the movement of ions to generate and propagate electrical
currents.

Facilitated Diffusion
As in simple diffusion, in facilitated diffusion drug molecules move passively down their
concentration gradient, but at a faster rate because they are facilitated by a special
carrier molecule in the membrane (Fig. 2.2C). Like simple diffusion, this is also a
passive movement because no energy is required. The tissues richest in these carrier
molecules are the intestines, kidney, and liver, the cells of which require to actively
import a range of substances: the intestines for absorption, the kidneys for excretion,
and the liver for metabolism. Carrier mechanisms allow relatively water-soluble drugs to
transfer across plasma membranes, for example, the secretion of penicillin and
diuretics into the filtrate in renal tubules. Other examples include vitamin B12
absorption in the intestine. These carrier mechanisms can represent a rate-limiting step
in the transfer of drugs from one side of the membrane to the other. Once carrier
mechanisms are fully saturated and operating at their maximal capacity, increasing drug
concentrations does not increase transfer.

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Active Transport
Active transport mechanisms use energy in the form of ATP to move a molecule from
one side of the membrane to another and are useful when the drug is poorly lipid-
soluble and diffusion rates are low (Fig. 2.2D). They also allow a drug to be moved
against its concentration gradient, i.e. from low to high. Active transport mechanisms
are frequently involved in the transfer of cytotoxic drugs including 5-fluorouracil, as
well as iron salts, levodopa, and propylthiouracil. A point worth noting regarding
active transport mechanisms is that they have a maximum work rate, and so there is an
upper limit on the speed of drug transfer: the mechanism can become saturated at
higher drug concentrations.

pH, drug ionisation, and drug transfer across membranes

pH is a measure of the acidity or alkalinity (basicity) of a solution. An acidic substance
releases hydrogen ions (H+, also called protons) when in solution; an acidic solution
therefore is rich in H+ ions. The higher the [H+], the more acidic is the solution. A base
binds H+ ions and may release hydroxyl ions (OH-) when in solution. The pH of a
solution is measured using the pH scale (Fig. 2.3). The midpoint is assigned a value of 7
and represents pH neutrality, meaning the concentrations of OH- and H+ ions are equal.
pH values below 7 represent increasing acidity as the value approaches 1; each whole
value represents a tenfold increase in [H+], so that a solution of pH 4 has 10 times as
many H+ ions as a solution of pH 5. pH values from 7 up to 14 represent increasing [OH-
] or increasing alkalinity.
Most drugs are weak bases, although some (e.g. aspirin, warfarin, penicillin) are
weak acids. On arrival in the acidic environment of the stomach, because they are weak
bases and H+ ion acceptors, they pick up H+ ions and become positively charged. This
reduces their ability to travel across the stomach wall, and so they remain trapped in the
stomach fluids. However, when they arrive in the small intestine, where the pH is much
higher than in the stomach because the digestive juices are alkaline, they lose their H+
and revert to their uncharged form. This increases their ability to cross plasma
membranes, and as a result, they are absorbed across the intestinal wall into the
bloodstream (Fig. 2.4A).
For drugs that are weak acids, the opposite applies. Arriving in the stomach, the drug
molecules remain un-ionised (uncharged) because the gastric environment is already so
rich in H+ ions that they are unable to release their protons. As they remain un-ionised
(uncharged), even though the stomach is not designed for absorption, some drug
molecules diffuse into the tissues of the stomach wall and from there diffuse into the
bloodstream. Once in the small intestine, where the pH is much higher, they give up
their H+ ions, acquiring a net negative charge, and their ability to cross the intestinal
wall is greatly reduced (Fig. 2.4B). Having said that, most absorption of an acidic drug
still takes place in the small intestine, because although ionisation of the drug slows its
transfer across the tract wall, the total surface area of the small intestine is vast, which
favours absorption and compensates for the slow transfer.

FIG. 2.3 The pH scale. From Waugh A and Grant A (2020) Ross &
Wilson anatomy and physiology in health and illness, 14th ed, Fig.
3.2A. Oxford: Elsevier.

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 FIG. 2.4 The effect of pH on the ability of drugs to cross biological
membranes.A. The absorption of basic drugs is inhibited in the
stomach because the drug molecules attach H+ ions and become
ionised, but it is facilitated in the small intestine, where they lose the
H+ ions and revert to their uncharged form. B. The absorption of
acid drugs is facilitated in the acidic environment of the stomach,
where the molecules remain un-ionised, but it is slower in the
alkaline environment of the small intestine, because they give up H+
ions and acquire a net negative charge.

pH partitioning and ion trapping

The take-home message from the previous section is that acidic drugs tend to be
attracted into and accumulate in basic environments, where they give up their H+ ions
and acquire a net negative charge, reducing their ability to travel out of that
environment. By the same reasoning, basic drugs tend to be attracted into and
accumulate in acidic fluids: once in an acidic environment, they pick up H+ ions,
acquiring a positive charge, which reduces their ability to cross membranes and escape.
pH differences between body fluids therefore affect how acidic and basic drugs
distribute between them. This is called pH partitioning and leads to ion trapping (Fig.
2.5). Altering the pH of body fluids can be useful in certain circumstances to facilitate
the movement of a drug from one body fluid to another. For example, aspirin is weakly
acidic and so will tend to remain in the blood plasma, which is weakly alkaline (pH 7.4)
in preference to the urine, which is weakly acidic (pH 6). In overdose, to accelerate
urinary excretion of aspirin, a bicarbonate infusion may be given. The excess
bicarbonate is excreted in the urine, causing a temporary rise (alkalinisation) in urinary
pH and facilitating the movement of aspirin from the bloodstream into the renal filtrate.

FIG. 2.5 pH partitioning.Acid drugs are un-ionised in an acid

environment and so can leave and enter a basic environment, where
they ionise and are trapped. Basic drugs are un-ionised in a basic
environment and so can leave and enter an acid environment, where

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 they ionise and are trapped.

Drug disposition (ADME)

The four main pharmacokinetic processes (absorption, distribution, metabolism, and
excretion) are described below individually for convenience and represented in Fig. 2.6,
but it is important to remember that a drug present in the body will be undergoing all
four processes simultaneously.

Absorption
Absorption is the process by which drug molecules travel from their site of
administration across biological membranes into the bloodstream. The term
bioavailability refers to the percentage of administered drug that reaches the systemic
circulation. Drugs given intravenously therefore have 100% bioavailability, but the
figure is often much lower for drugs given orally, due to drug degradation in the
intestine, first-pass metabolism (see below), and/or incomplete absorption. As
described above, the properties of a drug molecule that promote absorption are small
size, high fat solubility, and little overall electrical charge (an un-ionised state). Some
drug molecules are too large, too water-soluble, and/or too highly charged to transfer
across cell membranes, but this can be clinically useful. For example, nystatin is too
toxic to be used systemically, but because it is not absorbed from the gut, it can be given
orally to clear fungal infections of the gastrointestinal (GI) tract.

FIG. 2.6 Summary of ADME.GI, gastrointestinal. From Burchum

 JR and Rosenthal LD (2016) Lenhe’s pharmacology for nursing care,
9th ed, St. Louis: Elsevier.

Most absorption of an orally administered drug takes place in the small intestine, and
to get there it must pass through the stomach. The gastric environment is designed to be
hostile to protect the body against potentially dangerous ingested substances: gastric
fluids are strongly acidic, which denatures peptides and proteins, and contain the
proteolytic enzyme pepsin. Some drugs are completely destroyed here, and others
significantly are degraded. Enteric-coated formulations can protect the drug until it
reaches the intestine.
The rate of gastric emptying is a major determinant of the speed at which a swallowed
drug reaches the duodenum, and therefore factors that reduce gastric motility delay
drug absorption. Gastric emptying is generally fastest when a drug is taken on an empty
stomach with a glass of cold water. Gastric emptying is slowed in pain, in shock, in
neuropathies (including diabetic neuropathy), and when there are foodstuffs in the
stomach, especially fatty foods. Some drugs, including opioids and drugs with
antimuscarinic activity, reduce gastric motility. Some foodstuffs can bind certain
drugs, reducing their absorption; for example, tetracyclines should not be taken with
dairy products because they bind the calcium present in these food items, forming an
insoluble complex which cannot be absorbed.
Conditions that reduce blood flow through the GI tract, like heart failure, can also
slow absorption.

Distribution
Distribution is the transfer of a drug from the bloodstream into body tissues and fluids.
Drugs do not distribute evenly throughout body tissues, and the main principles
governing this are explained below. For example, water-soluble drugs tend to remain in
the plasma, whereas very fat-soluble drugs are rapidly taken up and concentrated in
body fat stores. Drug delivery is usually proportional to the blood flow: the higher the
blood flow, the greater the drug delivery to the area. The kidneys, central nervous
system (CNS), and liver receive a high proportion of cardiac output relative to their
weight, and therefore can be exposed to particularly high levels of any circulating drug.

Distribution into tissues and fluids

Drugs absorbed in the small intestine pass through the liver (see ‘First-pass metabolism’
below) into the systemic circulation. From here they distribute into other body tissues

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and fluids, and given enough time, the drug will equilibrate between these
compartments (Fig. 2.7). For example, circulating plasma levels of a drug which enters
the cerebrospinal fluid (CSF) will equilibrate between the blood and CSF, and, provided
plasma levels remain constant, CSF levels will also remain constant. However, if plasma
levels fall because dosing is stopped, drug levels in the CSF will also fall as drug
redistributes from the CSF into the blood to maintain equilibrium. This two-way
movement of drug is indicated in Fig. 2.7 by the two-way arrows.
Body fat (adipose) tissue is an important compartment when considering drug
distribution because fat-soluble drugs are taken up and stored here. The percentage
contribution to total bodyweight from fat varies considerably and can make a significant
difference to drug dosages and plasma half-lives.

FIG. 2.7 Drug distribution.Drug absorbed from the plasma

equilibrates between body tissues and fluids. CNS, central nervous
system; GI, gastrointestinal. Modified from Ha CE and Bhagavan NV
(2023) Essentials of medical biochemistry, 3rd ed, Fig. 35.3. San
 Diego: Academic Press.

Drug levels in the body are usually measured as plasma concentrations because it is
easy and convenient to take blood samples; however, it must be remembered that
probably only a small fraction of the drug is likely to be found in the blood because most
of it will have distributed out of the plasma and into the tissues. Assuming the drug
molecules are capable of efficient transfer across biological membranes, they are likely
to access all body tissues and fluids, although this is influenced by how much of the drug
is bound to plasma proteins and how much is free (see below). Because of this extensive
distribution, very little of the administered dose reaches its target tissue.

Volume of Distribution
The volume of distribution (Vd) is an important concept in clinical pharmacokinetics
because it gives an indication of how much of the total body drug has been retained in
the plasma and how much has distributed into other body tissues and fluids. This is
important when deciding what dose of drug to use to achieve a desired plasma level, and
it determines the half-life (see below) of the drug.

Key c onc ept

To calculate the Vd, plasma levels are measured following administration of a known
quantity of drug. In a hypothetical example, 100 mg of drug A is given intravenously.
After the drug has been allowed to distribute out of the blood and into the tissues, the
drug plasma concentration is measured. In our hypothetical case, the plasma level of
drug A is 1 mg/L. Vd is calculated by dividing the total amount of drug in the body (100
mg) by plasma levels of that drug (1 mg/L), giving a Vd of 100 L. This is the total volume
of fluid that would be needed for our 100 mg of drug to achieve a homogenous plasma
concentration of 1 mg/L. Clearly, the body does not possess 100 L of plasma, and so
most of the drug must have left the plasma and entered other body compartments (Fig.
2.8A). Compare this to an intravenous (IV) 100 mg dose of hypothetical drug B. If the
plasma concentration following administration of 100 mg of drug B is 20 mg/L, the Vd is
100 mg/20 mg/L, or 5 L. This shows that a much higher proportion of the drug has

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remained in the plasma and much less has distributed into peripheral tissues, and in
this example, much lower doses of drug B are likely to be needed to reach a desired
plasma level than drug A (Fig. 2.8B).
Therefore, the more of an administered dose of a drug that escapes from the plasma
into other compartments, including body fat stores and general body tissues, the higher
the Vd. Because the drug must be in the plasma to be cleared from the body, whether by
metabolism or renal excretion, if most of the drug is elsewhere, then clearance is going
to be slow and the plasma half-life (see below) long. High Vd values are therefore
associated with long plasma half-lives, and drug A in the above example will likely have
a much longer half-life than drug B.
FIG. 2.8 Relationship between volume of distribution, plasma
levels, and half-life.A. When most drug leaves the circulation, plasma
levels are low and the volume of distribution is high. B. When most

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 drug stays in the circulation, plasma levels are high and the volume
of distribution is small.

Sanctuary compartments
Drug distribution can be limited by membranes specially adapted to reduce their
permeability. The placenta, for example, reduces the transfer of unwanted substances
from the mother’s bloodstream into the fetal circulation. The blood vessels supplying the
testis are also less permeable than standard capillaries, to protect the sperm-producing
stem cells from exposure to potentially toxic substances in the circulation. The largest
sanctuary compartment comprises most of the brain and spinal cord and is protected by
the blood–brain barrier.

The Blood–Brain Barrier

The first scientist to demonstrate that some substances circulating in the bloodstream
cannot access large areas of the brain and spinal cord was Paul Ehrlich (1854–1915),
who injected mice with methylene blue dye and noted that while other body organs
stained heavily, the dye was excluded from most of the CNS. The specialised features of
brain capillaries responsible for this protective mechanism are collectively called the
blood–brain barrier (BBB). Fig. 2.9 shows the main features of the BBB compared with
a typical blood capillary. Typical capillaries are porous, with loose and leaky junctions
between the endothelial cells forming their walls, allowing rapid and free exchange of
small molecules. Endothelial cells in brain capillaries are however joined at tight
junctions, which are much less leaky, and capillaries are wrapped in an additional layer
of extensions from astrocytes, providing an extra barrier to the movement of substances
between the brain tissue and the blood. In addition, specific transporter mechanisms in
the capillary wall can export any drug molecules that do escape into the brain and return
them to the blood.
However, it must be emphasised that brain tissue is very lipid-rich, and the CNS has a
very high blood supply. This means that most drugs reach the CNS, even if at lower
concentrations than in the plasma, and transfer across the BBB increases as the dose
rises. Many drugs, being small and fat-soluble, have no difficulty in crossing the BBB
and equilibrate quickly between the CSF and the blood.

Body fat partitioning

Because most drugs are fat-soluble, a proportion of a drug dose will be taken up into
adipose tissue. Adipose tissue acts as a drug reservoir, and large quantities of drugs with
particularly high fat solubility, like benzodiazepines, can accumulate here.

Drug Distribution in People with High Body Fat Content

People with high body fat content can store considerable quantities of fat-soluble drugs
in their adipose tissue. At the start of a course of treatment, a large proportion of a fat-
soluble drug can be rapidly taken up into fat stores, and plasma levels remain low until
fat stores are saturated. It can therefore take longer to reach therapeutic blood levels,
and if a rapid effect is needed, it may be necessary to give initial loading doses to bring
plasma levels up rapidly. When the drug is withdrawn, as drug levels in the plasma fall,
drug leaches out of adipose tissue and can keep blood levels high for an extended period
even though drug administration has stopped. Older people, even those of a healthy
weight, are also likely to store larger quantities of drug because ageing is usually
accompanied by loss of lean tissue, and fat therefore contributes a larger proportion of
body mass. This is one reason why drugs can accumulate more readily in older people.

FIG. 2.9 The main features of the blood–brain barrier.Compared

with a general capillary (left), capillaries supplying much of the brain
feature tight junctions and an additional insulating layer of astrocyte
foot processes. Modified from Lundy-Ekman L (2023) Neuroscience,
6th ed, Fig. 26.12. St. Louis: Saunders.

Drug Distribution in People With Low Body Fat Content

Conversely, people with below average fat content may need below average drug doses
because less is taken up into body fat and more remains in the plasma, resulting in
higher blood drug concentrations.

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Plasma protein binding
Blood plasma contains a range of large-MW proteins, including albumins, globulins, and
the clotting protein fibrinogen. Most plasma proteins are synthesised in the liver.
Almost all drugs bind loosely and reversibly to plasma proteins, mainly albumin. This
binding is not specific like drug-receptor binding; instead, it is a non-specific
electrostatic attraction between negatively and positively charged groups on the drug
and protein molecules. Bound drug (the ‘bound fraction’) cannot leave the bloodstream
because the drug–protein complex is too large; this means that it does not get into the
liver cells for metabolism and does not pass through the glomerular filter in the kidney.
Bound drug is therefore protected from metabolism and renal excretion. Because it
cannot leave the circulation, bound drug is also unable to reach its target tissue, and so,
although it is chemically and biologically active, it is unable to produce its
pharmacological effect. On the other hand, unbound drug, the so-called ‘free fraction’, is
subject to metabolism and excretion and is free to leave the bloodstream and enter
tissues (Fig. 2.10). The pharmacological effect of the drug is therefore exerted by the
free fraction, and depending on the degree to which a drug is plasma protein-bound, the
free fraction might be only a small proportion of the total drug present in the
bloodstream.
 FIG. 2.10 Free and bound drug in the bloodstream.Unlike the free
fraction, drug molecules bound to plasma proteins are unable to
leave the circulation. Modified from Lilley LL, Collins S, and Snyder
J (2023) Pharmacology and the nursing process, 10th ed, Fig. 2.4. St.
Louis: Mosby.

For nearly all drugs at therapeutic concentrations, when administered regularly, the
free and bound drug fractions reach an equilibrium, and the proportion of drug
molecules bound to plasma proteins remains constant. This means that as plasma levels
of the free fraction fall, drug molecules dissociate from their binding sites to maintain
this equilibrium. For example, for a hypothetical drug that is 50% bound and 50% free,

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half the drug molecules are plasma protein-bound and half are free in the plasma. As the
free drug is cleared from the plasma by metabolism or excretion, drug molecules
dissociate from their plasma proteins to maintain the 50:50 ratio (Fig. 2.11). For this
reason, bound drug can be considered a ‘reservoir’, like drugs stored in body fat: present
in the bloodstream, not pharmacologically active, but which can replenish and maintain
plasma levels even after the drug is withdrawn.

FIG. 2.11 Equilibrium is maintained (50:50 ratio) between free

and bound fraction as free drug is lost from the circulation by
metabolism and excretion.

Because there is normally an excess of plasma protein-binding sites available, even

when multiple drugs are present in the plasma, they are generally not saturated. One
important potential interaction however is between warfarin and aspirin, which
compete for the same plasma protein-binding sites. The principle behind this potential
interaction is shown in Fig. 2.12. Fig. 2.12A represents the situation in an individual
stabilised on warfarin where the free and bound fractions have equilibrated. Warfarin in
the plasma is usually more than 98% bound, meaning that fewer than 2% of the warfarin
molecules in the blood are free. Introduction of aspirin (Fig. 2.12B) leads to
competition between the drugs for the available binding sites, and the free fraction of
each drug rises, increasing the risk of side-effects, e.g. warfarin-induced bleeding.
Factors that reduce plasma protein levels can reduce the bound fraction of a drug
because fewer binding sites are available: for example, liver disease or protein
malnutrition.

Metabolism
Metabolism refers to any enzymatic alteration to the structure of the parent drug. Most
body tissues can metabolise drugs to some degree, but the liver and kidneys are the
main organs of metabolism, and liver and/or renal impairment can significantly reduce
an individual’s capacity to metabolise drugs. Conditions such as heart failure that reduce
blood flow to the liver and kidneys can reduce delivery of the drug to these organs and
reduce the rates of metabolism and clearance. Thyroid disease can also affect drug
metabolism because thyroxine is an important regulator of metabolism.
Hypothyroidism can reduce drug metabolism, whereas hyperthyroidism accelerates it,
and drug doses may need to be adjusted accordingly in these conditions.
The ability of metabolising enzymes to keep up with rising plasma drug levels is not
infinite; this is explored in more detail in the section headed ‘First-order and second-
order kinetics’ below.
Liver cells (hepatocytes) are packed with metabolising enzymes responsible for the
phase 1 and phase 2 reactions described below. Hepatic metabolism therefore relies
upon drugs being able to cross hepatocyte membranes and enter the cell. Because most
drugs used in clinical practice have the chemical properties to do this (small, fat-soluble,
and un-ionised), this is usually straightforward. Larger, highly charged, and more water-
soluble drug molecules such as penicillin, digoxin, and the aminoglycoside antibiotics
(e.g. gentamicin) cannot enter hepatocytes and so are poorly metabolised. The body
relies on renal excretion (see below) to clear such drugs.

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 FIG. 2.12 Warfarin and aspirin competing for plasma protein-
binding sites.A. Warfarin alone. B. Introduction of aspirin can
displace bound warfarin and increase free warfarin levels, potentially
causing adverse effects. Modified from Howe T and Burton A (2021)
Pharmacology for the surgical technologist, 5th ed, Fig. 1.14. St.
Louis: Elsevier.

Because the biological activity of a drug is usually tied very closely to its precise
chemical shape and structure, metabolism often reduces or abolishes a drug’s
pharmacological action. However, the primary function of metabolism is not actually to
deactivate drugs, but to make them more water-soluble and enhance their excretion in
the urine. Any product of a metabolic step is called a metabolite.
Key Points
In terms of activity, there are three possible scenarios by which metabolism can affect
drugs:

• An active drug is metabolised to one or more inactive metabolites. This is

frequently the case because, as explained above, changes to the drug’s chemical
structure usually alter its biological activity.
• An active drug is metabolised to one or more active metabolites. Sometimes
metabolites retain significant pharmacological activity. This prolongs the drug’s
duration of action. Examples include many benzodiazepines, e.g. diazepam, and
opioids, e.g. morphine, codeine, and diamorphine.
• An inactive drug is metabolised to one or more active metabolites. A drug given in
an inactive form is called a pro-drug and it relies on metabolism to produce the
active form. Important pro-drugs include zidovudine, acyclovir, enalapril,
and cyclophosphamide.

The two types of metabolism are phase 1 and phase 2 reactions (Fig. 2.13).

Phase 1 metabolism
Phase 1 reactions increase the water solubility of the parent molecule by adding or
exposing one or more charged groups: these are usually oxidation, reduction, or
hydrolysis reactions. The metabolite is often more reactive than the parent molecule,
which prepares it for a phase 2 reaction. This can mean that the metabolite is more toxic
than the original drug: for example, cyclophosphamide, paracetamol, ethanol,
and halothane all produce highly toxic metabolites which must undergo immediate
further metabolism to render them harmless.

The Cytochrome P450 Enzyme Family

The cytochrome (CYP) P450 superfamily of enzymes contains 57 members classified
into four main families (CYP1–CYP4), and each family is further subdivided. The main
CYP enzymes involved in drug metabolism are shown in Fig. 2.14. They perform phase
1 reactions by oxidising their target molecule. CYP enzymes are found in the liver, the
wall of the GI tract, and multiple other tissues, and it is likely that they metabolise
around 90% of the most commonly used drugs. Genetic variation in the ability to
produce CYP enzymes is an important factor in an individual’s ability to metabolise

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drugs. Poor metabolisers clear drugs more slowly and are more likely to experience side-
effects, whereas rapid metabolisers clear drugs very quickly and may not respond to
normal doses.

Other Phase 1 Enzymes

A range of other enzymes perform phase 1 reactions. Examples include esterases in the
plasma which hydrolyse aspirin (acetylsalicylic acid), removing the acetyl group and
releasing salicylic acid. Alcohol dehydrogenase is one of the enzymes that metabolises
ethanol; it oxidises alcohol, producing acetaldehyde, which is even more toxic than
alcohol itself, and which is further broken down into harmless substances. Monoamine
oxidase (MAO) is involved in the breakdown of the neurotransmitters noradrenaline,
dopamine, and serotonin. MAO inhibitors such as phenelzine have been used for
decades as antidepressants although their use nowadays has largely been supplanted by
newer drugs.

FIG. 2.13 Phase 1 and phase 2 metabolism. Images used to

generate this figure were modified from Servier Medical Art, licensed
under Creative Commons Attribution 3.0 Generic License,
 http://smart.servier.com/

FIG. 2.14 The main CYP enzymes involved in drug

metabolism.CYP, cytochrome The data for the chart were taken from
Zanger UM and Schwab M (2013) Cytochrome P450 enzymes in
drug metabolism: regulation of gene expression, enzyme activities,
and impact of genetic variation. Pharmacology and Therapeutics,
138 (1), 103–141.

Phase 2 metabolism
Phase 2 reactions may follow a phase 1 reaction, or the parent drug may undergo phase
2 metabolism directly. The water solubility of the drug or its metabolite is further
increased by adding a water-soluble group such as an acetyl group or glucuronate.
Adding another group to the drug is called conjugation. As with phase 1 reactions, there
is significant genetic variation in people’s ability to undergo phase 2 reactions: for
example, acetylation is the main mechanism by which several drugs, e.g. isoniazid,
hydralazine, procainamide, and sulphonamides, are metabolised. Poor

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acetylators metabolise these drugs significantly more slowly than fast acetylators.

Inducers and inhibitors

An enzyme inducer increases the activity of a metabolising enzyme, and an enzyme
inhibitor reduces it. Enzyme induction therefore increases the metabolism of an affected
drug and reduces its plasma levels, and so is likely to reduce its expected activity,
potentially to a level where there is no therapeutic effect. Enzyme inhibition suppresses
metabolism and so slows the clearance of an affected drug, increasing plasma levels,
enhancing its action, and increasing the risk of adverse effects. Fig. 2.15 shows the
changes in plasma levels of a hypothetical drug when an inhibitor or an inducer is
introduced. An important exception to this is when the affected drug is a pro-drug and
relies on metabolism to activate it. In this circumstance, inhibition of metabolism
actually reduces the therapeutic action of the drug by preventing its activation.
Induction and inhibition of metabolising enzymes, especially CYP enzymes, are
important causes of interactions. Table 2.1 lists some important inducers and
inhibitors. Polypharmacy increases the likelihood that one drug may affect the
metabolism of another, but note that foodstuffs, alcohol, so-called ‘natural’ therapies,
and cigarette smoking are also implicated. For example, broccoli, smoking, and grilled
foods induce CYP enzymes, whereas grapefruit juice contains flavonoids which inhibit
CYP enzymes and reduce the metabolism of a range of drugs including calcium-
channel blockers, oestrogens, and statins.
 FIG. 2.15 Changes in plasma levels of a hypothetical drug following
the introduction of an enzyme inhibitor or an enzyme
inducer.Inhibition of metabolism increases drug concentrations, and
induction of metabolism reduces them. Modified from Atkinson A Jr,
Abernethy D, Daniels C, et al. (2007) Principles of clinical
pharmacology, 2nd ed, Fig. 15.2. San Diego: Academic Press.

Table 2.1

Examples of Enzyme Inhibitors and Inducers

Inhibitors Inducers
Cimetidine Some anticonvulsants including phenytoin,
carbamazepine, and primidone
Chloramphenicol Alcohol
Erythromycin Rifampicin
Allopurinol Cigarette smoking
Ribonavir

ALGrawany
 Ciprofloxacin Spironolactone
Isoniazid St. John’s wort
Some foodstuffs including Some foodstuffs including Brussels sprouts,
grapefruit and grapefruit juice broccoli, barbecued meats

Autoinduction is the property of a drug to induce its own metabolising enzymes.

When this happens, the drug’s half-life reduces with time. For example, the half-life of
an initial dose of carbamazepine can be up to 48 hours, but it falls to 10–20 hours on
repeated administration because the liver rapidly increases the levels of CYP enzymes to
metabolise it.

First-pass metabolism
This refers to any metabolism of an orally administered drug occurring between the
intestine and systemic circulation (Fig. 2.16). Significant drug loss can occur in the
hostile gastric environment because of the low pH and the action of the proteolytic
enzyme pepsin. The main site of absorption is the small intestine, whose walls are
packed with digestive enzymes, and the drug can be degraded here. Substances
absorbed from the stomach and most of the intestine travel in the hepatic portal vein to
the liver, the organ most strongly associated with first-pass metabolism. The liver has an
important role in detoxification of unwanted substances and regulating the levels of key
blood constituents, and so this arrangement ensures that potentially toxic substances
including drugs, or materials absorbed in excess from the intestines, pass first through
the liver before being delivered into the systemic circulation. After passing through the
liver, the blood then travels in the hepatic vein to the inferior vena cava.
 FIG. 2.16 First-pass metabolism. Modified from Townshend A,
Worsfold P, and Poole C (2005) Encyclopedia of analytical science,
2nd ed, Fig. 3. Oxford: Elsevier.

For some drugs, like glyceryl trinitrate, the liver removes 100% of an absorbed
drug, so oral bioavailability is zero. Other drugs, such as morphine, are not completely
eliminated, but most of the dose is destroyed and only a small proportion of the drug
reaches the systemic circulation.
The veins draining the upper and lower parts of the GI tract do not empty into the
hepatic portal vein but deliver their blood directly into the systemic circulation. Drugs
absorbed across the membranes of the mouth and the rectum are therefore not exposed
to first-pass metabolism. For this reason, glyceryl trinitrate is given sublingually.
Drugs are often given rectally for reasons other than avoidance of first-pass metabolism,
e.g. for a local anti-inflammatory action in haemorrhoids or anal fissures. However,
avoiding first-pass metabolism can be a significant advantage when administering drugs
rectally for systemic absorption; analgesics, sedatives, and anticonvulsants may
all be given by this route to maximise the amount of drug reaching the circulation.

Excretion
Excretion is the removal of drugs or their metabolites from the body. The main route of
excretion for most drugs is via the kidney, but drugs may be excreted in any body fluid

ALGrawany
or tissue, including bile, faeces, breast milk, hair, nails, sweat, and exhaled droplets.

Faecal excretion
Orally administered drugs that are poorly absorbed remain in the GI tract and are
excreted in the faeces. In addition, some drugs conjugated in the liver are passed into
the bile, which is then secreted into the duodenum. Conjugated drugs can pass through
the intestines and be excreted in the faeces, but some can be reabsorbed via
enterohepatic recycling.
FIG. 2.17 Enterohepatic recycling.A drug may be conjugated in the
liver and be passed into the bile. Once in the colon, bacteria may
metabolise the drug–conjugate complex, releasing the lipid-soluble
drug again, which can then be reabsorbed into the circulation. From
Waller DG, Sampson A, and Hitchings A (2022) Medical

ALGrawany
 pharmacology and therapeutics, 6th ed, Fig. 2.13. Oxford: Elsevier.

Enterohepatic Recycling
Conjugated drugs, which are now very water-soluble, can be passed into the bile and
from there into the intestines. They travel in this form through the tract, too water-
soluble to be reabsorbed. In the colon however, the environment changes: this region is
richly populated with a range of bacteria, producing enzymes which can split the drug
from its conjugated group, releasing the original fat-soluble drug molecule. The drug is
therefore reabsorbed across the tract wall, keeping drug levels in the bloodstream high
(Fig. 2.17). Enterohepatic recycling prolongs plasma levels of a range of drugs,
including morphine, digoxin, and some antibiotics.

Renal excretion
The main functions of the kidney include regulation of the composition of body fluids
and the excretion of unwanted substances, including drugs and their metabolites. Renal
physiology is discussed in more detail in Chapter 9, and the anatomy of the kidney and
its functional unit, the nephron, are shown in Figs. 9.1 and 9.2. Low-MW substances
are filtered under pressure out of the bloodstream into the glomerular capsule, forming
filtrate which travels through the nephron towards the collecting duct. The nephron has
three segments: the proximal convoluted tubule, the loop of the nephron (loop of
Henle), and the distal convoluted tubule. From here, urine, the final product, drains into
the renal pelvis and ultimately into the ureter towards the bladder. As the filtrate passes
through the nephron, important substances like glucose are reabsorbed from the filtrate
back into the bloodstream, and unwanted substances like ammonium ions are actively
secreted out of the bloodstream into the filtrate for excretion in the urine. The amount of
drug present in the urine therefore depends on how much is filtered at the glomerulus,
how much is reabsorbed from the filtrate, and how much is secreted into the filtrate.
Fig. 2.18 summarises these processes, although except for the glomerulus, for clarity, it
does not show the different regions of the nephron. A significant degree of metabolism
may also take place as the drug passes through the renal tissues.

Filtration
Small-MW drugs and metabolites are filtered out of the bloodstream into the filtrate,
although they do not necessarily stay there. Drugs bound to plasma proteins are not
filtered because the drug–protein complex is too large. Drug molecules too large to cross
the glomerular filter also stay in the bloodstream and do not enter the filtrate.

Reabsorption
As the blood flows from the glomerular capillaries into the peritubular capillaries
supplying the remainder of the nephron, further exchange of drugs and their
metabolites may take place. Filtered drugs that are very water-soluble remain in the
filtrate, but if they retain some lipid solubility, they may be reabsorbed across the tubule
wall and return to the bloodstream. Water-soluble drugs like digoxin and gentamicin
are poorly metabolised because they cannot diffuse into hepatocytes and so escape
metabolism and arrive in the kidney in their active forms. As the filtrate passes through
the nephron and most of the water is reabsorbed, they become progressively more
concentrated. Gentamicin causes significant renotoxicity because of this. An
additional consideration here is that the body relies on renal clearance to get rid of
drugs that are not metabolised, and so renal function must be carefully assessed when
these drugs are used. Some drugs are actively reabsorbed, piggybacking on carrier and
transport mechanisms used to reabsorb nutrients and other substances the body needs
to retain, but this is not of much clinical importance as few drugs are not reabsorbed this
way.
Urinary pH also influences drug reabsorption into the bloodstream. Normal urine has
a pH of 5–6, and so acidic drugs will tend to stay un-ionised (uncharged) and be
reabsorbed into the plasma (pH 7.4). Basic drugs will tend to ionise in the acid urine and
so be less able to diffuse out of the tubule back into the bloodstream, promoting their
excretion in the urine (see section on pH and pH partitioning above).

Secretion
Drugs too large to pass through the glomerular filter may be actively secreted out of the
bloodstream into the tubule, allowing the kidney to clear unwanted substances that
escape filtration: examples include furosemide, metformin, digoxin, many
antivirals, and penicillin. The transporters responsible for secretion are saturable,
meaning that they have a maximum work rate. If two or more drugs are competing for
the same transport mechanism and the transport maximum is reached, then the level of
both drugs in the blood may rise. This is an important source of drug interactions: for
example, secretion of digoxin is reduced when co-administered with verapamil or
amiodarone, because these drugs compete for the digoxin transporter, increasing
plasma digoxin levels. Plasma protein binding protects most drugs from secretion,
although diuretics including furosemide are actively secreted in their bound form; this
is the route by which they reach the lumen of the nephron, where they exert their
pharmacological effect (p.174 and Fig. 9.6).

FIG. 2.18 Filtration, absorption, and secretion of drugs in the renal

tubule.MW, molecular weight.

Half-life and steady state

Plotting plasma levels following oral, intramuscular (IM), and IV administration of a
single dose of a drug against time gives curves similar to those shown in Fig. 2.19. The
curves demonstrate three phases. The absorption phase shows plasma levels rising.
Here, absorption from the IM injection and the oral preparation in the GI tract is
proceeding, and so although as soon as the drug hits the bloodstream it begins to
distribute into the tissues, there is a net gain into the blood, and plasma levels rise. The
absorption phase seen with the IV curve does not actually represent absorption and is
very steep, because the drug is being delivered directly into the bloodstream. Peak
plasma levels are reached when the amount of drug being delivered into the
bloodstream is equal to the amount being removed by distribution, metabolism, and
excretion. Most orally administered drugs reach peak plasma levels within 1–3 hours of
dosing; absorption from an IM site is usually faster than from the gut, so this curve
peaks more quickly. Following the peak, irrespective of the route of administration,
plasma levels begin to fall. This is the elimination phase, and drug is leaving the
bloodstream because of distribution, metabolism, and excretion.

FIG. 2.19 A typical plasma concentration curve following a single

 dose of a drug, given orally, intramuscularly, and
intravenously. Modified from Page C, Anand R, and DeWilde S
(2022) Trounce’s clinical pharmacology for nurses and allied health
professionals, 19th ed, Fig. 1.2. Oxford: Elsevier.

Half-life
The half-life (t1/2) of a drug is the time required for its concentration to reduce by 50%.
It can be measured in any body fluid or tissue, but in practice for convenience it is
generally measured in the plasma. It is an important pharmacokinetic measurement,
although it is not applicable in every situation (see saturation kinetics below).
The relationship between half-life and plasma levels is shown in Fig. 2.20. The x-axis
shows time, and the y-axis shows drug levels, measured in percentage of the starting
drug concentration. After one half-life, the drug level has fallen by half and is now 50%
of the starting concentration. After another half-life, the drug level has fallen by another
50% and is now only 25% of starting levels. Another half-life later, the drug
concentration is now 12.5% of the original.
Bear in mind that drug half-lives, in absolute time, vary hugely. For example, the
plasma half-life of penicillin is less than half an hour, whereas the half-lives of some
antidepressants and some anticonvulsants can be days. Plasma half-lives are
affected by a range of factors. Rapid metabolism and/or excretion shorten the plasma
half-life; penicillin’s short half-life is due to exceptionally efficient renal clearance.
Conversely, poor metabolism and/or sluggish renal excretion extend half-lives. Very fat-
soluble drugs which are stored in large amounts in adipose tissue, or drugs which are
highly plasma protein-bound, also tend to have long half-lives because of these
significant drug reservoirs: when the drug is withdrawn, plasma levels can remain high
for an extended time as drug lost to elimination processes is replaced by drug leaching
from these stores.

First-Order (Linear) Kinetics and Zero-Order (Saturation) Kinetics

Drug metabolism is an important contributor to a drug’s plasma half-life. For most
drugs given at therapeutic doses, metabolising enzymes process the drug at a rate
proportional to its concentration. This means that as drug levels rise, metabolism
increases as well, and there is a direct and predictable relationship between drug
concentration and the rate of metabolism. As long as drug levels remain within a certain
range, metabolising enzymes can cope, and metabolism obeys the half-life rule as shown
above. This is called first-order or linear kinetics because there is a direct, linear
relationship; if the plasma level is 100 μg/mL, after one half-life, 50% will have been
metabolised, reducing the original plasma levels to 50 μg/mL, and after another half-life
the 50 μg/mL level is reduced by half to 25 μg/mL, and so on. When drug metabolism
follows linear kinetics, predicting changes in plasma drug levels is more straightforward.
This can be clinically useful. For example, when switching from one drug to another, it
may be important to predict how long it will take for the first drug to disappear from the
circulation and when the second drug may be safely started. In general, a drug’s plasma
levels become so low that its biological effects are lost after 5–6 half-lives (Fig. 2.20).

FIG. 2.20 Half-life. Modified from Page C, Anand R, and DeWilde

S (2022) Trounce’s clinical pharmacology for nurses and allied
health professionals, 19th ed, Fig. 1.2. Oxford: Elsevier.

In some cases, this direct relationship between drug levels and metabolism is lost.
This is usually because the metabolising enzymes become saturated: that is, they are
working at their maximal capacity and cannot work any harder. This is called saturation
or zero-order kinetics.
 Metabolism switches from first- to zero-order kinetics with any drug if the
concentration rises high enough, but fortunately this does not happen with most drugs
within normal therapeutic drug ranges. However, for some drugs, including
phenytoin, salicylates, and sodium valproate, enzyme saturation occurs within the
therapeutic range. This presents a problem in drug management, because when the
enzyme’s maximum work rate is exceeded, additional drug accumulates in the plasma,
and plasma levels rise rapidly and steeply. When adjusting doses of drugs in this
scenario, special care is needed, because even a small dose increase can result in sudden
onset of toxicity. In addition, there is significant variability between individuals, adding
further unpredictability. Fig. 2.21 shows the effect of increasing dose on plasma levels
of phenytoin in three patients. The black line shows the shape of curve expected if
phenytoin metabolism followed first-order kinetics: there is a proportionate,
predictable, and steady rise in plasma levels as the daily dose increases. At lower doses,
all three curves show this relationship, but at plasma concentrations below therapeutic
levels, drug metabolism is maximal and additional drug accumulates, sending plasma
levels sharply and steeply upwards. Patient 1 reaches the maximum therapeutic plasma
level of 80 μM at around 200 mg daily; for patient 3, the corresponding dose is nearly
500 mg, showing significant inter-individual variation.
 FIG. 2.21 Saturation kinetics. From Waller DG, Sampson A, and
Hitchings A (2022) Medical pharmacology and therapeutics, 6th ed,
Fig. 2.13. Oxford: Elsevier.

Steady state and the therapeutic dose range

In most clinical situations drugs are given not as a single dose but as a course of
treatment, either in the short, medium, or long term, and the concept of steady state
becomes important.
Steady state is the situation where drug levels remain consistently within a certain
range. IV infusion gives constant plasma levels with little fluctuation, but oral
administration gives a steady state curve featuring a series of peaks and troughs because
of the time lapse between individual doses. Plasma levels peak shortly after an
administered dose, and they begin to fall as distribution, metabolism, and excretion
clear it from the circulation. The lowest point, the trough, is reached just before
administration of the next dose. Dosing intervals are usually informed by the drug’s
half-life, and frequently doses are given at time intervals close to its half-life: drugs with
long half-lives are given less frequently and drugs with shorter half-lives need to be
given more frequently.
Fig. 2.22 shows changing plasma levels following repeated administration of three
different doses of a hypothetical drug at half-life intervals. The sub-therapeutic dose (10
μmol/kg), therapeutic dose (30 μmol/kg), and supra-therapeutic dose (40 μmol/kg) are
shown. The desired therapeutic range, 50–100 μmol/L, is also shown. Steady state is
achieved after five or six doses. This means that a drug with a half-life of 4 hours will
reach steady state within 24 hours, but a drug with a half-life of 24 hours may take
nearly a week. To reduce the time to achieve steady state for drugs with long half-lives, a
loading dose can be given to initiate therapy; this accelerates the rise in drug plasma
concentration and steady state is reached more quickly (Fig. 2.24).

FIG. 2.22 Steady state with repeated oral dosing.Steady state is

 achieved with all three doses shown, although only 30 μmol/kg gives
steady state in the therapeutic range. 40 μmol/kg exceeds the
therapeutic range and is likely to cause toxicity. 10 μmol/kg is too
low a dose to achieve therapeutic drug levels. Curves were calculated
with the Sympak pharmacokinetic modelling program written by Dr.
J G Blackman, University of Otago.

The therapeutic dose range is the interval between the upper desired plasma level,
above which toxic effects are likely, and the lowest desired plasma level, below which the
drug is unlikely to exert a therapeutic action. Steady-state plasma levels should normally
fall within this range. The dose and the dosing frequency should be such that peak levels
do not reach toxic levels and (usually) that trough levels do not fall so low that the
therapeutic action of the drug is lost, i.e. that the steady-state range remains within the
therapeutic dose range for the drug.

Therapeutic drug monitoring

For the drugs for which even small increases in plasma concentrations can cause
toxicity, it is sometimes useful to regularly measure plasma levels, especially at times
when dose adjustments are being made. Typical examples include digoxin,
gentamicin, methotrexate, and phenytoin.

Administration
Choosing the appropriate route of administration is crucial to ensure optimal drug
delivery to the desired target site with minimal side-effects. Oral administration is often
the best choice, with the added benefit of often being the cheapest option, but in some
situations an alternative route may be better.

Drug formulations
The active drug is only one component of a medicine. The term given to the combination
of the active drug with other ingredients is its formulation. The formulation determines
the medicine’s physical properties and the pharmacokinetics of the drug, including its
stability, palatability, solubility, particle size, rates of absorption, and rate of release. It
should not be assumed that one manufacturer’s formulation of a drug, even across
equivalent doses, will give identical plasma levels and effects to another’s, and care
should be taken when switching formulations of certain drugs, including
anticonvulsants and digoxin.
 Ingredients other than the active drug are called excipients and generally contribute
about 90% to the bulk of the final product. Typical excipients include stabilisers,
colourants, diluents, binding agents, and coatings and films used to seal tablets and
capsules. An ideal excipient is biologically inert, non-toxic, and non-allergenic, but this
ideal is rarely achieved, and excipients can cause adverse reactions to medicines. A
number have been associated with allergic responses: for example, lanolin (wool fat)
used as an emulsifier in some topical preparations, the colouring agent tartrazine, and
the antioxidants sodium metabisulphite and propyl gallate.
Different formulations of the same drug allow it to be given by different routes, to
modify its rate of release from the site of delivery or to target specific cells or tissues.
Hydrocortisone, for example, is formulated differently in preparations intended for
oral, IV, or topical use. Acid-sensitive drugs, e.g. omeprazole, may be formulated as
enteric-coated tablets or capsules to protect them against gastric juices and to release
the drug in the alkaline environment of the small intestine. Conversely, drugs irritant to
the stomach, including non-steroidal anti-inflammatory drugs, can be enteric-
coated to help protect the gastric lining. Drugs given by IM injection may be formulated
in an oil base to give a depot in the muscle, from which the drug is released over an
extended period, removing the need for frequent injections. Examples include
contraceptive preparations and antipsychotic medications. Other modified
formulations include sustained or slow-release preparations, which release their drug
slowly in the intestines and keep plasma levels high over an extended period.
Formulation technology is becoming progressively more sophisticated, producing a
number of novel drug delivery vehicles. For example, liposomes are tiny, artificially
engineered spheres made of lipid, used to deliver drugs that may be poorly absorbed or
poorly delivered into cells because of low lipid solubility or large MW (Fig. 2.23). Fat-
soluble (hydrophobic) drugs can be inserted into the lipid bilayer, and water-soluble
(hydrophilic) drugs can be enclosed within the liposome. For example, many
anticancer drugs are much more water-soluble than lipid-soluble, so their ability to
cross biological membranes is limited. Packaging the drug in liposomes, which readily
cross membranes, greatly enhances drug delivery to its target. In addition, the outer
surface of liposomes can be coated with molecules that bind specifically to target cells,
allowing the drug to be selectively delivered to the desired location. The advantage of
this, for example in cancer chemotherapy, is obvious: cytotoxic drugs cause significant
damage to healthy cells as well as malignant cells, so targeted therapy reduces general
toxicity. Liposomes modified with polyethylene glycol (PEGylated) are more stable than
standard liposomes and reduce the uptake of liposomes by macrophages in the liver and
spleen, prolonging the drug’s presence in the bloodstream.

FIG. 2.23 The basic structure of a liposome. From Dua K, Hansbro

PM, Wadhwa R, et al. (2020) Targeting chronic inflammatory lung
diseases using advanced drug delivery systems, Fig. 6. San Diego:
Academic Press.

Oral administration
Advantages of oral administration include convenience and ease. For people with
difficulty swallowing tablets or capsules, liquid formulations are often available,
although some may taste unpleasant. Oral administration is not an option for patients
who are unable or unwilling to swallow, who are actively vomiting, or whose
consciousness is lost or impaired. Additionally, acid-sensitive drugs are destroyed in the
stomach and protein-based drugs are digested or degraded here. If blood flow to the GI
tract is reduced, i.e. in acute pain, developing shock, or heart failure, oral absorption of
medication is slowed. Malabsorption and inflammatory conditions of the GI tract can
also reduce absorption.
Because it usually takes some time for plasma levels to rise, oral administration is not
ideal if a rapid response is needed. To accelerate the rise in plasma levels following oral
administration, an initial loading dose may be used: this increases the concentration
gradient between the intestinal lumen and the bloodstream and speeds up drug transfer
into the blood (Fig 2.24).

Topical administration
Topical absorption means the drug is applied directly to a body surface or membrane.
Often this is the preferred route when localised drug action is needed, e.g.
hydrocortisone cream for a skin allergy. A range of drugs, including anti-
inflammatories and antimicrobials, can be formulated for direct application to the
eye or ear canal. One important advantage of topical application for local effect is that
lower drug concentrations are required, and although some drug is likely to be absorbed
into the circulation, exposure of other body tissues to the drug is greatly reduced.
Application of drugs to the skin and internal mucosal surfaces, e.g. buccal (tucked into
the pouch between the cheek and teeth), nasal, vaginal (per vagina, PV), or rectal
membranes, may also be useful for a local effect, but sometimes the drug is intended to
be absorbed across the membrane and reach the systemic circulation. Drug absorption
across the healthy skin barrier (transdermal absorption) is generally slow, but this can
be advantageous in some circumstances, giving slow and sustained drug release;
examples of drugs that can be given in skin patches include fentanyl, nicotine, and
contraceptive hormones.
 FIG. 2.24 Blood drug levels following a loading dose compared to
standard dose.Therapeutic drug levels are reached more quickly
when a loading dose is used. Modified from Taylor K and Aulton M
(2022) Aulton’s pharmaceutics, 6th ed, Fig. 22.8. Oxford: Elsevier.

The mucous membranes of the mouth and rectum have a good blood supply, and
drugs are generally absorbed reasonably well here. Rectal (per rectum, PR), sublingual
(SL, under the tongue), and buccal administration have the advantage that absorbed
drug is not subject to first-pass metabolism (see above). Rectal administration may be
an alternative route for drugs that are destroyed in or irritant to the stomach, like non-
steroidal anti-inflammatory agents. It may also be used when the oral or IV routes
are not available or potentially hazardous, for example the use of benzodiazepines to
terminate a seizure, or in severe vomiting or gastric stasis.

Intravenous administration
Drugs given directly into the bloodstream are usually injected into a vein (IV) rather
than an artery (intra-arterial, IA) because veins are thinner and easier to penetrate, tend
to run more superficially under the skin so are more accessible, and carry blood under
lower pressure so bleeding from the site is usually less likely. First-pass metabolism is
bypassed, and bioavailability is 100%. There is no risk to the drug from gastric acid
degradation, the onset of drug action is rapid, and providing venous access is available,
this route permits medication delivery when the patient is asleep or unconscious. Drugs
may be given as a one-off (bolus) dose and/or a continual infusion and stopped
immediately at any time. Potential risks include infection, bleeding, and local tissue
damage, especially if an in-situ cannula dislodges and infusion continues into local
tissues rather than the vein.
IA injection is used to target delivery of a drug to a particular organ, e.g. cytotoxic
drugs can be injected directly into a tumour’s arterial blood supply.

Intramuscular administration
The main skeletal muscles used for IM injection (Fig. 2.25) are the gluteal muscles of
the buttock, the deltoid muscle which forms the fleshy part of the shoulder, and the
vastus lateralis of the thigh. Skeletal muscle has a good blood supply and drug
absorption is usually reliable; IM administration may be suitable if the patient cannot
take medication orally or other routes are not suitable. Depot formulations given as deep
IM injection release active drug slowly over an extended period, but it must be borne in
mind that the drug cannot then be withdrawn, and adverse effects may therefore be
prolonged. Risks include infection, bleeding, and damage to adjacent structures if the
injection is too deep or not accurately placed, and of course it is likely to be painful.
Absorption from the muscle is reduced if blood flow to skeletal muscle falls, for example
in developing shock.

FIG. 2.25 Intradermal, subcutaneous, and intramuscular

injection. From Bonewit-West K (2012) Clinical procedures for
medical assistants, 8th ed. St Louis: Saunders.

Subcutaneous/intradermal administration
Immediately below the epidermis of the skin lies the dermis and below that lies the
subcutaneous tissue, which is rich in poorly perfused adipose tissue (Fig. 2.25).
Subcutaneous injection therefore delivers the drug into a very fat-rich environment with
little blood flow, so drugs given this way are absorbed slowly into the bloodstream; this
is ideal when sustained blood levels are required: insulin and heparin are routinely
given by this route. Only small volumes (up to 2 mL) can be delivered by a single
subcutaneous injection, but some drugs, e.g. opioid analgesics in terminal care, can
be administered by subcutaneous infusion. In situations where skin blood flow is
reduced, such as in developing shock, absorption from subcutaneous tissue can be
significantly impaired. Potential complications include infection and abscess formation,
and in the case of repeated injections in the same site, degenerative tissue changes
(lipodystrophy).
 FIG. 2.26 Sites of needle placement for intrathecal and epidural
drug administration.CSF, cerebrospinal fluid. From Waugh A and
Grant A (2020) Ross & Wilson anatomy and physiology in health
and illness, 14th ed, Fig 7.14. Oxford: Elsevier.

Intradermal administration (Fig. 2.25) is infrequently used to give drugs. One

example of its use is in allergy testing, in which potential allergens are instilled into the
dermis.

Inhalation
Inhalation of drugs is usually used to deliver drugs locally into the airways, but
occasionally for systemic drug administration, e.g. inhaled general anaesthetics.
Inhalation, for example, of anti-inflammatory drugs and bronchodilators in
obstructive airway disease such as asthma gives targeted delivery and allows drug doses
to be kept small. It must be borne in mind that airway tissues have a good blood supply,
and drug absorption into the systemic circulation is a real possibility, especially at
higher doses and with frequent administration. Delivery of drugs by inhalation is
discussed in more detail on p. 158.

Intrathecal and epidural administration

Fig. 2.26 shows the placement of the needle for intrathecal and epidural administration
of drugs.
Intrathecal administration is delivery of drug directly into the subarachnoid space,
which is filled with CSF. This bypasses the blood-brain barrier and allows therapeutic
agents, e.g. contrast media, anaesthetics, analgesics, antibiotics, or cytotoxic
drugs, to be introduced directly into the CNS. The needle is inserted between adjacent
vertebrae and punctures the dura and arachnoid mater to deliver the drug directly into
the CSF, which circulates around and through the brain carrying the drug with it.
Potential complications include bleeding, introduction of infection into the CSF, and
CSF leakage.
Epidural administration is delivery of a drug into the epidural space, which lies
between the vertebrae and the dura mater. The arachnoid mater is therefore not
punctured. Drugs instilled into the epidural space do not circulate, because there is no
CSF in the epidural space, and epidural administration is most frequently used to
introduce anaesthetics or analgesics around spinal nerve roots, giving loss of
sensation, including pain, from the legs and lower body regions served by the affected
nerves. It is commonly used to eliminate the pain of labour and childbirth.
Complications include the introduction of infection or accidental puncturing of the
arachnoid mater, which would allow the drug to access the CSF.

Administration into body cavities

Occasionally, drug delivery into body cavities or specific structures is used: for example,
intra-articular injection of anti-inflammatory steroids into the joint cavity can
relieve pain and stiffness in arthritis. Drugs that inhibit the growth of abnormal blood
vessels in macular degeneration can be given directly by intraocular injection into the
vitreous humour of the eye. Intraosseous (into the medullary cavity of the bone) delivery
is used particularly in paediatrics when IV access is not available.

Drug interactions
Drug interactions refer to the situation where a drug interferes with some aspect of the
pharmacokinetic or pharmacodynamic properties or behaviour of another. They are a
common cause of problems and adverse effects with drug therapy, and consideration
should always be given to interactions caused by foodstuffs, non-prescription medicines,
and herbal and natural remedies.
It must also be borne in mind that not all interactions are harmful or unwanted. For
example, beta agonists like salbutamol and anti-inflammatory steroids such as
budesonide are regularly used together in maintenance treatment of asthma. In
combination, the therapeutic effects of these two drugs synergise and enhance each
other (see also p.166 and Fig. 8.11).
Pharmacokinetic interactions occur when a drug interferes with the disposition of
another in the body, and several examples are discussed in earlier sections of this
chapter. Pharmacodynamic interactions occur when a drug interferes with the biological
activity of another, often by antagonising or acting additively to it. Pharmacodynamic
principles are the subject of Chapter 3, but pharmacodynamic interactions are
discussed here for consistency. This section does not attempt to provide a
comprehensive list of all important drug interactions because the list of potential and
confirmed interactions is vast, but rather offers a selection of examples to illustrate the
main principles. A suitable drug formulary should always be consulted for detailed
information on potentially hazardous drug combinations.

Pharmacokinetic interactions
Drugs can interfere with another’s absorption, distribution, metabolism, or excretion.
Most pharmacokinetic interactions are due to one drug interfering with another’s
metabolism, and this is discussed above.

Absorption
Dairy products, which are rich in calcium, interfere with tetracycline absorption
because the calcium complexes with the drug to form an insoluble complex. Drugs that
reduce gastric motility, e.g. opioids, and drugs with antimuscarinic properties, e.g.,
some antihistamines and antidepressants, slow the rate of absorption of other
drugs because they impair drug delivery into the small intestine. Adrenaline co-
injected with a local anaesthetic acts as a vasoconstrictor, reducing the loss of the
anaesthetic from the area in the bloodstream and prolonging its effect, and is thus useful
in longer procedures.

Distribution
Drugs may potentially compete for plasma protein-binding sites: the standard example,
aspirin and warfarin, is discussed above.

Excretion
Drugs that impair renal function or reduce renal blood flow can reduce excretion of
other drugs and increase their circulating blood levels. Carrier mechanisms in the renal
tubule that secrete particular drugs may be inhibited by competing drugs. For example,
non-steroidal anti-inflammatory drugs inhibit the secretion of methotrexate
and can increase methotrexate levels in the blood.

Pharmacodynamic interactions
Drugs can interfere with each other’s physiological activity in a range of ways because
pharmacodynamic processes are so complex. Some interactions are beneficial and
exploited clinically, and some are not. The most serious drug interactions can be lethal.

Beneficial interactions
The combined use of analgesics with different mechanisms of action, e.g. codeine and
paracetamol, is common. The analgesic action of the drugs is additive and allows the
doses of the individual drugs to be kept lower than if each was being used alone,
reducing the likelihood of adverse effects. Another example of a therapeutically
exploited interaction is the use of reversal agents when two drugs compete for the same
binding site, for example, when naloxone or another opioid antagonist is used to
reverse morphine overdose.

Unwanted/dangerous interactions
Sometimes both drugs have the same biological effect, and when used together, produce
an excessive response: for example, the risk of haemorrhage is increased when drugs
that increase bleeding times, including warfarin, heparin, and aspirin, are used
together. Another example is the use of dopamine receptor agonists such as ropinirole
to treat Parkinson’s disease and dopamine receptor antagonists such as olanzapine in
the treatment of psychiatric disorders: this drug combination is avoided as they directly
interfere with each other’s pharmacological action. Many diuretics, including
furosemide, predispose to hypokalaemia, which increases the risks of digoxin
toxicity.

Pharmacokinetic special situations

Even in health, drug disposition can vary significantly between individuals.

Older age
Physiological processes tend to decline in older adults. Gastric emptying may be slower,
delaying drug delivery into the small intestine. Age-related reduction in liver and kidney
function may affect metabolic and excretory mechanisms in healthy older people,
although there is significant variability in the degree to which this affects drug
disposition, and patients should be carefully assessed on an individual basis. First-pass
metabolism may be reduced, increasing the amount of an orally administered drug
reaching the general circulation and necessitating a reduction in drug dose. From the
age of 50 years, the glomerular filtration rate (GFR) may be reduced by 25% and by 50%
by 75 years, reducing renal drug excretion.
Plasma protein levels are lower in older people, potentially increasing the drug-free
fraction and necessitating lower doses, especially at the start of a course of drugs or
when drugs are being administered in an acute setting. In general, the adipose–lean
body mass balance tips towards the deposition of adipose tissue, increasing the potential
for drug accumulation in body fat stores. Older people may be more sensitive to the
central effects of drugs, including sedation, confusion, amnesia, and impaired cognition.

Babies and children

There are significant differences between children and adults in the pharmacokinetic
disposition of drugs. In addition, ADME processes change with the developing child,
and distinction must be made between a premature baby (born before 37 weeks of
gestation), a neonate (up to 4 weeks old), an infant (between 4 weeks and 1 year of age),
and a child (up to 11 years of age). Great care must therefore be taken in neonatal and
paediatric drug therapy: this is definitely a situation where children are not just small
adults!
Physiological processes in the very young may be immature, particularly in
prematurity. Topically applied drugs are absorbed more readily because children’s skin
is thinner and there is less subcutaneous fat. Oral administration may not be the best
way to give drugs because GI motility is sometimes erratic, especially if the baby is ill.
Gastric emptying times may not reach young adult values until about 6 months of age.
Gastric pH is higher in babies, so drugs which are normally subject to significant acid
degradation, e.g. penicillin, are better absorbed. Drug elimination is slow because liver
and kidney function is immature at birth.
It can take up to 2 years for full liver function to be achieved, and metabolic patterns
for a particular drug in children may be different in adults. Importantly, drug
metabolism and half-life changes according to the age of the child and the
developmental stage of the liver. For example, some members of the CYP450 family are
relatively more important in metabolising some drugs in children than in adults, which
perhaps counterintuitively means that the half-life of the drug may be shorter in the
child than the adult and can change according to the developmental stage of the liver.
For example, the half-life of phenytoin in the adult is typically 20–30 hours. In the
neonate, its typical value is 30–60 hours. This falls to 2–7 hours in neonates, as one
particular CYP enzyme matures, and extends to 2–20 hours in children. With other
drugs, metabolism in babies and children is lower at all stages than in adults.
The GFR in the newborn is only 20% of adult values, which generally increases to
young adult level within 6 months. Fully mature renal excretion of drugs may not be
achieved until 18 months of age. Plasma protein levels do not reach young adult levels
until about 3 months of age, and the free fraction of drug can be elevated in very young
babies. Central effects of drugs in the very young are likely to be exaggerated, partly
because the blood-brain barrier does not fully mature until around 4 months of age, but
also because the brain is proportionately larger in children than in adults and so receives
a greater blood supply.

Pregnancy
Drug use in pregnancy presents possible dangers to two people: the mother and the
baby. Fetal liver and kidney function are immature throughout pregnancy, and so the
baby is largely reliant on the mother to eliminate circulating drugs. Even in a healthy
pregnancy, physiological changes affect the pharmacokinetic profiles of drugs.
Pregnancy-associated nausea and vomiting can limit the usefulness of orally
administered drugs. Blood volume rises in pregnancy, diluting plasma proteins and
potentially increasing the free fraction. Cardiac output rises, increasing blood flow
through the kidney and liver, and potentially accelerating drug elimination. In addition,
hepatic metabolism increases because enzyme levels rise, which also speeds up drug
clearance. When therapeutic drugs must be used in pregnancy, particular care must be
taken in monitoring the health of both the mother and the baby.

Genetic variability
A significant source of inter-individual variation in metabolism is genetically
determined, discussed in more detail above. However, genetic differences can also affect
receptor populations, absorption mechanisms, and hypersensitivity responses and affect
both how the body deals with the drug as well as how the drug affects the body.
Identifying important genetic differences in pharmacokinetic and pharmacodynamic
profiles and using this information in planning and prescribing drug therapy is
becoming slowly but increasingly a part of personalised medicine. One drug may be
chosen over another because it is known that the patient will metabolise it better, is
likely to have a better clinical response to it, or is likely to have less severe adverse
effects with it. This is truly a situation of the story being written in the genes!

References
1. Fernandez E, Perez R, Hernandez A, et al. Factors and mechanisms for
pharmacokinetic differences between pediatric population and
adults. Pharmaceutics. 2011;3(1):53–72.

Online resources
Haywood A, Glass B.D. Pharmaceutical excipients – where do we begin? Aust
Prescr. 2011;34:112–114 Available at:. https://www.nps.org.au/australian-
prescriber/articles/pharmaceutical-excipients-where-do-we-begin.
Le J. Overview of pharmacokinetics. MSD Manual. 2022 Available
at:. https://www.msdmanuals.com/en-gb/professional/clinical-
pharmacology/pharmacokinetics/overview-of-pharmacokinetics.
Pharmacology Education Project, . Clinical pharmacokinetics Available
at:. https://www.pharmacologyeducation.org/clinical-
pharmacology/clinical-pharmacokinetics, 2023.
Yartsev A. Required reading: pharmacokinetics. Deranged
Physiology. 2024 Available
at:. https://derangedphysiology.com/main/cicm-primary-
exam/required-reading/pharmacokinetics.
3: Pharmacodynamics:
What the Drug Does to the Body

Introduction to Pharmacodynamics
The Levels of Drug Action
Principal Targets of Drug Action
Drug Receptors
Receptors and Their Actions
Ion Channels
Receptor Desensitisation and Drug
Tolerance
Membrane Transport Mechanisms
Enzymes
Non-Mammalian Cell Targets
Assessment of Drug Action
Dose–Response Relationships
Therapeutic Index
Adverse Drug Reactions
Mechanisms of Adverse Drug Reactions
Immunologically Mediated Adverse Drug
Reactions
Pharmacologically Mediated Adverse Drug
Reactions

Biochemically Mediated Adverse Drug

Reactions
 Common Adverse Drug Reactions
Hepatic Adverse Drug Reactions
Renal Adverse Drug Reactions
Cutaneous Adverse Drug Reactions
Red Bone Marrow Toxicity
Reproductive Function

Nervous System Adverse Drug Reactions

Classification of Adverse Drug Reactions
Type A (Augmented) Reactions
Type B (Bizarre) Reactions
Type C (Chronic) Reactions
Type D (Delayed) Reactions
Type E (End-of-Dose) Reactions
Drug Dependence
Withdrawal Syndromes

Introduction to Pharmacodynamics
Pharmacodynamics is the umbrella term describing the mechanisms by which drugs
exert their effects on body tissues, sometimes simply put as ‘what the drug does to the
body’. The response of the body to a typical drug is likely to be complex. A drug given to
treat a specific condition or to relieve a specific symptom will frequently produce
additional, usually unwanted adverse effects, often affecting the function of organs or
systems that are not the desired target of the drug and often at drug doses in the desired
therapeutic range. A sound grasp of basic pharmacodynamic principles is essential to
understanding why this occurs.

The Levels of Drug Action

Drug action can be considered at different levels. Although the effects of a drug are often
assessed or measured by its success in achieving an intended aim, like relief of a
headache with paracetamol or reduced blood pressure when taking an
antihypertensive such as ramipril, its action is almost always via specific molecular
targets: for example, a cell-surface receptor, an enzyme, or an ion channel controlling
the movement of specific ions in or out of the cell. Understanding drug action at the
molecular level not only facilitates understanding of the therapeutic action of the drug,
but also sheds light on the potential for adverse effects. Fig. 3.1 shows an example of
the different levels of action of salbutamol, a bronchodilator drug used in asthma (see
also p. 164).
At the whole-person level, salbutamol relieves the physiological and emotional
distress of an impending asthma attack; it improves alveolar ventilation, ensuring
adequate oxygenation of the blood and elimination of carbon dioxide. This clearly has
beneficial consequences for all body organs. At the (respiratory) system level,
salbutamol increases airway diameter to maximise air flow. At the tissue level, it relaxes
bronchial smooth muscle tissue, dilating the airway. At the cellular and molecular level,
salbutamol is a beta (β) receptor agonist. It binds directly to β receptors on bronchial
smooth muscle cells and activates them, triggering a series of biochemical events within
the cell which ultimately reduce intracellular calcium (Ca2+) levels. Because Ca2+ is
essential for muscle contraction, bronchial smooth muscle relaxes and the airway
dilates.
FIG. 3.1 The levels of drug action.Drug action can be examined on
the whole person, on the physiological system, in a specific organ, at
the tissue/cellular level, and at the molecular level. The figure uses
salbutamol as the example.
 This explains why salbutamol is useful in asthma, but put in a wider context, it also
explains why adverse effects of the drug may include tachycardia and hypertension. β
receptors are found in a number of body tissues; they belong to the adrenoceptor family
(Table 3.1), receptors which respond to the sympathetic mediators, adrenaline and
noradrenaline. The sympathetic nervous system prepares the body for fight or flight,
and bronchodilation is part of that response: dilating the airways improves airflow to
the lungs and supplies the additional oxygen required in a physiologically stressful
situation. However, salbutamol may also activate β receptors in the heart, increasing the
rate and force of cardiac contraction and raising blood pressure, also important
components of the sympathetic response. Understanding the underlying mechanism of
action of a drug at the cellular/molecular level therefore explains why β agonists should
be used with care, if at all, in people with cardiovascular disease.

Principal Targets of Drug Action

Most drugs act through one or more general mechanisms: for example, they may bind to
and activate or block cell-surface proteins (receptors), or they may enter the cell, cross
the nuclear membrane, and bind to one or more genes, either inhibiting or activating
gene expression and production of the gene-specific protein. In doing so, they alter the
cell’s activity, which in turn alters the activity of the tissue and the organ to which the
affected cells belong. Sometimes a drug target is a body enzyme. A drug may bind to and
affect (usually inhibit) the enzyme’s activity, blocking a step in a metabolic pathway.
Other drugs may affect the transport of substances across the cell membrane, inhibiting
the ability of the cell to regulate its internal environment. The precise chemical structure
of the drug molecule is usually critical to its ability to interact with its molecular target,
and alterations to this can abolish the drug’s pharmacological activity.

Drug Receptors

Key Definitions

• Ligand:

the general term for any chemical binding to a receptor.

• Agonist:

a drug which binds to a receptor and activates it. Using a ‘lock and key’ analogy, the
drug is the equivalent of a key which fully engages a lock (the receptor) and can either
lock or open it.

• Antagonist:

a drug which binds to a receptor and blocks it. Using a ‘lock and key’ analogy, an
antagonist acts like a key that is a close enough match to enter a lock but not a close
enough fit to operate it. However, while this ‘false’ key occupies the lock, it prevents a
‘true’ key from being inserted, and so the lock is useless.

The human body is a community co-operative composed of around 30 trillion cells,

each occupied with its specialised function, but not living in isolation: all work together
to maintain homeostasis and health. This requires that every cell must interact with and
respond to chemical signals such as hormones, neurotransmitters, growth factors, and
inflammatory mediators in its local environment. One of the most important
mechanisms allowing this complex communication system to work are the populations
of receptor molecules present on the cell surface (see Fig. 2.1) and within the cell,
including nuclear DNA receptors. It is important to remember that these receptors are
present to mediate endogenous physiological activities, and so drugs are usually either
mimicking or blocking an endogenous function, i.e. acting as agonists or antagonists at
the receptor (Fig. 3.2). The example of salbutamol in Fig. 3.1 illustrates this point: β-
receptor agonists bind to receptors whose physiological function is to mediate
sympathetic responses. Another example is the use of opioid analgesics like morphine
in pain control. Two groups of naturally occurring substances with analgesic activity, the
endorphins and enkephalins, are found in the central nervous system and in some
peripheral tissues, particularly in nerve pathways concerned with the transmission and
processing of pain signals. They are agonists at mu (μ) opioid receptors (MORs) present
on nerves in pain pathways, and shut down transmission there, diminishing pain
signals. Morphine and other opioid drugs are agonists at MORs and activate the same
pain-relieving mechanisms as the internal analgesics.

Table 3.1
5-HT, 5-hydroxytryptamine
 FIG. 3.2 The action of an endogenous agent, an agonist, and an
antagonist at a receptor. Modified from Lilley LL, Collins S, and
Snyder J (2023) Pharmacology and the nursing process, 10th ed,
Fig. 2.7. St. Louis: Mosby.

Excitatory and Inhibitory Receptor Responses

It feels intuitive that the binding of an agonist to a receptor should activate a process or
in some way excite or stimulate some aspect of the cell’s behaviour. However, it is
important to realise that drug–receptor binding may either stimulate or inhibit a
response in the target cell, depending on the nature of the receptor and the biochemical
mechanisms to which the receptor is linked. For example, in the central nervous system,
it is important that neuronal activity can be suppressed as well as activated; like a
dimmer switch controlling light levels in a room, it permits finely tuned control of nerve
activity. The endorphins, enkephalins, and morphine discussed earlier are
agonists (they activate the MOR) but the effect produced in their target cells is
inhibitory, and they reduce the transmission of pain signals. Another example is
gamma-amino butyric acid (GABA), an important inhibitory neurotransmitter
widespread in the central nervous system. It reduces nerve activity by acting as an
agonist at its GABA receptor on chloride (Cl−) ion channels on nerve endings (see ion
channels below) and opens the channel; the entry of negatively charged Cl− ions inhibits
the nerve and reduces its firing rate. Benzodiazepines like diazepam and midazolam
are in widespread clinical use as sedatives, anxiolytics, and anticonvulsants: they work
by enhancing GABA’s action (see also p. 61). On the other hand, acetylcholine (ACh), a
neurotransmitter found widely in both the central and peripheral nervous systems, is
usually excitatory, and it stimulates its target cell.

Specificity, Selectivity, and Receptor ‘Families’

Key Definitions

• Specificity:

the ability of a drug to discriminate between different receptor families; e.g.

histamine binds to histamine receptors but not prostaglandin receptors.

• Selectivity:

the ability of a drug to differentiate between subtypes of the same receptor family:
e.g. antihistamines (H1 receptor antagonists) selectively block H1 receptors but not H2
receptors.

Receptor Specificity
Receptors are usually protein molecules folded into complex and specific three-
dimensional shapes. This means they can only bind chemicals that have a
complementary shape and ‘fit’ the receptor binding site, like a lock and a key. The ability
of a ligand such as a neurotransmitter, hormone, or drug to discriminate between
different receptor types and to bind to one and not another, even if the two are
structurally very similar, is called specificity and is essential in normal healthy body
function. For example, there are currently more than 100 known neurotransmitters in
the human nervous system, each with its own particular and precise range of roles to
play in the sophisticated and finely tuned neurological control of body physiology. It is
essential that each is only active at its own receptors and does not affect receptors for
other transmitters because this would significantly disrupt this intricate and complex
control network. In clinical pharmacology, drug specificity is very important, because
the more specific the drug is for its intended receptor, the less likely it is to cause
unwanted adverse effects through binding to other receptor types. The lower the drug–
receptor specificity, the greater the risk and incidence of adverse effects unrelated to the
drug’s intended therapeutic aim. Many drugs are not absolutely specific for their target
receptor and affect other receptor types. Fig. 3.3A shows that older (first-generation)
antihistamines, such as chlorphenamine, block H1 histamine receptors, the
mechanism by which they exert their anti-inflammatory effect. However, although the
fit is not perfect, they also bind to and block muscarinic cholinergic receptors in the
autonomic nervous system. Unwanted antimuscarinic effects (p. 51), including dry
mouth, sedation, and blurred vision, are therefore common with these drugs. There is
no interaction with, for example, dopamine receptors, because there is no molecular fit.

Receptor ‘Families’ and Receptor Selectivity

A further important consideration regarding receptor populations for any particular
ligand is that they are not homogeneous throughout the body, giving rise to the concept
of ‘receptor families’. Receptor families contain two or more receptor subtypes, all
responding to their principal ligand, but which differ slightly in structure and may be
differentially distributed in different tissues and associated with different functions. A
knowledge and understanding of receptor subtypes is important in clinical
pharmacology because the use of drugs selective for particular subtypes narrows their
therapeutic target, usually improving their clinical performance and reducing the risk of
adverse reactions. The ability of a drug to discriminate between subtypes of the same
receptor is called selectivity. Important receptor families and some of their clinically
important subtypes are summarised in Table 3.1. Although the expanding array of
receptor subtypes in some families, e.g. serotonin (5-hydroxytryptamine/ 5-HT), may
seem overwhelming, this research area has paved the way for the design of increasingly
targeted drugs.
 FIG. 3.3 Specificity and selectivity.A. Specificity. Older
antihistamines, e.g. chlorphenamine, typically bind to and block
other receptor types as well as histamine H1 receptors. Blocking
muscarinic cholinergic receptors gives the antimuscarinic side-
effects characteristic of these drugs. Other receptor types, e.g.
dopamine receptors, are not affected. B. Selectivity. Atenolol binds to
and blocks both β1 and β2 adrenoceptors but achieves best fit with β1
receptors. At higher doses, however, it blocks both.

For example, consider the histamine receptor family. Currently four histamine
receptor subtypes have been identified, named H1, H2, H3, and H4. Although they are all
in some way involved in immunity and body defence and they all respond to histamine,
they are not distributed evenly throughout histamine-responsive tissues, and they
mediate different functions of histamine. The pharmacology of histamine and its
receptors is discussed in more detail in Chapters 6 and 10, but let us use the example
here to briefly illustrate the point that different receptor subtypes mediate different
functions of the same chemical and can be blocked by different drugs. H1 receptors are
found in blood vessels and secretory epithelia (e.g. the linings of the nose), and
histamine acting here produces the standard signs and symptoms of allergic
inflammation: an insect bite gives red, swollen, itchy skin, and hay fever gives a runny
nose and red, itchy eyes. Antihistamines like chlorphenamine and cetirizine block
H1 receptors and relieve these symptoms. H2 receptors are found in the stomach, and
histamine acting here increases gastric acid secretion, another important defence
mechanism. However, antihistamines have no effect on H2 receptors; a different class of
drugs, the H2 receptor blockers including cimetidine and famotidine, are used to
reduce gastric juice secretion in conditions associated with excess acid production.
Increasing dose can affect the specificity and selectivity of a drug. For example, the β-
receptor family all respond to adrenaline and noradrenaline, but different subtypes
are found in different tissues. The myocardium in the heart has mainly β1 receptors, and
airway smooth muscle has mainly β2 receptors. Some β-blockers, for example atenolol,
have relative selectivity for β1 cardiac receptors and bind preferentially to this subtype
over other subtypes (Fig. 3.3B). However, as atenolol doses increase, its effects on
other subtypes become more significant, including β2-mediated bronchoconstriction,
which may be a problem in people with obstructive airways disorders such as asthma.

Reversible and Irreversible Drug–Receptor Binding

The term ‘binding’ used to refer to drug–receptor interactions might suggest that a drug
molecule arrives at the target receptor and locks onto it, like someone sitting down in a
chair and staying there. However, in physiology, this arrangement would not work
because it would limit the degree of control possible over the interaction and the
subsequent biological action. Physiological systems need to be able to exert moment-to-
moment control over their activity, and ligand–receptor interactions in living systems
are reversible. Drug molecules actually bind to and release from their receptor
repeatedly, like someone bouncing up and down in their chair. However, the time frame
for each binding is very short––a tiny fraction of a second––and so a drug molecule
binds, releases, binds, releases, many times each second. The more drug molecules
present, the greater the proportion of receptor sites occupied at any one time and the
greater the drug response.

Competitive Antagonism
This model of drug–receptor interactions explains why a reversal agent can be used to
block the action of a drug already in the system. For example, naloxone is a MOR
(Table 3.1) antagonist that can be used to reverse an opioid overdose. Because the
opioid molecules bind and dissociate from their MORs multiple times a second,
naloxone molecules can also bind while the receptor is momentarily free. This is called
competitive antagonism (Fig. 3.4), because the reversal agent competes with the opioid
for receptor occupancy, and while naloxone molecules are present in appropriate
concentrations at the receptors, they limit opioid binding and reduce opioid effects.

Irreversible Drug–Receptor Binding

Examples of this are fairly rare in clinical pharmacology; most drug–receptor
interactions are reversible as described above. Aspirin (acetylsalicylic acid) binds
irreversibly to its target enzyme, cyclo-oxygenase, as described in Chapter 6, which
means that a once-daily low dose (75 mg) produces a sustained and effective anti-
platelet action. Omeprazole (p. 186), used to reduce gastric acid secretion, irreversibly
inhibits the proton pump in gastric parietal cells. A single dose of omeprazole reduces
gastric acid secretion for up to 2 days, increasing to 5 days when the drug is used
regularly.

Regulation of Receptor Numbers

Receptor proteins are synthesised on the cell’s ribosomes and transferred to the plasma
membrane. Receptor numbers are controlled by the cell and can be increased
(upregulated) or decreased (downregulated) as required. In the absence of any drug
with activity at a receptor type (which may upregulate or downregulate receptor
numbers as described below), the main factor determining receptor numbers is the
presence (or absence) of its physiological ligand. In general, if the ligand concentration
falls, the cell will usually upregulate receptor numbers to compensate for reduced
receptor stimulation and to bring the signal back up to its normal range. On the other
hand, if the concentration of the ligand goes up, increasing receptor stimulation, the cell
responds by downregulating receptor numbers to dampen the excessive signal.
 FIG. 3.4 Competitive antagonism, showing reversal of morphine
with naloxone.A. Morphine alone. B. Morphine is displaced from its
receptors because naloxone is competing for binding.

Regular or sustained exposure of tissues to a drug acting on a particular receptor can

induce the cells to adjust their receptor numbers to control their sensitivity to a signal.
For example, prolonged use of an antagonist and the consequent receptor blockade can
induce a tissue to upregulate its receptor numbers (Fig. 3.5A). This may cause
problems when the antagonist is withdrawn. For example, medium- to long-term use of
a β-blocker like propranolol may upregulate β1 receptors in the myocardium. If
propranolol is suddenly withdrawn, tachycardia and hypertension can follow because
with its increased β-receptor population, the myocardium is more sensitive to the effects
of sympathetic stimulation.
On the other hand, overuse of β-agonist bronchodilators such as salbutamol in
asthma can reduce its effectiveness, because in the constant presence of the drug, the
smooth muscle cells of the airway downregulate their receptor population to reduce the
excessive signal (Fig. 3.5B). The individual with asthma finds that they must use their
inhaler more frequently to relieve or prevent their symptoms, downregulating receptor
numbers even further and establishing a vicious cycle.

FIG. 3.5 Upregulation and downregulation of receptor numbers.A.

Upregulation when receptors are blocked by an antagonist. The
reduced signal causes the cell to synthesise more receptors. B.
Downregulation when a cell is exposed to high concentrations of an
agonist. The cell reduces its receptor numbers to dampen the
excessive signal. Modified from Power-Kean K, Zettel S, El-Hussein
 MT, et al. (2023) Huether and McCance’s understanding
pathophysiology, Canadian edition, 2nd ed, Fig. 18.3. Toronto:
Elsevier Canada.

Receptors and Their Actions

Most clinically relevant drug receptors are found on the cell membrane and allow the
cell to respond to chemical signals in the extracellular environment. Some drugs, e.g.
steroid hormones, cross the cell membrane and bind to cytosolic receptors, from
where they travel into the nucleus and bind to receptor sites on DNA, either stimulating
or inhibiting the production of proteins coded for in the cell’s genes. Some receptors are
an integral part of the structure of ion channels (see below), and when their ligand binds
to them, they open or close the channel, regulating ion movements across the cell
membrane. This is especially important in excitable tissues such as nerve and muscle
which rely on ion movements to generate and transmit electrical signals. Fig. 3.6 shows
the main locations of cellular receptors.

Cell-Surface Receptors
Drug–receptor binding on the cell membrane is only the first stage in a chain of steps
which convert the interaction of the drug with its receptor to its final biological effect. It
could be likened to speaking to a receptionist at the front door of an office block, which
is only the first step in making it to your appointment with someone on the fifth floor.
The receptionist must trigger a chain of communication within the building, perhaps by
telephoning or emailing someone to let them know you have arrived, or by asking an
assistant to take you in the lift to the correct floor. A similar chain of messages is
triggered by drug–receptor binding. Drug–receptor binding usually initiates a
conformational change in the receptor which triggers a series of biochemical
communication steps within the cell, transferring the message from the receptor to
intracellular mechanisms that will produce the final cellular response. These are called
transduction mechanisms, and there are several different types. Only G protein-coupled
receptor mechanisms are discussed here in more detail because they are particularly
important.

G Protein-Coupled Receptors
Around a third of therapeutically important cell-surface drug receptors are linked to a
special protein called a G protein, which is bound to the internal surface of the cell
membrane. They are therefore called G protein-coupled receptors (GPCRs). They are a
large and diverse receptor family, including receptors for many neurotransmitters,
inflammatory mediators, and peptide hormones. A GPCR is formed from a long protein
chain, folded seven times, and embedded in the cell membrane. One end is exposed on
the outer surface of the cell membrane and acts as the drug receptor. The internal end of
the receptor protein is directly linked to the G protein (Fig. 3.7). G proteins are
sometimes called go-between proteins because they act as intermediaries between the
cell-surface receptor and the final stage in the sequence of events transmitting the drug’s
message into the cell’s interior. The final stages in the communication chain, responsible
for generating the final effect of the drug on the cell, are called second-messenger
pathways.

Second-Messenger Pathways
The two most important second-messenger pathways are the cyclic AMP
(cAMP)/adenylate cyclase system and the phosphatidyl inositol/phospholipase C
systems. Although the biochemical cascades are different for each, they both involve the
activation of intracellular enzymes called kinases. Kinases are key enzymes in the
regulation of protein activity in the cell. They convert ATP to ADP, releasing energy-rich
phosphate groups which phosphorylate and activate or inactivate a wide range of
cellular enzymes and other proteins, including ion channels and transport proteins.
There are hundreds of different kinase subtypes in the human cell, reflecting their
central role in cellular biochemistry and metabolism.
 FIG. 3.6 The main locations of drug receptors.

Adenylyl Cyclase/cAMP Pathway

ATP is converted to cAMP by the action of the enzyme adenylyl cyclase (Fig. 3.7). cAMP
is a very important second messenger with multiple functions in the cell: for example, it
controls a wide range of cellular functions, including growth, differentiation, energy
metabolism, and muscle contraction. Adenylyl cyclase is constantly active, and so cAMP
levels are controlled by the family of phosphodiesterase enzymes (PDEs), which destroy
cAMP (and the related second-messenger nucleotide, cyclic guanosine monophosphate,
cGMP). A range of drugs including sildenafil (p. 179, used mainly for erectile
dysfunction) and theophylline (p. 165) are PDE inhibitors used clinically; by blocking
PDE, cAMP/cGMP levels in the cell rise.
Inhibitory and Stimulatory G Proteins
Two important subtypes of G protein are an inhibitory (Gi) and a stimulatory (Gs) form.
If the receptor is coupled to a Gi protein, it exerts an inhibitory effect on the cell. For
example, MORs (Table 3.1), to which endogenous opioids like endorphins and opioid
analgesics like morphine attach, are linked to Gi proteins. MORs are found, among
other locations, on nerve endings at synapses within pain pathways, and they modulate
pain signals in the brain and spinal cord. Binding of either the endogenous opioid or an
exogenous opioid drug to a MOR activates the Gi protein, which in turn inhibits synaptic
transmission here and blocks the pain signal. On the other hand, if the receptor is
coupled to a Gs protein, its effect is excitatory. An example is the β adrenoceptor, which
responds to adrenaline and noradrenaline and β agonists such as salbutamol.
Activation of the β receptor activates adenylyl cyclase, increases cAMP levels, and
among other effects, phosphorylates a range of enzymes important in metabolic
pathways (Fig. 3.8).

Nuclear Receptors
Some drugs, e.g. steroid hormones, do not bind to a cell-surface receptor. They are
highly fat-soluble, so they cross the plasma membrane and bind to their receptor, called
a steroid-binding protein, in the cytosol. The drug–receptor complex then crosses the
nuclear membrane and binds directly to a specific binding site on one or more genes
contained within the cell’s DNA. This may activate the gene, resulting in the production
(transcription) of a molecule of messenger RNA (mRNA). The mRNA molecule leaves
the nucleus and attaches to ribosomes in the cytoplasm, which produce the protein that
the gene encodes (Fig. 3.9). Alternatively, steroid binding to a gene may switch the
gene off and halt protein production. For example, anti-inflammatory glucocorticoids
such as hydrocortisone switch off genes that code for pro-inflammatory proteins and
activate genes that code for proteins that suppress inflammation. The onset of action of
drugs which affect gene expression is often slow because it takes time for the target
protein levels to either rise or fall sufficiently to make a difference to cell function.

Ion Channels
Ion channels embedded in the cell membrane open and close to control the flow of ions
such as Ca2+, sodium (Na+), and Cl− across the cell membrane. Opening the channel
allows ions to travel down their concentration gradient and either enter or leave the cell.
Because ions are electrically charged, their movement in or out of the cell regulates the
electrical excitability of the cell and allows nerve and muscle cells to generate and
propagate electrical signals. Sodium and calcium channels permit Na+ and Ca2+
respectively to flow into the cell, which depolarise (activate) nerve and muscle cells.
Potassium (K+) channels allow K+ to leave the cell, which hyperpolarises (desensitises)
an excitable cell, making a nerve, for example, less able to fire. Chloride channels allow
Cl− to enter the cell, which hyperpolarises it, making nerve cells less likely to fire.
Generally, drugs which affect ion channel function have a rapid onset of action because
they cause an immediate change in ion concentrations in the cell.

FIG. 3.7 G protein-coupled receptors and the cyclic AMP (cAMP)

second-messenger system.Phosphodiesterases (PDEs) block adenylyl
 cyclase and reduce cAMP levels. PDE inhibitors therefore increase
cAMP levels and increase its cellular effects.

FIG. 3.8 The role of Gi and Gs proteins in regulating cell responses

to G protein-coupled receptors.Gi, inhibitory G protein; Gs,
stimulatory G protein.

Drugs affecting ion channel function usually work in one of two ways: they may bind
to a receptor site attached to the channel and regulate the channel opening, or they may
bind directly to the channel protein and physically block the channel opening.
 FIG. 3.9 The mechanism of action of steroid drugs. Modified from
Jones R and Lopez KH (2006) Human reproductive biology, 3rd ed,
Fig. 1.5. San Diego: Academic Press.

Drugs Which Bind to a Receptor Site on the Channel

Ion channels are formed from several protein subunits assembled around the central
channel pore. Receptor sites on one or more of the subunits control the opening and
closing of the channel. Some neurotransmitters including ACh acting on nicotinic
receptors and GABA operate this way, permitting very fast control (in milliseconds) of
synaptic transmission. GABA (p. 16) is an important inhibitory transmitter in the brain,
and it hyperpolarises neurons, reducing synaptic transmission. It binds to a subunit on
Cl− ion channels on nerve endings, opening them and increasing the entry of inhibitory
Cl− ions into the nerve. Benzodiazepines like midazolam bind to a different receptor
site on the Cl− channel and enhance the inhibitory effect of GABA, prolonging channel
opening, increasing Cl− flow into the nerve, and further reducing its excitability. This
underpins the sedative, anxiolytic, and anticonvulsant action of this group of drugs.

Drugs That Block Ion Channels

Local anaesthetics like lignocaine block Na+ channels in nerve axons. The influx of
positively charged Na+ ions into the axon generates the electrical current that sweeps
along the nerve as the action potential, and when a local anaesthetic molecule plugs the
channel and prevents sodium entry, the nerve is silenced. Ca2+-channel blockers like
verapamil and nifedipine have been used for decades to treat cardiovascular disease
and hypertension. They prevent Ca2+ entry into cardiac and smooth muscle cells;
deprived of Ca2+, the cells become less excitable. Cardiac contractility is reduced,
producing an anti-arrhythmic action, and vascular smooth muscle relaxes, reducing
blood pressure.

Receptor Desensitisation and Drug Tolerance

Drug tolerance is the reduction in the response to a drug seen with continued
administration. It is a very common phenomenon and can cause significant problems in
therapeutics. It usually occurs over a period of time and generally develops more quickly
at higher drug doses. As tolerance develops, higher and higher drug doses are needed to
achieve the same effect, and at its extreme it may mean that the drug response is
completely lost; the tissue is now said to be refractory.
Tolerance may be due to, for example, increased metabolism because sustained drug
levels induce hepatic enzymes (p. 16). However, as explained above, cells exposed to
persistently high drug levels reduce (downregulate) receptor numbers to reduce the
excessive receptor signalling. This too can cause tolerance. Another mechanism by
which tolerance can develop is if the receptors themselves become less sensitive to the
drug. This is called receptor desensitisation and can occur after even a single dose of a
drug: for example, tolerance to the analgesic effects of morphine can be seen after only
a single dose. Loss of receptor sensitivity can be due to an uncoupling of the receptor
from its second-messenger systems; the drug can still bind but cannot activate internal
pathways, like cutting the wire from a doorbell, and its effect is lost.

Membrane Transport Mechanisms

To control the composition of its cytosol, a cell must be able to regulate what enters and
leaves. For this purpose, the plasma membrane is populated with a range of pumps and
carriers, which import essential substances like glucose. One example of a tissue where
such transport mechanisms are important is the kidney: in the renal tubule, ion-specific
pumps and co-transport mechanisms control reabsorption or secretion of key
electrolytes. Some diuretics, including the thiazides and the loop diuretics, work by
interfering with Na+ transport mechanisms in the tubule wall and increase Na+
excretion; increasing Na+ levels in the urine pulls water with it and increases urine
volume.
Other important membrane pumps include the Na+/K+ ATPase pump (sometimes
just called the Na+–K+ pump). This pump is found in the membrane of all body cells. It
operates continuously, exchanging Na+ for K+ across the membrane. By pumping Na+
out of the cell and pumping K+ into the cell, it maintains high Na+ concentrations in the
extracellular fluids and high K+ concentrations inside cells. Extracellular Na+
concentrations regulate water distribution and cell volume, and the Na+/K+ gradients
across the cell membrane maintain the electrical excitability of nerve and muscle tissue.
Digoxin inhibits this pump in cardiac muscle cells, reducing the contractility of the
myocardium; it is used to treat some cardiac arrhythmias and to reduce cardiac
workload in heart failure.
Another example is the proton pump, which exchanges hydrogen (H+) ions for K+ in
parietal cells in the gastric lining. It concentrates H+ in gastric fluids, maintaining the
low (1–2) pH of normal stomach fluids. Proton-pump inhibitors like omeprazole are
used to reduce gastric acidity in conditions such as acid reflux.

Enzymes
Enzymes are biological catalysts and speed up chemical reactions inside and outside
cells without themselves being changed: the ultimate recyclers! The body contains tens
of thousands of enzymes, each driving one or more steps in the millions of chemical
reactions taking place every second. Drugs can themselves be enzymes: for example,
streptokinase is a thrombolytic drug used to break down a blood clot blocking a
coronary or cerebral artery and restore blood flow. More commonly, drugs affecting
enzyme action are inhibitors and block the enzyme; for example, ibuprofen blocks the
enzyme cyclo-oxygenase, which produces pro-inflammatory prostaglandins. This is the
basis of ibuprofen’s anti-inflammatory action, but because prostaglandins have
additional physiological functions, inhibiting their production causes a range of other
side-effects (see Chapter 6).

Non-Mammalian Cell Targets

Not all drugs target some aspect of human cell function. For example, osmotic diuretics,
e.g. mannitol, work by increasing the osmotic pressure of filtrate in the kidney tubules,
which passively pulls water from the bloodstream into the tubule to be excreted in the
urine. Antimicrobial drugs target infecting or invading organisms. A key tenet of
antimicrobial therapy is that the drug should have as little impact on host cells as
possible, while being sufficiently toxic to the infecting organism to treat the infection.

Assessment of Drug Action

Assessing the effectiveness, safety, and nature of drug action is an important aspect of
drug development and testing, as well as evaluating its performance when approved for
use.

Affinity, Efficacy, and Potency

The affinity of the drug to its receptor is a measure of how strong the drug–receptor
attraction is. Drugs with high affinity spend more time bound to the receptor than drugs
with lower affinity. This usually means that the drug is more potent and that a lower
concentration of drug is needed to produce a given response. Efficacy, on the other
hand, is the power of the drug, once bound, to activate the receptor. Agonists, by
definition, have affinity and efficacy because they bind and activate their receptor.
Antagonists, on the other hand, must have affinity but no efficacy; i.e. even though they
bind to their receptor, they cannot activate it.
Potency describes the relationship between drug concentrations and a given response.
The lower the drug concentration needed to produce a given response, the more potent
the drug is said to be. To illustrate, imagine you have two hypothetical antihypertensive
drugs, A and B. Both drugs in clinical trials reduce average systolic blood pressure by 10
mmHg, but the dose of drug A needed to do this is 100 mg compared to 10 mg for drug
B. Drug B is therefore the more potent of the two.

Dose–Response Relationships
In general, there is a direct relationship between drug dose and the biological response it
produces: the higher the dose, the greater the effects, both therapeutic and unwanted.
This can be quantified using dose–response (DR) curves, which demonstrate key
features of drug action including the therapeutic range and the maximally effective dose.
The y-axis plots the drug response under consideration. The x-axis of the DR curve
shows drug concentrations, usually plotted as their logarithms (logs) to allow a wide
range of values to be plotted along a shorter axis, and gives a characteristic sigmoid (S)-
shaped curve with a central linear portion (Fig. 3.10).
 DR curves can be constructed to show the activity of a drug in a lab-based experiment;
for example, to show how increasing drug concentrations inhibit the activity of a specific
enzyme (in which case it is more properly known as a concentration–response curve) or
to show the effect of a drug in a living system. Fig. 3.10 shows a DR curve presenting
the relationship between increasing dose of a hypothetical diuretic drug and the increase
in daily urine output. It clearly shows that as drug concentration rises, there is a steady
rise in urine output. It also shows that below the point marked with one star, the drug
shows little or no effect: this is the sub-therapeutic drug range. Above the point marked
with two stars, the diuretic effect plateaus, and increasing the dose to supra-therapeutic
levels gives no further clinical benefit. In this example, the therapeutic range
(sometimes called the therapeutic window), which is the dose range across which
maximal therapeutic benefit is likely to be obtained, is also shown. It is important that
drug concentrations in body tissues, usually measured in the plasma, fall within the
therapeutic range. If they fall below the therapeutic minimum, the drug is unlikely to
produce its desired benefits. If they exceed the therapeutic maximum, the risk of adverse
effects increases. It is important to realise that for most drugs, some adverse effects may
occur even when plasma levels fall within the therapeutic range. Whether or not this is
acceptable to the patient and the clinical team is likely to depend upon the situation.
Significant unwanted effects occurring within the therapeutic range may be tolerated if
the disease is serious or if other treatment options are limited; for example, cytotoxic
agents used in cancer can produce horrible adverse effects which may be accepted
because the treatment may be life-saving.
 FIG. 3.10 Dose–response curve for a hypothetical diuretic drug,
showing the therapeutic range and the ED50.

The ED50 (the dose producing an effective therapeutic response in half of a test
population) is also shown on this graph. The ED50 is important when calculating the
therapeutic index (TI; see below).

Therapeutic Index
DR curves can be used to show the relationship between dose and likely toxicity. The TI,
in its simplest form, is a measure of the difference between the therapeutic dose of a
drug and the dose likely to cause a particular adverse effect. It is calculated as a ratio of
the toxic dose to the effective dose. The closer the toxic dose is to the therapeutic dose,
the closer the ratio is to 1. A low TI therefore indicates that adverse effects are likely to
be seen at drug doses close to the therapeutic dose. Higher TI values indicate a wider
difference between therapeutic and toxic doses, which is clearly more desirable.
Fig. 3.11 demonstrates this relationship for the same hypothetical diuretic drug
shown in Fig. 3.10 and used to treat high blood pressure. Its standard DR curve is
shown in green. It has two known unwanted effects: renal toxicity and hair loss. We can
plot the DR curve showing the relationship between drug dose and hair loss; this is
shown in orange. We can see that the two curves are very close together, so that for most
doses across the therapeutic range, there is also likely to be hair loss. The DR curve
showing the relationship between drug levels and kidney toxicity is shown in grey. This
curve is significantly shifted to the right, showing that renal toxicity is likely only at
supra-therapeutic drug doses.
It seems obvious from simply eyeballing the graph that hair loss is a much more
common adverse effect than renal toxicity, but the TI is a quantitative value usually
calculated as a ratio. The TI is expressed as the ratio between the TD50, which is the dose
of the drug producing the adverse effect in half of a test population, and the ED50, and it
is calculated as TD50/ED50. The closer the TD50 is to the ED50, the higher the risk of the
given side-effect. If TD50 and ED50 are the same or very close, the ratio is 1 or close to 1,
and the toxic effect is pretty much guaranteed to occur at therapeutic doses. For
example, if the TD50 is 20 mg and the ED50 is 10 mg, the TI is 20/10=2, which is low and
suggests a high likelihood of the adverse effect occurring. However, if the TD50 is much
higher than the ED50, the ratio is much higher and reflects a greater safety margin with
respect to toxicity. For example, if the TD50 is 1000 mg and the ED50 is 1 mg, the TI is
1000/1=1000.
It is important to realise, however, that not all adverse effects are seen more
frequently or more severely with increasing dose. Allergic and anaphylactic drug
reactions can occur even after minimal exposure, and cough, a common and
troublesome side-effect of angiotensin-converting enzyme (ACE) inhibitors like
captopril, is not dose-dependent. In these circumstances, DR curves and TI are not
relevant.
FIG. 3.11 Dose–response curves for a hypothetical diuretic drug,
illustrating a narrow therapeutic index for hair loss and a wide
therapeutic index for renal toxicity.
Adverse Drug Reactions
Adverse drug reactions (ADRs) are common, often troublesome, and occasionally
catastrophic. Management of unwanted effects caused by one drug by prescribing
additional drugs is an important cause of polypharmacy, which in turn greatly increases
the risks of further side-effects and interactions. For example, Ca2+-channel blockers
like verapamil can cause acid reflux, which can be troublesome enough to require the
addition of a proton-pump inhibitor like omeprazole to the prescription. ADRs are a
common reason for people to consult their healthcare provider and are the cause of a
significant proportion of hospital admissions. Risk factors for ADRs include renal and
liver insufficiency, female sex, serious illness and/or immunocompromise, extremes of
age, and polypharmacy.

Mechanisms of Adverse Drug Reactions

ADRs can usually be classified into one of four main groups. Any given drug may have
unwanted effects in one or more of these groups.
FIG. 3.12 Facial rash from penicillin hypersensitivity. From
 Cawson R and Odell EW (2008) Cawson’s essentials of oral
pathology and oral medicine, 8th ed, Fig. 35.2. Edinburgh: Churchill
Livingstone.

Immunologically Mediated Adverse Drug Reactions

Sometimes the drug itself or one of the constituents of a medicine (for example, lanolin
in topical preparations) triggers an allergic response. There are four types of allergies
(the Coombs and Gell classification), and all are implicated in immunological drug
reactions. Drugs may cause reactions in more than one category: for example,
penicillin and other β-lactam antibiotics can cause type I, II, and III reactions. Some
unwanted effects may seem to be immune-mediated but are not; for example, opioids
can cause itch in some people. This is not an allergic reaction as might intuitively be
supposed but is due to a direct effect of the opioid on mast cells, which synthesise
histamine: morphine binds to the mast cell and stimulates histamine release.
Immune-mediated ADRs are more common in women and in people with a history of
allergy.

Type I: Immediate Hypersensitivity

This form of allergy is associated with excessive IgE levels and histamine release from
mast cells, and it causes conditions like hay fever and anaphylaxis, the most dangerous
form of allergy. The organ most commonly affected in type I allergic reactions is the skin
(Fig. 3.12). A range of drugs including aspirin, penicillin and other antibiotics, and
monoclonal antibodies cause immediate hypersensitivity reactions.

Type II: Cytotoxic

In type II drug-mediated allergic reactions, the drug binds to a component of the plasma
membrane of a particular cell type, e.g. platelets, erythrocytes, or connective tissues,
which makes the cell a target for immune attack. Penicillin, cephalosporins,
thiazide diuretics, oral hypoglycaemics, and phenothiazines like
chlorpromazine can cause haemolytic anaemia by this mechanism: the drug binds to
erythrocyte membranes and stimulates an immune response which destroys the red
cells. Penicillamine can cause myasthenia gravis and systemic lupus erythematosus by
type II-mediated reactions.

Type III: Immune-Complex Mediated

In type III drug-mediated immune reactions, the body makes antibodies to the drug,
which bind to the drug molecules in the bloodstream, forming large immune complexes.
Immune complexes may deposit in a range of tissues and organs and trigger an immune
response against that tissue, damaging and possibly destroying it. For example,
hydralazine and sulphonamides can cause a systemic lupus erythematosus-like
syndrome.

Type IV: Delayed

Delayed-type drug-mediated immune reactions involve the activation of T-cells directed
against the target; this can take hours or days, and so the immune response is not
immediate. Topical antihistamines can cause contact dermatitis by a type IV
mechanism, and pulmonary toxicity caused by bleomycin, sulphonamides, and
amiodarone is thought to be type IV-mediated. Stevens–Johnson syndrome (Fig.
3.13A) and toxic epidermal necrolysis (TEN; Fig. 3.13B; see below) are also examples
of type IV reactions.

Pharmacologically Mediated Adverse Drug Reactions

These ADRs are caused by known pharmacological actions of the drug, including both
therapeutic and non-therapeutic effects. They are very common. For example,
antihypertensive drugs can cause hypotension, and diuretics can cause
dehydration; these are both instances where the adverse effect is due to an
overextension of the desired therapeutic effect. Another example is aspirin-induced
bronchoconstriction, likely to be particularly problematic in people with asthma.
Although bronchoconstriction is not the intended therapeutic aim of aspirin
administration, which is usually used for either its antiplatelet or anti-inflammatory
activity, its effect on the airways is well understood and predictable (p. 120).

Biochemically Mediated Adverse Drug Reactions

A drug may interact with cell molecules other than their target molecule and interfere
with some aspect of cell structure or biochemistry. For example, one of the hepatic
metabolites of paracetamol is a reactive and highly hepatotoxic substance called N-
acetyl-p-benzoquinone imine (NAPQI), which irreversibly binds to key proteins in the
liver cell and induces necrosis. Drugs, for example cytotoxic agents used to treat
cancer, which affect the structure of DNA (i.e. are mutagenic) interfere with cell division
and are associated with significant ADRs, including birth defects and the development
of further cancers.
Common Adverse Drug Reactions
Tissues with high metabolic activity and/or high cell turnover rates are often most likely
to be adversely affected by drugs. ADRs are easiest to spot when they occur quickly
following drug treatment, and when they are common, significant, and/or unusual. For
example, a drug that causes a mild, non-itchy rash on the back which does not appear
until a few days after the initiation of treatment might not even be noticed, but if it turns
the urine bright purple on the day after treatment starts, the link between the drug and
the adverse effect is likely to be made immediately!
FIG. 3.13 A. Stevens–Johnson syndrome caused by
carbamazepine. B. Toxic epidermal necrolysis. From (A) Paller A and
Mancini A (2011) Hurwitz clinical pediatric dermatology, 4th ed, Fig.
 20.21. St. Louis: Elsevier, and (B) Micheletti R, James W, Elston D,
et al. (2023) Andrews’ diseases of the skin clinical atlas, 2nd ed, Fig.
2.41. Oxford: Elsevier.

Hepatic Adverse Drug Reactions

The liver is metabolically very active, and because its key functions include metabolism
and excretion of unwanted substances, hepatocytes concentrate drugs and so are
exposed not only to high levels of the parent drugs but also to potentially toxic
metabolites. Many agents, including halothane, paracetamol, statins,
chlorpromazine, ketoconazole, and sodium valproate, are strongly associated
with drug-induced liver injury. With all drugs, care should always be taken when there is
known or suspected liver impairment, including age-related decline in liver function in
healthy older people.

Renal Adverse Drug Reactions

The kidney concentrates unwanted substances within the renal tubules, which exposes
its tissues to high levels of drugs and drug metabolites, some of which are actively
renotoxic. Many drugs, including non-steroidal anti-inflammatory drugs,
proton-pump inhibitors, and ACE inhibitors, can impair kidney function. Drugs
that are poorly metabolised in body tissues, for example furosemide, streptomycin,
and digoxin, are concentrated in the kidney in their active form, and can cause
considerable toxicity. Care should always be taken when there is known or suspected
renal impairment, including age-related decline in kidney function in healthy older
people.

Cutaneous Adverse Drug Reactions

A wide range of drugs, including anticonvulsants, antibiotics, and non-steroidal
anti-inflammatory agents, cause skin reactions. Sometimes these are delayed
following starting the offending medication, so the link is not always obvious. Cutaneous
ADRs range from a mild, possibly itchy rash to potentially lethal conditions such as
Stevens–Johnson syndrome and its more widespread form, TEN. In Stevens–Johnson
syndrome (Fig. 3.13A) and TEN (Fig. 3.13B), the epidermis sloughs away from the
dermis and there are painful erosions of mucous membranes, e.g., in the mouth and the
urogenital tract. It carries a 25% mortality rate and is particularly associated with
anticonvulsants, allopurinol, and sulphonamides.
Red Bone Marrow Toxicity
The red bone marrow produces around 2 million new red blood cells every second, the
highest rate of new cell production of any of the body’s tissues. It also produces platelets
and white blood cells. With such high turnover, the red bone marrow is a particular
target for drugs which inhibit cell division, in particular cytotoxic drugs used in
cancer treatment, which cause neutropenia, anaemia, and thrombocytopaenia. Red cells
and platelets may be involved in immune reactions to drugs, leading to anaemia and
thrombocytopaenia. Haemolytic anaemia is a recognised side-effect of a range of drugs
including diclofenac, piperacillin, and the cephalosporin antibiotics. Immune-
mediated platelet destruction causing thrombocytopaenia include quinine,
sulphonamide antibiotics, heparin, and vancomycin. Chloramphenicol carries
a small but significant risk of irreversible complete bone marrow failure (aplastic
anaemia); the mechanism is not known.

Reproductive Function
The use of both prescription and non-prescription drugs in pregnancy presents potential
risks to the developing baby. Most drugs, being fat-soluble, cross the placenta and many
do so in significant concentrations. The decision to prescribe new drugs or to continue
with pre-existing prescriptions in pregnancy or in women wishing to become pregnant
must be carefully weighed up in terms of the risk-benefit ratio to both mother and child.
In the first 3 months, while the baby’s cells and tissues are differentiating and the organ
systems are being laid down, drugs may cause fetal abnormalities; drugs that do this are
called teratogens. Significant teratogens include ethanol, many anticonvulsants
including phenytoin and valproate, cytotoxic drugs, warfarin, ACE inhibitors,
methotrexate, and retinoids. In the second two trimesters, when organogenesis is
completed, ADRs on the fetus are often similar to those seen post-natally: for example,
anticoagulants increase the risk of bleeding, oestrogens can feminise male fetuses,
and ACE inhibitors can interfere with fetal kidney function. Ethanol can cause
significant developmental retardation at all stages of pregnancy, including low
birthweight and facial and cardiac malformations.
Quantitative and evidence-based data on the effect of drugs on mother and baby
during pregnancy and in breastfeeding women is often limited, because for obvious
reasons it is not ethical to include pregnant women in clinical trials. In general, the use
of drugs in pregnancy should be avoided if possible, especially in the first trimester. If
drug treatment is unavoidable, the lowest possible doses of long-standing drugs that are
believed to be safe should be used.
 Some drugs can interfere with sperm production and ideally should be avoided in men
trying to father a child. These include ethanol, opioids, anabolic steroids, and
cytotoxic agents.

Nervous System Adverse Drug Reactions

The brain represents only 2% of total bodyweight, but it receives 12% of the cardiac
output. Despite the blood–brain barrier (see Fig. 2.9), which is at best an imperfect
protection for the brain, this means that brain tissues are exposed to significant drug
levels. Central ADRs include sedation, visual impairment, seizures, confusion, sleep
disorders, and cognitive impairment.

Classification of Adverse Drug Reactions

The ABCDE (Rawlins–Thomson) classification system is convenient and easily
remembered.

Type A (Augmented) Reactions

These are unwanted effects that are extensions of the drug’s known pharmacological
activity: for example, hypoglycaemia with insulin, bradycardia with beta-blockers,
hypokalaemia with loop diuretics, peptic ulceration with non-steroidal anti-
inflammatory drugs, and bleeding with anticoagulants. They are generally
predictable, dose-dependent, and reversible on withdrawal of the drug or reduction of
dose. Type A are the most common type of ADRs.

Type B (Bizarre) Reactions

These unwanted effects are not dose-related. They are not linked to the drug’s known
pharmacological activity and often involve an immunological reaction to it: for example,
penicillin allergy is a type B reaction. Although in many cases they are unpredictable,
there may be indications that an individual may be at increased risk: for example, a
history of allergy may indicate an increased risk of drug allergy. In general, type B
reactions are more severe than type A reactions, and because they are rare, they are
often not picked up until after a drug has been licensed for clinical use.

Type C (Chronic) Reactions

Type C reactions are associated with chronic drug use and may themselves be persistent:
for example, gum hyperplasia seen with phenytoin and growth retardation in children
treated with corticosteroids are type C reactions.
Type D (Delayed) Reactions
These ADRs do not appear until after the drug is withdrawn and may not appear until
years later: for example, the development of blood malignancies later in life following
cytotoxic treatment for an unrelated cancer when younger, and post-antibiotic rashes.

Type E (End-of-Dose) Reactions

These are the ADRs seen after a drug is withdrawn, for example, withdrawal syndromes
when opioids or benzodiazepines are stopped and adrenal insufficiency when a
medium- to long-term course of corticosteroids ends. These reactions can often be
avoided or ameliorated if the drug is withdrawn slowly (stepped down) over a period of
time.

Drug Dependence
Substance dependence occurs when an individual is unable to function without regular
intake of a substance, experiences distress when deprived of it, and continues to use the
substance despite associated problems. It is frequently associated with recreational
drugs, including ethanol, but can also arise with drugs used therapeutically, including
opioid analgesics, antidepressants, and benzodiazepines.
It is characteristic of human behaviour that we like to repeat pleasurable and
rewarding experiences. The evolution of powerful reward pathways, seen across the
animal kingdom and not just in humans, ensures the continuation of the species because
it reinforces essential survival behaviours such as eating, sexual and reproductive
activity, and parent–child bonding. The key nerve pathways in the brain responsible for
regulating reward-related behaviour are found in the mesolimbic system, and the main
neurotransmitter involved in promoting rewarding behaviours is dopamine. Although
other brain centres are also involved, the key areas associated with reward are the
ventral tegmental area (VTA) in the midbrain and the nucleus accumbens (NA), located
anteriorly to the VTA (Fig. 3.14A). The VTA projects dopamine-releasing neurones to
the NA, which is the main centre for reward-orientated learning and behaviour.
Dopamine, acting on D1 receptors in the NA, reinforces activities found to be positive,
beneficial, or enjoyable and increases the likelihood that the behaviour will be repeated.
A range of drugs via a direct or indirect action on the VTA increase dopamine levels in
the NA and so increases the likelihood that the drug will be taken again (Fig. 3.14B).
Repeated use of the drug produces sustained elevated dopamine levels in reward
pathways and brain structures, which over time leads to neuroadaptive changes, which
may be irreversible. The reward pathways become tolerant of consistently elevated
dopamine levels and cannot function without them. When drug levels fall, and
dopamine levels fall as a consequence, unpleasant withdrawal effects motivate the
individual to repeat their drug-taking.

FIG. 3.14 The reward pathway.A. The ventral tegmental area and
 the nucleus accumbens. B. The action of drugs that cause
dependence on dopamine levels in the nucleus accumbens. (A)
Modified from National Institute on Drug Abuse. The Neurobiology
of Drug Addiction. Available at
http://www.nida.nih.gov/pubs/teaching/Teaching2/Teaching.html,
and (B) from Waller DG, Sampson A, and Hitchings A (2022)
Medical pharmacology and therapeutics, 6th ed, Fig. 54.1. Oxford:
Elsevier.

Withdrawal Syndromes
Withdrawal syndromes are collections of signs and symptoms seen when a drug is
discontinued, and they can be severe: for example, delirium tremens following alcohol
withdrawal can necessitate intensive care support, and seizures following
benzodiazepine withdrawal can be life-threatening.

References
1. Pasternak A.L, Ward K.M, Luzum J.A, et al. Germline genetic variants with
implications for disease risk and therapeutic outcomes. Physiol.
Genomics. 2017;49(10):567–581.

Online Resources
Farinde A. Overview of Pharmacodynamics. 2023 Available
at:. https://www.msdmanuals.com/en-gb/professional/clinical-
pharmacology/pharmacodynamics/overview-of-pharmacodynamics.
Pharmacology Education Project, . Clinical Pharmacodynamics. 2024 Available
at:. https://www.pharmacologyeducation.org/clinical-
pharmacology/clinical-pharmacodynamics.
Yartsev A. Required Reading: Pharmacodynamics. 2024 Available
at:. https://derangedphysiology.com/main/cicm-primary-
exam/required-reading/pharmacodynamics.
4: Drugs and Neurological Function

CHAPTE R OU TLINE

Introduction
Nerve Conduction and Synaptic Transmission
The neurotransmitters of the nervous system

The Peripheral Nervous System: the Autonomic and

Somatic Divisions
Pharmacology of Important Neurotransmitters
Antidepressants, mood stabilisers, and anxiolytics
Antidepressant and Mood-Regulating Drugs
The Biology of Depression
Antidepressants that Block Monoamine Re-
Uptake
Drugs that Block Monoamine Breakdown
Monoamine Receptor Blockers
Other Antidepressant Drugs
Anxiolytic and Sedative Drugs
Non-Benzodiazepine Anxiolytics
Hypnotics
Mood-Stabilising Drugs
Antipsychotic drugs
Schizophrenia
Antipsychotic Drugs
Typical (First-Generation) Antipsychotics
 Atypical (Second-Generation) Antipsychotics
Anaesthetics
General Anaesthetics
Inhalational Anaesthetics
Intravenous Anaesthetics
Anticonvulsants

Causes of Seizures
Types of Seizure
Pharmacological Management of Seizures
Anticonvulsants that Block Sodium Channels
Anticonvulsants that Enhance Gamma-
Aminobutyric Acid
Anticonvulsants that Block Calcium
Channels
Anticonvulsants that Reduce Glutamate
Activity

F OCUS ON

Focus on: Adrenergic Pharmacology p. 47

Focus on: Cholinergic Pharmacology p. 49
Focus on: Antimuscarinic Side-effects p. 51
Focus on: Dopamine and Parkinson’s Disease p. 53
Focus on: Benzodiazepine Pharmacology p. 61
Focus on: Local Anaesthetics p. 69

Introduction
The nervous system controls multiple aspects of body function, and because of this,
drugs that affect neurological processes often have significant and widespread effects.
Nerve conduction and synaptic transmission
Neurones are specialised cells that generate and conduct electrical impulses (action
potentials), allowing them to communicate with each other and to control activity in
muscles, glands, and other organs. A typical nerve cell has a cell body, which has
multiple fine extensions called dendrites and contains the nucleus, as well as an
extended filament called an axon, which conducts the action potential (Fig. 4.1A). The
axon terminates in a sheaf of tiny extensions called axon terminals, each of which comes
into very close association (but not direct contact) with the dendrites of another
neurone, or with a target cell of peripheral tissue, e.g. smooth muscle or a gland. Some
nerve axons have a myelin sheath, which increases the speed of nerve conduction.

The Synapse
A nerve cell does not physically make contact with other nerve or target cells: the tiny
gap between an axon terminal and the dendrite of another neurone, or the axon
terminal and a target cell, is called the synaptic cleft and the site of connection is called
the synapse. The nerve conducting an action potential towards the synapse is called the
pre-synaptic neurone, and the cell receiving the action potential is called the post-
synaptic cell (Fig. 4.1B).
 FIG 4.1 A. Nerve cell structure. B. General structure of a
synapse. Modified from Waugh A and Grant A (2018) Ross & Wilson
anatomy and physiology in health and illness, 13th ed, Figs 7.2 and
7.7. Oxford: Elsevier.

Without physical contact between pre- and post-synaptic membranes, the electrical
action potential cannot be directly transmitted from cell to cell. Instead, the pre-
synaptic axon terminal synthesises a chemical called a neurotransmitter, which is
released in response to the arrival of an action potential. Neurotransmitter molecules
diffuse across the narrow synaptic cleft and bind to receptors on the post-synaptic
membrane. This produces a response in the post-synaptic cell, which may be activated
or inhibited depending on the neurotransmitter and the nature of the post-synaptic
receptors. Inhibitory neurotransmission is an essential component of neurological
control and an important target for clinically important drugs. Neurotransmitter
synthesis, release, and action on its receptors are very important drug targets.

Termination of Neurotransmitter Action

Nervous control is fast and flexible, allowing body functions to be rapidly activated or
inhibited and finely tuned and controlled. Neurotransmitter levels in the synapse must
therefore be tightly regulated. Once released, a neurotransmitter requires only a fraction
of a second to diffuse across the synaptic cleft and activate its receptors and must be
immediately removed so that its action can be rapidly terminated if required. There are
two main ways in which this happens at the synapse, both of which are important
targets for drug action.

Re-uptake Pumps
Specialised pumps and carriers in the pre-synaptic nerve cell membrane are in
continuous operation, constantly removing the transmitter from the synapse and taking
it back up into the pre-synaptic nerve (Fig. 4.2). Sometimes the transmitter is then
simply repackaged into vesicles, allowing it to be reused––an efficient recycling
mechanism! Sometimes the pumps are found on the post-synaptic membranes, in which
case the transmitter is then broken down by enzymes in the post-synaptic cell. Drugs
that block these pumps increase neurotransmitter levels in the synapse and prolong its
action. Key examples include tricyclic antidepressants and serotonin-specific re-
uptake inhibitors (SSRIs).
 FIG 4.2 Removal of a neurotransmitter from the synapse by re-
uptake pumps. Modified from Burchum J and Rosenthal L (2022)
Lehne’s pharmacology for nursing care, 11th ed, Fig. 35.1. St. Louis:
Saunders.

Degradative enzymes
Enzymes in the synapse or in either the pre- or post-synaptic cells destroy the
transmitter. Important examples of drugs that inhibit these enzymes, therefore
increasing transmitter levels in the synapse and prolonging its activity, include anti-
cholinesterase drugs like neostigmine, which prolong the action of acetylcholine
(ACh), and monoamine oxidase (MAO) inhibitors like phenelzine and selegiline,
which prolong the actions of noradrenaline (NA) and related monoamine
neurotransmitters.

Generation and Conduction of Action Potentials

Action potentials, the electrical signals that sweep along nerve and muscle membranes
at speeds of up to 100 m/s, are generated and propagated by the transfer of electrically
charged particles (ions) across the cell membrane through specific ion channels. When
the concentration of an ion is higher on one side of the membrane than the other, a
potential is said to exist, because there is the potential that the ions will move across the
membrane until their concentrations are equal on both sides. This ion movement
generates an electrical signal measured in volts (or in the case of cells, millivolts,
because the electrical potentials are small). Nerve cells control their electrical activity by
opening and closing specific ion channels, regulating ion transfer from one side of the
membrane to the other. In nerves, the main ions involved are sodium (Na+) and
potassium (K+), both positively charged ions (cations). Although these are the principal
players in nerve action potential generation, other electrically charged ions, both cations
and negatively charged ions (anions), are present, and changes in their movement
across the membrane also affects its electrical state. Examples include chloride (Cl-) and
calcium (Ca2+) ions.

The Resting Membrane Potential and the Sodium–Potassium Pump

When the nerve is resting, i.e. not firing, there is a potential difference across the
membrane called the resting membrane potential, because Na+ and K+ ion
concentrations on either side of the membrane are unequal. Na+ is concentrated outside
the cell, and K+ is concentrated inside the cell, and this is maintained by the sodium–
potassium (Na+/K+) pump. This pump, found in cell membranes of all body cells, is a
critically important mechanism in maintaining Na+, K+, and water balance between
intracellular and extracellular fluids. It constantly pumps Na+ leaking through the
membrane into the cell back out, and K+ that leaks out of the cell back in. The resting
membrane potential in neurones is -90 mV: that is, the interior of the cell is negatively
charged compared to the outside of the cell, because although K+ is concentrated in the
cell, so are Cl- ions and intracellular proteins, most of which carry a negative charge.

The Nerve Action Potential (Fig. 4.3)

In the resting neurone, K+ and Na+ channels are closed. Activation of the nerve is
initiated at the post-synaptic membrane when an excitatory neurotransmitter binds to
its receptors. This opens Na+ channels in the nerve cell membrane, and Na+ floods into
the cell down its concentration gradient. This influx of positively charged ions reverses
the charge inside the cell, which goes from negative to positive. This is called
depolarisation, and as each area of the neuronal membrane depolarises, it triggers
opening of adjacent Na+ channels, so that the action potential travels along the nerve
axon towards the axon terminal. The Na+ channels are open for only a tiny fraction of a
second, and close almost immediately. At this point, the K+ channels open and K+ floods
out of the cell down its concentration gradient. The rapid efflux of these positively
charged ions returns the charge inside the cell to negative compared to the outside. This
is called repolarisation.

FIG 4.3 The nerve action potential.The nerve is depolarised when

sodium channels open in the membrane, allowing sodium to flood
into the nerve. Repolarisation occurs when potassium channels
open, allowing sodium to flood out of the nerve. Modified from
Herlihy B (2022) The human body in health and illness, 7th ed, Fig.
10.6. St. Louis: Elsevier.

The membrane potential is now back to where it was before activation, at about
-90mV, but the distribution of Na+ and K+ ions is reversed, because they are now on
opposite sides of the membrane from where they started. Na+ is rapidly driven out of the
cell and K+ pulled back in by the continuous action of the Na+/K+ pump, restoring the
original excitability of the nerve. Interfering with ion movements across the nerve cell
membrane eliminates the action potential and prevents nerve conduction. Local
anaesthetics block the Na+ channels in nerve cell membranes, preventing Na+ flow
and silencing the nerve.

The neurotransmitters of the nervous system

Conventionally, the nervous system is considered in two parts: the central nervous
system (CNS) comprising the brain and spinal cord, and the peripheral nervous system
(PNS), comprising nerves and associated tissue carrying nerve impulses between the
CNS and body tissues.

The peripheral nervous system: the autonomic and somatic divisions

The PNS is considered in two functional divisions: the somatic and autonomic divisions.
The somatic nervous system is under voluntary control and supplies skeletal muscle.
The synapse between a motor nerve and a skeletal muscle fibre is called the
neuromuscular junction. The autonomic nervous system (ANS), on the other hand, is
not under voluntary control and regulates the huge range of physiological and
biochemical activity constantly operating below the level of consciousness. This includes
control of the smooth muscle found in the walls of passageways and hollow organs, e.g.
regulating blood vessel and airway diameter and the motility of the gastrointestinal
tract. The ANS also influences the rate and strength of the heartbeat, the secretion and
activity of many glands, and essential metabolic functions relating to energy production
and storage (e.g. blood glucose levels). Drugs that affect ANS function therefore often
have a wide range of often predictable actions and side-effects.

The Autonomic Nervous System

The ANS is further divided into two branches: the sympathetic and the parasympathetic.
Most body structures receive both sympathetic and parasympathetic innervation, whose
effects usually oppose each other. Sympathetic nervous system (SNS) activity tends to
prepare the body for physical activity and emotional, psychological, and pathological
stressors, and supports the body during these episodes. This may be something as trivial
as preventing a fall in blood pressure when going from sitting to standing, or a major
event like surgery or a systemic infection. Parasympathetic nervous system (PSNS)
activity, on the other hand, is usually associated with states of physical rest and low
stress. Autonomic nerve supply to the main body organs and its actions are shown in
Fig. 4.4. Sympathetic pathways leave the spinal cord from the thoracic and lumbar
regions, and parasympathetic outflow is from the cervical and sacral regions.
 FIG 4.4 A. The autonomic nervous system. B. Sympathetic and
parasympathetic pathways, showing neurotransmitters. ACh,
acetylcholine; GI, gastrointestinal. Modified from Ritter JM, Flower
RJ, Henderson G et al. (2020) Rang & Dale’s pharmacology, 9th ed,
Fig. 13.1. Oxford: Elsevier; and Hemmings H and Egan T (2019)
Pharmacology and physiology for anesthesia, 2nd ed, Fig. 13.2.
Philadelphia: Elsevier.

Autonomic pathways from the CNS to body tissues always contain two nerves (Fig.
4.4B). There are therefore two synapses per pathway, both potential targets for drug
action. The first nerve, called the pre-ganglionic nerve, leaves the CNS and terminates in
a ganglion (a collection of cell bodies), where it synapses with the cell body of the second
nerve in the pathway, the post-ganglionic nerve. The ganglia of sympathetic pathways lie
very close to the vertebral column, so the pre-ganglionic nerve is very short, and a long
post-ganglionic nerve is needed to reach the target organ. However, in the PSNS, the
pre-ganglionic nerve is very long, requiring only a short post-ganglionic nerve to reach
the target tissues. The neurotransmitter at sympathetic post-ganglionic nerve endings is
noradrenaline (NA), and acetylcholine (ACh) is the transmitter at both sympathetic and
parasympathetic ganglia and at parasympathetic nerve endings.
The receptors on which acetylcholine and noradrenaline act are not all identical but
are subdivided into subtypes, found in different tissues (see also Table 3.1).
Understanding the difference between the subtypes of autonomic receptors is important
because some drugs act at one subtype and not others, which has a direct impact on
their clinical action.

Pharmacology of important neurotransmitters

A wide range of clinically important drugs work by interfering in some way with
neurotransmitter activity, either by blocking, mimicking, or enhancing its effects. The
number of known neurotransmitters currently stands at over 100, but some are more
widespread than others. The most abundant neurotransmitters include acetylcholine,
dopamine, gamma-aminobutyric acid (GABA), glutamate, noradrenaline, and
serotonin. Others have more restricted distributions but are still important drug
targets, including histamine and the endogenous opioids.

Serotonin
Serotonin (5-hydroxytryptamine, 5-HT), has multiple physiological functions, including
in the gastrointestinal tract and as an important platelet activator in clotting. The role of
serotonin in these tissues is discussed in more detail in the relevant chapters. It is
widespread in the CNS; it regulates mood and arousal, eating behaviours, vomiting,
cognitive function, sleep, sensory pathways including pain, and body temperature; and
it is hallucinogenic.

Serotonin Receptors
There are seven types of serotonin receptor, named 5-HT1-7, and each type has multiple
subtypes (see Table 3.1). All seven types are found in the brain, and the development of
drugs that act selectively at particular subtypes has yielded drugs with specific clinical
usefulness. For example, 5-HT3 receptors are found in the area postrema in the medulla,
which controls vomiting. 5-HT release by these nerves stimulates vomiting.
Ondansetron is a selective 5-HT3 antagonist and a potent anti-emetic. Methysergide
is a 5-HT2 antagonist used to treat migraine. 5-HT2C receptors are found extensively in
brain regions associated with mood and emotional responses, and stimulation of these
receptors reduces dopamine levels and is associated with depressive states. Certain
atypical antidepressants, e.g. trazodone, block these receptors.

5-Hydroxytryptamine Synthesis and Breakdown

5-HT is synthesised from the amino acid tryptophan and, like noradrenaline and
dopamine, is classified as a monoamine transmitter. It is removed from the synapse by
re-uptake pumps (targeted by the serotonin-specific reuptake inhibitors) and is
destroyed by monoamine oxidase, the same enzyme that destroys NA and dopamine.
MAO inhibitors (MAOIs) are used as antidepressants.

Gamma-Aminobutyric Acid
GABA is the brain’s main inhibitory neurotransmitter. It is widespread in the brain and
controls a wide range of pathways and neurotransmitter activity. Drugs that increase
GABA levels, e.g. benzodiazepines (BDZs), sedate, cause sleep, and reduce anxiety,
aggression, and activity. They are also used to reduce the excessive, abnormal electrical
discharge that causes seizures.

Gamma-Aminobutyric Acid Receptors

There are two types of GABA receptors: GABAA and GABAB. When GABA binds to either
of its receptors, it opens ion channels in the nerve cell membrane, allowing a flow of ions
into the nerve cell that reduce its resting potential (Fig. 4.2), reducing its excitability
and increasing the size of stimulus required to activate the nerve. GABAA receptors are
linked to Cl- channels (BDZs are GABAA agonists), and GABAB receptors are indirectly
linked to K+ channels (the antispasmodic baclofen acts here).

Gamma-Aminobutyric Acid Synthesis and Breakdown

GABA is synthesised in the pre-synaptic nerve from the amino acid glutamate. After
release into the synapse, it is removed by specific re-uptake pumps in the pre-synaptic
nerve membrane, allowing it to be recycled. Some clinically important anticonvulsant
drugs block GABA re-uptake (e.g. tiagabine) or breakdown (e.g. vigabatrine) and are
discussed in the relevant section.

Dopamine
Dopamine is a neurotransmitter in both the PNS and CNS. It is an intermediate in the
biosynthetic pathway for NA and adrenaline, so it too is a catecholamine (Fig. 4.12).
Tyrosine is converted to dihydroxyphenylalanine (DOPA, specifically, L-DOPA or
levodopa) by the enzyme tyrosine hydroxylase. Levodopa is converted to dopamine by
DOPA decarboxylase. Dopamine in turn is converted to NA by dopamine β-hydroxylase,
and noradrenaline to adrenaline by phenylethanolamine N-methyltransferase. Seventy-
five percent of the brain’s dopamine content is found in the nigrostriatal pathway,
concerned with voluntary muscle control. Dopamine is also found in pathways
concerned with behaviour, reward, motivation, and addiction; with vomiting; and with
endocrine control. Key drugs in the treatment of Parkinson’s disease and schizophrenia
work by changing dopamine levels in the brain. Several dopamine antagonists, e.g.
domperidone and metoclopramide, are used as anti-emetics.

Dopamine Receptors
There are two groups of dopamine receptors: D1 and D2. Dopamine, like many other
neurotransmitters, has both inhibitory and excitatory actions depending on the nerve
pathway involved. For example, it activates reward pathways

F oc us on: Adrenergic Pharmac ology

Noradrenaline is an abundant neurotransmitter, found in both the peripheral and
central nervous systems. In the peripheral nervous system, it is released at
sympathetic post-ganglionic nerve endings (Fig. 4.4B), and in the brain it is found in
cardiovascular control pathways and in pathways regulating mood, alertness, reward,
learning, and memory. NA is very similar chemically to the hormone adrenaline,
acts on the same receptors, and produces the same effects. Chemically, both are
catecholamines, derived from the amino acid tyrosine and consisting of an amine
group bound to a catechol ring (Fig. 4.12). The term ‘monoamine’ is also used for
transmitters derived from a single amino acid; the monoamine transmitters include
NA, dopamine, and serotonin. Receptors that bind NA and adrenaline are called
adrenergic receptors, and drugs that stimulate adrenergic receptors are called
sympathomimetics, because they produce the same effects as NA and adrenaline.
Key Point: Adrenergic Receptors
There are two main types of adrenergic receptors: ⍺ and β, and subtypes of each of
these include ⍺1, ⍺2, β1, and β2. Sympathomimetics, including noradrenaline and
adrenaline, exert their effects on tissues by binding to one or more of these receptor
types.
Fig. 4.5 shows the effects of sympathetic stimulation on some key tissues, and the
subtype of adrenergic receptor responsible. Most blood vessels constrict in response
to sympathetic stimulation; this increases blood pressure and maintains blood flow,
and this action is mediated by ⍺1 receptors. However, some blood vessels, for
example, coronary arterioles and arterioles supplying skeletal muscle, contain β2
receptors, which cause them to dilate. This ensures that during stress of whatever
origin, the heart and skeletal muscle receive an increased blood supply to maintain
performance. The radial muscle of the iris contracts to open the pupil and ensure
adequate light for good vision. This is mediated by ⍺1 receptors. ⍺1 receptors in the GI
tract reduce motility and secretions, because in a time of stress, digestion and
absorption are not a priority. The liver contains ⍺1 and β2 receptors, which both
promote the breakdown of glycogen to increase blood glucose levels and ensure that
key body tissues have an adequate energy supply. The airways dilate because of β2
receptor activation in the smooth muscle in their walls, and the heart rate and cardiac
contractility rise because of β1 receptor activation in the myocardium. Both actions
improve cardiorespiratory function and increase oxygen supply to the tissues. Some
drugs acting on adrenergic receptor subtypes are shown in Fig. 4.6.
⍺2 Receptors
⍺2 receptors need a special mention. These receptors are found on pre-synaptic
membranes and, perhaps counterintuitively, they oppose the action of
sympathomimetics because they decrease NA release from the nerve terminal. They
are part of the nervous system’s intrinsic control mechanisms; if sympathetic activity
is high and NA levels in the synapse are elevated, this activates ⍺2 receptors which
inhibit further NA release (Fig. 4.7). This is called autoinhibition. An example of an
⍺2 agonist in clinical use is clonidine, used sometimes in hypertension. Yohimbine
is an ⍺2 antagonist not used clinically in the UK except in veterinary medicine but is
available as a supplement in some herbal and complementary preparations to treat a
variety of conditions including erectile dysfunction.
FIG 4.5 Subtypes, distribution, and function of adrenergic
receptors.GI, Gastrointestinal; NA, noradrenaline.

FIG 4.6 Examples of drugs acting on adrenergic receptor

subtypes. Modified from Partin AW, Dmochowski RR, Kavoussi
LR, et al. (2020) Campbell Walsh Wein urology, 3rd ed, Fig. 145.4.
Philadelphia: Elsevier.
 FIG 4.7 The role of α2 receptors in reducing noradrenaline
release from sympathetic nerves. Modified from Rosenthal LE and
Burchum JR (2021) Lehne’s pharmacotherapeutics for advance
practice nurses and physician assistants, 2nd ed. St. Louis:
Elsevier.

Removal of Noradrenaline From the Synapse

NA’s action is terminated by two main mechanisms. Most is pumped back into the
pre-synaptic nerve ending by re-uptake transporters (Fig. 4.2), and some is recycled
and reused. Blockade of these pumps increases NA concentration in the synapse and
prolongs its action, enhancing sympathetic effects. Re-uptake inhibitors, e.g. SSRIs,
are used in depressive illness. In addition, NA is destroyed by two key enzymes:
monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). Inhibitors of
these drugs are clinically useful in depression and other disorders and are discussed
in the relevant sections.
F oc us on: Cholinergic Pharmac ology
Acetylcholine, identified in 1913, was the first neurotransmitter to be discovered. It is
widespread in both the peripheral and central nervous systems. In the PNS, it is
released at sympathetic and parasympathetic ganglia and by the post-ganglionic
neurone in parasympathetic pathways (Fig. 4.4B). It is also the neurotransmitter
released by a somatic nerve supplying a skeletal muscle; this synapse is specifically
called the neuromuscular junction. In the brain, ACh is found in pathways controlling
voluntary muscle movement, memory and learning, and alertness. Receptors that
bind ACh are called cholinergic receptors.
Key point: Cholinergic receptors
There are two main classes of cholinergic receptor: nicotinic receptors and muscarinic
receptors. There are subdivisions of each. Nicotinic receptor subtypes are not
discussed here. Muscarinic receptor subtypes are classified as M1 to M5.
Fig. 4.8 shows the distribution and activity of cholinergic receptors in key body
tissues. All respond to ACh. Nicotinic receptors are found on skeletal muscle fibres at
the neuromuscular junction. ACh released here acting on these nicotinic receptors
causes skeletal muscle contraction. They are also found at the ganglia in both
sympathetic and parasympathetic nerve chains in the PNS. They are widespread in
the brain, where they are often responsible for regulating the release of other
neurotransmitters. The main locations and functions of the subtype of muscarinic
receptors are also summarised in Table 4.1. Some drugs acting on cholinergic
receptor subtypes are shown in Fig. 4.9. Most muscarinic agonists and antagonists
cannot differentiate between the different subtypes and act on them all. This leads to
unwanted and widespread side-effects, which often limits their use (see Focus on:
Antimuscarinic Side-Effects box). Design and production of selective drugs that work
only on one subtype could be of great clinical value.
Removal of Acetylcholine From the Synapse
The enzyme acetylcholinesterase (AChE) is the main mechanism by which ACh is
removed from the synapse. It breaks ACh down into acetyl groups, which are
destroyed, and choline, which is pumped back into the pre-synaptic nerve to produce
more transmitter (Fig. 4.10). Drugs that inhibit the action of AChE, called
anticholinesterases, therefore increase ACh levels in the synapse and prolong its
action. Anticholinesterases are used therapeutically to reverse neuromuscular
blockade and to improve cholinergic transmission in myasthenia gravis. Some
anticholinesterase agents are among the most toxic on the planet. Organophosphates,
e.g. malathion, are highly potent anticholinesterases used in low concentrations as
insecticides. Other organophosphates have been used for much more sinister
purposes: as agents of chemical warfare (now banned by the Geneva Convention) and
for terrorist attacks, for example, the Tokyo subway atrocity of 1995, in which the
anticholinesterase sarin killed 12 and injured thousands more. Excessive ACh levels
stimulate muscarinic and nicotinic receptors throughout the body, causing
widespread disruption of organ function. This is reflected in a wide range of signs and
symptoms including diarrhoea, nausea and vomiting, excessive salivation and tear
formation, bradycardia, bronchoconstriction, and increased respiratory secretions.

FIG 4.8 Subtypes, distribution, and function of cholinergic

receptors.ACh, Acetylcholine; GI, gastrointestinal.

Table 4.1

Subtypes of the Muscarinic Receptor

Subt
Location Function
ype
M1 Central nervous Widespread functions in CNS; stimulates glandular
system secretion
(CNS); glands
M2 Heart Slows heart rate and reduces cardiac contractility
M3 Smooth muscle; Increases gastrointestinal motility; stimulates glandular
glands secretion; stimulates bladder contraction;
bronchoconstriction
M4 Mainly CNS Widespread functions in CNS
M5 Mainly Motor control (see Parkinson’s disease)
substantia
nigra of brain

FIG 4.9 Examples of drugs acting on cholinergic receptor

subtypes.
 FIG 4.10 The action of acetylcholinesterase.ACh, Acetylcholine;
AChE, acetylcholinesterase. Modified from Rosenthal LE and
Burchum JR (2021) Lehne’s pharmacotherapeutics for advance
practice nurses and physician assistants, 2nd ed, Fig. 12.6. St.
Louis: Elsevier.

F oc us on: Antimusc arinic Side-E ffec ts

The terms ‘anticholinergic’ and ‘antimuscarinic’ are often used interchangeably
when talking about drugs used in medicine and their side-effects, but the
explanation in the Focus on: Cholinergic Pharmacology box shows the difference
between them. Muscarinic and nicotinic receptors are subtypes of the cholinergic
receptor. Both respond to ACh, although their distribution and function are
different, so that nicotinic receptor blockade gives a very different picture from
muscarinic receptor blockade. Antimuscarinic drugs are themselves used for a range
of conditions, to block the effects of parasympathetic nervous system ‘rest and
digest’ activity in peripheral tissues, or to block muscarinic receptors in the brain.
For example, the antispasmodic oxybutynin reduces bladder motility in some
forms of urinary incontinence, ipratropium is a bronchodilator sometimes used in
asthma, and hyoscine reduces secretions prior to surgery. Many commonly used
drugs have antimuscarinic side-effects because, in addition to their therapeutic
target, they block muscarinic receptors: these include antihistamines,
antidepressants, antipsychotics, and opioids. Antimuscarinic side-effects can
impose a significant and potentially dangerous burden, especially in elderly people,
and they may be easily missed because they are so widespread and non-specific. The
characteristic collection of antimuscarinic side-effects include:

• Cardiovascular system: The PSNS slows the heart rate, so antimuscarinic drugs
cause tachycardia. Blood vessels in the skin dilate, causing flushing.
• Gastrointestinal system: The PSNS promotes digestive activity, so
antimuscarinic activity reduces gastrointestinal motility, with delayed gastric
emptying, vomiting, gastro-oesophageal reflux, and constipation. The
production of digestive secretions, including saliva, is reduced, and dry mouth
is a very common complaint. Reduced salivary production increases the risk of
dental caries.
• Respiratory system: The PSNS contracts bronchial smooth muscle and causes
bronchoconstriction. It also promotes the production of respiratory secretions,
so antimuscarinic activity gives rise to bronchodilation and reduces respiratory
secretions.
• Secretory activity: Sweat and tear production are reduced, resulting in dry skin
and dry eyes.
• Smooth muscle: The PSNS promotes bladder contractility, and drugs with anti-
muscarinic properties cause urinary retention and overflow incontinence.
• Central effects: ACh is widespread in the brain, and its activity is reduced by
drugs with anti-muscarinic activity that cross the blood–brain barrier. This
leads to sedation, confusion and cognitive impairment, hallucinations, and
memory problems.
• Visual problems: The PSNS controls the ciliary muscle of the eye, which controls
focussing of the lens, and constricts the circular muscle of the iris, constricting
the pupil. Antimuscarinic side-effects therefore include blurred vision and
widely dilated pupils. A consequence of these actions may be raised intraocular
pressure and the development of glaucoma. When the circular muscle of the iris
and the ciliary body are constricted by parasympathetic activity, the iris is
stretched and thinned. This opens the canal of Schlemm in the iris–corneal
 angle, allowing aqueous humour to drain from the interior of the eye and
keeping intraocular pressure within normal limits (Fig. 4.11A). Antimuscarinic
agents dilate the pupil by allowing the iris to relax and bulge; this can obstruct
the canal of Schlemm, block aqueous humour drainage, and predispose to
closed-angle glaucoma (Fig. 4.11B). In some people, there is little space
already between the cornea and the iris, and any drug with antimuscarinic
effects is absolutely contraindicated because it can cause a rapid rise in
intraocular pressure with permanent damage to the optic nerve.

in the mesolimbic system, contributing to the development of addiction to euphoric

substances such as cocaine. However, dopamine released by the hypothalamus inhibits
the release of prolactin by the anterior pituitary and is the physiological ‘brake’
preventing breast development and lactation in males and in non-pregnant and non-
lactating females (in this context it is called prolactin inhibitory factor; see Fig.
5.2).
 FIG 4.11 The effect of antimuscarinic drugs on aqueous humour
drainage and intraocular pressure.

Dopamine Synthesis and Breakdown

Because it is synthesised from an amino acid, dopamine, like NA and serotonin, is
classed as a monoamine transmitter. The monoamine produced by a particular tissue
depends on the enzymes available. Neurones that release dopamine as their transmitter
do not contain dopamine β-hydroxylase, and so dopamine production is the terminal
event in the pathway. However, in sympathetic nerves, dopamine is further converted to
NA, and in the adrenal medulla, NA is converted to adrenaline (Fig. 4.12). Dopamine is
removed from the synapse of dopaminergic nerves by specific dopamine re-uptake
pumps and broken down by MAO and COMT, the same enzymes responsible for NA and
serotonin destruction.
 FIG 4.12 Dopamine is an intermediate in adrenaline
synthesis. Modified from Ritter JM, Flower RJ, Henderson G, et al.
(2020) Rang & Dale’s pharmacology, 9th ed, Fig. 14.1. Oxford:
Elsevier.

Histamine
Histamine’s best-known activity is as an inflammatory mediator in allergy, but it is also
an important neurotransmitter in the CNS, with a role in sleep–wake rhythms, appetite,
thermoregulation, and vomiting pathways. This is the reason why many antihistamines
are sedative and explains why antihistamines are useful anti-emetics.

Key Point: Histamine Synthesis and Breakdown

Histamine is synthesised from the amino acid histidine and broken down by
enzymatic action following its release into the synapse.

Histamine Receptors
There are four main types of histamine receptors: H1–H4. Each type has a characteristic
distribution in body tissues, relating directly to the different physiological roles of
histamine. This is summarised in Table 4.2, and each is further discussed in relevant
chapters. H1, H2, and H3 receptors are all found in the brain and mediate the effects
triggered by histamine released by histaminergic nerves. Some clinically important
antagonists at the different subtypes of histamine receptors are also listed in Table 4.2.
Note that the term ‘antihistamine’ is reserved for drugs that block H1 receptors.
Antihistamines (p. 122) are in widespread use as anti-allergy medications, sedatives, and
anti-emetics. H2 receptor blockers (p. 187) are used to reduce gastric acid levels.

Histamine and the Sleep–Wake Cycle

Histamine has an important role in the body’s circadian rhythm. Histamine-releasing
neurones originating in the posterior hypothalamus radiate widely throughout the brain,
stimulating activity and promoting wakefulness. These nerves fire during the day and
are silent at night. Blocking the action of histamine in the brain with antihistamines, e.g.
chlorphenamine and cyclizine, produces sedation and sleep. Current research in the
field of narcolepsy is investigating the use of drugs that target H3 receptors to increase
histamine levels in the brain and reduce daytime sleepiness. The first drug to be used
successfully in this area is pitolisant, approved by the European Medicines Agency in
2016.

Table 4.2

F oc us on: Dopamine and Parkinson’s Disease

This disorder of voluntary muscle control was first described by Dr. James Parkinson
in 1817. Voluntary muscle movement is normally very finely controlled, allowing for
continuous, subconscious, smooth, co-ordinated, and sometimes split-second
adjustments in skeletal muscle activity. Movement of the body or individual body
parts requires stimulation of appropriate skeletal muscle groups and simultaneous
relaxation of opposing muscle groups. For example, when flexing the arm at the elbow
to pick up a book from a table, the biceps brachii must contract, but the triceps must
relax. Voluntary muscle movement is initiated by the motor cortex in the brain, which
is stimulated by the thalamus. The stimulatory input to the motor cortex from the
thalamus is in turn regulated by the basal ganglia, collections of highly interconnected
cell bodies deep in the brain that include the globus pallidus and the corpus striatum.
The globus pallidus applies constant inhibition to the thalamus, preventing
inappropriate skeletal muscle contraction. The corpus striatum in turn controls the
globus pallidus. The corpus striatum receives input from the substantia nigra via a
collection of nerves, collectively called the nigrostriatal pathway, which release
dopamine at their nerve terminals in the striatum (Fig. 4.13 and 4.19). The function
of dopamine in regulating the corpus striatum is complex, but its overarching effect is
to stimulate the globus pallidus, increasing inhibition of the thalamus and ensuring
that skeletal muscles are not inappropriately or excessively contracted, and
appropriate skeletal muscle relaxation can take place. In PD, the neurones of the
nigrostriatal pathway progressively degenerate and the dopamine content of the
corpus striatum falls, giving the increased muscle tone and rigidity associated with the
disorder. Pharmacological management focusses primarily on replacing the lost
dopamine to restore the key regulatory function of the corpus striatum in motor
control.
As expected in such a complex control system, this description is only part of the
story and other areas of the brain and other neurotransmitters, including GABA and
glutamate, are also intimately involved but not described here for simplicity’s sake.
However, an additional point relevant to the following discussion of PD treatment is
that acetylcholine is also released in the corpus striatum, acting mainly on M5
receptors. It has the opposite effect to dopamine, so that while dopamine release in
the nigrostriatal pathway dampens skeletal muscle activity, ACh is excitatory. When
the nigrostriatal pathway degenerates and dopamine levels fall, the excitatory action
of ACh is allowed to predominate. This explains the use of anticholinergic drugs in the
management of PD, especially in drug-induced parkinsonism.
Signs and Symptoms of Parkinson’s Disease
PD is characterised by an inhibition of voluntary movement (bradykinesia),
accompanied by increased muscle tone and rigidity. Once a movement sequence is
initiated, the ability to alter or adjust is impaired: for example, once an individual has
begun walking, changing speed or direction, or stopping altogether, may be difficult
or impossible. Dystonias, involuntary and repetitive contraction of skeletal muscle,
may occur, causing twisting of body parts, e.g. ankle inversion or toe curling, and
abnormal body postures, e.g. trunk curling or the head turned to one side. They may
be painful and significantly inhibit normal movement. A resting tremor is usually an
early symptom, often unilateral in the early stages but becoming bilateral with disease
progression. There is higher than average incidence of depression and Alzheimer’s
disease in people with PD.
Drug treatment in Parkinson’s disease
No currently available drug treatment prevents or reverses the ongoing
neurodegeneration in the nigrostriatal pathway. The main focus lies in replenishing
dopamine levels in the corpus striatum. Although 75% of the brain’s dopamine
content is found in the nigrostriatal pathway, dopamine has key functions in other
pathways, e.g. vomiting, that cause many of the adverse effects of dopamine
replacement therapy.
 FIG 4.13 Coronal section of the brain showing the key structures
involved in voluntary muscle control and in Parkinson’s disease.1.
Neurones projecting from the thalamus to the motor cortex exert a
constant excitatory stimulus. 2. Thalamic activity is restrained by
inhibitory nerves from the globus pallidus. 3. The corpus striatum
stimulates the globus pallidus, maintaining its inhibition of the
thalamus. 4. The nigrostriatal pathway regulates the corpus
striatum. When these nerves degenerate in Parkinson’s disease, the
striatum can no longer stimulate the globus pallidus and the train
of inhibitory nerve signals (2) falls. The thalamus, released from
inhibition by the globus pallidus, increases its stimulation of the
motor cortex, leading to increased muscle tone and rigidity. DA,
Dopamine.

Dopamine Receptor Agonists

Examples: ropinirole, pramipexole, rotigotine (newer agents), bromocriptine,
apomorphine (older agents, now less frequently used)
The newer dopamine agonists are often first-line treatment, especially in younger
patients, because although they are not the most effective treatment (which is L-
DOPA/levodopa, see below), they are better tolerated and delay the onset of the
troublesome side-effects associated with levodopa. Most are given orally, although
rotigotine is available as a transdermal patch, which levels out the fluctuations in
plasma levels associated with oral dosing, and apomorphine, which must be given
by intravenous or intramuscular injection or by infusion. They are relatively selective
for the D2 receptors present in the corpus striatum, but through their action in other
dopaminergic pathways in the brain, they cause nausea, vomiting, and sudden
daytime sleepiness and can trigger impulsive and compulsive behaviours, such as
gambling, shopping, and increased sexual interest. Patients and their families should
be warned of this possibility. Hallucinations, confusion, and postural hypotension can
also occur. Apomorphine can be used as a ‘rescue’ treatment in more advanced
disease when the effectiveness of other treatments is diminishing, but because it is a
powerful emetic, it usually needs to be used with the anti-emetic domperidone.
L-Dopa (Levodopa)
The discovery of the effectiveness of levodopa in the treatment of PD dramatically
revolutionised the management of the disease, which till that point was essentially
untreatable. Levodopa was isolated in 1913, but for 50 years after this the general
belief was that dopamine was merely a stepping-stone in the synthesis of adrenaline,
and little interest was taken in studying either dopamine or levodopa. Work in the
early 1960s, however, showed that the corpus striatum of post-mortem brains from
people who had died with PD contained much less dopamine than normal. Once the
connection between PD and dopamine depletion was made, it was reasoned that
supplying levodopa, the dopamine precursor, would increase dopamine synthesis in
the brain and reverse the signs and symptoms of the disease. Dopamine itself cannot
be used because it does not cross the blood–brain barrier, and because it is a
precursor in NA and adrenaline synthesis, it produces extensive and unacceptable
sympathetic side-effects including hypertension and tachycardia. Levodopa was
licensed for use in 1970 and in the 50-plus years since, no more effective drug has
been developed.
Levodopa is converted to dopamine by the enzyme DOPA decarboxylase (Fig. 4.11)
and is further converted to NA and adrenaline in sympathetic nerves and in the
adrenal medulla, respectively. This leads immediately to an obvious problem: of an
oral dose of levodopa, only 1%–2% actually crosses the blood–brain barrier, and the
remainder distributes in the periphery, where it is rapidly converted to dopamine and
to NA and adrenaline in sympathetic nerves and the adrenal medulla, respectively.
This gives intolerable and unacceptable side-effects. The solution is to block the
conversion of dopamine in peripheral tissues with DOPA-decarboxylase inhibitors,
but it is essential that these inhibitors do not cross the blood–brain barrier, otherwise
the production of dopamine in the brain will also be blocked (Fig. 4.14). The main
DOPA-decarboxylase inhibitors are carbidopa and benserazide, usually given in
combination with levodopa. Using DOPA-decarboxylase inhibitors to reduce levodopa
loss by peripheral conversion means that levodopa doses can be significantly reduced,
which also helps to reduce side-effects.
On starting levodopa treatment, up to 80% of people report improvement, some of
whom experience complete remission. With continued treatment, however,
levodopa’s efficacy declines, requiring increasing doses, and the incidence of side-
effects rises. Managing symptoms for as long as possible on as low a dose as possible
is important, and combining levodopa with other drugs, such as dopamine agonists,
can help.
Levodopa has many side-effects. Nausea and vomiting are common because
dopamine stimulates the chemosensitive trigger zone (CTZ) in the medulla oblongata,
which lies outside the blood–brain barrier. It can be managed with domperidone,
an anti-emetic that blocks the D2 receptors in the CTZ but does not interfere with
dopamine function in the brain because it does not cross the blood–brain barrier.
With extended therapy, most patients eventually develop tardive dyskinesias
(unwanted, repetitive, involuntary movements) usually of the face and limbs,
including lip smacking, grimacing, or slow writhing movements, which can become
severely disabling. Another feature of levodopa treatment is the ‘on-off’ phenomenon,
in which the patient can become suddenly and completely immobilised. This seems to
correlate with the dips in plasma concentrations of levodopa in between doses, and it
can be helped by dividing the dose and giving smaller quantities more regularly to
even out plasma concentrations. Apomorphine can be given to reverse the
immobility of the ‘off’ state, and it can be spectacularly and immediately effective,
restoring movement to a ‘frozen’ patient.
 FIG 4.14 The use of DOPA-decarboxylase inhibitors to increase
levodopa delivery into the brain.

Monoamine Oxidase and Catechol-O-Methyl Transferase Inhibitors

MAO and COMT are responsible for dopamine destruction and termination of its
action at healthy dopaminergic synapses. Blocking the activity of either or both the
enzymes increases dopamine levels in the corpus striatum and improves motor
function in PD. However, although these drugs reduce levodopa requirements, they
are not effective enough treatments alone and are usually used in conjunction with
levodopa.
Selegiline is a monoamine oxidase inhibitor relatively selective for MAO-B, the
form of the enzyme found in the corpus striatum (for further explanation, see below
and Fig. 4.17). Although its half-life is short (1–3 hours), it irreversibly inactivates
MAO-B, so its action is long-lived and it is given only once daily. It can cause
gastrointestinal side-effects including constipation, dyspepsia, and nausea, and
because it is metabolised in the liver to amphetamine-like substances, it can also
cause hallucinations, strange dreams, confusion, agitation, and insomnia.
Entacapone inhibits COMT. COMT deactivates both levodopa and dopamine, so
entacapone used in conjunction with levodopa preserves levodopa levels, increasing
conversion to dopamine, and protects dopamine from destruction. It can reduce
levodopa requirements by 30% but is also associated with dopaminergic side-effects
such as increased sexual urges and compulsive and pleasurable behaviours like
gambling.
Antimuscarinic Drugs
Examples: orphenadrine, procyclidine
Before levodopa was discovered, the only useful treatments for PD were
anticholinergic drugs, mainly atropine. It is thought that as dopamine levels in the
corpus striatum fall, the dopamine:ACh balance is tilted in favour of the excitatory
ACh and contributes to disruption of motor control. Antimuscarinic drugs have
significant and widespread side-effects, including tachycardia, sedation, dry mouth,
and constipation (see Focus on: Antimuscarinic Side-Effects) because they block
muscarinic receptors throughout the body. Nowadays their use is generally restricted
to managing PD-like side-effects caused by antipsychotic drugs used in schizophrenia
and other psychotic conditions, whose principal action is to block dopamine
receptors.
Fig. 4.15 summarises the mechanisms of action of the main drugs used in PD.

FIG 4.15 Mechanisms of action of the main drugs used in

Parkinson’s disease.COMT, Catechol-O-methyl transferase; MAO,
monoamine oxidase.

Histamine and motion sickness

Motion sickness is believed to arise when information from the eyes and information
from the vestibular apparatus (semi-circular canals and utricle) in the inner ear,
reporting information on movement and balance, conflict. For example, when reading a
book in a swaying ship, the eyes are not reporting movement, but the semi-circular
canals are. The visual and sensory information relating to body movement, posture, and
balance is received by the vestibular nuclei in the brainstem, which use a number of
transmitters, including histamine acting on H1 and H3 receptors, ACh acting on
muscarinic receptors, and serotonin. When the vestibular nuclei receive conflicting
input, they activate various autonomic responses, including sweating, nausea, and
vomiting. Antihistamines are widely used to treat the nausea and vomiting associated
with motion sickness. Antimuscarinic drugs like scopolamine are also effective.
Additionally, ginger is reported to suppress motion sickness, probably due to blockade
of serotonin receptors.

Endorphins (Endogenous Opioids)

The term ‘opioid’ refers to any substance with a range of pharmacological effects similar
to morphine. First isolated in 1975, endorphins represent a family of naturally occurring
opioids produced in many body tissues. Their discovery was not by chance. Opioid
receptors for morphine and morphine-like drugs had been isolated a few years earlier,
and researchers reasoned that for these receptors to exist, they must be functional: that
is, there must be a natural agent synthesised by the body that activates them. The
endorphins are strongly associated with pain modulation, and their pharmacology and
that of morphine and other opioids is discussed on p. 104.

Glutamate
Glutamate is an amino acid in widespread use in the CNS as an excitatory
neurotransmitter.
There are several types of glutamate receptors, of which the N-methyl-D-aspartate
(NMDA) receptor is the best studied. Ketamine is an antagonist at this receptor.

Antidepressants, mood stabilisers, and anxiolytics

Changes in mood and anxiety levels are normal features of good mental health. Feelings
of sadness, excitement, and anxiety are all normal emotional responses in a range of
situations. However, some mental health conditions are associated with excessive,
inappropriate, or distorted emotional states and/or inappropriate, sometimes disabling,
anxiety levels. Disorders of mood are also referred to as affective disorders.

Antidepressant and mood-regulating drugs

Depressive illness is common: the Global Burden of Disease collaboration (2018)
estimates that more than 264 million people globally are affected. Women are more
frequently affected than men, and depression is a major factor in mortality from a range
of causes, including suicide and cancer. Depressive episodes requiring therapeutic
intervention are usually associated with significant life events, e.g. bereavement, illness,
or childbirth, but about 10% occur with no such obvious trigger. This is called
endogenous depression, which often has a genetic component and may affect a
susceptible individual several times over their lifetime. Depressive episodes are a feature
of bipolar disorder.

Signs and Symptoms of Depression

A wide range of signs and symptoms of depression may be present, but feelings of
sadness and negativity and persistent low mood that interfere with normal daily
function or significantly affect enjoyment of normal activities are highly characteristic.
There may be feelings of guilt, worthlessness, hopelessness, low self-esteem, and
anxiety. There is loss of enjoyment in the company of friends and family, and in
activities and hobbies that previously gave pleasure. The individual may withdraw from
social contact, become irritable and intolerant of others, and become unwilling to leave
the house for even necessary activity such as food shopping. There is often poor
concentration, an inability to make decisions, loss of libido, and sleep disturbances. Loss
of energy, motivation, and appetite contribute to the inability to engage with normal
daily living. Severely depressed people can become completely unable to function.
Depression is thought to contribute to up to 50% of all suicide attempts, and depression,
particularly severe depression, increases the lifetime risk of suicide.

Treatment of Depression
Pharmacological management of depression is usually only part of a treatment package
and is not necessarily the most effective option; up to 80% of people suffering from
depression do not respond to standard antidepressants, emphasising the complex
pathophysiology of this condition. Drug treatment of depression is generally most
effective when combined with non-pharmacological approaches, including cognitive
behavioural therapy and counselling. Mild to moderate depression generally responds
poorly to standard antidepressant drugs, and all current antidepressant drugs show a
time lag between beginning of treatment and the onset of a therapeutic effect. Most
antidepressants increase the activity or concentrations of monoamine
neurotransmitters, mainly norardenaline and 5-HT, in central synapses, and their
mechanisms of action are summarised in Fig. 4.16. In general, SSRIs are first-line
treatment. Tricyclic antidepressants and monoamine oxidase inhibitors are used much
less frequently, but may be useful in some situations, and both classes of drugs are
finding a place in the treatment of other conditions, e.g. amitriptyline is used in
neuropathic pain, and selegiline is used in Parkinson’s disease.
The biology of depression
Depressive illness is associated with changes in brain structure, metabolism, and
neurotransmitter release, but there is as yet no overarching understanding of the
underlying pathophysiology. There is strong evidence that depletion of key excitatory
monoamine transmitters, mainly 5-HT and NA, as well as dopamine, can lead to
depressive states. This is called the monoamine theory of depression and dates from the
mid-1960s, but not all research in the area supports it; some supporting and
contradictory evidence is summarised in Table 4.3. In addition to the monoamines,
links have been made between depression and abnormal glutamate neurotransmission,
elevated plasma cortisol levels, neuroinflammatory conditions, and reduced
neurogenesis and nerve–nerve communication, particularly in the hippocampus.

FIG 4.16 Summary of the actions of antidepressant drugs affecting

monoamine function.5-HT, 5-Hydroxytryptamine; DA, dopamine;
NA, noradrenaline; SNRI, serotonin and noradrenaline re-uptake
inhibitor; SSRI, selective serotonin re-uptake inhibitor; TCA,
tricyclic antidepressant.

Table 4.3

Supporting and Inconsistent Evidence in the Monoamine Theory of

Depression
Depression
Evidence inconsistent with the
Supporting evidence
theory
Monoamine levels are reduced in the Drugs that increase monoamine
brain in depression and monoamine levels in the brain do so rapidly,
oxidase activity is higher in depressed but clinical improvement can
individuals take weeks
Depressive symptoms can be induced by Not all drugs that increase
drugs that reduce monoamine levels in monoamine levels in the brain
the brain are antidepressants
Some drugs that increase monoamine Not all drugs with antidepressant
levels in the brain have antidepressant activity increase monoamine
activity levels in the brain

Antidepressants that block monoamine re-uptake

Re-uptake mechanisms (Fig. 4.2) clear transmitters from the synapse by actively
transporting them back into nerve endings. Blocking re-uptake of monoamine
transmitters is an important mechanism of action for several important groups of
antidepressant drugs.

Tricyclic antidepressants (TCAs)

Examples: amitriptyline, nortriptyline, clomipramine
These are old drugs, first developed in the 1950s. Although they have multiple side-
effects, a recent (2018) meta-analysis by Cipriani and colleagues showed that
amitriptyline produced the most significant improvement in acute depression in adults
when compared with 20 other commonly used antidepressants. These agents block re-
uptake of NA and 5-HT from synapses (Fig. 4.16), thereby increasing neurotransmitter
levels in the brain. Their efficacy in treating neuropathic pain is probably due to their
additional ability to block Na+ channels.

Pharmacokinetics
TCAs are all given orally, are well absorbed, and are metabolised mainly in the liver.
They leave the bloodstream and bind to body tissues, which extends their half-life and
increases the risk of accumulation and toxicity. Long half-lives are characteristic of these
drugs. The half-life of amitriptyline is 24 hours, which lengthens even more in older
people and those with liver impairment.

Adverse Effects
TCAs have multiple adverse effects and should always be used with great care. They
sedate, particularly in elderly people. They interact with numerous other drug groups
and can cause life-threatening respiratory depression when used with alcohol. They
block muscarinic receptors, producing the characteristic range of antimuscarinic side-
effects: dry mouth, constipation, urinary retention, tachycardia, etc. They cause cardiac
arrhythmias and seizures, both common causes of death in TCA toxicity, because they
block Na+ channels in myocardial and nerve cell membranes, interfering with the
generation and conduction of action potentials. There are characteristic
electrocardiography (ECG) changes, including prolongation of the PR interval and wide
QRS complexes. Excitation, agitation, confusion, delirium, and coma are all seen,
especially in toxicity.

Serotonin-Selective Re-Uptake Inhibitors

Examples: fluoxetine, sertraline, citalopram
The first SSRI marketed for the treatment of depression was fluoxetine (Prozac),
available from the late 1980s and by 1990 was the most prescribed drug in the USA.
SSRIs selectively increase 5-HT levels in the brain by selectively blocking the serotonin
re-uptake pump (Fig. 4.16). SSRIs are also used in panic disorder, some phobias, and
obsessive-compulsive disorder.

Pharmacokinetics
SSRIs are taken orally, are well absorbed, and are metabolised in the liver. Many have
long half-lives; for example, fluoxetine, sertraline, and citalopram have half-lives
ranging from 23–75 hours. Even longer half-lives are seen in reduced liver function.
Fluoxetine metabolism produces an active metabolite that has a half-life in the order
of 6 days. The likelihood of accumulation and toxicity should therefore always be borne
in mind with this group of drugs.

Adverse Effects
Largely because noradrenaline levels are relatively unaffected, SSRIs have a different
spectrum of adverse effects and interactions to the TCAs. They are generally less toxic in
overdose, less sedative, and do not cause the antimuscarinic side-effects of the TCAs.
However, they commonly cause nausea and vomiting, and they can reduce libido and
prevent orgasm, which are distressing side-effects in sexually active people. Serotonin
syndrome is a rare but potentially life-threatening adverse effect associated with mania,
confusion, hyperthermia, tachycardia, and muscle tremor and rigidity. Suicidal thoughts
and behaviour have also been reported, especially in younger people. Hyponatraemia
can occur, possibly due to reduced antidiuretic hormone secretion, which increases
blood volume and dilutes plasma sodium.

Serotonin and Noradrenaline Re-Uptake Inhibitors

Examples: venlafaxine, duloxetine
Like the TCAs, serotonin and noradrenaline re-uptake inhibitors (SNRIs) block re-
uptake of both NA and 5-HT (Fig. 4.16), but they have fewer side-effects, including
antimuscarinic side-effects, and they do not cause cardiac arrhythmias. They may be
used in other disorders: venlafaxine and duloxetine are used to treat anxiety, and
duloxetine can be helpful in treating urinary incontinence. Both have long half-lives
and can cause nausea and vomiting, sexual dysfunction, drowsiness, insomnia, and
confusion. Venlafaxine can cause cardiac arrhythmias and should not be used in
susceptible people.

Drugs that block monoamine breakdown

Examples: phenelzine, iproniazid
MAO is one of the main enzymes that degrades monoamine neurotransmitters,
namely NA, 5-HT, and dopamine. Inhibitors of this enzyme, the MAOIs, first introduced
in the 1950s to treat depression, increase levels of these transmitters in the brain, and
their antidepressant action is traditionally attributed to this activity. Because these
neurotransmitters are widespread in both the central and peripheral nervous systems,
MAO distribution is also widespread. Two main forms of the enzyme exist, MAO-A and
MAO-B, with different substrate preferences (Fig. 4.17). MAO-A is found in neurones
that release NA or 5-HT and is therefore more active in breaking down NA and 5-HT
than dopamine. MAO-B is found in dopaminergic neurones and is more active in
breaking down dopamine than NA or 5-HT. Most MAOIs block both forms of the
enzyme and reduce breakdown of NA, 5-HT, and dopamine; an important exception is
selegiline, which is relatively selective for MAO-B and is used in Parkinson’s disease to
increase dopamine levels in the corpus striatum. MAO is also found in the wall of the
gastrointestinal tract, where it destroys tyramine and other related amines found in a
wide range of common foodstuffs including cheese and red wine (see Key Point: The
Cheese Reaction below).

Pharmacokinetics
MAOIs are given orally, are well absorbed, and are metabolised in the liver. Most bind
irreversibly to MAO, permanently deactivating it. Because it may take 2 or 3 weeks to
restore the depleted MAO levels to normal, the effects of these drugs are long lasting and
not easily reversed in overdose. An exception is moclobemide, which inhibits MAO
reversibly and has a half-life of 2 hours.

Adverse Effects
MAOIs have multiple adverse effects, mainly relating to their inhibition of NA, 5-HT,
and dopamine breakdown. Counterintuitively for drugs that increase the levels of
sympathetic neurotransmitters, a common side-effect is postural hypotension. This is
thought to be due to increased levels of tyramine, which would normally be destroyed by
MAO being taken up into sympathetic nerve endings and converted to an inactive ‘false’
transmitter which when released does not have sympathetic activity. There may be
tremor, excitement, agitation, convulsions, and antimuscarinic side-effects.

FIG 4.17 The two forms of monoamine oxidase and their main
substrates.MAO, Monoamine oxidase. From Waller DG, Sampson A,
and Hitchings A (2022) Medical pharmacology and therapeutics, 6th
ed, Fig. 22.3. Oxford: Elsevier.

Key Point: The Cheese Reaction

The so-called ‘cheese reaction’ is potentially one of the most dangerous side-effects of
monoamine oxidase inhibitor therapy. An individual taking monoamine oxidase
inhibitors must avoid foods containing significant levels of tyramine, including many
cheeses, red wine, cured and aged meats, and fermented foods including sauerkraut,
beer, and concentrated yeast extracts like Marmite. In the presence of a monoamine
oxidase inhibitor, tyramine in these foods cannot be metabolised in the wall of the
gastrointestinal tract and is absorbed, taken up into sympathetic nerves, and causes
noradrenaline release, leading to widespread sympathetic stimulation. This can cause
hypertension, a crashing headache, tremors, excitement, cardiac failure, myocardial
infarction, agitation, and increased appetite. This interaction (the ‘cheese reaction’)
led to these drugs falling out of regular use when alternative agents (tricyclic
antidepressants) became available in the 1960s.

Preparations containing adrenaline or other sympathomimetics (e.g. nasal

decongestants) should not be taken with MAOIs.

Monoamine receptor blockers

It may seem counterintuitive that drugs that block monoamine receptors should have
antidepressant activity, given that the major groups of antidepressant drugs enhance
monoamine activity. It underlines the complexity of neurotransmitter function and
communication in the pathogenesis of affective disorders.

Mirtazapine
This drug blocks several receptor types, including 5-HT2C and H1 receptors (Fig. 4.16).
Its main mechanism of action is thought to be by blocking pre-synaptic ⍺2 receptors. As
explained earlier (Fig. 4.7), these receptors are part of the synaptic self-regulation
system, and when they are strongly stimulated by rising transmitter levels, they shut
down transmitter release at that synapse. Blocking them shuts down this feedback
control and increases synaptic concentrations of NA and 5-HT. Mirtazapine is sedative,
because of its antihistamine action, and can cause increased appetite and weight gain.

Trazodone
Trazodone blocks 5-HT2C receptors (Fig. 4.16), which indirectly leads to increased NA
and dopamine activity in the brain, thought to underpin its antidepressant activity. It is
sedative and may be used to treat insomnia. Unlike the TCAs and SSRIs, it has little
antimuscarinic activity, and so may be useful in patients for whom antimuscarinic
effects may be especially troublesome, e.g. in chronic constipation or benign prostatic
hypertrophy.

Other antidepressant drugs

St. John’s wort is a popular herbal remedy taken to improve mood, although there is
little evidence of any benefit in mild to moderate depression. It is important to be aware
that it is an inducer of liver enzymes and therefore can increase the metabolism of other
drugs, including antidepressants.

Agomelatine
Disruption of sleep patterns and poor sleep quality are frequently seen in depression
and can significantly reduce quality of life and cause slow recovery. The suprachiasmatic
nucleus (SCN) in the hypothalamus is the main driver of the circadian rhythms directing
the body’s internal 24-hour body clock. The SCN is linked to the pineal gland, which
releases melatonin, and at night, the SCN stimulates melatonin release from the pineal
gland, promoting sleep. SCN function is disrupted in depressive disorders, interrupting
the sleep–wake cycle, and agomelatine, a melatonin analogue, is used to regulate sleep
patterns in depression (and other conditions featuring sleep disorders). It promotes
sleep by activating the body’s natural melatonin receptors. Agomelatine also antagonises
5-HT2C receptors (see also trazodone), which may contribute to its usefulness in
depression. It is generally well tolerated, although adverse effects include insomnia,
gastrointestinal disturbances, increased sweating, headache, drowsiness, and dizziness.

Future Developments
Ketamine, introduced in the 1960s as an anaesthetic, has a history of illegal and
recreational use. In the early 2000s, researchers trialled the closely related agent
esketamine in severely depressed patients resistant to standard treatments, and not
only did the drug relieve the signs and symptoms of depression, it did so rapidly,
sometimes within hours of administration. This contrasts markedly with conventional
treatments, all of which require weeks for achievement of full therapeutic effect. It is
believed to act by increasing levels of the excitatory transmitter glutamate in the brain.
It is not currently licensed for use in the UK because of safety concerns but research is
ongoing in the search for analogues with fewer side-effects and less potential for
addiction and abuse.

Anxiolytic and sedative drugs

Anxiety, and the fear reaction linked to it, is a normal emotional response to unfamiliar
and potentially hazardous situations. It confers survival advantage, because it increases
alertness and triggers a sympathetic flight or fight response, e.g. increased heart rate
and raised blood glucose levels, to ensure a rapid and effective physical reaction to
potential threats. Appropriate levels of anxiety reduce risk-taking behaviours and
improve judgement associated with potentially dangerous situations. However, in
psychiatric and psychological disorders with an anxiety component, the anxiety
response is exaggerated, inappropriate, and detrimental to both physical and mental
health. This in turn interferes with sleep, exacerbating mental health issues.

Anxiety Disorders
Anxiety disorders are common and include generalised anxiety disorder, phobic states,
and panic disorder. They may co-exist with depression, and there is often a genetic
component. The main neurotransmitters in the brain thought to be important in anxiety
disorders include GABA, noradrenaline, serotonin, and dopamine, and structural
changes in areas of the brain involved in emotional and anxiety responses, including the
amygdala, hippocampus, and other limbic system structures, have been identified. The
main anxiolytic drugs include the benzodiazepines, but other agents including the
SSRIs (increasingly the first choice in treating anxiety disorders), beta-blockers,
certain anticonvulsant drugs like gabapentin, and some atypical (second-generation)
antipsychotics, e.g. olanzapine, have all proved useful in anxiety disorder
management.

Non-benzodiazepine anxiolytics
BDZ-mediated sedation can be a significant disadvantage in treating anxiety disorders
because daytime sleepiness interferes with normal daily living. In addition, the risk of
dependence is high. The search for non-sedative agents with anxiolytic activity has led
researchers to investigate medications acting at a range of other neurotransmitters,
including glutamate.

Buspirone
Buspirone was initially developed as an antipsychotic agent, but its activity in this area
was disappointing, and its anxiolytic activity was explored instead. It is most useful in
generalised anxiety states and is usually tolerated better than BDZs because it is not
sedative and does not interfere with motor control. Buspirone is an agonist at 5-HT
receptors, although how this translates into its anxiolytic effect is uncertain. There is a
delay of 2–3 weeks between starting treatment and improvement of symptoms, so it is
believed that whatever its mode of action, buspirone must trigger some form of
adaptation in the brain, particularly in the amygdala, which takes time to develop. It
also activates a range of other receptors, including dopamine and noradrenaline
receptors, but the relevance of this to its clinical action is unknown.

Pharmacokinetics
Buspirone is given orally and is well absorbed, with a half-life of 2–4 hours. Much of an
oral dose is destroyed by the liver in first-pass metabolism, and its bioavailability is
therefore low. Because of this, it is important to consider hepatic function when
prescribing. Reduced liver function can increase the proportion of an oral dose reaching
the bloodstream several fold, causing potentially toxic plasma levels.

Adverse Effects
Buspirone commonly causes dizziness, reported by over 10% of patients. Other side-
effects include nausea, diarrhoea, headache, confusion, drowsiness or excitement, mood
changes, and nervousness. It is not associated with tolerance or dependence and does
not interfere with sexual desire or performance, unlike SSRIs.

Hypnotics
Hypnotics, drugs that induce sleep, are used to treat insomnia. Insomnia is a persistent
inability to fall asleep or stay asleep despite appropriate time and opportunity, leading
to daytime fatigue, irritability, poor concentration and memory, and impairment of
normal daily function, and it is experienced by nearly everybody at some point in their
lives. Insomnia is frequently short-term, e.g. related to jet lag or the stress of an
upcoming examination. More prolonged periods of insomnia may follow bereavement
or other personal stressors. Chronic insomnia may be caused by psychiatric or physical
illness, e.g. in chronic obstructive pulmonary disease, dyspnoea can interrupt sleep.
Pain, acute or chronic, and snoring can also cause poor sleep. Chronic insomnia is
associated with increased rates of depression and poor quality of life and requires
careful investigation. The initial approach to treatment should attempt to identify the
cause of the insomnia through taking of sleep history, a general medical and psychiatric
history, a review of the patient’s current social and personal situation, and a review of all
medications, including caffeine, tobacco, and alcohol use. Following good sleep
hygiene practices, e.g. avoiding stimulants and screen use prior to bedtime, following a
regular bedtime routine, and ensuring a comfortable and quiet sleep environment, often
improve or resolve sleep problems. Hypnotics may provide a temporary improvement in
sleep times and sleep quality, but they disrupt the normal sleep cycle (described below)
and can reduce the length of time spent in deep sleep or in rapid-eye movement (REM)
sleep.

The Physiology of Sleep

Sleep is a physiologically active condition essential for health and indeed for life itself. In
fatal familial insomnia, a rare degenerative brain disorder, progressive insomnia is the
characteristic symptom, and the sleep deficiency leads to physical and mental
deterioration and eventual death. Sleep–wake cycles are a key feature of the body’s
circadian rhythm and are governed by the suprachiasmic nucleus, a group of neurones
in the hypothalamus. Light-sensitive ganglion cells in the retina send constant input to
the suprachiasmic nucleus so that the circadian sleep–wake rhythm synchronises with
light–dark cycles. During waking periods, the hypothalamus maintains arousal
pathways in the brain (see also histamine above), and when dark, these pathways are
silent, allowing the brain to sleep.

Rapid-Eye Movement and Non-Rapid-Eye Movement Sleep

Recording electrical activity in the brain during sleep shows two distinct phases, which
cycle during an average night’s sleep: REM sleep and non-REM (NREM) sleep. The first
phase of sleep entered when falling asleep is NREM sleep, which accounts for 75%–80%
of total sleep. Sleep in the initial stages of NREM activity is light, moving into the
deepest phases of sleep after about 15 minutes, and is thought to be induced by
increased activity in GABAergic neurones. Metabolic activity falls, growth hormone
secretion is increased, skeletal muscle is deeply relaxed, and blood flow to the brain is
significantly reduced. From NREM sleep, the sleeper moves into REM sleep. Dreaming
occurs during REM sleep, and metabolic activity and cerebral blood flow are equivalent
to those seen when awake. Heart rate and respiratory rate rise, blood pressure increases,
and there may be sexual arousal. REM sleep episodes in the early part of the night are
short, likely about 10 minutes long, and they get longer in the later parts of the sleep
period. The final REM period may be up to an hour long. There are generally four to five
such cycles in a good night’s sleep.

Benzodiazepines
BDZs, discussed in detail in the Focus Box below, all have hypnotic activity. Their action
in enhancing GABA activity promotes the onset of sleep, and they are widely used in
sleep complaints. However, they predispose to dependence; reduce the length of time
spend in deep sleep; cause hangover effects the next day because of their long half-lives;
increase the risk of accident, injury, and falls, especially in elderly people; and cause
cognitive and memory impairment.

F oc us on: B enzodiazepine Pharmac ology

Examples: diazepam, clonazepam, midazolam, lorazepam
Prior to the 1960s, barbiturates were the main drugs used to manage anxiety
(anxiolytics), to calm and soothe (tranquillisers/sedatives), and to induce sleep
(hypnotics). These were not ideal from a clinical point of view because they strongly
induced dependence, caused multiple side-effects including respiratory depression,
and overdose was difficult to manage. The first benzodiazepine (BDZ),
chlordiazepoxide (Librium), was marketed in 1960, with a number of related
BDZs, including diazepam (Valium), clonazepam, and lorazepam, following
within the next 15 years. Initial excitement in the medical community for these new,
safer tranquillisers and hypnotics led to widespread prescribing and, although it is
now firmly established that BDZs cause significant dependence and potentially
dangerous withdrawal syndromes, they remain globally in the top three most
frequently prescribed drugs. Diazepam, lorazepam, and midazolam are on the
World Health Organisation’s list of essential drugs, but most healthcare systems
regulate BDZ prescribing, recognising the challenges presented by their use, and they
are no longer considered first-line treatment in anxiety disorders.
Mechanism of Action
BDZs modulate the activity of GABAA receptors, which are widespread in the CNS.
GABA is the most common inhibitory neurotransmitter in the CNS, and when it is
released by a pre-synaptic nerve and binds to its receptors on the post-synaptic nerve,
the post-synaptic nerve is hyperpolarised, i.e. inhibited.
GABAA receptors are a structural component of CNS Cl- ion channels (Fig. 4.18).
When GABA binds to its receptor, the Cl- channel opens, allowing Cl- to flow into the
neurone, which hyperpolarises and desensitises it (Fig. 4.18A). BDZs enhance this
effect, i.e. they potentiate GABA-mediated nerve inhibition. In the presence of a BDZ,
the Cl- channels spend more time in the open state, increasing Cl- entry and
deepening nerve inhibition (Fig. 4.18B).
Pharmacodynamics
Because GABA-mediated inhibitory control of neurones is widespread in the brain,
the dampening of neuronal activity by BDZs gives wide-ranging clinical effects. BDZs
are sedative, anxiolytic, anticonvulsant, hypnotic, and reduce skeletal muscle tone.
They impair short-term memory, causing amnesia, which may be useful when used in
patients undergoing potentially stressful procedures such as dental extractions, but
which has been exploited by individuals using them for criminal purposes, e.g. as
date-rape drugs. The main clinical uses of the BDZs are listed in Box 4.1.
Pharmacokinetics
The pharmacokinetics of the various members of the BDZ family are similar in many
respects, and the choice of drug usually depends on its half-life and duration of action.
They are highly fat soluble, so they are rapidly and completely absorbed following oral
administration and are taken up into fat stores. This leads to accumulation, especially
in older people, and increases the risk of toxicity. Some may be given intravenously;
shorter-acting agents like midazolam and lorazepam are used as preoperative
medication or for conscious sedation in procedures like endoscopy. Midazolam may
be given buccally to control seizures if intravenous access is difficult, and diazepam
is available in rectal formulations for the same purpose. The spectrum of half-lives is
wide and often long. Most are highly plasma protein-bound, so there is significant
reservoir of drug circulating in the bloodstream, which contributes to the long half-
lives of many BDZs. Several are metabolised to active products, extending the effects
of the drug even further. Consideration of a BDZ’s half-life is a significant factor in
choosing a specific agent for a particular clinical situation. For example, midazolam
is favoured in conscious sedation because it has a relatively short half-life and
minimises recovery times after a procedure. Diazepam has a half-life of around 40
hours and is an active metabolite, so when used regularly as, for example, as a night-
time sedative or as an anticonvulsant, the incidence of accumulation and daytime
sleepiness is high. Clonazepam is used as prophylactic treatment in epilepsy
because of its long duration of action. Temazepam is used as a night-time hypnotic
because its relatively short half-life and absence of active metabolites reduce the
likelihood of a morning ‘hangover’ effect on waking. Half-lives and metabolite
activities for some key BDZs are summarised in Table 4.4.
 FIG 4.18 GABAA and benzodiazepine receptors and chloride ion
channels on brain neurones.GABA, Gamma-aminobutyric
acid. Modified from Stevens V, Redwood S, Neel J, et al. (2007)
Rapid review behavioral science, 2nd ed, Fig. 10.2. Philadelphia:
Mosby.

B ox 4 . 1 The M ain Clinic al Uses of B enzodiazepines

Anxiety
Acute panic attacks
Insomnia
Prevention of seizures
Emergency treatment of status epilepticus/febrile convulsions/seizures
caused by poisoning
Adjunct to anaesthesia/conscious sedation
Muscle relaxant: useful in reducing physical tension in anxiety, when used as
an adjunct to anaesthesia, and in conditions featuring muscle spasm
Alcohol withdrawal

Adverse Effects
BDZs cause sedation, impaired memory, confusion, and cognitive impairment,
especially in elderly people. They cause skeletal muscle weakness and ataxia, and
impair co-ordination and fine motor control, increasing the risk of accidents, falls
(especially in elderly people), and injury, e.g. from operating machinery. They
potentiate the effects of other CNS depressants, including alcohol and opioids, and
in combination with these agents can cause life-threatening respiratory depression.
Tolerance develops rapidly, requiring steady increase in dosing when used in the
medium to long term. Dependence is common in medium- to long-term treatment,
and it is recommended that treatment should not exceed 4 weeks. Both physiological
and psychological dependence develop, with well-defined withdrawal syndromes. The
likelihood of dependence increases with the duration of treatment, with higher doses,
and with shorter-acting agents such as lorazepam. Withdrawal symptoms include
anxiety, insomnia, irritability, depression, and sometimes convulsions.
Benzodiazepine Toxicity
BDZs are safer in overdose than older anxiolytic and hypnotic agents like the
barbiturates, and if taken alone in excessive doses generally produce extended sleep
from which the person eventually wakes naturally. However, if overdose reversal is
required, for example if other CNS depressants such as opioids or alcohol have also
been taken, the BDZ antagonist flumazenil is given. Flumazenil binds to and blocks
the BDZ receptor, but its half-life is only about 1 hour, considerably shorter than that
of the BDZs it is being used to reverse, so is usually given by infusion rather than as a
one-off dose.

The Z-Drugs: Zolpidem, Zaleplon, and Zopiclone

Like the BDZs, these drugs bind to the Cl- channel associated with the GABAA receptor,
increase its opening time, and increase Cl- flow into the nerve. This hyperpolarises the
cell, enhancing the inhibitory action of GABA. They are not chemically similar to BDZs,
however, and do not bind to the same site on the Cl- channel. They have no anxiolytic
activity.

Pharmacokinetics
These drugs are given orally, are well absorbed, and are metabolised in the liver to
inactive metabolites. One advantage over the BDZs is their shorter half-life, usually no
longer than 5 hours, reducing the incidence of accumulation and hangover effects in the
morning.

Adverse Effects
The Z-drugs cause dependence, cognitive impairment, and hangover effects despite
their relatively short half-life.

Other Hypnotic Drugs

Melatonin, a hormone naturally released by the pineal gland to shift the brain into
sleep mode (see above), is given to manage short-term insomnia, for example, in jet lag.
Some antihistamines, e.g. diphenhydramine and doxepin, are used clinically as
sedatives and hypnotics. They are effective here because histamine is an important
neurotransmitter in arousal pathways (see above). Chlormethiazole
(clomethiazole) is used in severe insomnia, especially in older people. It binds to the
GABAA receptor, although at a site different from the BDZs or the Z-drugs, and
facilitates GABA’s action, causing hyperpolarisation and inhibition of nerve activity.

Table 4.4

Half-Lives and Metabolite Activity of Some Key Benzodiazepines

Drug Average half-life Metabolites
Diazepam 20–40 h, often Diazepam is metabolised to temazepam and
longer in older oxazepam, both active agents in their own
people and in right, and N-desmethyldiazepam, which has
liver a half-life of 100 h
insufficiency
Temazepam 10 h, often longer No active metabolites
in older people
Midazolam 2h Active metabolite produced, with half-life of
about 2 h
Lorazepam 10–20 h No active metabolites
Clonazepam 30–40 h No active metabolites

Mood-stabilising drugs
The main mood-stabilising agent is lithium, but the range of drugs used for this
purpose is expanding and includes certain anticonvulsant drugs, e.g. lamotrigine and
sodium valproate, and some atypical antipsychotics, e.g. risperidone and
olanzapine. Mood stabilisers prevent mood swings in bipolar disorder.

Bipolar Disorder
This condition has a strong hereditable component and usually manifests in young
adulthood. It is characterised by fluctuating and alternating episodes of depression,
episodes of mania (elevated mood), and periods of euthymia (normal mood). The
depressive component is usually more marked than the manic condition and is treated
with standard antidepressant therapy. The manic episodes feature euphoria, reckless
and impulsive behaviour, loss of inhibition and increased libido, and even psychotic
symptoms such as delusions and hallucinations. The risk of suicide is significantly
increased in bipolar disorder. Lithium or sodium valproate (p. 75) are the mainstays
of treatment, with antidepressants, antipsychotics, and anticonvulsants used as
supplementary agents.

Lithium
Lithium is usually effective in regulating mood and preventing relapse, but it has
significant side-effects and toxicity, and controlling plasma levels is challenging. It is
given as lithium carbonate, which dissociates to release lithium ion (Li+), the active
agent. The mechanism by which lithium stabilises mood is not known, although it has
been shown to have multiple effects on enzyme activity, gene expression, and nerve
excitability in the brain, and accumulates inside body cells because it passes through
Na+ channels.

Pharmacokinetics
Lithium is given orally and is excreted by the kidney. Because it is not metabolised,
clearance of lithium from the body depends entirely on renal function, so care must be
taken in individuals with any degree of renal compromise. Lithium has a long half-life,
partly because so much of it collects within cells via Na+ channel uptake. Initiating
lithium treatment must therefore be done gradually, with regular measurements of
plasma levels, because it takes 2 weeks or more to achieve steady state, and reversing
toxic levels is slow because excretion is slow. The therapeutic plasma range is narrow,
only 0.4–1 mmol/L, making safe lithium management even harder.

Adverse Effects
Lithium’s side-effects are common and significant and contribute to the declining use of
this drug despite its well-documented efficacy in stabilising mood. It causes nausea in
up to 20% of patients, diarrhoea in up to 10% of patients, and vomiting. Up to 70% of
patients experience excessive thirst (polydipsia) and production of large volumes of
dilute urine (polyuria). Polyuria is due to lithium’s interference with the kidney’s ability
to respond to anti-diuretic hormone, which acts on the distal tubules and collecting
ducts, increasing water reabsorption and concentrating the urine. Lithium blocks this
action, leading to the production of large quantities of dilute urine, and triggering thirst.
Tremor is seen in about 25% of patients and can be severe or inconvenient enough to
require additional management, usually with a β-blocker. Weight gain is common and
frequently a reason for the patient failing to comply with treatment or wishing to
discontinue. The reasons for lithium-induced weight gain are not known, but it is
thought that the drug interferes in some way with fundamental control mechanisms in
the brain that regulate bodyweight, metabolism, or appetite. Lithium accumulates in the
thyroid gland and can impair thyroid hormone synthesis and release, causing goitre and
hypothyroidism.

Antipsychotic drugs
Psychotic illness is characterised by a loss of contact with reality. It features
hallucinations (experiencing events that are not happening), delusions (false and
abnormal beliefs), and emotional blunting and disordered thinking, and the person has
no insight into their condition. Although psychotic episodes may be caused by a range of
situations, e.g. alcohol withdrawal, recreational drug use (e.g. cocaine,
amphetamines, cannabis), childbirth (post-puerperal psychosis), and some
therapeutic drugs (e.g. vigabatrin), it may manifest itself as part of a chronic
psychiatric illness, notably schizophrenia. The term ‘antipsychotic agent’ is generally
taken to mean a drug used to treat schizophrenia.

Schizophrenia
This is a common and serious psychiatric condition, affecting 20 million people
worldwide, and is more common in men than women. It generally manifests early in life,
has a strong hereditable component, and increases the risk of premature death, partly
because of higher suicide rates. The signs and symptoms of schizophrenia are classified
into four groups: positive symptoms, negative symptoms, cognitive symptoms, and
mood symptoms, shown in Box 4.2. Positive symptoms are ‘add-ons’ to normal
behaviour, whereas negative symptoms are elements of behaviour and emotional
responses that are missing or depressed compared to normal. Individuals whose
schizophrenia displays predominantly positive symptoms tend to respond better to drug
treatment than those whose illness features mainly negative symptoms.

B ox 4 . 2 Clinic al F eatures of Sc hizophrenia

Neurophysiology of Schizophrenia
The underlying neurophysiology is not fully understood, but in schizophrenia there are
abnormalities in brain structure and volume and neurotransmitter activity. The most
clearly implicated neurotransmitter is dopamine, and all known antipsychotic drugs
block dopamine receptors, particularly D2 receptors, emphasising the role of dopamine
in the aetiology of schizophrenia. Dopamine is released at nerve endings in four main
pathways in the brain, three of which are shown in Fig. 4.19. The nigrostriatal pathway
is essential to skeletal muscle control, and its degeneration is the cause of Parkinson’s
disease. The fourth important pathway releasing dopamine, not shown here, is the
tuberoinfundibular pathway, which controls prolactin release and therefore breast
growth and lactation. Release of dopamine here inhibits prolactin release (see Fig. 5.2).

The Mesocortical Pathway and D1 Receptors

The mesocortical pathway links the ventral tegmental area in the midbrain to the
cerebral cortex and is thought to be important in cognitive functions, motivation and
reward, and emotional responses. Dopamine released by these nerves acts mainly
through D1 receptors in the cortex. It is thought that decreased function in this pathway
is responsible for the negative and cognitive features of schizophrenia.

The Mesolimbic Pathway and D2 Receptors

The mesolimbic pathway links the ventral tegmental area to structures of the limbic
system, including the amygdala, hippocampus, and nucleus accumbens. It is strongly
associated with memory formation, reward, and emotional responses, and it is believed
that overactivity in this pathway is responsible for the positive symptoms in
schizophrenia. Dopamine released by these nerves acts mainly through D2 receptors.

Serotonin and Glutamate in Schizophrenia

Although abnormalities of dopamine transmission are undoubtedly involved in
schizophrenia, other neurotransmitters may also play a part. It is interesting that
clozapine, possibly the most effective antipsychotic agent, is actually a fairly weak
dopamine receptor blocker. It does, however, block a range of other receptors, including
histamine receptors, ⍺ receptors, muscarinic receptors, and 5-HT receptors, although
how this contributes to the clinical activity of the drug is not understood. There is also
more recent evidence that activity of the excitatory transmitter glutamate is abnormal in
schizophrenia, although this research is still in its early stages and has not produced any
useful antipsychotic drugs.
 FIG 4.19 Dopamine pathways in the brain. From Satoskar RS,
Rege N, Bhandarkar SD. (2021) Pharmacology and
pharmacotherapeutics, 26th ed, Fig. 5.1. New Delhi: RELX India
Pvt Ltd.

Antipsychotic drugs
These are generally considered under two main headings: the older, typical
antipsychotics, including chlorpromazine, haloperidol, and flupentixol, and the
newer atypical antipsychotics, sometimes also called second-generation antipsychotics,
including clozapine and risperidone. The distinction between the two groups is not
clear-cut, but in general, typical antipsychotics are fairly selective antagonists for D2
receptors, whereas the atypical agents have a wider spectrum of receptor-blocking
activity, including at 5-HT and histamine receptors.

Actions of the Antipsychotics

Because all antipsychotic drugs block dopamine receptors, particularly D2 receptors,
they all produce adverse effects related to dopamine blockade. Most block other receptor
types as well, giving several significant unwanted effects.

Extrapyramidal Adverse Effects

Antipsychotic drugs block D2 receptors in the nigrostriatal pathway, an integral part of
motor control. As a result, they cause motor disturbances including Parkinson’s-like
symptoms such as bradykinesia, tremor and dystonias, and tardive dyskinesias.
Dystonias, sustained muscular spasms, are most likely to occur in the first weeks of
starting treatment and may affect any body part: for example, there may be contraction
of muscles in the neck and shoulder causing torticollis (Fig. 4.20). Severe dystonia in
the head and neck area may threaten the airway. Dystonias disappear when the drug is
withdrawn. Tardive dyskinesias, similar to those seen with L-DOPA treatment in
Parkinson’s disease, develop in up to 40% of patients taking antipsychotic medication
and are a major reason for non-compliance with treatment. Dyskinesias generally
persist after the drug is withdrawn, suggesting that the drug has induced a long-term
change in dopamine signalling in the brain, perhaps by altering the population of
dopamine receptors. Akathisia is also seen: this is a feeling of needing to jump out of
one’s skin, leading to agitation, restlessness, and an inability to sit quietly. The incidence
of extrapyramidal side-effects may be less with atypical than typical agents, but studies
looking at this do not agree on this point.

Endocrine Effects
The release of dopamine in the tuberoinfundibular pathway switches off prolactin
secretion via D2 receptors (see Fig. 5.2). Dopamine antagonists release the
hypothalamus and the posterior pituitary from its suppression, and prolactin is secreted
into the bloodstream. This can cause swelling of the breasts and lactation in both men
and women.
 FIG 4.20 Torticollis: an example of an acute antipsychotic-induced
dystonia. From Wikipedia: James Heilman, MD

Anti-Emetic Activity
Dopamine is a transmitter in the chemosensitive trigger zone and stimulates vomiting.
Antipsychotic drugs including metoclopramide and domperidone are therefore
anti-emetic (see p. 194).

Blockade of Other (Non-Dopamine) Receptors

Most antipsychotic drugs, particularly the newer atypical agents, block a range of
receptors in the brain and in peripheral tissues, leading to related side-effects. H1
receptor blockade (an antihistamine-like action) in the brain causes sedation. Many
block muscarinic receptors throughout the body, giving rise to the usual range of
antimuscarinic side-effects: dry mouth, constipation, blurred vision, tachycardia, and
urinary retention. It is thought, however, that the antimuscarinic side-effects may help
to alleviate the Parkinson’s-like symptoms (for a fuller explanation, see Parkinson’s
disease). There may be loss of libido and other sexual dysfunction, thought to be due to
blockade of a combination of dopamine, muscarinic, and ⍺ receptors, and an important
reason for non-compliance.

Other Adverse Effects

Many antipsychotic drugs are cardiotoxic and increase the risk of sudden cardiac death,
probably by blocking ion channels in the membranes of heart muscle cells and inducing
life-threatening arrhythmias. For example, they extend the QT interval on the ECG,
delaying repolarisation of the ventricular muscle. This increases the chance that
abnormal ectopic foci may begin to fire, interrupting normal ventricular function and
precipitating ventricular fibrillation. It is therefore important to assess cardiac risk
before commencing treatment. Weight gain is a common side-effect, distressing for the
patient and increasing the risk of diabetes and cardiovascular disease. Hypotension is
also seen because antipsychotics block sympathetic receptors in the peripheral nervous
system.

Typical (first-generation) antipsychotics

Examples: chlorpromazine, haloperidol, flupentixol
The typical antipsychotics are highly effective in the control of the positive symptoms
of schizophrenia, thought to be directly linked to their blockade of D2 receptors in the
mesolimbic pathway. However, their use is often limited by the appearance of
movement disorders due to blockade of D2 receptors in the nigrostriatal pathway.

Chlorpromazine
This was the first drug introduced to clinical medicine specifically as an antipsychotic
and was in widespread use by the late 1950s. Structurally, it belongs to the same family
as the antihistamines, and like the antihistamines it is very sedative; this led
researchers to investigate the possibility of its being useful as a premedication before
surgery, and from there its usefulness in psychotic disorders was quickly recognised. It
is sometimes used for intractable hiccups and tics, and in nausea and vomiting in
serious illness when other anti-emetics have failed.
Pharmacokinetics
Chlorpromazine is well absorbed orally and is highly plasma protein-bound. It is heavily
metabolised in the liver and has a half-life of around 30 hours. It should not be taken
with alcohol, and it can be an irritant in the gastrointestinal tract, so taking with food is
recommended.

Haloperidol
Haloperidol is one of the most potent antipsychotic drugs and can be given orally or as a
depot preparation given as a deep intramuscular injection, giving effective plasma levels
over an extended period. This smooths out plasma levels and eliminates the possibility
of the patient forgetting to take a dose. It is sometimes used as an anti-emetic in serious
illness, and to calm and sedate in a range of conditions associated with agitated,
aggressive, or hyperactive behaviour, e.g. Tourette’s syndrome and acute psychotic
episodes.

Flupentixol
Flupentixol is absorbed slowly and incompletely after oral administration and is often
used as a depot preparation. It is highly bound to plasma proteins, and its half-life
generally falls between 19 and 39 hours. It is sometimes also used in depression.

Atypical (second-generation) antipsychotics

Examples: clozapine, risperidone, aripiprazole
The atypical antipsychotics may give better results in treatment-resistant disease and
in patients with a higher incidence of negative symptoms, and they tend to give fewer
extrapyramidal side-effects, but there is no evidence that they are more effective overall
than the typical antipsychotic drugs.

Clozapine
Clozapine and the related agent olanzapine bind to a wide range of receptors in the
brain, and their dopamine receptor blockade is actually fairly weak, which probably
accounts for their relative lack of extrapyramidal symptoms. They bind strongly to H1
receptors and so are sedative, although less so than the typical antipsychotics. They also
bind strongly to 5-HT receptors and muscarinic receptors. Clozapine is especially useful
in patients whose psychosis has not responded to other treatments. However, it can
cause dangerous intestinal obstruction, fatal agranulocytosis, and potentially fatal
myocarditis.
Pharmacokinetics
Clozapine is rapidly and almost completely absorbed following oral administration and
is very highly plasma protein-bound. Its average half-life is about 8 hours, and it is
metabolised in the liver.

Risperidone
Risperidone is used in a range of psychotic disorders and to treat mania. It is associated
with a higher incidence of extrapyramidal side-effects than clozapine, but less than the
typical antipsychotic agents. It is well absorbed from an oral dose, is highly plasma
protein-bound, and its half-life can range from 3 to 20 hours. It is metabolised in the
liver to the active metabolite paliperidone and cleared by the kidney.

Aripiprazole
Aripiprazole is also used in bipolar disorder. It is associated with fewer side-effects than
other atypical antipsychotics, possibly because it has an unusual interaction with
dopamine receptors. It has partial agonist activity, so that even though it occupies the
receptor and prevents dopamine from attaching, it causes a minor degree of receptor
stimulation. The incidence of extrapyramidal symptoms is reduced and prolactin levels
do not increase. In addition, weight gain is not usually a problem. It also has few
antimuscarinic side-effects.

Pharmacokinetics
Aripiprazole is well absorbed orally, although if taken with a fatty meal, absorption is
delayed. It is almost 100% plasma protein-bound and has a very long half-life of 75
hours. It is metabolised in the liver to an active product which has an even longer half-
life. This extended half-life means that aripiprazole can be useful in maintenance
treatment.

Anaesthetics
‘Anaesthesia’ means ‘absence of sensation’. General anaesthetics (GAs) depress
nerve function in the CNS and produce controlled unconsciousness associated with
analgesia and amnesia. Local anaesthetics (LAs) interrupt the conduction of action
potentials in peripheral sensory nerves and cause loss of sensation in the tissues served
by these nerves; clinically, eliminating pain signals is the primary aim, but temperature
and pressure sensation is also lost or impaired. In high enough concentrations, LAs
block conduction in all electrically excitable cells, and therefore also silence motor
nerves, central nerves, and muscle cells.

General anaesthetics
Before the introduction of the first successful inhalational anaesthetic, ether, used in
1846 for a dental extraction, surgical procedures had to be fast and crude, and the
unfortunate patient physically restrained. Many patients died of shock from the pain or
from infection. Alcohol and opioids could be given beforehand, but doses that
achieved adequate sedation were in themselves life-threatening. The horrors and
dangers of pre-anaesthetic surgery were such that people tolerated intensely painful or
debilitating conditions rather than present themselves for treatment. The introduction
of general anaesthesia transformed surgery, giving surgeons time to perform
increasingly complex and precise procedures. Early anaesthetics included ether,
hazardous because of its high flammability, and chloroform, which was associated
with a high death rate because of cardiovascular and hepatic toxicity. Both have been
superseded with newer, safer agents, and both inhalational and intravenous drugs are
available.
Chemically speaking, GAs are a diverse group of substances. The inert gas xenon and
nitrous oxide (N2O), both simple structures, induce anaesthesia. Other agents have
much more complex molecular structures. However, they do have one important
property in common: they are all highly lipid-soluble and on administration are rapidly
and extensively taken up into tissues, including the CNS. Anaesthetic potency therefore
increases with lipid solubility.

Mechanism of Action of Anaesthetic Agents

There is no single, tidy, and well-established explanation for the anaesthetic action of
this structurally diverse group of drugs. It is currently thought that GAs affect ion
channels at synapses, regulating the entry of ions into nerves, which in turn controls the
excitability of the nerve. Several are believed to act at GABAA receptors, enhancing
opening of the associated Cl- channels, allowing Cl- entry into the nerve and inhibiting it
(Fig. 4.18). There is also evidence that some inhibit the action of excitatory
transmitters, e.g. glutamate acting at NMDA receptors.

Drugs Used as Adjuncts in Anaesthesia

Premedication, often with a benzodiazepine, sedates and reduces pre-operative
anxiety. GAs may have analgesic and muscle relaxant properties, in addition to their
anaesthetic actions, but they are not all equally potent in each respect (Table 4.5). The
use of preoperative sedatives and additional analgesics and muscle-relaxant agents
supports anaesthesia and reduces the dose of anaesthetic required. For example,
although GAs cause muscle relaxation, some surgical procedures, e.g. abdominal
surgery, require complete paralysis of skeletal muscle not achievable at safe anaesthetic
concentrations with anaesthetic alone. Neuromuscular blocking drugs, e.g.
pancuronium, are therefore used as adjuncts. Other drugs frequently used include
anti-emetics, e.g. metoclopramide, because many inhalational anaesthetics, as well as
opioid analgesics, trigger nausea and vomiting by acting on the chemosensitive
trigger zone in the medulla oblongata. Antimuscarinic agents, e.g. hyoscine, are
sometimes used to dry up respiratory and salivary secretions, which can be stimulated
by intubation and the irritant action of some inhalational anaesthetics, e.g. isoflurane,
and which threaten the airway and increase the risk of aspiration.

The Stages of Anaesthesia

Depth of anaesthesia is assessed according to four named stages, I–IV (Table 4.6). The
higher centres of the brain in the cortex, limbic system, and hypothalamus are most
sensitive to the inhibiting action of GAs and are suppressed first, with unconsciousness,
analgesia, and amnesia. Higher anaesthetic concentrations are needed to suppress the
neural circuits used to maintain involuntary activity, including withdrawal and laryngeal
reflexes and autonomic nervous system function that must be inhibited for surgical-level
anaesthesia. Even higher concentrations eventually suppress the basic life-support
functions of cardiovascular and respiratory control and threaten life.

Table 4.5

Table 4.6

The Four Stages of Anaesthesia

Stage Physiological events
I: Analgesia Sedation, disorientation, confusion but not unconsciousness
Analgesia
II: Excitation. Airway reflexes including coughing are intact and laryngeal
Safe spasm may occur if intubation attempted
anaesthetic Hypertension, tachycardia
practice Disinhibition, delirium and may physically struggle or fight
should Vomiting, which can threaten the airway
minimise Amnesia
 this stage
III: Surgical There are four planes, I–IV, representing deepening anaesthesia.
anaesthesia Loss of consciousness; loss of protective reflexes, e.g. corneal,
pupillary, and laryngeal reflexes; progressive loss of muscle
tone; progressive respiratory depression which becomes severe
in plane IV with diaphragmatic paralysis and apnoea
IV: Medullary Loss of spontaneous respiratory effort
depression Loss of cardiovascular control: hypotension and reduced
cardiac contractility
Cardiorespiratory support essential to maintain life
Skeletal muscle flaccidity

Progression through these stages correlates with anaesthetic concentration and is

affected by other drugs given before and during anaesthesia. For example, effective
analgesia during anaesthesia is important because even in an anaesthetised state,
painful stimuli from the surgical procedure trigger various stress responses, including
increased sympathetic activity, e.g. increased heart rate and blood pressure. This
increases the risk to the patient, and although it can be suppressed by increasing the
dose of the anaesthetic, this exposes the patient to the greater risks of very profound
anaesthesia. Most anaesthetics have no inherent analgesic activity (Table 4.5), so
administering adequate analgesia, usually with opioids, during surgery reduces this
pain-evoked sympathetic stimulation and allows anaesthetic doses to be reduced.

Induction and Maintenance of Anaesthesia

Rapid induction of anaesthesia, i.e. getting the patient from full consciousness to
surgical anaesthesia as quickly as possible, is desirable because it reduces the time spent
in stage II. Inhalational anaesthetics induce anaesthesia relatively slowly because of the
time needed for the drug to equilibrate between the alveoli and the bloodstream and
then between the bloodstream and the CNS. A bolus dose of intravenous anaesthetic can
be used for rapid induction, with anaesthesia then maintained with an inhalational
agent. Total intravenous anaesthesia, in which anaesthesia is both induced and
maintained using intravenous agents, can be performed in some short procedures.

Inhalational anaesthetics
These are low-molecular-weight gases or volatile liquids (i.e. liquids that release gas).
They are inhaled into the alveoli of the lungs, from where they rapidly diffuse into the
bloodstream. Because they are so lipid-soluble, they dissolve poorly in the water-based
medium of the blood and are rapidly taken up into the CNS because of its rich blood
supply and relatively high lipid content.

The Minimum Alveolar Concentration of an Inhaled Anaesthetic

Anaesthetic potency is measured as the minimum alveolar concentration (MAC) of the
drug required to achieve anaesthesia.

Key Point: Anaesthetic Potency and Minimum Alveolar Concentration

Potent anaesthetic agents achieve anaesthesia at lower minimum alveolar
concentrations, whereas less potent anaesthetics require higher alveolar
concentrations to induce anaesthesia.

The MAC decreases with age and is reduced in certain situations, e.g. anaemia,
hypoxia, pregnancy, and alcoholic intoxication. It is increased in chronic alcohol use and
in people with (naturally) red hair.

Pharmacokinetics
Achieving MAC depends on the concentration of inhaled anaesthetic, the rate and depth
of respiration, and the presence of certain pathologies, e.g. emphysema. The higher the
anaesthetic concentration and the deeper and faster the respiratory effort of the patient,
the faster the MAC is reached. In emphysema, total lung volume is increased, although
the number of functional alveoli is reduced, so the anaesthetic concentration in
functional alveoli is diluted and it takes longer to achieve MAC. With continued
administration, the drug equilibrates between the alveoli, the bloodstream, and the
tissues, including the CNS (Fig. 4.21A). Blood flow to an organ is an important
determinant of equilibration; well-perfused tissues receive higher quantities of drug and
equilibrate quickly, whereas tissues with a lower blood supply, e.g. adipose tissue,
equilibrate more slowly. Termination of action (reversal) of an inhaled anaesthetic relies
almost entirely on pulmonary excretion. On withdrawal of the anaesthetic, its alveolar
concentration immediately falls, meaning that it is no longer in equilibrium between
alveolar air and the bloodstream, and the drug transfers down its concentration gradient
into the alveoli and is excreted in the breath (Fig. 4.21B). As blood levels fall, the drug
transfers from tissues into the bloodstream, reducing levels in the CNS and initiating
recovery. The ‘hangover’ effect seen with some inhalational anaesthetics is due to the
accumulation of the drug in body fat stores. Because adipose tissue has a poor blood
supply, anaesthetics are taken up relatively slowly despite their high fat solubility, but
for the same reason, they are released slowly after reversal and can lead to drowsiness
and impaired motor function for up to 24 hours. In recovery, the patient passes through
the four stages of anaesthesia (Table 4.6) in reverse, including the excitation stage. An
ideal inhaled anaesthetic therefore reverses very quickly, minimising time spent in this
potentially dangerous period. Factors that depress respiration, e.g. opioid
administration, slow down recovery.

Modified Ethers
Examples: desflurane, isoflurane, sevoflurane
These are simple molecules based on the chemical structure of ether. They target
multiple channels and molecular sites in the CNS, inhibiting synaptic transmission and
reducing nerve activity. Sevoflurane and desflurane give faster induction and
recovery than isoflurane. They all suppress respiration by reducing the sensitivity of
the respiratory centres in the brainstem to carbon dioxide, an important stimulant to the
inherent rate and rhythm of breathing. They relax smooth muscle, including in blood
vessel walls, causing vasodilation and hypotension. This reduces perfusion of key organs
including the heart and the liver. In addition, they may directly depress myocardial
contractility, worsening any hypotension. They relax the uterus, which can slow labour
and increase the risk of haemorrhage, because the contracting uterus normally
compresses blood vessels that are damaged as the placenta separates during the third
stage of labour. They induce postoperative nausea and vomiting because they stimulate
the chemosensitive trigger zone of the medulla oblongata, and they may irritate the
respiratory tract, causing coughing and laryngospasm. Sevoflurane is the least irritant
in this group.
 FIG 4.21 Equilibration of inhaled anaesthetic between lungs,
tissues, and blood.A. Induction and maintenance. 1: The anaesthetic
equilibrates between alveolar air and arterial blood. Provided the
minimum alveolar concentration (MAC) has been reached, this
means that blood levels are high enough to achieve anaesthesia. 2:
Well-perfused tissues, e.g. the central nervous system (CNS), liver,
and other organs, rapidly equilibrate. Provided arterial drug levels
remain high enough, anaesthesia is induced and maintained. 3:
Poorly perfused tissues, e.g. adipose tissue, also equilibrate but more
slowly. B. Reversal. 1: When administration stops, alveolar
anaesthetic concentration rapidly drops. The drug diffuses rapidly
out of the bloodstream into the alveoli and is excreted in the breath.
2: As blood levels fall, anaesthetic diffuses rapidly down its
concentration gradient from the tissues, including the CNS, into the
blood. Well-perfused tissues clear the drug very quickly. 3:
Anaesthetic levels fall more slowly in poorly perfused tissues, which
may still contain measurable levels of anaesthetic for hours after
administration has stopped.

Nitrous Oxide
N2O induces anaesthesia rapidly and is pleasant to use because it is odourless and non-
irritant. Its mechanism of action has not been clearly explained, but it is known to
interact with a range of neurotransmitter receptors in the brain, including inhibition of
the excitatory NMDA receptor family. It also releases endogenous opioids in the
brainstem, activating endogenous pain-modulating pathways in the spinal cord, and
presumably contributing at least in part to its excellent analgesic activity. It is less
cardiodepressant and less emetic than the modified ethers, but it does not achieve high
enough alveolar concentrations to give full anaesthesia on its own. It is often used with
other inhaled anaesthetics, which allows the concentration of the second agent to be
reduced, and it is used as an analgesic in labour and other situations where short-term
or emergency pain relief may be needed, e.g. after fracture or burns.

Intravenous anaesthetics
Examples: thiopental, propofol, etomidate, ketamine
These may be used as a bolus to induce anaesthesia or by infusion to maintain
anaesthesia in shorter procedures.

Pharmacokinetics
These lipid-soluble drugs enter the CNS within seconds following intravenous injection,
giving fast onset of anaesthesia. If given as a single bolus, anaesthesia is short-lived,
because although the drug is initially taken up into the CNS due to its rich blood supply,
it then steadily distributes throughout body tissues and CNS levels quickly fall. Reversal
therefore depends upon drug distribution. If the anaesthetic is infused over a period of
time, it equilibrates throughout body tissues, and reversal becomes dependent upon
metabolism.

Thiopental
Thiopental is a barbiturate, a class of drugs largely abandoned in clinical medicine
because of dangerous side-effects. It is very lipid-soluble and gives a very fast induction,
but it has significant depressant activity on cardiovascular and respiratory function.
Thiopental induces anaesthesia by enhancing GABA activity.

Propofol
Propofol potentiates the inhibitory action of GABA at GABAA receptors. It is mainly
used as an induction agent and in lower doses for conscious sedation. It depresses
cardiovascular and respiratory function and can cause pain on injection because it has
very low solubility in water and is formulated as an oil-in-water suspension. However, it
causes little nausea or vomiting, reverses rapidly with little hangover, and its amnesiac
action is useful for patients undergoing short procedures with conscious sedation.

Etomidate
Etomidate potentiates the inhibitory action of GABA at GABAA receptors, but it is not
chemically related either to the benzodiazepines or the barbiturates. It is very rapid
acting and has a short plasma half-life of 6–10 minutes, because it is rapidly degraded
by plasma and liver esterases to inactive products. It causes less cardiovascular
depression than propofol, but it can be painful on injection and causes postoperative
nausea and vomiting. It is not used for maintenance of anaesthesia because it causes
adrenal suppression. Adrenal steroids, e.g. cortisol, are essential for an effective stress
response, essential to supporting physiological function in illness and trauma, including
surgery. Adrenal suppression therefore increases risk, especially in severely ill patients.

Ketamine
Ketamine affects the function of a range of receptors in the brain, including blockade of
excitatory NMDA receptors. Its analgesic properties are probably due to activation of
internal opioid pain modulation mechanisms. It gives slow induction and slow recovery,
and causes hangover effects and postoperative nausea and vomiting. It induces a state
called ‘dissociative anaesthesia’, in which the patient appears awake, with eye opening,
good muscle tone, and preserved laryngeal reflexes, but with excellent analgesia. It
stimulates the sympathetic nervous system, supporting cardiovascular and respiratory
function, and has a significant psychotropic effect––people report hallucinations, vivid
dreams, and detachment from reality.

F oc us on: Loc al Anaesthetic s

Examples: cocaine, lidocaine, tetracaine, benzocaine, bupivacaine
LAs are used to deaden sensation in a well-defined body part. The original LA,
cocaine, is found in the leaves of the coca bush, whose natural habitat is the tropical
areas of South America, particularly the Peruvian Andes. The psychostimulant
properties of the plant were well known to the local people, who had chewed the
leaves as part of their religious, medicinal, and social practices for thousands of years
prior to the arrival of European explorers in the 16th century. The numbing of the
mouth, tongue, and throat that accompanied chewing was a well-recognised
consequence of the habit. Because the leaves did not travel well, it was some time
before coca extracts became common outside its native lands, but by the 19th century,
cocaine was used in a range of products, including wines, tablets, medicinal
formulations, and Coca-Cola, which were in widespread use and available for general
sale. In the early 20th century, legislation and restrictions were introduced in the sale
and use of cocaine (it was removed from Coca-Cola in 1904, although the company
fought a successful battle to retain the name and a cocaine-free extract of the coca leaf
is still used in the recipe). Although cocaine is still used as a local anaesthetic in some
specialities, e.g. ophthalmic surgery, its use is restricted due to its psychotropic,
addictive, and cardiotoxic properties. Newer agents, e.g. lidocaine and benzocaine,
are amides, structurally different from cocaine, and other than their local anaesthetic
action, behave differently from cocaine.
Mechanism of Action
LAs block Na+ channels in the membranes of excitable tissues, mainly muscle and
nerve (Fig. 4.22). LA molecules are generally weak bases and diffuse through nerve
cell membranes into the neurone in an uncharged form, from where they enter Na+
channels and block them. This prevents the nerve from conducting action potentials
(Fig. 4.23). If the Na+ channel is in its closed state, as in a resting nerve, the LA
cannot enter.
Factors Affecting Local Anaesthetic Efficacy
The effectiveness of LAs is changed in the following situations:
Blood Flow
LA action is terminated when the drug distributes away from the site, and the primary
route for this is via the bloodstream. The drug is therefore lost faster from well-
perfused tissues. In addition, most LAs cause vasodilation because they block Na+
channels in vascular smooth muscle, relaxing it. Vasodilation increases blood flow
and accelerates drug loss from the site of administration. To counteract this, a
vasoconstrictor, usually adrenaline, is combined with the anaesthetic. Care must be
taken, however, to avoid ischaemia, and it should not be used in areas with a
restricted blood supply, e.g. the fingers. Additionally, great care must be taken not to
deliver the combination into a blood vessel because of adrenaline’s cardiovascular
actions.
Inflamed or Infected Tissues
The pH of injured or infected tissues falls, i.e. becomes acidic, because microbial and
tissue metabolic products are generally acidic. In addition, blood flow through these
tissues is usually reduced, and these waste products are not washed away. This affects
the ability of LA molecules to cross the nerve cell membrane. Because LA molecules
are weak bases, they attract and attach excess hydrogen ions in the acidic medium of
infected or inflamed tissues. This positive charge impedes the ability of the molecules
to diffuse into the nerve, and since they can only block Na+ channels from the nerve
interior, their anaesthetic activity is lost. This presents a practical problem when
trying to achieve anaesthesia in, for example, dental surgery, where there may be
infection or inflammation present. It may be necessary to pre-treat with antibiotics
before surgical intervention can be attempted under LA.
FIG 4.22 Mechanism of action of local anaesthetics.LA, Local
anaesthetic.
 FIG 4.23 The effect of a local anaesthetic on the nerve membrane
potential.By blocking sodium channels, the threshold potential is
not reached and the action potential is prevented. Modified from
Stoelting RK and Miller RD (1994) Basics of anesthesia, 3rd ed.
New York: Churchill Livingstone.

Table 4.7

Neuronal Factors
Small-diameter neurones are more susceptible to LA action than larger ones. This is
fortunate, because pain neurones are small-diameter free nerve endings, whereas
other sensory and motor nerves are larger and require higher drug concentrations
before their conductance is impaired. Additionally, a myelin sheath presents an extra
barrier to LA penetration, so that non-myelinated nerves are more susceptible than
myelinated ones. This too is clinically advantageous, because sensory pain fibres are
non-myelinated. In addition, the duration of the action potential affects tissue
susceptibility. Pain neurones and cardiac muscle cells both have longer than average
action potentials, meaning their Na+ channels stay open for longer. This is beneficial
when abolishing pain signals and explains why LAs can significantly depress heart
function if they achieve high enough levels in the bloodstream. Sensory modalities are
lost in a predictable order as LA concentration rises, reflecting the sensitivity of
sensory and motor nerves to LA: pain sensation is lost first, followed by temperature,
then touch, then deep pressure, and finally motor function.
Use-dependence
Neurones with high rates of firing, e.g. pain fibres, are highly susceptible to LA action
because their Na+ channels spend more time in the open state. This is clearly
clinically useful. High rates of firing are also characteristic of other electrically active
tissues, including ectopic foci in the heart. This is the reason why LAs, e.g. lidocaine,
are used to treat some arrhythmias.
Pharmacodynamics
LAs are lipid-soluble, allowing them to diffuse across nerve cell membranes, and the
more lipid-soluble they are, the more potent they are. The degree to which they bind
to tissue proteins determines their duration of action; strong protein binding helps
the drug to be retained at its site of administration and prolongs its action. Cocaine
and tetracaine have a very short plasma half-life (less than 3 minutes), because they
are metabolised by plasma enzymes, but the amides, e.g. lidocaine and
benzocaine, are metabolised in the liver and have plasma half-lives ranging from 1
to 3 hours. The key properties of some important LAs are given in Table 4.7.

Side-Effects
There may be a localised allergic reaction, but the most dangerous side-effects of LAs
occur when they escape into the circulation in high enough concentrations to inhibit
excitable tissues elsewhere. They reduce myocardial contractility and can interfere
with the heart’s internal pacemaker activity and impulse conduction. This
cardiodepressant activity along with their hypotensive action can lead to
cardiovascular collapse and death. Cocaine is an exception to the general pattern of
hypotension and cardiac depression because it causes vasoconstriction, stimulates the
heart, and increases blood pressure. Local anaesthetic toxicity in the CNS shows a
biphasic pattern, with initial excitation followed by depression. Excitation might seem
counterintuitive, since these drugs inhibit neural function, but it occurs because the
first nerves to be blocked are inhibitory neurones that suppress excitatory pathways.
With their inhibitory neurones silenced by the anaesthetic, overactivity of these
excitatory pathways leads to a spectrum of effects ranging from mild excitement to
convulsions. With increasing doses, a generalised depression of CNS function follows,
including shutting down of basic life-support mechanisms in the cardiovascular and
respiratory centres in the brainstem, coma, and death.

Anticonvulsants
A seizure is caused by a sudden and uncontrolled episode of electrical disturbance in the
brain, originating in a group of hyperexcitable neurones called the epileptogenic focus.
Epilepsy, sometimes called seizure disorder, is a chronic condition characterised by
recurrent, unprovoked seizures, but not all seizures are associated with epilepsy. The
aim of anticonvulsant therapy is, whenever possible, to prevent seizures from occurring,
or at least to reduce their frequency and severity as much as possible.

Causes of seizures
A wide range of diseases and disorders, not necessarily neuropathological in origin, can
trigger seizures. The most common cause of seizures is epilepsy, but one-off seizures
may be caused by infection, hyponatraemia (e.g. in poorly monitored diuretic therapy),
high fever (especially in young children), hypoglycaemia, recreational drug use (e.g.
cocaine), or during alcohol withdrawal. Traditionally, epilepsy has been considered to
be caused by an imbalance between excitatory and inhibitory nerve activity, permitting
episodic dominance of excitatory neurotransmission. A range of brain abnormalities
have been associated with epilepsy, including neurodegeneration, inflammation, and
structural and functional changes in excitatory and inhibitory neurotransmitters and
their receptors and associated ion channels. Epilepsy can be caused by congenital brain
malformations, cerebral hypoxia, scarring following brain injury, a tumour,
haemorrhage, or stroke. In other people, epilepsy can arise with no obvious underlying
cause. Some forms of epilepsy have a strong hereditable component, and there is an
increasing list of ‘epilepsy genes’, an important area of research in the aetiology of
epilepsy.

Types of seizure
Seizures are classified according to the location of the epileptogenic focus in the brain,
their duration, and the characteristic features of the event, which is determined by
which part(s) of the brain are affected. For example, if the abnormal neuronal discharge
occurs in the motor cortex, the seizure will involve involuntary activity in skeletal
muscle.

Focal Seizures
If the abnormal electrical discharge remains localised within one cerebral hemisphere, it
causes a focal seizure. The patient may remain aware throughout the seizure and have
full memory afterwards (focal aware seizure) or may lose awareness with limited recall
(focal impaired awareness seizure). There may be a range of involuntary activities called
automatisms, including hand rubbing and lip smacking. Drugs with a range of modes of
action, including Na+-channel blockers, e.g. carbamazepine and phenytoin, drugs
that increase the activity of GABA, e.g. the benzodiazepines and vigabatrin, and
drugs that reduce the activity of glutamate, e.g. lamotrigine, are effective in treating
focal seizures.

Generalised Seizures
In generalised seizures, the abnormal electrical activity occurs in both cerebral
hemispheres, and may either evolve from a focal seizure or begin as a generalised
seizure. Consciousness is almost always lost. Two important forms of seizure in this
category are tonic-clonic convulsions and absence seizures.

Tonic-Clonic Seizures
In tonic-clonic seizures (formerly called grand mal), there is an initial sudden and
widespread stiffening of skeletal muscle, causing respiratory arrest and often
incontinence. This is followed by the clonic phase, in which skeletal muscles alternately
contract and relax, causing violent jerking of the limbs. Afterwards, the patient is
generally sleepy, confused, irritable, and disoriented. Drugs that block Na+ channels in
nerve axons, e.g. phenytoin, or that increase the levels of GABA, e.g. vigabatrin, are
effective in controlling tonic-clonic seizures.

Absence Seizures
In absence seizures, (previously called petit mal epilepsy) which are usually seen in
children, there are few motor symptoms. The child abruptly stops whatever they were
doing, including talking, and appears to be daydreaming, with no awareness of their
surroundings. Return of full awareness is also abrupt, and the child is not aware that the
seizure has occurred. The aetiology of absence seizures is not understood, but they seem
to be associated with a particular pattern of electrical discharge in a neuronal circuit
between the thalamus and the cortex. Abnormalities in Ca2+ channels and in GABA
activity have both been demonstrated in this circuit, reflected in the agents used to treat
absence seizures. The most effective drugs include sodium valproate and
ethosuximide, which block the abnormal Ca2+ channels. Agents that increase GABA
activity, e.g. vigabatrin, can make absence seizures worse, as can Na+-channel blockers
such as phenytoin.

Status Epilepticus
This is either a single extended seizure or a continuous series of seizures with no
recovery between them persisting for over half an hour. It carries a mortality of up to
15%, and there is high risk of permanent hypoxic brain damage following recovery. If the
seizure involves convulsions, skeletal muscle damage (rhabdomyolysis) can release
significant quantities of myoglobin into the bloodstream, which may cause acute kidney
injury. Benzodiazepines e.g. diazepam and midazolam, intravenous anticonvulsants,
e.g. phenytoin, and general anaesthetics, e.g. propofol or thiopental, are used to
terminate status epilepticus.

Pharmacological management of seizures

For most people with epilepsy, drug treatment can either completely prevent or at least
control their seizures, but anticonvulsant agents are often themselves quite toxic with
multiple interactions. They are a disparate group of drugs, associated with a range of
mechanisms of action, and are used to reduce or eliminate the abnormal neuronal
discharge causing the seizure rather than addressing any underlying pathology that may
be causing it.
It is important to realise that there is not one single electrical abnormality
underpinning all types of epilepsy. Neuronal function in the brain is controlled by a
range of ionic gradients and ion movements controlled by specific ion channels. The role
of Na+ and K+ in action potential conduction is a fundamental neurophysiological
mechanism and is described above, but the movement of other ions, including Ca2+ and
Cl-, also generate localised currents essential to the electrical circuitry of the brain. In
addition, fine control of neuronal function involves both excitatory (e.g. glutamate) and
inhibitory (e.g. GABA) neurotransmitters. An understanding of any molecular
abnormality and the role of relevant neurotransmitters in an epileptic condition is
therefore essential in choosing the best drug to manage it, especially as in some cases an
inappropriate drug choice can actually worsen the disorder.
The first documented use of a drug to control convulsions dates from 1857, when
Locock began treating epileptic patients with potassium bromide. This remained the
mainstay until 1912 when the barbiturate phenobarbital was introduced, followed by
phenytoin in 1938. Since then, the range of drugs available has expanded considerably,
advanced by huge improvements in the understanding of the neurochemistry underlying
seizure pathophysiology, which has allowed for rational drug design and much improved
tailoring of treatment for individual patients. In particular, the introduction of newer
drugs such as sodium valproate and carbamazepine in the 1970s increased the
proportion of patients who could be successfully treated with a single anticonvulsant
(monotherapy).
Monotherapy is preferred whenever possible over treatment with two or more drugs,
which increases the incidence and severity of side-effects and introduces the possibility
of drug interactions. Many anticonvulsants are strongly associated with fetal
abnormalities, and the management of epilepsy in pregnancy needs specialist care.
Many anticonvulsant drugs affect multiple sites in the brain and probably work
through more than one mechanism of action. They are described here under the heading
thought to represent their main therapeutic activity, and some key drugs and their
targets are illustrated in Fig. 4.24.

Anticonvulsants that block sodium channels

Conduction of action potentials along nerve axons depends upon the opening of Na+
channels in the neuronal membrane, allowing Na+ to flood into the nerve. Blockade of
these Na+ channels therefore reduces their capacity to conduct electrical signals and
reduces their excitability. The hyperexcitable nerves of an epileptogenic focus are more
susceptible to the inhibitory action of these drugs because their Na+ channels spend
more time in the open state. Good seizure control with these drugs therefore depends
upon getting the dose just right: high enough to selectively inhibit the hyperactive
epileptogenic nerves but not so high that normally functioning neurones are depressed.

Phenytoin
Phenytoin is used in all types of epilepsy except absence seizures.

Pharmacokinetics
Phenytoin is completely absorbed after oral dosing, and is 90% bound to plasma
proteins, giving a substantial reservoir of drug in the bloodstream. Its metabolism is
complex because it induces a range of liver enzymes, including those that catalyse its
own breakdown. This means that in the initial stages of treatment, phenytoin has a long
half-life (36 hours) which falls to 12–18 hours with continued use. It increases the
breakdown of a range of other drugs, including anticoagulants, an important cause of
interactions.
Phenytoin’s metabolism is not straightforward. As plasma levels rise, its metabolism
shifts from linear to saturation kinetics (p. 19 and Fig. 2.21). Fig. 2.21 shows plasma
levels in three individuals receiving phenytoin treatment. For all individuals, the
transition between linear kinetics and saturation kinetics, i.e. the point at which the
metabolising enzymes are working at full capacity and any additional drug simply
accumulates in the bloodstream, is seen at subtherapeutic levels. In addition, this figure
demonstrates the significant variability between individuals in the ability to metabolise
phenytoin, an additional complicating factor in safe management of phenytoin
treatment. The daily dose of phenytoin required to achieve mid-therapeutic levels for
the patient whose plasma levels are represented by the red curve is three times lower
than the patient results shown by the green curve. It also reinforces the point that even
small changes in daily dose can have significant effects on plasma levels, which would
impact on seizure control and the likelihood of side-effects. Therapeutic drug
monitoring is important to ensure that plasma levels remain in the therapeutic range,
especially when adjusting drug dose or introducing other drugs.
 FIG 4.24 Summary of the mechanism of action of some important
anticonvulsant drugs.BDZ, Benzodiazepine; GABA, gamma-
aminobutyric acid.

Adverse Effects
Phenytoin has a narrow therapeutic index, and a range of dose-dependent adverse
effects caused by its interference with CNS function appear at the upper end of its
therapeutic dose range. Ataxia, tremor, and vertigo are common, and in higher doses the
drug is sedative and causes confusion and reduced intellectual function. Allergy occurs
in a small number of patients and may manifest as a mild skin rash or can involve life-
threatening desquamation reactions, including Stevens–Johnson syndrome (Fig. 3.13).
Phenytoin stimulates connective tissue growth, particularly affecting the gums, and
causes acne and hirsutism, probably through a stimulation of testosterone release. It
increases the risk of fetal and facial and digital malformations when used in pregnancy.
It can also cause blood disorders because it interferes with the metabolism of folic acid,
an essential factor in blood cell synthesis.

Carbamazepine
Carbamazepine is used in most types of epilepsy except absence seizures. It is also
sometimes used in neuropathic pain, e.g. trigeminal neuralgia and diabetic neuropathy,
because it silences the pain signals generated by abnormal or injured neurones and can
also be effective in bipolar disorder.

Pharmacokinetics
Carbamazepine is well absorbed when given orally and is up to 80% plasma protein-
bound. Like phenytoin, carbamazepine induces liver metabolic enzymes, including its
own. Its half-life in the initial stages of treatment is about 36 hours, but with continued
administration and autoinduction of metabolism, this falls to 12–17 hours. It induces the
metabolism of other drugs, notably oestrogens in contraceptive preparations, leading
to rapid clearance of oestrogen and possible contraception failure. Carbamazepine
metabolites are inactive and are mainly excreted in the urine.

Adverse Effects
Carbamazepine causes a range of dose-dependent neurological side-effects related to its
depressant activity on the CNS; they include ataxia, headache, and drowsiness. There
may be hypersensitivity reactions, mainly skin rashes, but occasionally severe allergy is
seen, including Stevens–Johnson syndrome (Fig. 3.13). It can cause water retention
and oedema because it antagonises the effects of antidiuretic hormone, and the
increased fluid load dilutes blood Na+ levels and causes hyponatremia.

Anticonvulsants that enhance gamma-aminobutyric acid

As discussed above, GABA is a key inhibitory neurotransmitter widespread in the brain.
It is thought that deficiency in GABA function is a factor in the pathophysiology of some
epilepsies, and enhancing its levels or activity has been an important focus in the
development of anticonvulsant agents.

Benzodiazepines
All BDZs have anticonvulsant activity, but because they are sedative and induce
dependence and tolerance, their usefulness in long-term therapy is limited. The main
agents used in maintenance treatment are clobazam and clonazepam. However,
BDZs are the drugs of choice in controlling status epilepticus and are given rectally or
intravenously. Diazepam, lorazepam, and midazolam are the main agents used.
The pharmacology of the BDZs is described above.

Vigabatrin
Vigabatrin irreversibly blocks GABA transaminase, the enzyme that destroys GABA.
Reducing its enzymatic destruction elevates GABA levels in the brain and enhances its
inhibitory action. It is an example of rational drug design, having been formulated
specifically to act against this specific enzyme. It is a second-line agent used in
combination with other anticonvulsants to improve control when the primary agent is
not fully effective. Vigabatrin is highly effective in some forms of childhood epilepsy and
in most adult epilepsies, but its use is restricted because it causes permanent peripheral
vision loss in up to 40% of patients.

Pharmacokinetics
Vigabatrin is well absorbed from an oral dose, does not bind significantly to plasma
proteins, and is not metabolised. Its plasma half-life is about 10 hours, but because it
irreversibly deactivates GABA transaminase, its duration of action depends on how
quickly the brain synthesises new enzyme rather than how long the drug persists there.
This also means that plasma levels of the drug do not correlate with its therapeutic
activity and measuring them is not useful.

Adverse Effects
The most significant side-effect of vigabatrin is permanent impairment of peripheral
vision because the drug damages retinal neurones and causes them to atrophy. The risk
is greater in males than females and increases with the duration of treatment, but it has
been reported after only 4 weeks of using the drug. It is common, with up to 40% of
patients developing constriction of their visual field. Although central vision is
unaffected, restricted peripheral vision can have a range of negative effects, including
reducing one’s ability to play sports requiring awareness of players or a ball approaching
from the side, or limiting a driver’s ability to see pedestrians stepping onto the road
(Fig. 4.25). Regular vision tests are therefore essential for patients taking this drug,
especially in children who are likely to be unaware of their gradual vision loss. A wide
range of other side-effects, including dizziness, drowsiness, memory loss, and
paraesthesias, have also been reported.

Tiagabine
Tiagabine is a GABA analogue: that is, its chemical structure is very similar to GABA,
and once it enters the brain, it competes with GABA for the GABA transporter that
removes GABA from the synapse. This preserves GABA levels in the synapse and
prolongs its inhibitory activity. It is used in conjunction with other anti-epileptic drugs
to improve seizure control when a single drug is not effective enough on its own.
FIG 4.25 Reduction of peripheral visual fields by vigabatrin.A.
Normal field of view. B. Vigabatrin treatment reduces peripheral
 vision.

Anticonvulsants that block calcium channels

Ca2+ movement through Ca2+ channels in nerve cell membranes generates local
electrical currents that regulate and modify a range of nerve functions in the brain. For
example, Ca2+ entry into nerve endings is essential for neurotransmitter release.
Another example of Ca2+ function is in certain circuits between the thalamus and cortex,
important in the maintenance of arousal, and which is dysfunctional in absence
seizures.

Gabapentin and Pregabalin

Gabapentin is so-called because it was originally designed in 1975 as a GABA analogue,
but its anti-epileptic activity, and that of the similar drug pregabalin, is thought to be
mainly through blocking Ca2+ channels and inhibiting the release of excitatory
neurotransmitters like glutamate. Pregabalin is better absorbed after oral dosing than
gabapentin. Both drugs are excreted largely unchanged by the kidney, so it is important
to be aware of any renal impairment. With normal renal function, their half-lives are 5–
7 hours, but these are significantly extended if renal function is poor. Both are also used
in neuropathic pain. Adverse effects are generally less severe than those of the older
anticonvulsants: they include arthralgia, malaise, and tremor.

Ethosuximide
This anticonvulsant is used mainly in absence seizures in children (see above). It is well
absorbed when taken orally and has a half-life of around 60 hours in adults, although
this is shorter in children (30 hours) because of increased hepatic metabolism.

Sodium Valproate
This drug was discovered by accident in a series of experiments in 1962, during which
valproic acid was used to dissolve several experimental compounds undergoing a range
of pre-clinical tests, including seizure tests. As part of the standard experimental design,
valproic acid was used alone as a control and its anticonvulsant effect was immediately
obvious. It is now one of the most prescribed anticonvulsants worldwide, used in most
types of epilepsy including absence seizures. It is included here with drugs that block
Ca2+ channels in the brain, but this is thought to be only one of its mechanisms of
action. It also blocks Na+ channels in axon membranes, and it inhibits GABA
transaminase, the enzyme that degrades GABA, so it is likely that both action potential
inhibition and increasing GABA levels in central synapses contribute to its
anticonvulsant action. It may also increase GABA synthesis, and it suppresses the action
of pro-epileptic genes. Its full spectrum of action is clearly wide and not yet fully
understood. It is also used in bipolar disease and to prevent migraine.

Pharmacokinetics
Valproate is well absorbed after oral administration, has a plasma half-life of about 15
hours, and is metabolised in the liver.

Adverse Effects
Valproate is strongly teratogenic, causing spina bifida and other neural tube defects, and
it should not be used in sexually active women without effective contraception. It may
also cause potentially fatal hepatitis, but fortunately this is rare. It is a potent enzyme
inhibitor, reducing the metabolism and increasing the plasma levels of a range of other
drugs, including other anticonvulsants: this is an important cause of valproate-mediated
drug interactions. It has a range of other adverse effects, including hair loss (not
permanent, and the regrowth may be curly), confusion, memory loss, and tremor.

Anticonvulsants that reduce glutamate activity

As discussed above, glutamate is a key excitatory transmitter widespread in the brain.
Drugs that reduce glutamate levels and activity have effective anticonvulsant activity.

Lamotrigine
Lamotrigine blocks glutamate release from excitatory neurones, which reduces the levels
of glutamate in the synapse and reduces excitatory transmission. Lamotrigine also has
appreciable Na+-channel blockade activity. It is used in many types of seizure disorders
either as monotherapy or in combination with other anticonvulsants and in maintaining
mood stability in bipolar disorder.

Pharmacokinetics
Lamotrigine is well absorbed after an oral dose, and its bioavailability is almost 100%
because there is almost no first-pass metabolism. It is metabolised in the liver and
mainly excreted in the urine. Its half-life is long and variable between individuals,
ranging from 22 to 37 hours. It is often used with valproate, a potent enzyme inhibitor,
in which case its half-life can increase to 60 hours.

Adverse Effects
Lamotrigine can cause headache, drowsiness, nausea and vomiting, and tremor, among
others. It is sometimes associated with serious skin conditions, including Stevens–
Johnson syndrome (Fig. 3.13).

Topiramate
Topiramate was discovered by accident by researchers looking for antidiabetic agents. It
blocks glutamate receptors on the post-synaptic membrane. This reduces the excitability
of the nerve by inhibiting its ability to respond to this excitatory neurotransmitter. This
drug also blocks Na+ channels and probably Ca2+ channels, so its mechanism of action
in seizure control is probably complex. It is also used in migraine.

Pharmacokinetics
Topiramate is well absorbed orally and is not strongly bound to plasma proteins. Up to
70% is excreted unchanged by the kidney, so care must be taken in people with any
degree of renal impairment. Its half-life is usually within 19–23 hours.

Adverse Effects
This drug can cause hair loss, confusion, gastrointestinal upset, nausea, and tremor. It is
strongly associated with congenital malformations, especially cleft palate.

References
1. Atkin T, Comai S, Gobbi G. Drugs for insomnia beyond benzodiazepines:
pharmacology, clinical applications and discovery. Pharmacol.
Rev. 2018;70(2):197–245.
2. Becker D.E, Reed K.L. Essentials of local anaesthetic pharmacology. Anesth.
Prog. 2006;53(3):98–109.
3. Cipriani A, Furukawa T.A, Salanti G, et al. Comparative efficacy and acceptability
of 21 antidepressant drugs for the acute treatment of adults with major
depressive disorder: a systematic review and network meta-
analysis. Lancet. 2018;391(10128):1357–1366.
4. Egan T.D. Are opioids indispensable for general anaesthesia? Br. J.
Anaesth. 2019;122(6):e127–e135.
5. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators, . Global,
regional and national incidence, prevalence and years lived with disability for 354
diseases and injuries for 195 countries and territories, 1990-2017: a systematic
 analysis for the Global Burden of Disease study
2017. Lancet. 2018;392(10159):1789–1858.
6. Gitlin M. Lithium side-effects and toxicity: prevalence and management
strategies. Int. J. Bipolar. Disord. 2016;4:27.
7. Guardiola-Lemaitre B, De
Bodinat C, Delagrange P, Millan M.J, Munoz C, Mocaër E. Agomelatine:
mechanism of action and pharmacological profile in relation to antidepressant
properties. Br. J. Pharmacol. 2014;171(15):3604–3619.
8. Guzman F. The four dopamine pathways relevant to antipsychotics
pharmacology. 2019 Available
at:. https://psychopharmacologyinstitute.com/publication/the-four-
dopamine-pathways-relevant-to-antipsychotics-pharmacology-2096.
9. Jesulola E, Micalos P, Baguley I.J. Understanding the pathophysiology of
depression: from monoamines to the neurogenesis model-are we there
yet? Behav. Brain Res. 2018;341:79–90.
10. Scammell T.E, Jackson A.C, Franks N.P, Wisden W, Dauvilliers Y. Histamine:
neural circuits and new medications. Sleep. 2019;42(1):1–8.
11. Wick J.Y. The history of benzodiazepines. Consult. Pharm. 2013;28(9):538–548.
12. Wilson T.K, Tripp J. Buspirone. In: StatPearls [Internet]. Treasure Island
(FL): StatPearls Publishing; 2020 Available
from:. https://www.ncbi.nlm.nih.gov/books/NBK531477/.
5: Drugs and Endocrine Function

Introduction

Hormone Levels and Negative Feedback

The Hypothalamic–Pituitary Axis
Control of Hormone Levels by the
Hypothalamic–Anterior Pituitary Axis
Hypothalamic and Pituitary Hormones in Therapeutics
Anterior Pituitary Hormones
Adrenocorticotrophic Hormone
Growth Hormone
Somatostatin
Gonadotropin-Releasing Hormone,
Luteinising Hormone, and Follicle-
Stimulating Hormone
Posterior Pituitary Hormones
Antidiuretic Hormone
Oxytocin
Drugs and Thyroid Function
Hypothyroidism
Drug Treatment in Hypothyroidism
Adverse Effects
Hyperthyroidism
Drug Treatment in Hyperthyroidism

Drugs and Pancreatic Function

 Insulin
Glucagon
Diabetes Mellitus
Type 1 Diabetes
Type 2 Diabetes
Insulin

Non-Insulin Antidiabetic Drugs

Pharmacological Control of Reproductive Function
Female Reproductive Function
Hormonal Control of the Female
Reproductive Cycle
Hormonal Contraception
Hormonal Changes at Menopause
Hormonal Treatment of Female Infertility
Male Reproductive Function

F OCUS ON

Focus on: Sex Hormone Pharmacology p. 94

Focus on: Hormone Replacement Therapy p. 99

Introduction
The endocrine system comprises a collection of glands and tissues dispersed around the
body and the hormones they produce and release. Many hormones are released into
local blood vessels and are carried to distant target tissues in the bloodstream. This is
called endocrine control. Other hormones act locally, in the tissues close to their site of
release, and regulate the activity and behaviour of cells in their immediate environment.
This is called paracrine control. Paracrine substances are referred to as mediators and
regulate local responses such as inflammation. They include growth factors;
inflammatory mediators including prostaglandins, histamine, and bradykinin; and
cytokines, a broad group of small peptides involved in inflammation, immunity, and the
production of blood cells. Mediators are increasingly important as drug targets in the
treatment of inflammatory, malignant, and immune disease and will be discussed, as
appropriate, in other chapters.

Key Point: Endocrine vs. Nervous Control

In conjunction with the nervous system, endocrine regulation provides the internal
communication system essential for integrated control of body function. Hormonal
control is generally of slow onset and is sustained over extended periods of time,
whereas nervous control can be adjusted within fractions of a second and provides
moment-to-moment regulation. The endocrine system therefore is the main regulator
of continuous, ongoing physiological processes like growth and reproduction, and the
nervous system is the primary controller of factors that require finely controlled and
rapid adjustments, such as cardiovascular control.
 FIG. 5.1 The main endocrine glands and tissues. From Waugh A
and Grant A (2020) Ross & Wilson anatomy and physiology in
health and illness, 14th ed, Fig 9.1. Oxford: Elsevier.

The main endocrine glands and tissues are shown in Fig. 5.1. Endocrine disorders
usually involve under- or over-secretion of hormones; thus, pharmacological
management generally involves hormone replacement or the use of hormone
antagonists or drugs that suppress hormone synthesis or release.

Hormone Levels and Negative Feedback

Hormone levels in the blood are usually kept within a pre-set normal range, and
secretion of the hormone is constantly adjusted, upwards or downwards, to maintain
this. Some endocrine glands autonomously control the level of their own hormone
product: for example, the pancreas, which produces insulin, constantly measures blood
glucose levels and regulates insulin secretion into the bloodstream accordingly. When
blood glucose levels rise, the pancreas increases insulin release, and when blood glucose
levels fall, it reduces it. This is an example of direct negative feedback control. Indirect
negative feedback, in which hormone secretion by one gland is controlled by another
gland, is a feature of the hypothalamic–pituitary axis, described below.

The Hypothalamic–Pituitary Axis

Certain key endocrine glands, including the thyroid and adrenal glands and the gonads,
are regulated by the hypothalamus and the pituitary gland: this control mechanism is
called the hypothalamic–pituitary axis. The hypothalamus has multiple roles in the
control of autonomic and endocrine function, one of which is control of hormone release
by the pituitary gland. In this respect, it functions as an endocrine gland, releasing a
range of hormones that govern hormone release by the pituitary. The pituitary gland is
directly linked to the hypothalamus via a stalk of tissue called the infundibulum, and has
two lobes, the anterior and the posterior. The hypothalamus communicates with the
anterior pituitary via a network of blood capillaries and with the posterior pituitary via a
tract of nerves that originate in the hypothalamus and terminate in the gland below.

Hypothalamus–Anterior Pituitary Communication

Glandular cells in the hypothalamus secrete a number of hormones into the capillary
network linking it to the anterior pituitary. Each hypothalamic hormone acts on specific
glandular cells in the anterior pituitary. Hypothalamic hormones are mainly
stimulatory, i.e. trigger release of a pituitary hormone, but some are inhibitory and
suppress pituitary secretion. The hypothalamic hormones and the pituitary hormones
they control are shown in Fig. 5.2.
 FIG. 5.2 The hormones of the hypothalamic–pituitary axis.CRH,
Corticotropin-releasing hormone; GHRH, growth hormone-releasing
hormone; GnRH, gonadotropin-releasing hormone; PIH, prolactin
inhibitory factor (dopamine); TRH, thyrotropin-releasing hormone.

• Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates

thyrotroph glandular cells in the anterior pituitary to release thyroid-stimulating
hormone (TSH), which in turn stimulates the thyroid gland to release thyroxine.
• Gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates
gonadotroph glandular cells in the pituitary to release follicle-stimulating
hormone (FSH) and luteinising hormone (LH). These hormones act on the
gonads (the male testis and the female ovary) to regulate the release of sex
hormones, mainly oestrogen, progesterone, and testosterone.
• Corticotropin-releasing hormone (CRH) from the hypothalamus stimulates
pituitary corticotroph glandular cells to release adrenocorticotropic hormone
(ACTH), which regulates steroid release from the adrenal glands.
• Growth hormone–releasing hormone (GHRH) from the hypothalamus
stimulates pituitary somatotroph glandular cells in the pituitary to release
growth hormone (GH), and somatostatin (SST) which blocks GH release. SST is
also released by δ-cells of the pancreatic islets.
• Prolactin inhibitory factor. This is dopamine (see also Chapter 4). It is
 released by the hypothalamus and inhibits release of pituitary prolactin.

Hypothalamus–Posterior Pituitary Communication

Glandular cells in the hypothalamus secrete two hormones, antidiuretic hormone (ADH)
and oxytocin, which travel by axonal transport down the nerves linking the
hypothalamus and the posterior pituitary and are released from there.

Control of Hormone Levels by the Hypothalamic–Anterior Pituitary Axis

As shown in Fig. 5.2, hypothalamic and pituitary hormones in turn control hormone
release by a range of other glands. Blood levels of these final hormones, including
thyroid hormones, oestrogen and progesterone from the ovary, and cortisol from the
adrenal cortex, are continuously measured by the hypothalamus and pituitary gland, not
by the gland responsible for their secretion. Rising levels of the final hormone suppress
release of the relevant hypothalamic and pituitary releasing hormones, switching off the
stimulus for their release and allowing blood levels to fall. When blood levels fall below
the normal range, this is detected by the hypothalamus and pituitary, which resume
their production of the relevant releasing hormones. This is called indirect negative
feedback control because the gland secreting the final hormone is not in direct control of
its own secretion, and it is illustrated in Fig. 5.3, using the thyroid gland as an example.
The hypothalamus releases TRH, which stimulates the pituitary gland to release TSH.
TSH stimulates the thyroid to release tri-iodothyronine (T3) and thyroxine (T4). Thyroid
hormone levels in the blood therefore increase, and when they exceed the normal range,
the hypothalamus reduces TRH production and the pituitary reduces TSH production.
Hormone release by the thyroid gland is therefore reduced and decreases until T3 and T4
levels dip below the minimum of the normal range, at which point TRH and TSH release
resumes.
 FIG. 5.3 Indirect negative feedback control of thyroid hormone
secretion. From Waugh A and Grant A (2020) Ross & Wilson
anatomy and physiology in health and illness, 14th ed, Fig 9.1.
Oxford: Elsevier.

Hypothalamic and Pituitary Hormones in

Therapeutics
Hormones of the hypothalamic–pituitary axis (Fig. 5.2) can be used therapeutically to
replace hormone deficiency in disorders that involve hypothalamic or pituitary failure.
Additionally, drugs that antagonise hormone synthesis, release, or activity can be used
in conditions associated with over-activity of these glands. Conditions disrupting
hypothalamic and/or pituitary function, e.g. malignant disease, trauma, or infection, can
affect secretion of more than one hormone if more than one type of secretory cell is
affected. Because the hypothalamic–pituitary axis is a complex physiological
mechanism, and normal control of any of its final hormones depends upon healthy
function of at least two glandular tissues, there are multiple opportunities to intervene
with therapeutic drugs. Fig. 5.4 summarises the main drugs relating to the
hypothalamic–pituitary axis.

FIG. 5.4 Drugs related to the hypothalamic–pituitary axis.

Anterior Pituitary Hormones
TSH and TRH are considered in the section discussing drugs and thyroid function.

Adrenocorticotrophic Hormone
The synthetic ACTH analogue tetracosactide is used to test adrenal cortex function. It
is given by injection, and the adrenal cortex response is measured by measuring plasma
steroid levels. In adrenocortical insufficiency, the adrenal cortex cannot respond
adequately to the stimulus, and steroid levels remain low.

Growth Hormone
Growth rates are controlled by GH from the anterior pituitary, which affects all body
tissues, stimulating cell division and increasing body mass, including skeletal muscle. It
promotes cartilage cell division in the growth plates of bones, and so it is essential for
increasing height in a growing child and young person. It increases blood glucose levels
by stimulating gluconeogenesis (glucose synthesis from non-carbohydrate nutrients, e.g.
amino acids) and increases blood fatty-acid levels, ensuring that nutrient supply to
growing tissues is adequate. GH deficiency is rare and can be due to hypothalamic
failure causing a lack of GHRH, or pituitary failure causing GH deficiency. It may be
congenital, a consequence of a traumatic head injury, meningitis or other central
nervous system infection, or irradiation. In children, it retards growth and reduces
height (dwarfism), and even though GH levels fall naturally with age, this hormone
seems to be important for normal metabolism and maintenance of body mass in adults.
Excessive GH release in childhood leads to gigantism, with long limbs and unusually tall
adult stature. In adults, however, in whom the growth plates of the limb bones have
closed, growing taller is not possible, and excess GH thickens and enlarges bone and
other connective tissues, a condition called acromegaly. Coarsening of facial features is
characteristic of this disorder, with enlargement of the nose, jaw, hands, and feet.

Somatropin: Recombinant Growth Hormone

GH used in medicine is produced by recombinant DNA technology and is called
somatropin. It is given by injection to treat GH deficiency in children or adults.
Adverse effects include carpal tunnel syndrome, painful joints and muscles, and
localised loss of adipose tissue, all of which are caused by the hormone mobilising
nutrient stores and stimulating tissue growth.

Somatostatin
SST inhibits GH release, and therefore reduces cell division and tissue growth. It also
suppresses the secretion of a range of digestive enzymes and hormones, including
insulin, gastrin, and pancreatic enzymes, which enhance its anti-growth activity.

Somatostatin Analogues
Lanerotide and octreotide are synthetic analogues of SST given by subcutaneous or
intramuscular injection to treat conditions associated with excessive GH activity, e.g.
acromegaly. They are also used in a range of conditions featuring excessive secretion of
gastrointestinal (GI) hormones, including GI tumours. Unsurprisingly, their main
adverse effects involve the GI tract and metabolic function, and include nausea,
vomiting, abdominal pain, diarrhoea, and impaired glucose tolerance. They also
increase the risk of gallstones because they reduce the release of cholecystokinin, which
triggers gallbladder contraction. In its absence, the gallbladder empties more slowly and
less frequently, allowing bile to stagnate and increasing the risk of stone formation.

Gonadotropin-Releasing Hormone, Luteinising Hormone, and Follicle-

Stimulating Hormone
GnRH stimulates pituitary release of LH and FSH in both males and females. It is
secreted in pulses rather than continuously, allowing blood levels to regularly fall, which
preserves the responsiveness of its receptors on the pituitary gland. LH and FSH control
the synthesis and release of male and female sex steroids (mainly testosterone in men
and oestrogen in women). The role of LH and FSH in female fertility and the drugs used
in contraception, fertility treatment, and the management of menopausal symptoms are
discussed below.

Gonadorelin
Gonadorelin is a synthetic preparation of GnRH used to test pituitary function. It is
administered by either intravenous or subcutaneous injection and the pituitary response
assessed by measuring plasma LH levels at set time intervals over the following 2 hours.

Gonadotropin-Releasing Hormone Analogues

This group of drugs includes goserelin and buserelin. They are structurally very
similar to GnRH and initially stimulate pituitary release of LH and FSH, which in turn
causes a short-lived surge of sex steroids. However, once steady-state drug levels are
achieved in the plasma, the GnRH receptors on the pituitary gland are rapidly
desensitised, because they are now being continually stimulated. This is unlike the
natural pulsatile secretion pattern, which allows plasma levels to fall in between peak
levels. The pituitary therefore stops responding, LH and FSH levels fall, and in turn,
testosterone and oestrogen levels fall. This is useful in conditions associated with
unwanted effects of these hormones: for example, many prostate cancers are
testosterone-dependent, and reducing testosterone levels is therapeutically beneficial.
Similarly, in oestrogen-dependent breast cancer, these drugs reduce oestrogen levels,
inhibit tumour growth, delay recurrence, and increase survival times. In general, these
drugs have short half-lives and are often given as depot formulations, which provide
slow and steady drug release that can maintain blood levels for several months,
depending on the preparation. Adverse effects are mainly due to the loss of sex
hormones. Both sexes may experience reduced libido; women develop menopausal
symptoms, and men may develop feminisation characteristics, e.g. gynaecomastia.

Posterior Pituitary Hormones

ADH (vasopressin) and oxytocin are almost identical small peptides composed of nine
amino acids, whose structures differ by a single amino acid. This explains the overlap in
their pharmacological effects: for example, both cause smooth muscle contraction.

AntiDiuretic Hormone
ADH increases water re-absorption by the kidney, which increases blood volume and
blood pressure. The stimulus for ADH release is a rise in plasma osmolarity, i.e. an
increase in the plasma concentration, or a reduction in plasma volume. ADH’s target
tissues are the proximal convoluted tubule and collecting ducts of the renal nephron, the
regions of the tubule mainly responsible for water re-absorption. ADH increases the
number of water channels in the wall of the nephron, increasing water re-absorption
into the bloodstream. The plasma osmolarity therefore falls as the plasma becomes
more dilute, the blood volume rises, and a smaller, more concentrated volume of urine is
passed. ADH also causes vasoconstriction, increasing blood pressure. It also reduces
bleeding time by activating platelets and stimulating clotting. ADH itself is sometimes
used to treat diabetes insipidus, a condition characterised by inadequate ADH secretion.

Synthetic Antidiuretic Analogues

Examples: desmopressin, terlipressin, felypressin
Desmopressin is more potent than ADH and is given by nasal spray to reduce
overnight urine production in children or adults who experience nocturnal enuresis
(bedwetting). It is also used in diabetes insipidus. Terlipressin has less ADH activity
than desmopressin but has more vasoconstrictor and pro-coagulant activity. It is used
intravenously to stop bleeding and prevent hypotension in bleeding oesophageal varices.
Felypressin is an effective and short-acting vasoconstrictor co-injected with local
anaesthetic to reduce loss of the anaesthetic from the site and prolong its action.

Oxytocin
Oxytocin stimulates uterine contractions during childbirth and milk ejection during
lactation and is important in a range of behaviours including eating, social interactions,
and developing relationships, including establishing the parent-child bond. Synthetic
oxytocin is given by intravenous infusion to induce and speed up labour when medically
indicated and to prevent and treat post-partum haemorrhage. It can cause fluid
retention because of its ADH-like activity, which can dilute body fluids and cause
hyponatraemia.

Drugs and Thyroid Function

The thyroid gland secretes two structurally closely related hormones: T4 and T3, which
have essentially the same function. T4 accounts for about 93% of the gland’s output, but
once released most of it is converted in the tissues to T3, which is metabolically much
more active. The thyroid gland is composed of large storage areas called follicles, each
full of a high-molecular-weight substance called thyroglobulin, which is produced by
linking together molecules of the amino acid tyrosine. Specialised iodide pumps in the
membranes of the cells forming the walls of the follicles actively extract iodine from the
bloodstream. The iodine is then added to tyrosine by the enzyme thyroid peroxidase
(Fig. 5.5). If a tyrosine molecule has one iodide unit attached, it is called mono-
iodotyrosine, and if it has two, it is called di-iodotyrosine. To release T3 and T4 from the
thyroglobulin superstructure, enzymes clip off the tyrosine residues in pairs. If the
released molecule is made of two di-iodotyrosine units, the resulting molecule, with four
iodine atoms, is T4; if it is made of a di-iodotyrosine unit and a mono-iodotyrosine unit,
it is T3.
In addition, C-cells embedded in the thyroid gland release calcitonin.
 FIG. 5.5 The synthesis of thyroid hormones.

Functions of Tri-Iodothyronine and Thyroxine

These hormones increase protein synthesis and metabolic activity in nearly all body
cells. They cross the plasma membrane, enter the cell nucleus, bind to specific genes
within the cell’s DNA, and activate them. This leads to the production of structural
proteins, enzymes, growth factors, and other substances required for cellular activity. T3
and T4 are therefore essential for growth and metabolism in all body tissues.

Key Points: Physiological Effects of Thyroid Hormones

Thyroid hormones increase heart rate, cardiac contractility, and blood pressure;
stimulate respiration; and are essential for normal libido and sexual function. They
increase cell division, basal metabolic rate, blood glucose levels, and the body’s
requirement for nutrients and oxygen; they trigger weight loss and increase
gastrointestinal activity. Deficiency during fetal development, infancy, or childhood
causes significant growth retardation and disrupts normal neurological development,
including impairment of cognitive development.

The plasma half-life of thyroxine is 5–7 days, but T3’s half-life is 24 hours.

Functions of Calcitonin
Calcitonin reduces plasma calcium levels, opposing the effects of parathormone from
the parathyroid glands. Its influence on plasma calcium levels is, however, thought to be
relatively minor.

Hypothyroidism
Underactivity of the thyroid gland, hypothyroidism, is common. The most common
cause, Hashimoto’s disease, is an autoimmune disorder in which autoantibodies are
produced to thyroid gland TSH receptors. The autoantibodies bind to and block the
receptor, meaning that the thyroid gland cannot respond to TSH from the anterior
pituitary, and thyroid hormone release falls. Other causes include a diet low in iodine,
reversible with iodine supplements, and congenital hypothyroidism. Hypothyroidism
also often follows antithyroid treatment for hyperthyroidism. In hypothyroid states
caused by thyroid failure, plasma T4 levels are low, but TRH and TSH levels can be
significantly elevated because the hypothalamus and pituitary try to stimulate the failing
thyroid to secrete additional T4. Characteristic signs and symptoms of an underactive
thyroid are listed in Box 5.1.

Drug Treatment in Hypothyroidism

The standard treatment for hypothyroidism is thyroid hormone replacement. Care must
be taken in patients with cardiovascular disease or cardiovascular risk factors because
thyroid hormones increase cardiac workload and blood pressure. In these people,
treatment is started at a lower dose than normal and titrated upwards with care and
regular cardiovascular monitoring. Care must also be taken in diabetes because the
increased metabolic rate associated with T4 is accompanied by hyperglycaemia; any
antidiabetic medications, including insulin, may need to be increased.

Levothyroxine
This is the standard treatment for hypothyroidism. It is a synthetic drug, prepared as the
sodium salt of the natural hormone and converted to T3 in peripheral tissues.

B ox 5. 1 Charac teristic Signs and Symptoms of Underac tive

and Overac tive Thyroid

Underactive Thyroid Overactive Thyroid

Decreased metabolic rate and weight Increased metabolic rate and weight
gain loss
 Cold intolerance Heat intolerance
Lethargy, fatigue, and apathy Irritability, fatigue, and inability to sit
still
Excessive sleepiness and sleep Insomnia
Mental impairment Inability to concentrate
Reduced libido and menorrhagia Reduced libido and amenorrhoea
Bradycardia and hypotension Tachycardia, palpitations, and
hypertension
Slow speech and hoarse, deep voice Tremor
Myxoedema (thickening of the skin) Exophthalmos (protrusion of the
eyeballs)
Dry skin and hair loss Excessive sweating and hair loss
Constipation Diarrhoea

Pharmacokinetics
Levothyroxine is given orally and moderately well absorbed. Absorption is reduced or
slowed in the presence of food and when gastric pH is higher than normal, e.g. in people
taking antacid medications. Levothyroxine has a long half-life, usually over a week in
hypothyroid patients, so it equilibrates slowly and can take several weeks to reach a
stable steady state. It is almost completely bound to T4-binding globulin, the plasma
protein responsible for transporting it in the bloodstream, which contributes to its long
half-life. It is metabolised in body tissues to T3 by removal of an iodine atom and from
there to inactive products.

Liothyronine
Synthetic T3 is available, also as a sodium salt, as the drug liothyronine. It has a much
shorter half-life than levothyroxine, usually less than 24 hours, and its onset of action is
faster. These properties mean that it is preferred to levothyroxine in acute or severe
hypothyroid states.

Adverse Effects
Excessive doses of levothyroxine or liothyronine give the same physiological effects as
the natural hormone. Cardiovascular stimulation can cause tachycardia, palpitations,
arrhythmias, and hypertension. There may be diarrhoea, weight loss, heat intolerance,
sweating, insomnia, tremor, and menstrual disturbances. Levothyroxine crosses the
placenta and can affect the fetus, so should be used very cautiously in pregnancy.

Hyperthyroidism
Overactivity of the thyroid gland, hyperthyroidism (thyrotoxicosis), is common. The
most common cause, Graves’ disease, is an autoimmune disorder in which
autoantibodies are produced to the TSH receptor on the thyroid gland. These
autoantibodies bind to and stimulate the TSH receptor, triggering thyroid hormone
production. Exophthalmos, protrusion of the eyeballs due to deposition of extracellular
matrix at the back of the eye sockets, is a characteristic of Graves’ disease. Other causes
of hyperthyroidism include toxic nodular goitre caused by a benign functional thyroid
tumour, which releases large quantities of thyroid hormone. Some drugs can also cause
hyperthyroidism; e.g. the antiarrhythmic agent amiodarone (p. 137) is structurally
similar to T4 and contains significant quantities of iodine: a 200 mg tablet (the usual
daily maintenance dose) delivers 75 mg of iodine. For reference, the daily recommended
iodine intake is only 0.14 mg/day.

Drug Treatment in Hyperthyroidism

Pharmacological treatment of hyperthyroidism may be used to reduce the size of an
enlarged gland (goitre) in preparation for surgery. Because the gland is very vascular,
shrinking it reduces the risk of bleeding during the procedure. It may also be used as
maintenance therapy.

Carbimazole
Like the similar agent propylthiouracil, carbimazole inhibits the enzyme thyroid
peroxidase, which catalyses the addition of iodine to tyrosine in thyroglobulin (Fig.
5.5), blocking the production of thyroid hormone. There is also evidence that these
drugs reduce levels of the anti-TSH receptor antibody that stimulates T4 production in
Graves’ disease. They are taken orally and metabolised in the liver.

Pharmacokinetics
Carbimazole is a pro-drug, converted in the bloodstream to the active agent
thiamazole. Both thiamazole and propylthiouracil are taken up and concentrated in
the thyroid gland. This means that although their plasma half-lives are relatively
short––carbimazole has a half-life of around 5 hours and propylthiouracil’s half-life is
even shorter––their effective duration of action is much longer. It can take several
weeks of treatment with carbimazole for thyroid hormone levels to fall to normal
(become euthyroid) because the half-life of T4 is so long, and there are usually
substantial T4 stores in the thyroid follicles that take some time to be used up.

Adverse Effects
The most significant adverse effect of these agents is bone marrow suppression, more
commonly with propylthiouracil than carbimazole. Although this is rare, it can cause a
rapid fall in white blood cell numbers with significant immunocompromise. Patients
must be warned to report any signs of infection, e.g. fever or sore throat. Bone marrow
function usually returns if the drug is stopped.

Radioactive Iodine
The radioactive isotope of iodine, 131I, given orally, is treated by the thyroid in exactly
the same way as the stable form: that is, it is rapidly and actively extracted by iodide
pumps in cell membranes of the thyroid cells, and built into thyroglobulin to form
mono-iodotyrosine and di-iodotyrosine. It emits radiation in the form of β particles,
which have a very short range, so that although over time they kill the thyroid gland
cells, they do not damage other local tissues. Because this agent permanently destroys
the glandular function of the thyroid, individuals invariably become hypothyroid and
need T4 replacement therapy.

Drugs and Pancreatic Function

The pancreas is mainly composed of exocrine tissue, which produces digestive enzymes
that are secreted into the duodenum to digest fats, carbohydrates, and proteins.
Additionally, scattered throughout the pancreatic tissue are nests of cells called islets,
which are endocrine in function and produce insulin and glucagon, hormones essential
for the body’s metabolic use and storage of nutrients, especially glucose. Islets comprise
only 2% of the mass of the gland but are richly supplied with blood vessels to carry their
hormone products away, and with autonomic nerves to regulate hormone production.

Insulin
Insulin is an anabolic hormone; its overarching function in metabolism is in
conservation and storage of energy-rich nutrients. It stimulates body cells to remove
glucose, fats, and amino acids from the bloodstream to use in energy production;
promotes the storage of excess fuel molecules as glycogen or fat; and increases protein
synthesis. It is a small-molecular-weight peptide composed of 52 amino acids,
synthesised in β-cells within pancreatic islets. The main stimulus for its release is rising
blood glucose, but an increase in blood levels of fatty acids and/or amino acids has the
same effect. Insulin therefore reduces circulating blood glucose––a hypoglycaemic
effect––and levels of other nutrients. Liver, skeletal muscle, and fat are the most
insulin-responsive tissues.

Glucagon
Glucagon is synthesised by ⍺-cells in the pancreatic islets, and the main stimulus for its
release is falling blood glucose levels. Falling blood fatty-acid levels also increase
glucagon secretion. It stimulates glycogen breakdown in the liver, releasing glucose, and
breakdown of adipose and muscle tissue, releasing fatty acids and amino acids,
respectively. Its metabolic actions therefore oppose those of insulin, and it is given
subcutaneously, intravenously, or intramuscularly to increase blood glucose levels in
insulin-induced hypoglycaemia. Glucagon also has an adrenaline-like effect on the heart
and is used to improve cardiac function in shock caused by β-blocker overdose. It can
cause vomiting, so it is important to protect the airway in unconscious patients treated
with glucagon.

Diabetes Mellitus
Diabetes mellitus (DM) is a very common condition characterised by high blood glucose
levels, as well as an inability of body cells to respond appropriately to insulin (insulin
resistance) and/or an absolute insulin deficiency. Without insulin, cells cannot import
glucose no matter how much is available in the blood and are forced to rely on other
energy molecules such as fats and amino acids. This is tolerable in the short term but
unsustainable in the long term. The discovery that the pancreas is the source of the
agent that prevents diabetes was made in 1890 when the pancreas was removed from a
dog, which rapidly developed diabetes and died. It was over 30 years following that
important discovery before the first clinical use of insulin. Prior to this, type 1 diabetes
(T1D), usually presenting in childhood, invariably led to a slow, miserable, wasting
death within a year or two of diagnosis. In 1922, a team of researchers in Toronto, led by
Frederick Banting, Charles Best, and John MacLeod, treated a ward of seriously ill
diabetic children with pancreatic extracts, with dramatic and immediate success:
comatose children were restored to full consciousness, and children facing imminent
and inevitable death were, to all intents and purposes, cured. Fig. 5.6 shows the
dramatic difference in a diabetic child before and after starting treatment with insulin.
Although life expectancy in DM is shorter than average, continuing improvements in
management, including better pharmacological treatment, is slowly closing the gap.

FIG. 5.6 An early insulin success story.The anabolic effects of

insulin are clearly seen in a diabetic child pre-treatment (left image)
and following treatment (right image). Reproduced with permission
from Eli Lilly and Company archives.

The Action of Insulin on Body Cells

Glucose is the cells’ preferred fuel molecule, and without insulin, they cannot extract it
from the bloodstream and so are deprived of their main energy source. Most body cells
express insulin receptors on their plasma membrane, although brain neurones take up
glucose using an insulin-independent mechanism. Insulin binding to its receptor
triggers a range of cellular effects, including an increased number of glucose
transporters (GLUTs) at the cell surface, through which the cell then actively imports
glucose from the extracellular fluid surrounding it. In addition to ensuring that all body
cells can import the glucose and other nutrients they need, insulin allows liver and
muscle cells to extract excess glucose from the bloodstream and convert it to glycogen
for storage. Glycogen storage capacity is limited, and when glycogen stores are full,
insulin allows cells to convert glucose to fat for storage in adipose tissue. Insulin
increases the uptake of amino acids into muscle, converts them into protein, and
promotes the storage of fats in adipose tissue. In liver cells, insulin prevents
gluconeogenesis, the conversion of non-carbohydrate molecules, mainly fats and amino
acids, into glucose.

Control of Insulin Secretion

The β-cells in the pancreas constantly monitor blood glucose levels. Their plasma
membranes contain a large number of GLUT-2 glucose transporters which permit
glucose to enter the cell (Fig. 5.7). The higher the blood glucose level, the more glucose
enters the β-cell, where it is used to generate ATP. ATP in turn shuts potassium
channels in the β-cell membrane, so that potassium cannot leave the cell, and potassium
levels in the cell rise. This activates (depolarises) the cell membrane, which in turn
opens membrane calcium channels and allows calcium to enter. Rising intracellular
calcium triggers fusion of insulin storage vesicles with the cell membrane and secretion
of insulin into the bloodstream. Some antidiabetic drugs enhance insulin release by
interfering with one or more components of this mechanism: for example,
sulphonylureas (e.g. glibenclamide) directly block potassium channels in the β-cell
membrane, depolarising the cell and stimulating insulin release.
Basal blood insulin levels are low in the fasting state but rapidly increase up to 10-fold
in the minutes following a nutrient-rich meal. This initial peak is stimulated most
strongly by rising blood glucose, but fatty acids and amino acids also trigger it. It
represents release of stored insulin, which is quickly depleted. However, after an initial
fall, insulin levels rapidly rise again as the pancreas produces and releases new insulin,
and they remain high until blood glucose levels are brought back within the normal
range (Fig. 5.8). Autonomic nervous system activity also influences insulin release.
Physiological stress, rising blood glucocorticoids, and sympathetic nervous system
activity inhibit insulin release; this allows blood glucose levels to rise, ensuring that
body cells have an adequate glucose supply to meet potentially increased requirements.
Parasympathetic nervous system activity, associated with rest, low physical activity, and
low physiological stress levels, increases insulin levels and promotes the packaging away
of blood-borne nutrients into storage areas.
FIG. 5.7 Mechanism of insulin release by pancreatic β-cells.1,
Rising blood glucose increases glucose entry into the β-cell. 2, This
generates large quantities of ATP, closes potassium channels, and
depolarises the cell. 3: Depolarisation of the cell opens calcium
channels, increasing calcium entry and stimulating insulin
release. Modified from Vaz M, Kurpad A, and Raj T (2020) Guyton
and Hall textbook of medical physiology, 3rd SAE ed, Fig. 93.6. New
Delhi: Elsevier India.
 FIG. 5.8 Blood insulin levels following glucose administration.First
phase represents release of pre-formed insulin, and second phase
represents release of newly synthesised insulin. Modified from
Penman ID, Ralston SH, Strachan MWJ, et al. (2023) Davidson’s
principles and practice of medicine, 24th ed, Fig. 21.4. Edinburgh:
Elsevier.

Insulin release is also stimulated by hormones released by the GI tract during eating.
This explains the perhaps unexpected observation that consuming glucose by mouth
raises blood insulin levels faster than an intravenous glucose infusion. GI hormones that
increase insulin release are collectively called incretins and include glucagon-like
peptide 1 (GLP-1). Their blood levels rise when foodstuffs enter the GI tract and
stimulate insulin release in anticipation of rising blood sugar levels as the products of
digestion are absorbed (Fig. 5.9). Some antidiabetic drugs, e.g. liraglutide, stimulate
insulin release by mimicking the action of incretins, i.e. act as incretin agonists.
Following their release, incretins are rapidly destroyed by the enzyme dipeptidyl
peptidase (DPP-4). The gliptins, including linagliptin and vildagliptin, inhibit DPP-
4, protecting incretins from destruction and therefore increasing insulin release.
 Fig. 5.10 summarises the main factors controlling blood insulin levels.

Energy Metabolism in Diabetes

In the absence of insulin, cellular metabolism is forced to switch from using glucose as
an energy source to using fats instead. Adipose tissue is broken down, and the individual
loses weight. Blood lipid levels rise, contributing significantly to the increased risk of
cardiovascular disease associated with DM. To release the energy they require, cells
deprived of glucose metabolise fats, producing ketone bodies (acetoacetic acid, β-
hydroxybutyric acid, and acetone), which body cells can use for fuel. This is the normal
route by which fats are broken down: for example, in a low-calorie diet for weight loss,
stored body fat is burned this way for energy. In non-diabetic people, the body’s energy
balance is maintained using both fats and carbohydrates as energy sources, but in DM,
fat breakdown becomes disproportionately important because the cells have no access to
glucose. Large quantities of ketone bodies are manufactured, causing ketosis and a
metabolic acidosis. Acute ketoacidosis is a medical emergency and can be fatal unless
rapidly treated.

FIG. 5.9 The role of incretins in insulin release.

Signs and Symptoms of Diabetes

Hyperglycaemia is characteristic. Glucose appears in the urine (glycosuria) because the
renal threshold for glucose is exceeded. Glucose is a small molecule that is filtered out of
the blood as it flows through the glomerulus and appears in the filtrate. Provided
glucose levels are not excessive, GLUTs in the nephron re-absorb it all back into the
bloodstream, and none appears in the urine. However, in DM, there is so much glucose
in the blood that the glucose load appearing in the filtrate is excessive. The GLUTs in the
kidney tubule are saturated, and their capacity to re-absorb glucose is exceeded, leading
to glycosuria. Glucose in the urine increases its osmolarity, drawing water with it and
causing dehydration and thirst. Body fat and protein stores are broken down to release
alternative fuel molecules to glucose, so there is weight loss and muscle wasting. Over
time, hyperglycaemia damages small blood vessels, partly because structural
components within their walls, e.g. collagen, take up glucose and form advanced
glycation end-products. The tiny blood vessels of the renal glomerulus are particularly
susceptible, and renal disease is very common in diabetes. Retinal capillaries and the
tiny blood vessels supplying nerves are also commonly affected, causing diabetic
neuropathy. In addition to these microvascular changes, large blood vessels are
progressively damaged by the hyperlipidaemia associated with diabetes, with
atherosclerosis, hypertension, and increased risk of thrombosis. The risk of myocardial
infarction and stroke are consequently increased. There are a few different forms of DM,
but the two most common are type 1 and type 2.

FIG. 5.10 The main factors controlling blood insulin levels.

Type 1 Diabetes
This form usually manifests in childhood. The pancreatic islets are progressively
destroyed, usually by an autoimmune reaction, and so the child’s pancreas stops
producing insulin. This is called absolute insulin deficiency, and the cornerstone of
treatment is insulin replacement. The aim of treatment is to stabilise blood glucose
levels, minimising hyperglycaemia and therefore reducing long-term cardiovascular
risk, but also avoiding potentially dangerous hypoglycaemia.

Type 2 Diabetes
This is associated with adult-age onset and obesity, and although the individual usually
continues to produce some insulin of their own (so-called relative insulin deficiency),
the cellular response to insulin is abnormal. Overeating and obesity are associated with
sustained elevated blood insulin levels, because constantly high blood nutrient levels
stimulate insulin release (Fig. 5.10). Over time, it is thought that the continual
exposure of insulin receptors on body cells to elevated insulin levels desensitises them
and disrupts the normal biochemistry of the cellular response to insulin. This is called
insulin resistance. Although type 2 diabetes (T2D) is treated with a range of drugs to
increase pancreatic release of insulin or to improve the cellular response to insulin,
many people eventually require supplementary insulin treatment too. Because these
patients usually produce at least some insulin, hypoglycaemic episodes are much less
likely than in T1D, and the main management goal is to minimise postprandial
hyperglycaemia to minimise long-term cardiovascular risk.

Insulin
Insulin cannot be given orally because it is a small peptide and is rapidly digested in the
stomach. It is generally given subcutaneously in maintenance treatment but can be
given intravenously or intramuscularly if a faster effect is needed. Its plasma half-life is
short––about 10 minutes––and it is metabolised in the liver to inactive products which
are excreted in the urine. The molecular action of insulin is described above, but there is
now a range of modified insulins which vary in their onset and duration of action, and
which can be combined in individualised and flexible treatment regimes. Insulin
molecules tend to assemble themselves into stable hexamers (six insulin molecules
grouped around zinc ions); they are found in this formation in pancreatic islets and
assemble into hexamers in the tissues following injection. The onset of action of injected
insulin then depends upon how quickly individual insulin molecules are released from
the hexamer structure. Insulin analogues are chemically modified to alter the speed at
which insulin dissociates from the hexamers; rapidly acting insulins dissociate the
fastest and long-acting insulins dissociate much more slowly. Pre-mixed insulins are
available, for example combining an intermediate-acting insulin with a short-acting
insulin, which reduce the number of daily injections required.

Short-Acting Insulins
Examples: soluble insulin, insulin aspart, insulin lispro
Short-acting insulins include soluble insulin, which can be used by regular
injections or by infusion. Insulin is absorbed slowly from its injection site due to the
assemblage of insulin hexamers in the tissue. Insulin aspart and insulin lispro are
modified insulins, in which very minor alterations to the structure of the insulin
molecule increase its release from the hexamers without reducing its pharmacological
activity. They therefore act more quickly than soluble insulin but have a shorter duration
of action.

Intermediate Insulins
Examples: isophane insulin
Isophane insulin is produced by treating soluble insulin with zinc and protamine. This
reduces its solubility at physiological pH and slows its release into the bloodstream,
avoiding a peak, and prolongs its action; it can be effective for up to 24 hours. Biphasic
insulin is produced by combining soluble insulin with isophane insulin, giving a
pre-mixed preparation that provides both short- and medium-term blood glucose
control.

Long-Acting Insulins
Examples: insulin glargine, insulin detemir, insulin degludec
Long-acting insulins are insulin analogues with very minor alterations to the amino-
acid structure. These structural changes reduce solubility, slow absorption from the
injection site, and extend their duration of action: this avoids a peak. Insulin glargine
is soluble at pH 4, and when injected into the tissues, which are pH-neutral, it loses
solubility and precipitates out as microcrystals from which it is slowly released into the
bloodstream. It takes over an hour before onset of action, but it is active for 24 hours,
providing the equivalent of naturally secreted basal insulin. Insulin detemir has fatty-
acid residues bound to the peptide structure, which promote hexamer formation and
slow its absorption, and increase its binding to plasma proteins, both of which extend its
duration of action. Insulin degludec also has a fatty-acid residue attached, which
causes it to precipitate out in the tissues after injection and slows its release into the
bloodstream.

Basal Bolus Regimes

Traditional insulin treatment plans involve regular insulin injections prior to mealtimes,
with insulin dose based on blood glucose readings. Once the insulin is administered, the
planned meal must be eaten, or hypoglycaemia will ensue. This is inflexible and does not
give optimal control. Basal bolus therapy is designed to mimic the body’s natural insulin
release patterns. A long- or intermediate-acting insulin is injected once a day to deliver
basal levels and ensure that there is always insulin in the bloodstream, and fast-acting
insulins are used just before, during, or just after meals to deal with rising blood
nutrient levels. Although it requires good patient education and motivation and multiple
injections, when used well, it optimises blood glucose control and minimises the
hyperglycaemia that causes long-term vascular damage.

Adverse Effects
The most frequent and most dangerous side-effect of insulin treatment, especially
hazardous at night, is hypoglycaemia, which may be caused by insulin overdose,
unexpected exercise, or inadequate food intake. Because the brain is highly dependent
on glucose for fuel, hypoglycaemia causes confusion, impaired cognitive function,
reduced conscious levels, and coma, and is potentially lethal. Falling blood glucose
activates a sympathetic nervous system response and adrenaline release, which usually
acts as an early warning of an impending hypoglycaemic episode, although not all
people experience this and hypoglycaemia can develop without warning. Regular
injections at the same site can cause a local accumulation of subcutaneous fat because of
the anabolic action of insulin. Occasionally, adipose tissue can break down (lipoatrophy)
around a site that is overused for injection, thought to be due to an immunologically
mediated tissue damage. Using a range of injection sites (usually the abdomen and
thigh) and not using the same site repeatedly helps to prevent these permanent tissue
changes. Although initial management of T2D does not include insulin because most
people with this form of diabetes produce some insulin of their own, about 50% of
people eventually require insulin treatment. Insulin in T2D causes weight gain and
increases cardiovascular risk, and its benefits should be weighed against this when
deciding whether to add insulin to a treatment regimen.

Inhaled Insulin
The discomfort and inconvenience of multiple daily injections drove the search for
alternative routes of insulin administration, and most work has been done in inhaled
insulin. The alveoli of the lungs are very thin-walled and richly supplied with blood
vessels and offer a very large surface area for drug absorption. Inhalable insulin is
formulated as a powder to be delivered as an aerosol via an inhaler device. It was first
licensed in the USA in 2006 by Pfizer, but it did not sell well mainly because of its cost.
Although it acts more rapidly than even the fastest-acting injected insulin, which could
in theory increase a patient’s ability to control post-prandial hyperglycaemia, it is
difficult to achieve precise dosing because pulmonary absorption may be unpredictable,
and repeated dosing may be needed to control post-prandial hyperglycaemia. Inhaled
insulin is not currently available on the National Health Service in the UK.

Non-Insulin AntiDiabetic Drugs

The mechanisms of action of the main groups of non-insulin antidiabetic drugs are
summarised in Fig. 5.11. Note that some drugs have more than one antidiabetic action.

Metformin
Chemically, metformin is a biguanide, derived from a chemical found in French lilac,
extracts of which were used in mediaeval Europe to treat diabetes. A range of biguanides
was developed in the 1920s, but metformin is the only survivor in clinical use, the others
having been discarded because they caused lactic acidosis. Metformin is frequently the
first choice of treatment in newly diagnosed T2D, and globally is the most common oral
antidiabetic drug. It has a range of actions that contribute to its hypoglycaemic action
(Fig. 5.11). It is an insulin sensitiser: that is, it enhances the effects of insulin and so it
is ineffective unless there is some circulating insulin present. It reduces glucose
absorption from the GI tract, inhibits glucose re-absorption in the kidneys, reduces
glucose production in the liver, and increases the uptake of glucose in body tissues,
including skeletal muscle. It enters body cells and accumulates in mitochondria, the
organelles responsible for energy metabolism, where it interferes with energy pathways,
leading to the effects described above. Unlike some other antidiabetic drugs, metformin
does not cause weight gain, so is particularly useful in overweight and obese patients,
and does not cause hypoglycaemia. There is also evidence that metformin reduces total
plasma cholesterol and low-density lipoprotein (LDL) cholesterol, both risk factors for
cardiovascular disease. Such an improvement in blood lipid profiles is likely to be
significantly beneficial in diabetes because of the increased risk of cardiovascular
disease. In many patients, metformin used as monotherapy gives good glycaemic
control, especially in milder disease. It can also be usefully combined with other
antidiabetic agents if required; with time and progressive deterioration of islet function,
second-line agents frequently need to be added to maintain good blood glucose control.

FIG. 5.11 Mechanism of action of non-insulin antidiabetic drugs.

Pharmacokinetics
The half-life of metformin is about 5 hours, and there are modified-release preparations
that extend this up to 8 hours. It is not metabolised in the liver, and is excreted largely
unchanged in the urine, so renal function must be assessed regularly to ensure that the
drug is not accumulating. In severely reduced renal function, it should be avoided
altogether.

Adverse Effects
Metformin reduces the uptake of the waste product lactate from the bloodstream by
liver cells. This can significantly increase blood lactate levels and precipitate lactic
acidosis, most commonly in older adults and in those with poor renal function. Poor
cardiac function also increases risk because it leads to hypoxia, and without adequate
oxygen, cells respire anaerobically, producing excess lactate. Liver disease can also
increase blood lactate and the drug should be avoided in severe liver impairment. Lactic
acidosis is fortunately a rare side-effect, but it can be fatal. Most other side-effects of
metformin are relatively mild and usually improve with time: they include a metallic
taste in the mouth, nausea, and diarrhoea, which may be reduced by taking with food.

Sulphonylureas
Examples: glibenclamide, gliclazide, glipizide
The sulphonylureas are chemically related to the sulphonamides, a group of
antimicrobial agents introduced in 1935 which caused hypoglycaemia as an unexpected
side-effect: this led to the development and introduction of tolbutamide, the first
sulphonylurea, in the 1950s. Tolbutamide remains in current use, although newer
agents like glibenclamide are more potent. Sulphonylureas increase insulin release by
the pancreas by blocking potassium channels in islet β-cells (Fig. 5.7). They are
therefore only effective if there are functioning β-cells in the pancreatic islets, and they
enhance both phases of insulin release: that is, the initial spike of pre-formed insulin
and release of newly synthesised insulin. Although they have traditionally been
considered the first choice when supplementation of metformin treatment is needed and
are generally well tolerated, DPP-4 inhibitors are now considered a superior option
because they have fewer side-effects.

Pharmacokinetics
Sulphonylureas are taken orally and absorbed well, although food in the GI tract slows
absorption. They bind extensively to plasma proteins and compete with other highly
bound drugs (e.g. warfarin, aspirin) for binding sites, and this is an important cause
of sulphonylurea-mediated interactions. Dose adjustment may therefore be necessary
when such drug combinations are used. Different drugs in this class have different half-
lives and duration of action, and increasing either increases the likelihood of
hypoglycaemia. For example, glibenclamide has a long half-life of over 10 hours and
produces an active metabolite, so it is particularly long-acting (sometimes more than 24
hours) and is prone to causing hypoglycaemia, especially at night and in older people.
Glimepiride has a shorter half-life (5–8 hours), but because it too produces an active
metabolite, its duration of action is 12–24 hours. Glipizide has a half-life of only 2–4
hours, produces no active metabolites, and is one of the shorter-acting agents in this
group. Although tolbutamide is the oldest and least potent drug in this group, it has a
short half-life (4 hours), meaning that there is little or no risk of hypoglycaemia. Most
sulphonylureas are excreted by the kidney, so they must be used with caution if there is
any degree of renal compromise.
When sulphonylureas are used with a number of other drugs, including alcohol,
some antifungals, some antibiotics, and non-steroidal anti-inflammatory
drugs, severe hypoglycaemia can occur. The basis of this interaction is probably caused
by inhibition of metabolising enzymes, meaning that metabolism and clearance of the
sulphonylurea is reduced and so its hypoglycaemic effect is enhanced.

Adverse Effects
Most sulphonylureas cross the placenta and appear in breast milk and should not be
used in pregnancy or by breast-feeding mothers. They usually cause weight gain, so they
must be used cautiously in overweight or obese people. Hypoglycaemia is a common
side-effect, especially with longer-acting agents. Long-term use may increase the risk of
cardiovascular disease, particularly concerning in DM. Less severe, although still
troublesome, side-effects include allergic rashes and GI upset.

Meglitinides
Examples: nateglinide, repaglinide
This group of drugs is chemically closely related to the sulphonylureas and work in
the same way, i.e. they block potassium channels in the β-cell membrane and increase
insulin release from the pancreas. They are faster acting and have a shorter duration of
action than the sulphonylureas, with a half-life of less than 2 hours, so they are less
likely to cause hypoglycaemia. Because they are short-acting, they can be used to reduce
post-prandial hyperglycaemia when metformin or the sulphonylureas are not
adequate. Other than hypoglycaemia, their main side-effects include diarrhoea and
abdominal discomfort.

Glitazones
Examples: pioglitazone, rosiglitazone
These are also called thiazolidinediones and are classed as insulin sensitisers because
they increase cells’ ability to respond to insulin. They reduce blood glucose levels by
increasing its uptake into body cells, particularly skeletal muscle and fat. Pioglitazone
is the only member of this group currently used in the UK, other glitazones having been
discontinued due to significant side-effects.

Pharmacokinetics
The onset of action is slow and maximal hypoglycaemic effects may not be seen for up to
8 weeks. Pioglitazone is over 99% bound to plasma proteins and is extensively
metabolised in the liver, producing active metabolites. Its plasma half-life is between 5
and 7 hours, but the active metabolites can significantly extend its duration of action. It
is mainly excreted in the faeces (less than 30% is excreted in the urine). It has a
beneficial effect on blood lipids, increasing levels of ‘good’ high-density lipoprotein
(HDL) cholesterol and reducing levels of ‘bad’ very-low-density lipoprotein. It also
reduces other cardiovascular risk factors and inflammatory markers, which in turn
reduces cardiovascular disease in T2D.

Adverse Effects
The side-effects of pioglitazone can be significant. Common adverse effects include
weight gain, caused partly by fat deposition, but it is also likely that fluid retention,
another of its side-effects, contributes. Fluid retention causes oedema and increases
circulating blood volume. Because of this, pioglitazone can precipitate heart failure,
particularly in older patients and people with pre-existing cardiovascular disease, and
when used in conjunction with insulin. There is also evidence that pioglitazone slightly
increases the risk of bladder cancer, especially in high doses and long-term treatment,
and it should be avoided in patients with risk factors for this tumour.

Dipeptidyl Peptidase Inhibitors (Gliptins)

Examples: linagliptin, saxagliptin
The gliptins were first approved in 2009 in the USA for the treatment of T2D. They
work by blocking the breakdown of incretins by the enzyme DPP-4, and because
incretins increase insulin release, when incretin destruction is blocked and incretin
levels rise, insulin secretion is enhanced (Fig. 5.12). They may be used as monotherapy
or in combination with other antidiabetic agents.

Pharmacokinetics
The gliptins have a long duration of action because they bind strongly to DPP-4,
inhibiting it over a prolonged period; they are generally given only once daily. For
example, saxagliptin has a plasma half-life of only 2.5 hours, and its active metabolite
has a half-life of about 3 hours, but its hypoglycaemic action lasts for 24 hours.

Side-Effects
The gliptins can cause headaches, nausea, and abdominal pain. There may be an
increased risk of infections, e.g. urinary tract and upper respiratory tract infection, but
the evidence for this is mixed.

Incretin (Glucagon-Like Peptide 1) Agonists

Examples: exenatide, liraglutide
Incretins, including GLP-1, increase insulin release from the pancreatic β-cells, slow
down gastric emptying, and inhibit glucagon release. Through these actions they reduce
blood glucose levels. GLP-1 itself cannot be used to treat T2D because it is too rapidly
destroyed by DPP-4 to be effective. However, synthetic drugs that bind to and activate
GLP-1 receptors on β-cells, the GLP-1 agonists, mimic this action (Fig. 5.12) and are
used as second-line therapy in combination with other oral antidiabetic drugs and/or
insulin. GLP agonists are associated with a range of beneficial effects, not all of which
are seen with the gliptins, including delayed gastric emptying and reduced appetite
(Fig. 5.13).

Key Point: Discovery of the Glucagon-Like Peptide 1 Agonists

The history of these drugs is interesting. The Gila monster is one of the world’s two
venomous lizards; its bite is extremely painful and produces a range of metabolic and
pro-inflammatory effects in the victim. Analysis of the salivary toxin isolated a
hypoglycaemic agent called exendin-4, chemically and biologically very similar to
glucagon-like peptide 1. From this, the first glucagon-like peptide 1 agonist,
exenatide, was synthesised, becoming clinically available in 2005.

FIG. 5.12 Mechanism of action of the DPP-4 inhibitors and

incretin agonists.DPP-4, Dipeptidyl peptidase.
 FIG. 5.13 Actions of the GLP-1 agonists.GLP-1, glucagon-like
peptide 1 From Penman ID, Ralston SH, Strachan MWJ, et al.
(2023) Davidson’s principles and practice of medicine, 24th ed,
Fig. 21.4. Edinburgh: Elsevier.

Pharmacokinetics
GLP-1 agonists are given by subcutaneous injection, not by mouth, because they are
proteins and are digested in the stomach. The drugs in this group vary significantly in
their duration of action; dulaglutide has a long half-life of approximately 5 days and is
given only once a week, whereas exenatide and liraglutide are given daily.

Adverse Effects
These drugs tend not to cause weight gain because they do not stimulate appetite and
can even help patients lose a little weight. Rarely, they can cause acute pancreatitis, and
patients must be warned to report any relevant signs and symptoms. Commonly, they
cause GI side-effects including abdominal pain, nausea/vomiting, and constipation or
diarrhoea.

Sodium/Glucose Co-Transporter Inhibitors

Examples: canagliflozin, empagliflozin
These drugs reduce blood glucose levels by inhibiting the GLUTs in the renal tubule,
reducing glucose re-absorption from the filtrate into the bloodstream, and therefore
increasing glycosuria (Fig. 5.14). They are very recent additions to the armoury of
antidiabetic agents; the first, dapagliflozin, was first approved in 2012. They are
unlikely to cause hypoglycaemia, and glucose loss in the urine can help weight control.

Pharmacokinetics
Because they have long half-lives, drugs in this group are given once daily.

Adverse Effects
Glycosuria increases the risk of urinary tract and genital infections, and because the
osmotic pressure of the urine is increased, it draws water with it, causing thirst and
dehydration. There is evidence that some sodium/glucose co-transporter 2 inhibitors
(canafliglozin, dapagliflozin, and empagliflozin) can sometimes cause serious
ketoacidosis, and patients taking these agents should be taught to recognise warning
signs, e.g. deep and rapid respiration, sudden weight loss, or a sweet odour to the
breath. This class of drug has also very recently (2017) been associated with an increased
risk of lower-limb amputation, particularly of the toes. The reason for this is not yet
known, but one study has suggested that they decrease blood volume, thickening the
blood and increasing the risk of blood clots. This would reduce tissue perfusion,
especially in the periphery, already likely compromised in T2D.

Acarbose
Acarbose inhibits the enzyme glucosidase, which in the intestine breaks down larger
carbohydrate molecules into glucose for absorption. This delays (but does not prevent)
carbohydrate digestion following eating, so glucose levels in the intestinal brush border
rise more slowly than normal, glucose absorption into the bloodstream is slowed, and
the rapid post-prandial rise in blood sugar levels is flattened. Hyperglycaemic peaks are
therefore reduced or avoided. It is generally used in conjunction with other antidiabetic
agents because it is less effective at controlling blood glucose than other oral antidiabetic
drugs and is usually insufficient on its own. Very little of an oral dose is absorbed into
the bloodstream; most is excreted in the faeces, and the main side-effects include
diarrhoea, abdominal bloating and discomfort, and flatulence. Its blood glucose-
lowering action is not usually profound enough to significantly increase the risk of
hypoglycaemia, but it does increase the overall risk when used with other hypoglycaemic
agents.

FIG. 5.14 Mechanism of action of SGLT-2 inhibitors in type 2

diabetes.SGLT-2, sodium/glucose co-transporter 2; T2D, Type 2
diabetes.

Pharmacological Control of Reproductive Function

Both male and female reproductive function is regulated by key hormones. The main
male sex hormone is testosterone, produced by the Leydig cells in the testis, and the
main female sex hormones are the oestrogens and progesterone, produced mainly by the
ovary. Insufficient or excessive sex hormones can significantly disrupt sexual desire and
activity, and reduce or eliminate fertility, and hormone treatment is used in the
treatment of infertility and to treat conditions associated with hormone deficiency.
Drugs that block sex hormone synthesis or function are used to treat cancers whose
growth is sex hormone–dependent: for example, tamoxifen, an oestrogen receptor
blocker, is a mainstay drug in the treatment of oestrogen-responsive breast cancer.

Key Point: Progesterone or Progestogen?

In this text, progesterone refers to the natural hormone. A progestogen is a synthetic
drug with progesterone-like properties.
 It is worth noting that the sex hormones are not sex-specific: testosterone plays a role
in female physiology, and oestrogens play a role in male physiology.

F oc us on: Sex Hormone Pharmac ology

Structure of the Sex Hormones

The sex hormones are all steroid hormones derived from cholesterol. Because of their
lipid-based structure, they travel easily across biological membranes, including cell
membranes, and so they are generally well absorbed and distribute widely. Their
biosynthetic pathways are interlinked (Fig. 5.15). The steps catalysed by aromatase
and 5⍺-reductase are shown because these enzymes are important therapeutic
targets. Aromatase inhibitors such as anastrozole are used to block oestrogen
production in women with oestrogen-dependent breast cancer, and 5⍺-reductase
inhibitors such as finasteride are used to inhibit growth of the prostate gland in
benign prostatic hyperplasia.
Mechanism of Action of the Sex Hormones
Being highly lipid-soluble, these hormones readily diffuse across cell membranes and
enter the cell cytoplasm, where they bind to a receptor protein. There are about 60 of
these steroid binding proteins, some of which bind oestrogen (oestrogen receptors,
ERs), some that bind progesterone, and some that bind testosterone (androgen
receptors, ARs). These hormone-receptor complexes then travel to the nucleus, where
they bind to specific genes, either activating or deactivating them. Target genes
include those involved in cell growth and division, and the sex steroids are important
in growth and proliferation of a range of body tissues.
Oestrogens
The ovary secretes three main oestrogens: oestradiol (the principal and most potent
oestrogen), oestrone, and oestriol (Fig. 5.15). Oestrogens promote the
development of the secondary sexual characteristics, e.g. growth of axillary and pubic
hair and breast development, initiated at puberty. They stimulate cell growth and
division in tissues that express oestrogen receptors, e.g. breast and uterine lining.
This mitogenic property may be associated with the development of cancer in these
tissues and offers a key therapeutic target in treatment. Oestrogens regulate the
reproductive cycle as described below, and additionally have a wide range of
metabolic and physiological activities; they promote bone growth and maintain bone
density and strength, they promote fat deposition, and they enhance sodium and
water retention by the kidney. They increase coagulability of the blood, making
thromboembolism more likely, but they also improve the blood lipid profile, reducing
the risk of atheroma forming in blood vessels. This protective, anti-atherogenic lipid
profile includes reduced total blood cholesterol and LDL cholesterol, and increased
levels of HDL cholesterol, which is protective for blood vessels. Oestrogens dilate
coronary arteries and protect blood vessels from atherogenic changes, reducing the
risk of ischaemic heart disease in women compared with that in men.

Pharmacokinetics
Oestrogens are well absorbed from a range of sites, extensively metabolised in the
intestinal lining and the liver, and excreted in the urine. Oestradiol metabolism
produces several active metabolites, which extend its duration of action and half-life
to up to 16 hours.
Oestrogen Receptors
ERs are found in the cytoplasm of oestrogen-responsive cells, including breast,
vagina, and uterus, where they mediate the reproductive functions of oestrogens.
However, ERs are found in a range of other tissues, including the bone, skin, heart
and blood vessels, and brain. There are two types of ER: ER⍺ and ERβ. Distribution of
these receptor types differs between tissues, e.g. ER⍺ is the main receptor type in the
breast and is often overexpressed in breast cancer, whereas ERβ is the main type
found in the brain.
Progesterone
Progesterone regulates the female reproductive cycle as described below and is
essential in the maintenance of pregnancy, including breast growth and development
in preparation for lactation. Synthetic progestogens, e.g. norethisterone and
gestodene, are more potent than natural hormones. Some progestogens are
androgenic (i.e. have masculinising action) because they are chemically very similar to
testosterone, bind to ARs, and can cause testosterone-related side-effects like acne
and hirsutism. Newer synthetic progestogens have less androgenic activity because
they do not bind to ARs. There is evidence that synthetic progestogens slightly
increase the risk of breast cancer, especially when combined with an oestrogen. The
reason for this is not clear, because while some studies show that progesterone
stimulates cell division in breast epithelial cells, other studies show inhibition. It is
likely to be due to the interaction of several factors, including oestrogen levels,
duration of exposure, and the woman’s age.
 FIG. 5.15 Simplified diagram showing the biosynthesis of the
main sex hormones, including key enzymes. Modified from
Aggarwal NR and Wood MJ (2021) Sex differences in cardiac
diseases, Fig. 2. St. Louis: Elsevier.

Pharmacokinetics
Progesterone is well absorbed from a range of sites, including the GI tract, but when
given orally it distributes rapidly from the bloodstream and is extensively
metabolised, with a plasma half-life of only 5 minutes. Peak plasma levels are reached
in about 2 hours post-dose, but then fall rapidly, which can compromise contraceptive
cover (see below). Progesterone metabolites are mainly excreted by the kidney.
Testosterone
Testosterone is the main androgenic hormone in humans, but it is converted in most
tissues to the more active agent dihydrotestosterone. At puberty in the males, it
promotes the development of secondary sexual characteristics, e.g. the growth of
axillary and pubic hair and deepening of the voice, and maturation of the male sexual
organs. It activates genes that produce muscle proteins and increases the bulk and
strength of skeletal muscle. It increases libido and physical vigour and promotes
sperm production in the testis. At puberty, rising levels of testosterone convert the
cartilage growth plates at the ends of long bones to bone tissue, terminating any
further increase in height. Testosterone and certain synthetic variants, e.g.
nandrolone and trenbolone acetate, are sometimes used to increase muscle mass
and power and athletic performance in professional and amateur sport or for
occupational or cosmetic reasons. These agents are called anabolic steroids and can
cause significant long-term harm, including infertility, acne, masculinisation in
females, and increased risk of prostate cancer.
Pharmacokinetics
Testosterone is well absorbed from a range of sites, and its plasma half-life is very
short (10–20 minutes) because it is rapidly metabolised by the liver. Synthetic
analogues usually have longer half-lives.

Female Reproductive Function

The female reproductive years begin at puberty, with the development of secondary
sexual characteristics and the onset of cyclical ovarian activity essential for fertility.
They end at menopause, after which time the ovary stops releasing oocytes and the
menstrual cycle ceases. Oestrogens and progestogens are used therapeutically if the
ovarian cycle fails to establish naturally, causing a failure of puberty and primary
infertility (infertility in a woman who has never been pregnant). They are used as
contraceptives, to initiate and regulate the reproductive cycle in fertility treatment, to
reduce the pain and blood loss in heavy menstrual bleeding, and to treat troublesome
menopausal symptoms in hormone replacement therapy (HRT).

Hormonal Control of the Female Reproductive Cycle

The ovary contains, matures, and releases the female oocytes, and is the body’s main
source of oestrogen. In turn, it is regulated by the hypothalamic–pituitary axis (Fig.
5.2). The hypothalamic hormone GnRH stimulates release of two pituitary hormones,
FSH and LH. Between them, FSH and LH drive the regular maturation and release of
one or more oocytes from the ovary, which in most women occurs roughly once every
28–30 days and is the physiological basis of the female reproductive cycle. Puberty
commences when GnRH production from the hypothalamus triggers FSH and LH
release from the anterior pituitary, which in turn establishes the ovarian cycle.

The Female Reproductive Cycle

The changing hormone levels and main physiological events of the female reproductive
cycle are shown in Fig. 5.16.
Conventionally, the first day of the cycle is taken as the first day of the menstrual
period, and bleeding usually lasts for 3–5 days. During this time, in the ovary, one or
more follicles, each containing an immature oocyte, begin to develop. This is driven by
FSH from the anterior pituitary (Fig. 5.16A). The developing follicle secretes oestrogen,
so as it develops and gets bigger, oestrogen levels in the blood steadily rise (Fig. 5.16B).
This feeds back onto the anterior pituitary and stimulates it to produce increasing levels
of FSH, which sustains and promotes the developing follicle and ensures that oestrogen
levels in the first half of the cycle continue to increase. At about the midpoint of the
cycle, oestrogen levels become so high that they trigger a surge of LH from the pituitary
(Fig. 5.16C). This is the event that stimulates ovulation (Fig. 5.16E): the maturing
follicle ruptures and releases the oocyte, which is then usually swept into the uterine
(Fallopian) tubes and travels towards the uterus. The oocyte has a brief lifespan of only
about 48 hours: if fertilisation does not take place in this time, it dies. Following
ovulation, the follicle that released it, now called the corpus luteum, continues to
function as an endocrine gland, but its main product now is progesterone (Fig. 5.16D),
and oestrogen level remains much lower than that in the first half of the cycle. The
combination of circulating oestrogen and progesterone suppress the anterior pituitary,
so that FSH and LH levels now begin to fall. This has two main consequences. With low
levels of circulating FSH, no more follicles begin development in the ovary because there
is the possibility of the current cycle ending in pregnancy. LH supports the corpus
luteum. In the early stages of the second half of the cycle, while LH levels are still high,
the corpus luteum maintains its output of progesterone and oestrogen, required for
enriching the uterine lining with blood vessels and glands in preparation for possible
implantation of a fertilised ovum (Fig. 5.16F). If there is no pregnancy, falling LH
levels because of pituitary suppression by progesterone and oestrogen lead to
deterioration and death of the corpus luteum. Progesterone and oestrogen levels
therefore also fall, the uterine lining regresses, menstruation starts, the suppression of
the anterior pituitary is released, and FSH and LH levels begin to rise again, initiating a
new ovarian cycle.
FIG. 5.16 The changing plasma hormone levels and main
physiological events of the female reproductive cycle.The solid curves
represent mean values and the shaded area shows the maximum and
minimum values, i.e. the complete range of values obtained in the
experiment. Modified from Ritter JM, Flower RJ, Henderson G,
et al. (2020) Rang & Dale’s pharmacology, 8th ed, Fig. 36.2. Oxford:
Elsevier.
Hormonal Contraception
Oestrogen and progesterone can be used together in a combined contraceptive
preparation. Progesterone-only contraceptive preparations are also available.

The Combined Oral Contraceptive

The combination of oestrogen and progesterone in these preparations mimics
conditions in the second half of the reproductive cycle: that is, after ovulation, when the
corpus luteum is secreting progesterone and oestrogen into the bloodstream, inhibiting
FSH and LH release from the pituitary, suppressing development of further follicles and
preventing the LH rise that triggers ovulation. This is their main contraceptive action,
but they cause other contributory physiological changes, including thickening the mucus
plugging the cervical canal, making it harder for sperm to journey from the vagina into
the uterus. Generally, the woman takes a daily hormone-containing pill for 21 days and
then has 7 pill-free days (sometimes there are seven inactive pills, so that the daily
routine of pill-taking is maintained). Patches and vaginal rings that slowly release the
hormones into the bloodstream are also available if the woman is unwilling or unable to
take a daily pill. The most common oestrogen is ethinyloestradiol, either at low dose
(20 μg daily) or standard strength (30–35 μg daily), combined with a progestogen.
Taken according to manufacturers’ instructions, the combined oral contraceptive (COC)
is almost 100% effective in preventing pregnancy. Bleeding experienced during each
pill-free week is usually lighter with less discomfort or pain than menstruation, and the
COC may sometimes be prescribed to treat pre-menstrual tension, reduce excessive
menstrual blood loss, or alleviate what can be disabling pain and cramps accompanying
the monthly period. The COC reduces the incidence of uterine fibroids, ovarian cysts,
and benign breast disease, and fertility usually returns within a few months of
withdrawing the drug. Key advantages, disadvantages, cautions, and contraindications
relating to the COC are summarised in Fig. 5.17. Note that much of this is also relevant
to the use of these hormones in HRT.
 FIG. 5.17 Key advantages, adverse effects, cautions, and
contraindications associated with the combined oral contraceptive.

Pharmacokinetics
The general pharmacokinetic profiles of the individual hormones are described above.
The natural hormone, progesterone, is not used because it is rapidly and extensively
metabolised by enzymes in the intestinal lining and in the liver, so its plasma levels are
unpredictable and poorly sustained. Synthetic progestogens, first developed in the
1950s, are used instead: examples include norethisterone, desogestrel, and
gestodene. An important drug interaction involves increased hormone metabolism by
several enzyme inducers. Oestrogen and some progestogens are metabolised in the liver
by the cytochrome P450 enzyme family, and drugs that induce cytochrome P450,
including some anticonvulsants (e.g. carbamazepine, phenytoin), some
antimicrobials (e.g. rifampicin, antiretrovirals, griseofulvin), and St. John’s
wort enhance hormone clearance and can reduce contraceptive effectiveness. Women
should be advised to use an additional method of contraception while taking the
interacting drug and for 4 weeks after stopping it.

Adverse Effects
For most women, adverse effects are relatively minor and acceptable when weighed
against the prospect of an unwanted pregnancy: commonly they include nausea, mood
swings, fluid retention, and a tendency to weight gain. Women prone to migraine may
find that this gets worse, and they should be instructed to report any changes in
headache frequency or intensity.

Increased Blood Pressure

The COC can increase blood pressure in some women. The risk increases the longer the
contraceptive is used and is more likely in women with pre-disposing factors or pre-
existing high blood pressure. The reason behind COC-induced hypertension is not clear,
although there are a few possible contributing factors. For example, oestrogen activates
the renin-angiotensin system, increasing sodium and water retention, although this is
associated mainly with higher-dose oestrogen preparations. It also impairs the anti-
thrombotic properties of blood vessel linings. Additionally, progesterone can increase
the breakdown of bradykinin and other vasodilators. The mechanism is therefore
probably multi-factorial, but although COC-induced hypertension is occasionally severe,
it is mild to moderate in most women and usually returns to normal once the drug is
stopped. Progesterone-only preparations are not associated with a rise in blood
pressure.

Androgenic Adverse Effects

These are caused by the synthetic progestogen and can include acne and hirsutism.

Venous Thromboembolism
Both oestrogen and progesterone increase the risk of venous thromboembolism, e.g.
deep venous thrombosis and pulmonary embolism. Newer (third-generation)
progestogens such as gestodene and desogestrel are more potent and less
androgenic than older progestogens such as norethisterone and levonorgestrel but
have a higher risk of thromboembolism. The risk is highest in the first year of treatment
and in women with pre-existing risk factors, e.g. smoking, overweight, and obesity, but
are not as high as the increased risk associated with pregnancy. Even though
progestogens are pro-thrombotic when used in combination with oestrogen, studies
have shown that the progestogen-only oral contraceptive does not carry an increased
risk of thromboembolism (although there is evidence that there may be a causative
association between injectable progestogens and thrombosis). The reason for this is not
clear.
Myocardial Infarction and Stroke
The increased incidence of venous thromboembolism is probably responsible for the
slightly increased risk of angina, myocardial infarctions, and stroke seen with the COC.
Women with additional cardiovascular risk factors, e.g. increased age, overweight or
obesity, smokers, high blood pressure, diabetes, and a personal or family history are
particularly at risk and should be carefully assessed before a decision to prescribe COC is
made. It may be that a progestogen-only preparation is a better choice in these patients
because it does not increase cardiovascular risk.

Neoplasia
The risks of certain cancers (e.g. breast and cervical) may be slightly increased but the
risks of endometrial and ovarian cancers are slightly reduced in COC users. Changes in
cancer risk are oestrogen-dependent and are not seen with progestogen-only
contraceptives.

Progestogen-Only Preparations
Because oral progestogens are so rapidly metabolised and cleared from the blood, it is
critical that doses are taken strictly at 24-hour intervals; if a tablet is late or missed,
levels become so low that contraceptive cover is compromised. Oral progestogen
contraceptives must be taken daily, with no pill-free break as with the COC. These
agents may be suitable for women for whom oestrogen-containing preparations are not
recommended, e.g. smokers, older women, women with hypertension, or women with
cardiovascular risk factors. They are also useful in short-term cover for times when
oestrogen might be contra-indicated, e.g. in breast-feeding, periods of immobility, and
before and after surgery, when the risk of thrombosis is elevated. Side-effects include
breakthrough bleeding and headaches. Intra-uterine devices impregnated with a
progestogen and long-acting progestogen depot injections are also available. Interaction
with enzyme-inducing drugs, as described above for the COC, can also reduce
contraceptive effectiveness of oral progestogen-only agents and progestogen-only
implants, and a barrier method of contraception should additionally be used.
Medroxyprogesterone acetate, a progestogen used as a depot injection for
contraception, is metabolised by a different enzyme family and so is not subject to this
form of interaction; no additional contraceptive precautions are needed when used with
an enzyme inducer.

Hormonal Changes at Menopause

Natural menopause is caused by ovarian failure. It usually occurs between the ages of 45
and 55 years, by which time nearly all the follicles have either matured and ruptured
during a reproductive cycle or have degenerated, a fate suffered by more and more
follicles as they age. As follicles are lost, oestrogen levels progressively decline, because
the ovarian follicles are the main source of oestrogen. Falling oestrogen levels are
detected by the hypothalamus and anterior pituitary, which significantly step up GnRH
and FSH/LH production in a useless attempt to restore oestrogen production. Low
levels of oestrogen and high levels of FSH and LH are characteristic of the early stages of
menopause. Post-menopausal women can suffer significantly because of oestrogen
deficiency, and HRT is used to alleviate the condition. Removal of the ovaries and
ovarian damage, e.g. by irradiation, both induce artificial menopause at any age.

Signs and Symptoms of Oestrogen Deficiency

Oestrogen protects bones, and the skeleton of post-menopausal women becomes lighter
and less calcified (osteoporosis), with an increased risk of fracture. The cardioprotective
effect of oestrogen is lost, and the rates of ischaemic heart disease in post-menopausal
women become equivalent to age-matched men. Reproductive tissues responsive to
oestrogen undergo degenerative changes: for example, vaginal dryness is common, and
breasts lose their glandular structure, which is replaced with fatty tissue. Hot flushes,
sudden and intense rises in body temperature accompanied by flushing and sweating,
are very common and range from mild, occasional events to hourly, disabling episodes
associated with significant anxiety and distress. The cause of hot flushes is not fully
understood, but it is believed that abnormal blood vessel structure and responsiveness is
involved. For example, the severity of hot flushes correlates with evidence for subclinical
cardiovascular disease, e.g. calcification of the aorta and thickening of blood vessel
walls. Another contributory factor may be abnormal hypothalamic function. The
hypothalamus contains the body’s temperature regulation centre, and hot flushes may
be due to sudden and inappropriate hypothalamic activation of heat loss mechanisms.
Other unpleasant effects of diminished oestrogen include decreased libido, changes in
sleep patterns, problems with concentration, mood swings, weight gain, and depression.

F oc us on: Hormone Replac ement Therapy

A significant minority of women experience such severe symptoms at menopause that
they seek medical advice. Hormone replacement therapy (HRT) was first offered in
the 1960s, and its popularity and use has oscillated ever since, reflecting episodes of
bad publicity associating it with increased risks of premature death, cardiovascular
disease, and cancer. Its benefits in terms of reversing the symptoms of oestrogen
deficiency and improving quality of life, including maintaining bone health,
eliminating hot flushes, and preventing the emotional and cognitive effects seen in
menopause, are well established and not in dispute: HRT has made an enormous
difference to the lives of countless menopausal women. Current evidence suggests
that although HRT is associated with increased risk of certain cancers, it does not
cause premature death. The risks and benefits of HRT vary depending on the age of
the woman, time since menopause, mode of administration, dosage, and treatment
regime, and so should be assessed for each individual woman. The important points
are summarised below.
Hormone Replacement Therapy and Cancer
In its early days, HRT was offered as oestrogen-only supplements, but within a decade
it became clear that this increased the risk of endometrial cancer. Introducing a
progestogen into the preparation actually reduces the risk of endometrial cancer,
although it is now recognised that combined preparations increase the risk of breast
cancer. In women without a uterus, consequently for whom endometrial cancer is not
a concern, oestrogen-only preparations may be appropriate. The increased risk for
breast cancer is generally accepted to be slight and may be less than other risk factors,
e.g. obesity and high alcohol intake. The excess risk disappears within 5 years of
stopping treatment. HRT also slightly increases the risk of ovarian cancer, although
the excess risk disappears within 5 years of stopping treatment.
Hormone Replacement Therapy and Cardiovascular Disease
Early studies suggested that HRT increased the risk of cardiovascular disease and its
consequences, including stroke and myocardial infarction. Recognition of sources of
error in these studies and results of newer studies have reversed this perception, and
there is increasing evidence that HRT is cardioprotective, reducing the risks of heart
disease, thromboembolism, and stroke, likely more marked in younger women, those
within 10 years of menopause, and those without pre-existing cardiovascular risk
factors.
Hormone Replacement Therapy and Thromboembolism
HRT increases the coagulability of blood and so increases the risk of
thromboembolism, especially in the first year of use and in women with pre-existing
risk factors such as smoking, diabetes, and overweight/obesity. This risk may be less
when oestrogen is delivered by transdermal patches rather than orally. Progesterone
formulation may also be important: evidence shows that micronised
progesterone carries less risk for thromboembolism than synthetic progestogens.
Micronised progesterone is derived from plants but is chemically identical to the
human hormone and formulated as tiny particles that are absorbed more efficiently
than synthetic progestogens, improving its bioavailability.
Hormone Replacement Therapy and Bone Health
HRT consistently reduces bone loss, increases bone mineral density, and reduces the
risk of fracture. This protective effect persists for a variable length of time after
cessation of treatment, depending on the length of treatment: the longer the
treatment time, the more extended the protection after stopping.

Hormonal Treatment of Female Infertility

Female infertility is sometimes due to anatomical abnormalities, e.g. inflammation,
fibrosis, and obstruction somewhere in the tract by conditions including endometriosis
and pelvic inflammatory disease, or by fibroids or malignancy. Infertility may also be
secondary to hypothalamic, pituitary, or ovarian failure, associated for example with
polycystic ovary disease or congenital failure of ovarian development, in which case the
normal cyclical release of hormones essential for follicular development, ovulation, and
preparation of the uterine lining is disrupted or absent. Pharmacological interventions
to restore fertility include treatment with FSH and oestrogen to stimulate follicular
development and ovulation. In women whose hypothalamus is failing to secrete GnRH,
an infusion pump to administer GnRH in pulses, mimicking natural release patterns,
can be used; the exogenous GnRH stimulates FSH and LH from the pituitary, initiating
ovarian activity.

Clomifene
Clomifene binds to and blocks oestrogen receptors in the anterior pituitary and
hypothalamus (Fig. 5.18). Unable to detect the presence of oestrogen in the blood, the
hypothalamus and pituitary hugely increase GnRH, FSH, and LH output. This massively
stimulates the ovaries, initiating follicular development, oestrogen secretion, and
ovulation. The likelihood of multiple pregnancies is increased with clomifene treatment.
It is not recommended for more than six cycles because its stimulatory action on the
ovary has been associated with increased risk of ovarian cancer.
 FIG. 5.18 The mechanism of action of clomifene.A. The ovary
secretes oestrogen in response to follicle-stimulating hormone (FSH)
and luteinising hormone (LH) from the anterior pituitary. The
hypothalamus and anterior pituitary have oestrogen receptors to
allow them to continually measure blood oestrogen levels and adjust
their own hormone output accordingly. B. In the presence of
clomifene, oestrogen receptors are blocked and the anterior pituitary
and hypothalamus can no longer detect oestrogen in the blood. They
therefore increase gonadotropin-releasing hormone (GnRH), FSH,
and LH output, causing massive ovarian stimulation.

Male Reproductive Function

Unlike in females, male fertility is not cyclical, and once established at puberty can often
be maintained well into old age. The principal androgen, testosterone, is used to
stimulate testicular development and initiate puberty in testosterone-deficient males
and to treat some hormone-responsive breast cancers in women, because testosterone
has anti-oestrogenic properties in the breast.

Anti-Androgens
Examples: cyproterone acetate, flutamide, bicalutamide
Anti-androgens, drugs that block testosterone receptors, are used in testosterone-
related disorders. These include prostatic hyperplasia and prostate cancer, early
(precocious) puberty in young boys, and hair loss. They are used in the management of
hypersexuality and compulsive sexual behaviours, which can be highly disruptive to
normal life, cause significant distress and anxiety in the affected male, and contribute to
unacceptable, risky, or deviant behaviours. By directly reducing testosterone action, they
reduce libido and diminish sexual activity. They are also used in the treatment of a range
of cancers in both men and women, although legislation varies in different countries and
much work in this area is in its early stages. Some anti-androgenic agents have shown
efficacy in some triple-negative breast cancers––i.e. breast cancers that do not express
oestrogen, progesterone, or HER2 receptors and for which anti-oestrogen, anti-
progesterone, or anti-HER2 agents are of no use. Triple-negative disease can be difficult
to treat, but a subset of these cancers express androgen receptors, and initial studies
suggest that they may respond to anti-androgens. Likewise, a proportion of ovarian
cancers express ARs, and early clinical trials have confirmed that enzalutamide may
be an effective treatment in some of these patients.

References
1. Deacon C.F, Lebovitz H.E. Comparative review of dipeptidyl peptidase-4
inhibitors and sulphonylureas. Diabetes Obes. Metab. 2015;18(4):333–347.
2. Grisham R, Giri D, Henson M, et al. 38 Phase II study of enzalutamide in
androgen receptor positive (AR+) recurrent ovarian cancer: final results. Int. J.
Gynecol. Cancer. 2019;29:A23.
3. Newson L.R. Best practice for HRT: unpicking the evidence. Br. J. Gen.
Pract. 2016;66(653):597–598.
4. Sola D, Rossi L, Schianca G.P.C, et al. Sulfonylureas and their use in clinical
practice. Arch. Med. Sci. 2015;4:840–848.

Online Resources
Cagnacci, A., Venier, M., 2019. The controversial history of hormone replacement
therapy. Medicina (Kaunas) 55 (9), 602. Available at:
https://doi.org/10.3390/medicina55090602
Collaborative Group on Hormonal Factors in Breast Cancer, . Type and timing of
menopausal hormone therapy and breast cancer risk: individual participant
 meta-analysis of the worldwide epidemiological
evidence. Lancet. 2019;394(10204):1159–1168 Available
at:. https://doi.org/10.1016/S0140-6736(19)31709-X.
White, J.R., 2014. A brief history of the development of diabetes medications.
Diabetes Spectr 27 (2), 82–86. Available at:
https://doi.org/10.2337/diaspect.27.2.82
6: Analgesics and Anti-Inflammatory
Drugs

The Physiology of Pain

From a survival point of view, pain is an important protective mechanism that informs
us of disease and injury and encourages us to seek appropriate help, to avoid situations
that may make the pain worse, and to protect damaged body parts while they heal. Pain
is a complex phenomenon, heavily influenced by psychological, emotional, social,
cultural, and cognitive factors. However, for most people it is a strongly negative
experience, and the global market for drugs that relieve pain (analgesics) runs into tens
of billions of pounds.

Definition and Classification of Pain

In 2020, the International Association for the Study of Pain (IASP) defined pain as ‘an
unpleasant sensory and emotional experience associated with or resembling that
associated with actual or potential tissue damage’. Acute pain tends to start suddenly, is
associated with and appropriate to a clearly defined cause, such as post-operative pain
or the pain of a sprained ankle, and resolves when the injury heals. Chronic pain is pain
that lasts for 3 or more months. The IASP considers chronic pain in two categories:
chronic primary pain, which is pain not clearly accounted for by another disease state
(for example, non-specific musculoskeletal pain), and chronic secondary pain, where the
pain is directly caused by an underlying condition (such as cancer or rheumatoid
arthritis).

Key Definitions

• Nociceptive pain:

pain caused by stimulation of pain receptors (nociceptors) in the tissues, by

physical damage, and/or by inflammatory mediators

• Neuropathic (neurogenic) pain:

pain caused by damage to the nervous tissue

 • Analgesia:

reduction or loss of the sensation of pain. An analgesic drug reduces or abolishes

pain.

• Hyperalgesia:

abnormally increased pain response to painful stimuli

• Allodynia:

a pain response to a stimulus that should not normally be painful, e.g. light touch

Pain Pathways and Pain Signalling

Pain signals from injured peripheral tissues travel along a chain of sensory nerves up the
spinal cord to key areas in the brain responsible for the perception, processing, and
modulation of pain (Fig. 6.1), and they activate nerve pathways that control the body’s
response. These nerves communicate using several neurotransmitters, including
endogenous opioids, noradrenaline, gamma-amino butyric acid (GABA),
serotonin (5-HT), and substance P. In the context of pain management, this is
important because it means that there are multiple sites where a pain signal can
potentially be interrupted or modified. Sensory receptors in the tissues that detect
painful stimuli are called nociceptors. Nociceptors are unmyelinated free nerve endings,
and the pain signals generated when they are activated are transmitted to the spinal
cord by sensory nerves called first-order neurones or primary afferents. There are two
main types of first-order neurones: Aδ (A-delta) and C fibres. Aδ fibres are larger than C
fibres and are myelinated; hence, they have fast conduction speeds and carry the initial,
sharp, ‘fast’ sensation of pain – for example, the acute, stabbing pain immediately
following a skin cut. They respond to mechanical and thermal stimuli. C fibres are small
and non-myelinated, and transmit slow, dull, burning, chronic pain – for example, the
throbbing, duller, persistent pain following the acute pain of a skin cut. C fibres respond
to a range of noxious stimuli including mechanical, thermal, and chemical input.
Chemical stimulation of nociceptors may be due to exposure to corrosive substances
including acids or alkalis and a wide range of inflammatory mediators released following
tissue damage.
FIG. 6.1 Ascending pain pathways.First-order neurones carrying
pain signals synapse in the dorsal horn of the spinal cord with
 second-order neurones. Second-order neurones travel via the
spinothalamic and the spinoreticular tracts to the thalamus and
synapse with third-order neurones. PAG, Periaqueductal grey
matter.

The axons of the first-order neurones enter the dorsal horn of the spinal cord and
synapse with the second sensory nerve of the pain pathway, called the second-order
neurone. The neurotransmitter here is usually substance P or glutamate. Second-order
neurones cross to the opposite side of the spinal cord and from the dorsal to the ventral
horn and carry pain signals to the thalamus in one of two main pathways (tracts): the
spinothalamic tract or the spinoreticular tract. In the midbrain, neurones from the
spinothalamic tract project to the periaqueductal grey matter (PAG), a region important
in descending inhibition. In the thalamus, the second-order neurones synapse with
third-order neurones, which project to a range of brain centres involved in pain
perception and processing. Some third-order neurones project to the limbic system,
which determines the emotional response to pain. Others project to the somatosensory
cortex, which localises the pain and interprets its intensity and characteristics. Other
centres in the cerebral cortex evaluate the pain in terms of previous experience and
expectations, which in turn help to determine the response to pain.

Central Modulation of Pain Signals

In 1965, Melzack and Wall published a seminal paper in pain theory. They suggested
that pain signal transmission from one nerve in the pain pathway to the next could be
suppressed by other nerves acting at these synapses, and that input from larger nerves is
given priority over input from smaller nerves. The analogy that this acts like a gate,
which prevents pain transmission when closed, gave rise to what is called the gate
control theory. It explains why rubbing a bumped head helps the pain: the pain signals
transmitted to the spinal cord along medium-sized Aδ and small C fibres are blocked out
by the mechanical stimulation of rubbing the area, which transmits sensory information
along much larger Aβ fibres. It is now known that there are multiple sites in the pain
pathways of the central nervous system (CNS) where internal mechanisms may reduce,
block, or sometimes enhance a pain signal. The capacity of the CNS to block pain
sensation has an obvious protective function: pain can be an overwhelming experience
that demands full attention, which may prevent an individual from escaping a
dangerous situation or making other potentially critical decisions. One important pain
control mechanism operates in the spinal cord: descending inhibition.
Descending Inhibition
The key brain area that controls descending inhibition is the PAG, a region in the
midbrain surrounding the central aqueduct, which links the third and fourth ventricles.
In the 1960s, research showed that electrical stimulation of the PAG during surgery in
rats produced complete analgesia and the animals showed no signs of being in pain, and
although it is now known that the PAG has a range of other functions including
vocalisation and emotional responses, most investigation has focussed on its role in pain
inhibition. Nerve pathways extending from the PAG travel down through the medulla,
descend in the spinal cord, and synapse in the dorsal horn at the synapse between the
first- and second-order neurones in the pain pathway (Fig. 6.2). These descending
pathways are activated when ascending pain signals travel up the spinothalamic tract
and signal to the PAG, and they are inhibitory. When they fire, they inhibit the release of
substance P or glutamate, and therefore, block transmission of pain signals between the
first- and second-order pain neurones in the dorsal horn.
FIG. 6.2 Descending inhibition in the dorsal horn of the spinal
cord.Ascending pain signals in the second-order neurones of the
 pain pathway travel to the periaqueductal grey matter (PAG) in the
midbrain. This activates inhibitory descending nerves, which block
the release of the neurotransmitter responsible for transmitting the
pain signal between the first- and second-order neurones in the
dorsal horn.

These inhibitory pathways use three main neurotransmitters: endogenous opioids

acting on mu (μ) opioid receptors (MORs), serotonin acting on 5-HT receptors, and
noradrenaline acting on ⍺-adrenoceptors. All of these are important targets for analgesic
drugs. Opioids like morphine are μ receptor agonists and so directly activate MORs on
nerves in the pathway. Tricyclic antidepressants like amitriptyline block the reuptake
of noradrenaline and serotonin from synapses, increasing their concentration there,
prolonging their activity and the inhibition of the pain signals. The analgesic action of
gabapentin and similar drugs is not fully understood but is thought to be partly due to
enhancement of the action of serotonin in the descending pathways. Other mechanisms,
including higher centres of the brain and other sensory input, may activate the PAG,
meaning that the experience of pain can be significantly altered by distraction,
emotional states, or prior experience.

Sensitisation in Pain Pathways

Sensitisation is increased sensitivity of pain nerves to sensory stimuli and occurs both in
the peripheral nervous system (PNS) (peripheral sensitisation) and the CNS (central
sensitisation). Peripheral sensitisation is part of the normal response to acute injury:
reducing the activation threshold of nociceptors makes them more sensitive to stimuli
and increases awareness of the injury and makes it harder to ignore. Peripheral
sensitisation causes the increased tenderness of injured tissues; this encourages us to
protect the damaged area while it heals.
In chronic pain of either nociceptive or neuropathic origin, functional and physical
changes occur in pain pathways, which alter the processing and response to pain. The
World Health Organisation considers chronic pain as a disease state, and effective
treatment presents particular challenges. Chronic pain is associated with central
sensitisation, in which pain pathways in the CNS become increasingly sensitive, leading
to hyperalgesia. In addition, this dysfunctional response may also cause allodynia, the
sensation of pain in response to harmless stimuli. Because central pathways are affected,
the hyperalgesia can be widespread and affect body parts not involved in the principal
disease process, leading to generalised pain.
Opioids
Key Definitions

• Opium:

the juice extracted from the seed head of the opium poppy Papaver somniferum (in
Greek: ‘poppy that brings sleep’)

• Opiates:

the naturally occurring (endogenous) opioids in opium, including morphine and

thebaine

• Opioid:

any agent with opiate-like activity, including endogenous opioids, substances

naturally occurring in opium, and all synthetic and semisynthetic agents, e.g.
diamorphine, fentanyl

Cave paintings, clay tablets, and other artefacts from a range of ancient civilisations
indicate that humankind has used opium for at least 5000 years, both for recreational
and medicinal purposes. Opium contains several pharmacologically active agents
including morphine, thebaine, and papaverine. Thebaine is too toxic to be given in
its natural form but is used to synthesise certain opioid drugs including oxycodone,
buprenorphine, and naloxone. Opioids are used in modern medicine for a range of
purposes, but most significantly as analgesics: they are potent pain relievers, so effective
in fact that despite their potentially lethal side-effects, they are still the first-line agents
in the management of moderate to severe pain.
The active opiate content of crude opium is highly variable depending on the
conditions under which the poppy was grown, leading to significant variation in the
potency and activity of different opium batches. At the beginning of the 19th century,
opium was widely available and sold over the counter to the general public in a range of
formulations including lozenges, tablets, and tinctures (a drug dissolved in alcohol).
Other than the obvious dangers of such a dangerous preparation being freely available
with no restriction or regulation, the potency of these formulations could not be
controlled or predicted. In 1803, morphine was purified from opium by a German
apothecary called Friedrich Sertürner. This meant that dosages could be accurately
quantified, which in theory should improve safety. Commercial morphine production
began in earnest in the 1820s, and when the hypodermic needle was invented in the
1850s, the popularity of purified morphine skyrocketed. Although it provided previously
unsurpassed benefits for physicians managing their patients’ pain, it also led to
widespread addiction in all strata of society with associated criminality and major family
and societal problems. In response to the growing awareness of such negative opioid-
related repercussions, in 1912, several countries including the US, Russia, and the UK
signed the International Opium Convention. It was the first attempt to control the
distribution, manufacture, and sale of opioids, and in modern times most global
countries have regulatory legislation around their use.

Opioid Receptors
There are three main types of opioid receptors in the CNS and PNS: μ (mu), δ (delta),
and ϰ (kappa), called MOR, DOR, and KOR, respectively. The brain, peripheral nerves,
and some other body tissues produce a family of endogenous opioids, the endorphins
and enkephalins, which act on opioid receptors and provide the body’s internal pain
management system. When the endogenous opioids were discovered in the 1970s, it was
realised that the opium preparations that mankind had been using as analgesics for
thousands of years worked by mimicking the action of the endogenous opioids and
activating internal analgesia mechanisms. In terms of pain relief and most other
clinically observed opioid effects, MOR is the most important opioid receptor type, and
the endogenous opioids and clinically useful opioid analgesics are all agonists here.
However, the KOR and DOR also play a role in analgesia, and the overall effect of an
opioid, including its adverse effects, are produced by the drug interacting with all three
receptor types.

MOR Distribution
MORs are found in high concentrations in pain pathways in the CNS, including in the
dorsal horn of the spinal cord, as well as brain regions involved in emotion, mood,
feeding, hormonal control, respiration, and immune function. They are also found on
peripheral sensory nerves, where they inhibit pain signals. Opioid action here
contributes to their analgesic effect. Ongoing research is directed towards developing
opioids that do not cross the blood–brain barrier and so would be free of central adverse
effects like dependence and respiratory depression, but which could provide effective
analgesia via this peripheral activity. MORs are also present on nerves in the
gastrointestinal system, where they reduce motility and secretion. Additionally, MORs
are found in non-neural tissue, including joint tissues, immune cells, and endocrine
cells.

MOR Signalling
All opioid receptors are linked to inhibitory G-proteins (Gi) and inhibit adenylyl cyclase
(see p. 32 and Fig. 3.7). When an opioid agonist binds to its receptor on a nerve cell
membrane and activates this signalling pathway, potassium channels open, allowing
potassium to enter the cell. This desensitises (hyperpolarises) the nerve and makes it
less likely to fire. In addition, calcium channels are closed, preventing calcium from
entering; calcium entry into nerve cells is needed for activation. By interfering with the
movement of these two key ions across the nerve cell membrane, opioids prevent the
nerve from releasing its transmitter, dampen neuronal transmission, and block synaptic
communication (Fig. 6.3). This is reflected in the key effects of opioids including
blockade of pain signals, sedation, inhibition of smooth muscle contraction, and
respiratory depression.

Actions of Opioids
Opioids produce a range of physiological effects via their action on opioid receptors.

Analgesia
Opioids produce effective analgesia mainly through their action on MORs in both the
CNS and PNS, particularly in nociceptive pain; they are of limited use in neuropathic
pain. They reduce neuronal excitability and transmitter release in pain pathways,
including in the mechanism of descending inhibition (Fig. 6.4). Fig. 6.4 shows the
synapse in the dorsal horn between the first- and second-order pain neurones in more
detail. Incoming pain signals activate this synapse; the excitatory neurotransmitter here
is usually substance P or glutamate, which depolarises the second-order neurone and
transmits the pain signal up the spinal cord towards the brain. The descending nerve
from the PAG synapses here and releases endogenous opioid, which acts on MORs on
the first-order nerve ending. This inhibits release of its excitatory transmitter and blocks
transmission of the pain signal between the first- and second-order neurones. Opioid
drugs mimic the action of the endogenous opioid transmitter by binding directly to the
MORs.
FIG. 6.3 Morphine receptor signalling and inhibition of
neurotransmitter release. Modified from Minneman KP and Wecker
L (2005) Brody’s human pharmacology: molecular to clinical, 4th ed.
St. Louis: Mosby.
 FIG. 6.4 Opioid inhibition of pain signal transmission between the
first- and second-order neurone in the spinal cord. MOR, Mu opioid
receptor; PAG, periaqueductal grey matter.

Opioids usually induce a profound sense of well-being, relaxation, and deep

contentment, and produce a sensation of dissociation from pain; this euphoric effect is
often beneficial in pain relief.

Sedation
Opioids sedate and may induce sleep by inhibiting central pathways responsible for
arousal and wakefulness. This may worsen their respiratory depressant effect but can be
clinically useful because it may relieve distress and anxiety. Alternatively, sedation may
be unwanted: for example, it may limit activities of daily living for people using opioids
to manage chronic pain.

Respiratory Depression
Neurones in the respiratory centre in the brainstem are normally very sensitive to even
slight increases in carbon dioxide levels and respond by increasing respiratory rate and
depth of breathing. Opioids depress this response, allow carbon dioxide levels to rise,
and produce hypoventilation, hypercarbia (high blood carbon dioxide levels), apnoea,
reduced respiratory rate, and potentially respiratory arrest. Opioid-induced respiratory
depression is more marked and therefore most dangerous when brain activity levels are
suppressed, e.g. in sleep, in anaesthesia, or in the presence of other central depressants
like alcohol or benzodiazepines. Habitual opioid use leads to a developing tolerance,
but respiratory arrest is still the most common cause of death in opioid overdose.

FIG. 6.5 Opioid-induced miosis. From Stern TA, Fava M, Wilens

TE, et al. (2018) Massachusetts General Hospital. Tratado de
psiquiatría clínica, 2nd ed. Madrid: Elsevier Spain.

Miosis
Opioids act directly on the oculomotor nerve (cranial nerve III), which controls the
muscle of the iris of the eye and therefore pupil diameter. They constrict the circular
muscle in the iris and reduce the size of the pupils (miosis). In overdose, pupil size may
be pinpoint (Fig. 6.5).

Nausea and Vomiting

Opioids directly stimulate MORs in the chemosensitive trigger zone (CTZ), located in
the medulla of the brain. The CTZ has an important protective function: it contains
specialised receptors that detect potentially toxic substances in the cerebrospinal fluid,
and because it lies outside the blood–brain barrier, blood-borne toxins as well.
Stimulation of the CTZ triggers the vomiting centre in the brain and elicits the vomiting
reflex. Opioids also reduce GI motility, which contributes to nausea and vomiting. Up to
40% of individuals experience nausea following opioid administration, and a significant
number actively vomit. Pre-treatment or concurrent treatment with an anti-emetic, e.g.
cyclizine or ondansetron, can prevent this.

Gastrointestinal Effects
The walls of the GI tract contain extensive networks of nerves (the enteric nervous
system) which regulate its function. Enteric nerves release a range of neurotransmitters,
including endogenous opioids, which act on MORs in GI smooth muscle to reduce
motility and secretions and increase sphincter tone. Administered opioids also act on
these MORs and therefore slow gastric emptying, which can significantly delay the
delivery of swallowed medication into the duodenum and delay absorption.
Constipation is a common and very troublesome adverse effect of opioids. However, due
to their ability to put GI smooth muscle into stasis, opioids have been used for
thousands of years to treat diarrhoea. Loperamide is a MOR agonist used by mouth
for this purpose. It is poorly absorbed, so its action is largely restricted to the GI tract,
and it does not cross the blood–brain barrier in high enough concentrations to produce
central effects. Other GI consequences of opioid use include bloating, abdominal
distension and discomfort, and sometimes gastro-oesophageal reflux. Tolerance tends
not to develop to GI side-effects, which persist during treatment, a particular challenge
when opioids are used to manage chronic pain. In addition to non-specific management
(e.g. high-fibre diets, good fluid intake, and laxatives), opioid-induced constipation can
be treated with methylnaltrexone bromide, an opioid receptor antagonist that does
not cross the blood–brain barrier; it therefore blocks peripheral receptors, including
those in the GI tract, without interfering with the central analgesic action.

Cough Suppression
Opioids suppress cough, i.e. they have an antitussive action, but the mechanism by
which they do this is not completely clear. They inhibit central neurones involved in
cough pathways, but there is probably also a peripheral component: for example, they
may decrease the sensitivity of sensory nerves in the airways and reduce their response
to irritants. For example, nebulised diamorphine is used to relieve persistent cough in
bronchial carcinoma. The antitussive action of opioids does not correlate with their
analgesic effect, so that even weak opioid analgesics like codeine effectively suppress
cough.

Immunosuppression
The interaction between opioids and immunity is complex and our understanding is
quite incomplete. There is substantial evidence that opioids, especially in long-term use,
are immunosuppressant, and may increase the risk of infection. Opioids act on MORs
on the cell membrane of a range of important immune cells, including T-cells, B-cells,
and macrophages, and suppress their activity. Immune cells themselves release opioids,
leading to some researchers speculating that activation of the body’s immune system
may also switch on an analgesic effect, which may offer another possible target in
designing new analgesic drugs. Opioids have no anti-inflammatory effect; in fact,
morphine triggers histamine release from mast cells, which can cause itch and
sufficient vasodilation to cause a drop in blood pressure.

Tolerance
Tolerance (and dependence) to opioids develops because continual exposure to the drug
changes the response of the receptors and reduces drug action. This means that the drug
dose must be increased to maintain its effect. Tolerance develops very slowly to GI
effects and to miosis, whereas it develops quickly to opioid-induced respiratory
depression, euphoria, emesis, and analgesia, especially if the drug is used intravenously.
This means that habitual opioid users may require 50 times the standard dose to achieve
a desired euphoric effect without obvious respiratory depression, but still experience
significant constipation and pupillary constriction. Several mechanisms by which
tolerance develops have been identified. One way involves the uncoupling of the
receptor from its signalling pathways, like cutting through the wire of a doorbell; the
drug binds to its receptor but cannot produce an effect inside the cell because the
receptor is no longer connected to its transduction pathways. Other tolerance
mechanisms include increased activation of excitatory nerve pathways to oppose the
inhibitory action of the opioids. There is a degree of cross-tolerance between clinically
used opioids, and switching between different agents when tolerance becomes a
problem with one can help to maintain their usefulness.

Addiction and Dependence

Opioids are strongly associated with the development of addiction, the inability to stop
using a substance. Historically, opioid addiction has fuelled major social and economic
issues, and a current global opioid addiction epidemic is causing significant health and
social problems. Pleasurable and addictive behaviours are self-reinforcing because they
activate reward centres of the brain, particularly in an interconnected circuit called the
mesocorticolimbic pathway, which connects several brain areas involved in motivation,
reinforcement, and reward (p. 40). A range of pleasurable activities can stimulate these
reward pathways, including sexual behaviour, eating enjoyable foods, and taking any of
a wide range of recreational and lifestyle drugs including alcohol and nicotine. This
creates self-reinforcing loops that motivate an individual to repeat the pleasurable
behaviour. The key transmitter in these pathways is dopamine, sometimes called the
‘pleasure hormone’ because of its role in reward pathways and in the development of
dependence and addiction. Opioids markedly increase dopamine release in these
pathways and thus reinforce the desire to persist with opioid consumption. Regular use
of opioids over even a few weeks causes adaptive changes in these dopamine pathways,
which become dependent upon the new, higher levels of dopamine and do not function
adequately without them. If dopamine levels begin to fall because opioid levels fall, the
individual experiences a range of well-defined and highly unpleasant withdrawal
symptoms, which motivates them to take more opioids and restore dopamine levels.
Opioid withdrawal causes sweating, tremor, anxiety, anorexia, insomnia, diarrhoea, and
goosebumps, caused by contraction of the piloerector muscles controlling the tiny hairs
of the skin: this is the origin of the phrase ‘going cold turkey’ to indicate someone
undergoing withdrawal.

The Main Opioids

Morphine is the gold-standard analgesic to which new analgesic drugs are compared
during clinical trials, but a range of synthetic and semi-synthetic agents have been
developed to improve efficacy and reduce adverse effects. Synthetic drugs, e.g. fentanyl
and pethidine, may have significantly different chemical structures than morphine,
accounting for clinically different adverse effects and routes of metabolism (Fig. 6.6).

Uses of Opioids
Opioids are extensively used as analgesics in both acute and chronic pain, usually for
moderate to severe pain of nociceptive origin. Other uses include:

• relief of persistent cough, e.g. in bronchial carcinoma

 FIG. 6.6 The chemical structures of synthetic drugs with
opioid activity, e.g. fentanyl and pethidine, are different from
naturally occurring opioids, e.g. morphine and codeine. From
Hemmings H and Egan T (2019) Pharmacology and physiology
for anesthesia, 2nd ed, Fig. 17.1. Philadelphia: Elsevier.

• relief of dyspnoea, e.g. in heart failure and pulmonary oedema

• pre-medication, to relieve anxiety, sedate, and provide analgesia
• treatment of diarrhoea

Morphine
Crude opium usually contains between 9% and 15% morphine, and global supplies of the
drug still rely on extracting it from the poppy seed head because all attempts to
synthesise it have failed.

Pharmacokinetics
Morphine is usually given orally, intravenously, rectally, or intrathecally. Absorption
from intramuscular sites can be slow and unpredictable, and so this is usually not the
route of choice. It has a half-life of 4–6 h and is available in modified release
preparations to extend its duration of action. Morphine is subject to significant first-
pass metabolism, so care is needed in patients with liver impairment in whom the drug
effect can be significantly enhanced. The metabolism of the main opioids, showing
morphine as the main agent, is shown in Fig. 6.7. Opioid metabolism produces several
metabolites, including codeine and active metabolites such as normorphine,
dihydrocodeine, and morphine-6-glucuronide, which contribute significantly to
morphine’s clinical effects.

Diamorphine (Heroin)
This semi-synthetic derivative of morphine was first synthesised in 1874. It is more
potent and more lipid-soluble than morphine and is not licensed for medical use in
many countries because of its significant abuse potential. Reflecting the lack of
legislation at the time around drug regulation and marketing, it was advertised initially
by the drug company Bayer under the trade name Heroin as a treatment for a range of
conditions including respiratory and cardiovascular disorders (Fig. 6.8) and was
available for public purchase. It was also recommended as a safer, non-addictive
alternative to morphine even though it is neither.

FIG. 6.7 Metabolism of the main opioids. From Dasgupta A and

Sepulveda JL (2013) Accurate results in the clinical laboratory, Fig.
15.1. San Diego: Elsevier.
Pharmacokinetics
Diamorphine is a pro-drug and metabolised to morphine in the liver (Fig. 6.7). Given
orally, it is subject to very high first-pass hepatic metabolism and almost completely
converted to morphine; it is therefore not given by mouth. Given by injection, its
increased lipid solubility means it rapidly crosses the blood–brain barrier, where it is
converted to morphine in brain tissues. Because it has no intrinsic action of its own, but
its increased solubility enhances its entry into the CNS, diamorphine is sometimes
referred to as a morphine delivery agent. This rapid uptake by the CNS gives heroin a
faster and more potent onset of action, one reason for its widespread illicit use. It can
also be given intranasally, subcutaneously, and by inhalation. Recreational users may
smoke or inhale (‘snort’) it.

Codeine
Codeine is used to relieve mild to moderate pain, as a cough suppressant, and to treat
diarrhoea.

Pharmacokinetics
Codeine is given orally and is well absorbed from the GI tract. It is a pro-drug and relies
upon metabolism by the hepatic CYP2D6 enzyme to convert it to morphine for its
activity. Only around 10% undergoes conversion to morphine, the reason why it is a less
potent analgesic, although it is an effective cough suppressant and causes significant
constipation. It is generally well tolerated, although genetic variations in CYP2D6
activity affects its metabolism to morphine. In rapid and ultra-rapid metabolisers, rapid
conversion of codeine to morphine can worsen opioid adverse effects such as respiratory
depression, whereas in poor metabolisers, the therapeutic effects of the drug can be
delayed and reduced (Fig. 6.9; see also Pharmacogenomics, p. 3).

Fentanyl
Fentanyl is a synthetic opioid structurally similar to pethidine (Fig. 6.6), with potent
MOR agonist activity. It was first produced in 1960 by Janssen and is currently in
widespread use globally to manage severe pain in various clinical settings including
cancer and acute post-surgical pain. It is around 100 times more potent as an analgesic
than morphine. Although it produces the typical range of opioid-induced adverse effects
including respiratory depression and constipation, it is less likely to cause histamine
release, hypotension, and itch than morphine, which has contributed to its rising
popularity. Other drugs in the fentanyl group include sufentanil, alfentanil, and
remifentanil.

FIG. 6.8 Early 1900s Bayer advertisement for heroin. From Koob
GF, Arends MA, and le Moal M (2015) Drugs, addiction, and the
brain, Fig. 5.3. San Diego: Academic Press.
 FIG. 6.9 The impact of metabolism on activation of the pro-drugs
codeine and tramadol.Poor metabolisers activate the drugs slowly,
and analgesia may be slow or incomplete. Fast metabolisers activate
the drugs quickly, which can cause toxicity. Modified from Magarbeh
L, Gorbovskaya I, le Foll B, et al. (2021) Reviewing pharmacogenetics
to advance precision medicine for opioids. Biomedicine &
Pharmacotherapy. 142: 112060.

Pharmacokinetics
Fentanyl has a rapid onset of action, acting within 5 minutes, although this depends on
the route of administration – it is faster with intravenous and intranasal administration
but slower with transdermal patches. It has a shorter duration of action (30–40
minutes) than morphine, although this is extended with transdermal or buccal
preparations because the drug is absorbed slowly. Fentanyl is metabolised in the liver by
cytochrome P450 enzymes, and so other agents that inhibit cytochrome P450, including
verapamil, some antifungal agents, and erythromycin, can reduce fentanyl
metabolism and increase plasma levels sufficiently to depress respiration.

Pethidine
Pethidine (also called meperidine) was discovered in 1939 by researchers screening a
range of compounds for antimuscarinic activity. By chance, it was noticed that it also
produced opioid-like activity in the test animals, and it was rapidly developed as an
analgesic. It acts on both MORs and KORs, although its molecular structure is different
from morphine (Fig. 6.6), and as a result, its pharmacological effects are not always the
same as the naturally derived opioids. It is 10 times less potent as an analgesic than
morphine and causes respiratory depression, constipation, and histamine release, but is
much less likely to cause nausea and vomiting and is less sedative. Because it has
antimuscarinic activity, it also causes typical antimuscarinic adverse effects including
dry mouth, blurred vision, and bradycardia.

Pharmacokinetics
Pethidine is only moderately well absorbed orally and is usually given parenterally, with
a half-life of 2–3 h. It undergoes significant first-pass metabolism in the liver, and care
is needed in patients with impaired liver function, in whom the half-life can be
significantly extended. One of its metabolites, norpethidine, has some analgesic
activity but can cause significant CNS excitation, including hallucinations and seizures,
if the drug accumulates (for instance, in overdose or in renal impairment).

Methadone
Methadone is a synthetic opioid with a long (24 h) half-life because the drug leaves the
bloodstream and accumulates in the tissues where it is slowly released. It binds to MORs
and produces a similar range of pharmacological activity to morphine, including
effective analgesia, euphoria, cough suppression, constipation, and respiratory
depression. Because of its sustained action, it is mainly used in opioid withdrawal
programmes and in maintenance treatment in opioid-dependent people.

Pharmacokinetics
Methadone is well absorbed orally and is also available for injection; its onset of action
is usually between 30 and 60 minutes and its duration of action 4–6 h. It is heavily
plasma protein-bound, which in addition to high levels of tissue binding contributes to
its long half-life. It is metabolised in the liver and eliminated by the kidney.

Tramadol
Tramadol is an interesting opioid analgesic because its action is attributable to at least
two different mechanisms acting synergistically. This synthetic drug is structurally
related to morphine and is a weak agonist at MORs with much lower affinity than
morphine. In addition to its opioid activity, it also acts as a serotonin and noradrenaline
reuptake inhibitor (SNRI). It blocks the reuptake of serotonin and noradrenaline in
serotonergic and noradrenergic nerve pathways, including descending inhibitory
pathways (Fig. 6.2) involved in pain modulation. This increases the level of these
transmitters, and therefore enhances the activity of the inhibitory neurones in blocking
transmission of pain signals from the first-order to the second-order neurones. SNRIs
are used to treat depression and anxiety (p. 58), both associated with chronically painful
conditions, and this action of tramadol may contribute to its analgesic effect in these
disorders. It is useful in a wide range of situations, including neuropathic pain, post-
operative pain, osteoarthritis, and rheumatoid arthritis.

Pharmacokinetics
Because it increases serotonin levels, tramadol may cause serotonin syndrome. It may
also reduce the anti-emetic action of ondansetron, an anti-emetic commonly used to
counteract opioid-induced nausea and vomiting. Ondansetron blocks 5HT3 receptors,
opposing the raised serotonin levels caused by tramadol. There is evidence that higher
doses of tramadol are needed to control pain in the presence of ondansetron, and that
the anti-emetic action of ondansetron is reduced in the presence of tramadol.
Tramadol is a pro-drug and genetic variations in the enzyme that activates it,
CYP2D6, can reduce or increase the rate at which the active agent is released, which in
turn can affect its analgesic action (Fig. 6.9).

Opioid Reversal Agents

MOR antagonists used to reverse opioid overdose include naloxone and naltrexone.
Naloxone is a fast-acting antagonist at all opioid receptor subtypes with a half-life of 1–
2 h depending on the route of administration (Fig. 6.10). It is usually given
intravenously, sometimes by infusion, or intramuscularly: it is not active when given
orally. Intranasal preparations are available in some countries, including the UK, the
US, and Europe. Non-injectable preparations can have significant advantage for first-
responders in emergency situations, including family and friends of users who may not
be appropriately trained to give injections, and avoid the risk of needlestick injuries in
all settings. Naloxone is generally safe to use, although it produces withdrawal
symptoms, including restlessness, nausea, and vomiting. If given to reverse opioids
given for pain, it reverses analgesia and has been associated with cardiovascular events
including arrhythmias and hypertension in susceptible people, thought to be secondary
to sympathetic activation following the sudden return of pain. Naltrexone is used
orally to prevent relapse in former users of opioids. Recently, very low doses of
naltrexone have been shown to improve certain symptoms in multiple sclerosis,
including cognitive function and mental health. Although the mechanism of action in
this regard is unclear, it may be that low-grade blockade of opioid receptors may
upregulate endorphin production.
 FIG. 6.10 The mechanism of action of naloxone.Naloxone binds to
all types of opioid receptor (mu, kappa, and delta) with an imperfect
fit, so it acts as a competitive antagonist to morphine. Modified from
Tyerman J, Cobbett S, Harding MM, et al. (2023) Medical-surgical
nursing in Canada, 5th ed, Fig. 10.9. Toronto: Elsevier.

New Directions
There would be huge clinical value in new opioid drugs with equivalent analgesic
potency to current agents, but with fewer adverse effects. One promising direction of
research is based on the observation that adjusting the precise molecular shape of the
drug can determine the signalling pathway activated in the cell when it binds to the
opioid receptor. The pharmacological effects of opioids binding to the MOR are due to
activation of signalling pathways within the cell, and recently it has become clear that
different drug effects are caused by different signalling pathways. The analgesic effect of
opioids in pain pathways is due to Gi-protein activation (see p. 32), but respiratory
depression and constipation seem to be the result of the MOR activating a different
pathway in the nerve, called the β-arrestin pathway. Standard MOR agonists, e.g.
morphine, activate both pathways, but it was realised that if an opioid drug could be
designed to activate G-protein signalling but not the β-arrestin signalling pathway, it
could produce an effective analgesic without these additional adverse effects. Research
in this area has produced a group of opioids called biased ligands, because they select
one signalling pathway over another, and which may represent one of the most
significant advances in analgesia development for some time. The first drug in this
group to reach clinical practice, oliceridine (TRV130), was approved by the FDA in
2020, and other agents are currently in development. Oliceridine is a MOR agonist that
preferentially activates Gi-protein signalling over β-arrestin signalling, and so gives
analgesia with fewer adverse effects, particularly respiratory depression. Its mechanism
of action is shown in Fig. 6.11.

FIG. 6.11 Mechanism of action of oliceridine.A. Standard mu

opioid receptor agonists (e.g. morphine) activate Gi-protein and β-
arrestin pathways in the cell, resulting in adverse effects as well as
analgesia. B. Oliceridine selectively activates the Gi-protein pathway,
resulting in analgesia with minimal respiratory depression or
constipation.

Inflammation and Anti-Inflammatory Drugs

Inflammation is the response of tissue to injury and the inflammatory response is a
complex and important protective mechanism that limits damage, prevents, or limits
infection and promotes healing. It involves a complex interplay between the damaged
tissue cells, local nerves, and blood vessels and defensive and immune cells recruited to
the area. All these cells and tissues synthesise and release a range of mediators and
cytokines that regulate inflammation and any associated immune response. Many of the
anti-inflammatory drugs in common use work by blocking the production or the activity
of one or more groups of these important pro-inflammatory chemicals.
Pathophysiology of the Inflammatory Response
The four main signs of the inflammatory response are redness (erythema), swelling,
heat, and pain at the site. Depending on the site and severity of the injury, there may
also be reduced or loss of function of the affected part. Tissue damage with or without
microbe entry triggers a response in defensive sentinel cells in the tissue, like
macrophages and mast cells, whose role is to initiate and regulate the tissue response to
injury. Non-specific antimicrobial defence mechanisms including the complement
cascade are activated. Blood vessels supplying the area dilate to increase blood flow.
This causes localised redness and warmth, and the increased blood flow improves
oxygen and nutrient supply to the damaged tissues, as well as bringing in additional
leukocytes for defence and repair. In addition, blood vessel walls become more
permeable because the endothelial cells that line them pull apart from each other,
opening gaps between them and allowing increasing amounts of fluid to escape from the
bloodstream into the tissues. This increased permeability also allows leukocytes to
adhere to the blood vessel wall and to migrate out of the blood more easily into the
tissues. Here they combat infection and begin to clear away dead and dying body cells in
preparation for regeneration and repair. A wide range of leukocytes, including
neutrophils, eosinophils, macrophages, and lymphocytes are involved in inflammation
and immunity, and their recruitment and activation by inflammatory mediators
promotes the development of the inflammatory response. Fig. 6.12 shows an overview
of a typical inflammatory response.
Table 6.1 and Fig. 6.13 show some of the most important inflammatory mediators
and their roles in the inflammatory response. Leukocytes migrating into the area
produce a range of cytokines including interleukins and tumour necrosis factor
(TNF). Damaged cells produce prostaglandins (PGs) and leukotrienes, and
damaged blood vessel endothelium releases nitric oxide. Mast cells release
histamine and injured sensory nerves release substance P. Plasma-derived proteins
include bradykinin and complement proteins, and platelets release serotonin and
platelet activating factor (PAF).

Inflammatory Mediators and Pain

Tissue swelling compresses and stimulates sensory nerves, contributing to the pain of
inflammation, but inflammatory pain is also generated because mediators like
bradykinin directly activate nociceptors. Prostaglandins are sensitising agents that act
directly on peripheral nociceptors to increase their sensitivity to other agents such as
bradykinin. There is also strong evidence that they are released in pain pathways in the
CNS and enhance transmission of pain signals.
Anti-inflammatory drugs relieve pain mainly through suppressing inflammation in
the injured tissue. There is strong evidence that anti-inflammatory drugs increase
healing times in a range of situations including post-operatively and following bone
fracture; this emphasises the important role of the inflammatory response in tissue
healing and repair.

Glucocorticoids
The adrenal cortex produces a range of steroid hormones, including mineralocorticoids,
some sex hormones, and glucocorticoids. The main glucocorticoid in humans is
cortisol, which is usually referred to as hydrocortisone when used therapeutically. In
addition, a range of synthetic and semi-synthetic agents is available. Glucocorticoids
have multiple, wide-ranging effects on immunity, inflammation, and energy
metabolism, and so great care is needed when using them.

Glucocorticoids and the Stress Response

Glucocorticoids are sometimes called the stress hormones because they are essential to
the body’s response to stress and are essential to life: removal or failure of the adrenal
glands causes a rapid decline in health and inevitable death unless steroid replacement
therapy is initiated. Physiological stressors are defined as any stimulus that disrupts
homeostasis, and the body is constantly exposed to such stressors, most of them
mundane and everyday (the fall in blood sugar when the last meal was some time ago,
fatigue, running for a bus, worry over a forthcoming exam or starting a new job). More
significant stressors include infection, injury, surgery, chronic illness, pain, and
psychological and emotional stress. In health, the adrenal cortex secretes cortisol in a
clear diurnal pattern reflecting the sleep-wake cycle (Fig. 6.14). Assuming a normal
day–night sleep cycle, cortisol levels are lowest in the late evening and into the night,
rising towards morning, and then falling over the course of the day. Additionally, there
are likely to be multiple smaller surges over the course of the day, caused by whatever
stressors are experienced. Chronic stress in whatever form causes sustained and
prolonged cortisol secretion, which is associated with a range of negative consequences
described below.

Control of Cortisol Secretion

Cortisol secretion by the adrenal cortex is regulated by the anterior pituitary and the
hypothalamus in the functional relationship called the hypothalamic–pituitary–adrenal
(HPA) axis. This is described in more detail in Chapter 5 and shown in Fig. 5.2.
Physiological stress triggers release of corticotropin-releasing hormone (CRH) from the
anterior pituitary. CRH travels the short distance in the portal blood vessels linking the
hypothalamus to the anterior pituitary and stimulates release of adrenocorticotrophic
hormone (ACTH) into the bloodstream. ACTH in turn stimulates the adrenal cortex to
release cortisol.

FIG. 6.12 The acute inflammatory response.Stages 1–7 are

described in the text. From Abbas AK, Lichtman AH, and Pillai S
(2021) Cellular and molecular immunology SAE, 10th ed, Fig. 4.14.
New Delhi: Elsevier India.

Physiological Effects of Cortisol

To help manage the physiological demands of stress, cortisol has profound effects on the
major energy metabolism pathways – the use of glucose, protein, and lipids. In general,
cortisol mobilises the body’s stored energy resources and limits their non-essential use
to keep their blood levels high so that they are available for essential tissues. This
produces hyperglycaemia, hyperlipidaemia, and increased circulating amino acid levels.
Cortisol also has profound anti-inflammatory and immunosuppressant properties,
achieved through a range of mechanisms. The main physiological actions of cortisol are
summarised in Table 6.2. The widespread activity of this family of hormones in so
many areas of body metabolism and function means that the potential for adverse
effects when using them therapeutically is very high.

Mechanism of Action of Glucocorticoids

Steroid hormones are synthesised from cholesterol, and so are highly fat-soluble. They
cross the cell membrane and enter the cytoplasm, where they bind to a specific steroid-
binding protein. This complex then enters the nucleus where it binds to its target gene.
It has been estimated that glucocorticoids regulate one-fifth of the cell’s genome,
emphasising the widespread range of effects produced by these hormones. Depending
on the steroid hormone and the target cell, this binding may either activate the gene and
initiate synthesis of the protein for which the gene codes, or block gene activation and
inhibit protein synthesis (Fig. 6.15). This usually means that it can take hours or even
longer for prescribed steroid drugs to take effect because of the time required for levels
of the target protein to either rise or fall. It also means that their duration of action is
often much longer than the plasma half-life might suggest: the steroid activates or
deactivates the gene, but the biological consequence of that is the result of stimulation
or inhibition of protein synthesis, ongoing processes sustained over extended periods.
For example, the plasma half-life of cortisol is only 1–2 h, but its duration of action is
up to 12 h. In terms of their anti-inflammatory action, glucocorticoids bind to genes that
produce pro-inflammatory proteins and switch them off. For example, they inhibit the
production of cyclo-oxygenase (COX), the enzyme that produces pro-inflammatory
Prostaglandins. Additionally, they bind to genes that produce proteins that suppress or
reverse inflammation, switching them on: for example, they increase production of
interleukin 1, an anti-inflammatory cytokine released from white blood cells. They
therefore have sweeping anti-inflammatory and immunosuppressant properties,
blocking multiple aspects of the inflammatory and immune responses.

Table 6.1
FIG. 6.13 Mediators of the inflammatory response and their source
cells.
 FIG. 6.14 Typical pattern of cortisol secretion over a 24-h
period. From Hall JE and Hall ME (2021) Guyton and Hall textbook
of medical physiology, 14th ed, Fig. 78.9. Philadelphia: Elsevier.

Glucocorticoids in Therapeutics
Glucocorticoids are used in a wide range of acute and chronic inflammatory and
immune conditions to suppress inflammation and modulate immune responses. They
are essential therapy in adrenal insufficiency or failure or following adrenalectomy and
are used for their immunosuppressant action in malignancies of lymphoid tissue and
leukaemia. Because of their wide-ranging adverse effects, they are used at the lowest
effective concentration and for as short a time as possible. Potency varies significantly
between different preparations, and low to moderate potency agents are used wherever
possible; high-potency glucocorticoids are only used if necessary and with great care.
Box 6.1 lists doses of some commonly used glucocorticoids required to give an anti-
inflammatory effect equal to 5 mg of prednisolone.

Routes of Glucocorticoid Administration

Because these agents are highly fat-soluble, they are well absorbed orally and from sites
of injection. Most glucocorticoids are available in a range of formulations for oral,
topical, inhalational, or parenteral administration. To minimise adverse effects, topical
or local administration is preferred to systemic wherever possible, allowing a high drug
concentration to be achieved locally. For example, steroids are given by inhaler in
maintenance therapy of asthma, and only used orally or intravenously in exacerbations.
Steroids are efficiently absorbed across the skin, especially if it is thin (e.g. in children or
the elderly) or broken, which must always be borne in mind with topical use. A person
applying a topical steroid should wear gloves to protect themselves and take care when
applying to avoid adjacent healthy skin, because glucocorticoids cause skin atrophy.

Table 6.2

FIG. 6.15 Mechanism of action of anti-inflammatory steroids.

B ox 6. 1 E q uivalent Anti-Inflammatory Doses of a Range of

G luc oc ortic oids Compared w ith 5 mg of Prednisolone

The significant differences indicate the potency range of these drugs, with
hydrocortisone being the least potent and betamethasone the most potent.
 Hydrocortisone 20 mg
Deflazacort 6 mg
Prednisolone 5 mg
Triamcinolone 4 mg
Dexamethasone 750 μg
Betamethasone 750 μg

Adverse Effects of Glucocorticoids

Glucocorticoids are usually well tolerated when used in low doses in short courses. The
risk of adverse effects increases with prolonged treatment, higher doses, systemic use,
and increased potency. Although these agents are widely used in chronic conditions,
they may be supplemented with other immunomodulatory drugs, for example,
methotrexate in rheumatoid disorders, to reduce steroid doses and minimise the long-
term impact of their unwanted effects. It must of course be noted that such
supplemental drugs also cause adverse effects.

Cushing’s Syndrome
In 1912, Harvey Cushing described the signs and symptoms of excessive glucocorticoid
production by the adrenal gland, and the syndrome produced by prolonged
glucocorticoid excess was named after him. Iatrogenic Cushing’s syndrome, caused by
administered glucocorticoids, is relatively common because of the widespread use of
these agents in medicine, and it consists of a wide constellation of signs and symptoms
listed below and shown in Fig. 6.16.

• Hyperglycaemia, which may precipitate diabetes mellitus

• Breakdown of muscle, particularly limb muscles, causing wasting and weakness
• Mobilisation of fats from adipose tissue: hyperlipidaemia; redistribution of
adipose tissue, giving abdominal obesity, moon face, buffalo hump, and
sometimes exophthalmos as adipose tissue is deposited behind the eyeballs
• Mineralocorticoid activity: fluid retention, hypertension, raised intracranial
pressure
• Immunosuppression, poor inflammatory response, and increased risk of
infection; acne
• Poor tissue repair; delayed healing; peptic ulceration
• Abnormal connective tissue formation: cataracts; easy bruising because blood
 vessel walls are fragile; striae as connective tissue in the skin becomes
weakened; skin atrophy and thinning; alopecia
• Loss of bone mass: osteoporosis; increased risk of fracture; loss of height because
of vertebral compression; vertebral deformity
• Psychological effects including euphoria, psychosis, depression, anxiety
• Increased appetite: weight gain, obesity, anti-emetic
• Menstrual disturbances and hirsutism in women
• Growth retardation in children
 FIG. 6.16 The main features of Cushing’s syndrome. Modified
from Innes JA (2016) Davidson’s essentials of medicine, 2nd ed, Fig.
10.6. Edinburgh: Elsevier.

Suppression of Endogenous Glucocorticoid Secretion

Systemically administered glucocorticoid drugs maintain artificially high plasma levels,
which feed back on the hypothalamus and anterior pituitary to suppress release of CRH
and ACTH respectively. This removes the internal hormonal stimulus for adrenal
production of endogenous cortisol. The adrenal cortex therefore halts cortisol secretion,
and adrenal atrophy occurs. At the end of a course of glucocorticoids, it is important to
step down treatment over time rather than withdrawing suddenly. Stepping down slowly
reduces blood steroid levels slowly, giving the HPA axis time to detect the change and
respond to it. The hypothalamus and pituitary gland resume production of CRH and
ACTH, respectively, which stimulates the adrenal gland to resume natural cortisol
secretion. Abruptly discontinuing steroid administration after an extended course of
treatment may lead to life-threatening adrenal crisis. Depending on the length of
treatment, the dose given, and the potency of the steroid used, it can take the adrenal
glands up to eight weeks to return to full function, although in some individuals adrenal
suppression may persist for much longer.
Adrenal suppression in people taking steroid treatment means that the normal
increased production of glucocorticoids in response to stress does not occur. Steroid
doses need to be increased in illness, infection, trauma, and prior to surgery and other
stressful situations, and individuals should always carry a steroid card to alert medical
teams to this in the event of accident or illness.

FIG. 6.17 The relative glucocorticoid and mineralocorticoid activity

 of some steroid drugs.

Glucocorticoid Drugs
Examples: betamethasone, dexamethasone, hydrocortisone, prednisolone,
triamcinolone
The choice of drug is made based on several considerations, including its
mineralocorticoid (sodium- and water-retaining) activity. A glucocorticoid with
significant mineralocorticoid activity is inappropriate in conditions where fluid
retention could be damaging, e.g. in raised intracranial or intraocular pressure, where
increased fluid load would worsen the condition. On the other hand, when adrenal
failure requires replacement therapy, mineralocorticoid activity is useful because it is
part and parcel of the normal physiological function of the missing hormones. Fig. 6.17
illustrates the relative glucocorticoid and mineralocorticoid potencies of a few steroids,
including the mineralocorticoid fludrocortisone. For comparative purposes, cortisol
is assigned the value of 1 for both glucocorticoid and mineralocorticoid activity and the
other agents are evaluated in comparison to this: for example, betamethasone is on
average 35 times as potent a glucocorticoid as cortisol but possesses almost none of its
mineralocorticoid action. Potency, half-lives, and duration of action of some of the main
glucocorticoids are given in Table 6.3.

Non-Steroidal Anti-Inflammatory Drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay in the management
of a wide range of acute and chronic inflammatory conditions. The history of the original
NSAID, aspirin, dates back to ancient Egypt and Sumeria, whose physicians were using
willow extracts as early as 3000 BC to treat painful or inflammatory conditions. In 400
BC in ancient Greece, Hippocrates is known to have prescribed a willow bark extract to
women in labour, although whether it helped is not recorded. The Reverend Edward
Stone, an English clergyman, submitted a report to the Royal Society in 1763 containing
data and observations from five years of his experiments examining the effects on willow
bark extract in the treatment of fevers.
In 1828, salicin, the active ingredient in willow, was isolated and named by the
German chemist Joseph Buchner. Although salicin is an effective anti-inflammatory, it
is an irritant when taken orally, ulcerating the membranes of the mouth, throat, and
oesophagus, and causing significant nausea, vomiting, and gastric pain. In 1897, Felix
Hoffmann, a German chemist working for Bayer, showed that adding an acetyl group to
the salicin molecule significantly reduced its irritant properties, and Bayer went on to
manufacture and market the new drug, acetylsalicylic acid, under the trade name
Aspirin.

Table 6.3
Aspirin rapidly became the most popular painkiller worldwide, but its mechanism of
action was not explained until the 1970s when Professor John Vane, working at the
University of London, showed that aspirin inhibits an enzyme called cyclo-oxygenase
(COX). COX produces prostaglandins, a family of inflammatory mediators generated in
large quantities in injured tissues, and which promote all aspects of the inflammatory
response. Inhibiting this enzyme blocked PG production and suppressed inflammation.
Vane was a co-winner of the Nobel Prize in 1982 for this work.
Aspirin’s popularity as an anti-inflammatory analgesic was tempered by the fact that
its adverse effects can be severe and potentially fatal, which drove research to find safer
alternatives including ibuprofen and naproxen. In addition, new uses for this old
drug were being explored: several large studies in the 1990s and 2000s demonstrated
clear benefit of aspirin use in cardiovascular disease and cancers.

The Biology of Prostaglandins

PGs were discovered by the Swedish physiologist Ulf von Euler in 1935. He called them
prostaglandins because he found them in semen and assumed the prostate gland was
the source. We now know that they derive from arachidonic acid, an important
constituent of cell membranes, and so all body tissues can produce them.

Biosynthesis of Prostaglandins
Fig. 6.18 shows the pathway by which PGs are produced. It names two important
enzymes involved: phospholipase A2 and COX.
Phospholipase A2 releases arachidonic acid from the cell membrane into the cell
cytoplasm. Glucocorticoids inhibit this step, one of the many anti-inflammatory
actions of these steroids. Arachidonic acid is the precursor for several inflammatory
mediators, the most important being the PGs and the leukotrienes (see p. 167 and Fig.
8.12). COX converts arachidonic acid into unstable intermediates, PGG2 and PGH2,
which are then converted into the five main PGs – PGD2, PGE2, PGF2⍺, PGI2
(prostacyclin), and thromboxane (TX) A2 – by specific synthases. COX is inhibited by
NSAIDs and also by paracetamol, which is interesting because paracetamol is not
classed as an NSAID due to its lack of anti-inflammatory activity.
Function of Prostaglandins
PGs are important drivers of the inflammatory response and mediate pain and fever, but
in healthy tissues they have a wide range of roles, sometimes called housekeeping
functions, essential to the normal functions of the cell. They include cell growth and
division, thermoregulation, blood clotting and cardiovascular function, appetite and
feeding behaviours, protection of the gastric lining, and smooth muscle contraction, and
are involved in the physiology of pain. Many of the most significant adverse effects of
NSAIDs arise because they block production of housekeeping PGs in healthy tissues, as
well as inflammatory PGs in injured tissues.

COX-1 and COX-2

COX is present in two main isoforms: COX-1 and COX-2. Both produce PGs from
arachidonic acid, but they are expressed in different concentrations and in different
tissues, depending on the stimulus. COX-1 is continually produced in small quantities by
most healthy body tissues and is mainly but not exclusively involved in producing the
‘housekeeping’ PGs. It is sometimes referred to as the ‘constitutive’ isoform because its
continual production suggests it performs necessary, constitutional functions. COX-2,
on the other hand, is generated in very large quantities following tissue damage and is
responsible for the high levels of the pro-inflammatory prostaglandins produced
following injury. It is sometimes referred to as the ‘inducible’ isoform because its levels
can be rapidly induced by tissue injury. It is also involved in the pathogenesis of cancer,
promoting cell division and metastasis. However, it is not the case that COX-1 is solely
responsible for the effects of PGs in healthy tissues and COX-2 is only produced in
injured or diseased tissues. COX-2 is important in healthy cardiovascular function: it
regulates blood flow in key organs including the heart and the kidneys and has
vasodilator and antithrombotic activity. Fig. 6.19 and Table 6.4 summarise the main
roles of COX-1 and COX-2 in PG production in healthy and injured/diseased tissues.
Traditional NSAIDs including ibuprofen and aspirin block both COX-1 and COX-2,
although not necessarily with equal affinity. Selective COX-2 inhibitors such as
rofecoxib will be discussed in more detail.
FIG. 6.18 The biosynthesis of prostaglandins and leukotrienes
from arachidonic acid. Modified from Waller DG, Sampson A, and
Hitchings A (2022) Medical pharmacology and therapeutics, 6th ed,
Fig. 29.1. Oxford: Elsevier.
 FIG. 6.19 The two main isoforms of COX. Modified from Bonavida
B and Johnson DE (2019) Targeting cell survival pathways to
enhance response to chemotherapy Vol 3, Fig. 6.2. San Diego:
Academic Press.

The therapeutic (i.e. anti-inflammatory) effects of NSAIDs are attributable to

blockade of the action of COX-2 released by injured tissues, which in turn blocks the
production of pro-inflammatory PGs. However, NSAIDs also block COX-1 and COX-2 in
healthy tissues, accounting for most of their adverse effects.

Prostaglandins in Inflammation and Pain

In damaged tissues, phospholipase A2 and COX-2 levels rise rapidly and PG production
increases sharply. The main agent produced in inflammation is PGE2, which causes
vasodilation, increases vascular permeability, and sensitises pain receptors. NSAIDs are
effective anti-inflammatory agents, and their analgesic activity is most effective in pain
of inflammatory origin.
Table 6.4

COX-1 and COX-2 Activity in Healthy and Injured/Diseased Tissues

In healthy tissues
In injury or disease
(‘housekeeping’ functions)
COX-1 Aggregates platelets (produces Pain signalling
platelet TXA2)
Protects gastric mucosa (produces May contribute to chronic
PGE2) inflammation
Regulates blood flow Increases blood pressure
COX-2 Protects blood flow, e.g. in kidneys Produces pro-inflammatory
and heart (prostacyclin) prostaglandins (mainly PGE2)
Protects gastric mucosa (mainly Produces fever (PGE2)
PGE2)
Inhibits platelet aggregation Promotes tumour growth and
(prostacyclin) metastasis
Uterine contraction in labour May contribute to the pathology of
(PGF2α) Alzheimer’s disease

Prostaglandins in Fever
The temperature control centre of the brain lies in the hypothalamus, which contains a
network of heat-sensitive neurones that maintain core body temperature at around 37°C
(98.6°F). In response to a range of inflammatory or infective substances circulating in
the bloodstream, the hypothalamus can adjust this internal thermostat to increase body
temperature. Substances that cause fever are called pyrogens. As with other aspects of
the inflammatory response, fever is protective because increased body temperature
usually inhibits microbial growth and enhances the activity of defence cells including
phagocytes. Most pyrogens are derived from microbes and include some bacterial toxins
and lipopolysaccharide (LPS) from bacterial cell walls. In addition, some products of
damaged tissues, and some inflammatory mediators, such as interleukin-6, act as
endogenous pyrogens. Pyrogens increase PGE2 synthesis by COX-2 in the hypothalamus
and this is the key event that sets the hypothalamic thermostat to the higher level and
causes fever. NSAIDs reduce fever because by blocking this pyrogen-induced rise in
PGE2, the hypothalamic thermostat remains at normal core temperature level.
PGE2 and the Stomach Lining
This important housekeeping function is performed by PGE2 secreted in the stomach
mainly but not exclusively by the action of COX-1: COX-2 is also thought to contribute.
PGE2 stimulates gastric mucus production, increases blood flow through the mucosa,
stimulates bicarbonate production, and reduces gastric acid production. All these
measures protect the integrity of the gastric mucosa and enhance its ability to
regenerate damaged cells.

Gastrointestinal Adverse Effects of NSAIDs

By reducing PGE2 production, NSAIDs block its protective actions, explaining their
profoundly irritant effect on the gastric mucosa. Agents with a high affinity for COX-1,
like aspirin, naproxen, and ibuprofen, are most likely to cause gastrointestinal
irritation. Because NSAIDs are acidic drugs, they remain un-ionised in the acidic
stomach fluids and are taken up and concentrated in the gastric mucosal cells,
promoting their irritant effect. Enteric-coated and parenteral formulations reduce but
do not eliminate gastric irritation, because circulating drug is taken up from the
bloodstream into the gastric mucosal cells. GI side-effects include nausea, vomiting,
abdominal pain, dyspepsia, gastric ulceration, gastric bleeding, and perforation. Pre-
existing inflammatory GI disease (e.g. inflammatory bowel disease) increases the risk.
Rectal administration causes local irritation and bleeding. Chronic low-grade
gastrointestinal bleeding may cause anaemia.

FIG. 6.20 Opposing actions of thromboxane A2 and prostacyclin

in clotting.

NSAIDs can be given in combination with misoprostol, a synthetic analogue of

PGE2, which inhibits gastric acid secretion, increases gastric mucus and bicarbonate
production, and promotes healing of the stomach mucosa. Another useful combination
is with a proton-pump inhibitor such as omeprazole. These gastroprotective agents
reduce the incidence and severity of gastrointestinal side-effects. It is also recommended
to take NSAIDs with food.

PGI2, TXA2, and Blood Clotting

This important housekeeping function mainly involves two PGs: PGI2 (prostacyclin) and
TXA2 (Fig. 6.20). PGI2 is produced in the healthy endothelium lining blood vessels by
the actions of both COX-1 and COX-2. It causes vasodilation and inhibits platelets, and
therefore has an anticoagulant effect, maintaining the fluidity of blood. TXA2 is
produced by COX-1 in platelets, and it activates platelets and causes vasoconstriction,
both of which predispose to clotting. In the healthy, uninjured vascular bed, the balance
between these two agents is important in keeping the blood flowing but ensuring that
rapid clotting can take place if necessary. Aspirin is over 130 times more selective for
platelet COX-1 than for COX-2 and accumulates rapidly in platelets at even low doses.
This explains why low-dose aspirin is such an effective antithrombotic agent and why
much higher doses are needed to block PG production in inflammation, which is
mediated by COX-2. In addition, aspirin irreversibly blocks platelet COX-1, and so its
antiplatelet action is much more prolonged than its effect in other tissues, strongly
tipping the balance towards inhibition of clotting.

Regulation of Cardiovascular Function, Including Renal Blood Flow

Prostacyclin is an important regulator of blood flow; this important housekeeping
function protects blood flow to, among other organs, the kidney and heart. Its potent
vasodilator and antithrombotic actions have led to its use in the treatment of pulmonary
hypertension and to prevent platelet aggregation during haemodialysis. COX-2 appears
to be particularly important for producing vascular prostacyclin, and NSAIDs that are
more selective for COX-2 inhibition than COX-1, like diclofenac, and COX-2 selective
agents, such as celecoxib, are more strongly associated with adverse cardiovascular
events than those that block both forms equally.
In the kidney, prostacyclin controls the diameter of renal blood vessels and is
responsible for renal autoregulation, the ability of renal blood vessels to control local
blood flow and pressure to protect them from changes in systemic pressure. Systemic
blood pressure in healthy people fluctuates significantly across a wide range; for
example, in sleep, it can fall to very low levels but rise temporarily into the hypertensive
range during heavy exercise. It is important that the renal vasculature is protected from
circulating vasoconstrictors and rising systemic blood pressure because not only would
this damage the delicate renal glomeruli, but also rising pressure here would increase
glomerular filtration rate and increase sodium and water loss. This could be
undesirable: for example, blood pressure rises in exercise, which would then lead to
excessive salt and water loss at a time when the body needs to preserve both. In the face
of fluctuating systemic pressures, renal blood vessels adjust their diameter to
compensate and to maintain glomerular filtration pressures at the appropriate values to
control the body’s salt and water balance. Prostacyclin-mediated vasodilation keeps
pressure low in the renal vasculature even when systemic blood pressure is high and is
therefore a key player in renal autoregulation.

Renal and Cardiovascular Adverse Effects of NSAIDs

NSAIDs block the synthesis of renoprotective prostacyclin and are therefore highly
renotoxic. They increase sodium and water retention, increase blood pressure, and can
trigger acute kidney injury, especially in older people whose renal function may already
be in decline. Because they increase blood pressure, NSAIDs reduce the effect of
antihypertensive medication, including diuretics and angiotensin-converting
enzyme (ACE) inhibitors.
Apart from aspirin, all NSAIDs increase the risk of cardiovascular events, including
myocardial infarction, both in people with cardiovascular risk factors (e.g. ischaemic
heart disease) and without. Extended use and higher doses increase risk. It has been
suggested that because of the widespread use of NSAIDs in the general population, a
significant proportion of myocardial infarctions and other cardiovascular adverse effects
may be attributable to NSAID use. This is thought to be due to NSAID-mediated
blockade of COX-1 and COX-2 activity, reducing prostacyclin levels in blood vessels.

Prostaglandins in Tumour Growth and Development

COX-2 levels are significantly increased in a range of cancers, including breast, lung,
and prostate tumours, and produce elevated levels of PGE2, which promotes tumour cell
division and contributes to tumour growth and metastatic potential. NSAIDs are
sometimes used as adjuncts to chemotherapy in the treatment of some cancers and
there is research interest in developing specific PGE2-receptor antagonists, which could
be used to suppress tumour growth. There is also evidence that NSAIDs reduce the risk
of developing certain cancers, including prostate, breast, and colorectal malignancies.

Prostaglandins in the Nervous System

PGs produced in the CNS have been associated with a range of neurological disorders,
including Alzheimer’s disease, multiple sclerosis, and sleep disorders. They do not
directly stimulate pain receptors in the tissues, but they sensitise them to the action of
mediators that do, including bradykinin, and release of PGs in the brain facilitates pain
signalling.

Non-Selective COX-1 and COX-2 Inhibitors

Examples: aspirin, diclofenac, ibuprofen, naproxen
Most NSAIDs block both COX-1 and COX-2, although not necessarily with equal
affinity. Fig. 6.21 shows the relative selectivity of a range of NSAIDs for the two
isoforms. NSAIDs are used as analgesics, anti-inflammatories, and antipyretics in a wide
range of acute and chronic conditions, including rheumatic and musculoskeletal
disorders, colds and other viral infections, headache, and dysmenorrhoea. They are
most effective in mild to moderate pain but are also used in combination with opioids
in the management of moderate to severe pain, as in cancer. In this situation, they
reduce inflammation in the tissues affected by the growth and expansion of a solid
tumour and can reduce the dose of opioids required in pain management. There are
about 50 NSAIDs available worldwide, and the annual value of the global market runs
into tens of billions of pounds sterling.

Adverse Effects of NSAIDs

Adverse effects of this group of drugs tend to be broadly similar, because they all inhibit
COX and prevent PG production. The mechanisms underpinning their gastrointestinal
and cardiovascular side-effects are discussed above.
NSAIDs are the most common cause of drug allergy and may affect up to 1 in 50
people. It is much more common in certain groups, including people with asthma, nasal
polyps, or a history of allergy. Allergy can manifest as skin rashes, rhinitis, and/or
asthma. Around 15% of people with asthma experience worsening of their asthma if
exposed to NSAIDs. This is because by inhibiting the conversion of arachidonic acid to
PGs, more arachidonic acid is available for conversion to leukotrienes via the action of
lipoxygenase (Fig. 8.12). The cysteinyl leukotrienes are bronchoconstrictors and
exacerbate symptoms in some people with asthma.
NSAIDs should be used with care or completely avoided in some groups of people.
They are contraindicated in people with a history of NSAID allergy. They are best
avoided in people with active or previous GI bleeding, but if there is no effective
alternative (e.g. in severe rheumatic disorders), then they are used with cytoprotective
treatments like misoprostol, proton-pump inhibitors, or antacids. They should
be used carefully, if at all, in individuals with a range of cardiovascular diseases
including heart failure and hypertension, with asthma, or with bleeding disorders. The
incidence and severity of side-effects increase with age, but in all ages they should be
used at the lowest possible dose for the shortest possible time. Paracetamol is usually
the preferred alternative analgesic, especially in older people.

FIG. 6.21 The relative selectivity of a range of non-steroidal anti-

inflammatory drugs for COX-1 and COX-2. From Thompson SA,
Courtney PM, and Fillingham YA (2023) Complications in
orthopaedics: adult reconstruction, Fig. 3.4. New Delhi: Elsevier.

Aspirin
Aspirin is currently used in medical practice mainly as an antithrombotic agent, and its
prior use as an anti-inflammatory has largely fallen out of favour because of adverse
effects. Aspirin is highly selective for platelet COX-1 and accumulates selectively in
platelets. At much lower doses (75 mg/day) than are needed for effective anti-
inflammatory action, it gives prolonged inhibition of platelet activity by irreversibly
blocking platelet COX-1, permanently preventing it from producing the pro-clotting PG
TXA2. This means the effects of aspirin last for the lifespan of the platelet (about 10
days).

Pharmacokinetics
Aspirin (acetylsalicylic acid) is a pro-drug and is rapidly broken down in the plasma and
the liver to release the active agent, salicylic acid. Oral doses are rapidly and completely
absorbed. Because it is an acidic drug, it is not ionised in the stomach and so there is
some gastric absorption; however, most is absorbed in the small intestine. The plasma
half-life of acetylsalicylic acid is less than 20 minutes, and the half-life of salicylic acid is
3–4 h. Salicylic acid is metabolised in the liver, and the main metabolic pathway
involved is saturated at higher doses. This means that the drug can accumulate and the
half-life of the drug increases. This can happen at the upper end of the therapeutic dose
range, and so clearance times in overdose or in liver impairment can be significantly
extended. Metabolites are mainly excreted in the urine, although this is strongly
influenced by urinary pH. Normal urine is acidic, which increases the reabsorption of
salicylic acid from the filtrate back into the bloodstream (see also p. 19). Increasing
urinary pH (i.e. making it more alkaline, for example, by administration of bicarbonate)
increases urinary excretion and is a key element in the treatment of aspirin overdose.

Adverse Effects
Aspirin can cause any or all of the NSAID adverse effects described above. Because of its
antiplatelet action, it can increase bleeding times and the risk of haemorrhage; the risk
of major haemorrhage increases with age. Additionally, it can cause a condition called
Reye’s syndrome in children. This is characterised by encephalopathy and fatty liver
failure and is fatal in a high proportion of cases. It was most commonly seen in children
recovering from a viral illness and who were treated with aspirin, an observation that led
to the recommendation that it should not be used in children under the age of 12.
Implementation of this recommendation led to an immediate and dramatic fall in the
incidence of Reye’s syndrome, which is now rarely seen.

Salicylism
Aspirin toxicity (salicylism) is characterised by headache, nausea, and vomiting. There is
also hyperventilation, because aspirin directly stimulates the respiratory centre; this
increases carbon dioxide loss and causes respiratory alkalosis. Hyperventilation and
vomiting lead to dehydration. Aspirin is neurotoxic and causes a range of neurological
signs and symptoms including tinnitus, nausea, vomiting, seizures, and
cardiorespiratory depression.

Diclofenac
Diclofenac was developed in the mid-1960s as the product of rational drug design, based
on the structures of pre-existing NSAIDs. It reversibly inhibits both COX-1 and COX-2
and is available in oral and parenteral formulations, including rectal preparations and
topical gel. Its plasma half-life is around 2 h, but its duration of action is usually
between 8 and 12 h. It has been associated with higher cardiovascular risks than other
NSAIDs, probably due to a relative selectivity for COX-2 inhibition over COX-1, thus
reducing prostacyclin levels in the cardiovascular system.

Ibuprofen
Ibuprofen, synthesised by Boots in the 1960s, is now globally the most common NSAID.
It is a propionic acid derivative, not a salicylate, and reversibly inhibits both COX-1 and
COX-2. It is well absorbed orally, has a plasma half-life of about 2 h, is over 99% bound
to plasma proteins, and almost completely metabolised in the liver to inactive products.

Naproxen
Naproxen reversibly inhibits both COX-1 and COX-2 and, like ibuprofen, is a propionic
acid derivative. Its plasma half-life is between 12 and 15 h, and so can be given only
twice a day.

Piroxicam
Piroxicam is well absorbed following oral administration, is mainly metabolised in the
liver, and has a long plasma half-life (more than 30 h), which means it needs only once
daily administration. It is associated with more significant GI toxicity and serious skin
reactions than other NSAIDs and is not normally a first-choice NSAID when initiating
anti-inflammatory treatment.

Coxibs
The coxibs are COX-2 selective inhibitors and were developed in the 1990s, when it was
believed that COX-1 and COX-2 had clearly separated roles in prostaglandin production.
COX-1 was clearly associated with housekeeping functions including protection of the
stomach lining. The researchers who initially identified COX-2 could only induce their
experimental tissues to produce it by exposing the tissue to pro-inflammatory stimuli,
and so it was initially thought that COX-2 was only expressed following tissue damage
and that it was exclusively responsible for the production of inflammatory PGs. Several
drugs, including celecoxib, etoricoxib, and rofecoxib, were developed to selectively
inhibit COX-2 and released onto the global market. These agents cause less GI irritation
and bleeding than non-selective NSAIDs and so are better tolerated in longer-term use.
However, they should still be used with care in those with GI disorders because they can
exacerbate inflammatory bowel disease and increase the risk of bleeding from GI ulcers.
They are unlikely to worsen asthma but should be avoided in people with a history of
allergy to NSAIDs. As with the non-selective agents, they increase the risk of
cardiovascular events and impair kidney function, probably because they block COX-2-
mediated prostacyclin production in blood vessels. Roche withdrew rofecoxib in 2004
because clear evidence was emerging linking the drug to increased risk of heart attacks
and strokes. Celecoxib has a plasma half-life of 8–12 h and is given orally. It is well
absorbed and metabolised in the liver. Etoricoxib has a longer half-life of around 20 h
and is given once daily.

Paracetamol
Paracetamol is an effective antipyretic and is analgesic in mild to moderate pain. The
mechanism of action of paracetamol is not fully understood and although it reversibly
inhibits COX, it seems likely that other mechanisms contribute to its pharmacological
activity. It does not block COX in peripheral tissues, so it has no anti-inflammatory
action, does not irritate the stomach, and has no effect on platelets. It inhibits COX-1 in
the CNS, which may explain its antipyretic action. When paracetamol is used in
combination with an NSAID like ibuprofen, the analgesic effect is better than either
drug used alone, suggesting that paracetamol has an additional pain-relieving action
that does not involve COX inhibition. Paracetamol is metabolised in the liver and some
of its metabolites may contribute to its analgesic action by increasing activity in pain
modulation pathways in the brain, and it is possible that further research in this area
will produce new analgesic drugs.

Pharmacokinetics
Paracetamol is well absorbed when given orally or rectally. Its plasma half-life is 2–3 h
and it is metabolised in the liver; some of its metabolites may be responsible for at least
some of the analgesic action of the drug. It is generally well tolerated and is often the
preferred analgesic in children, older people, and individuals unable to tolerate NSAIDs.
Overdose, however, can lead to serious liver injury and fatal liver failure. Paracetamol is
metabolised in the liver to more than one product. Around 10% is metabolised to n-
acetyl-p-benzoquinone imine (NAPQI), which is highly hepatotoxic: it binds irreversibly
to liver proteins, causing cellular necrosis. At therapeutic levels of paracetamol, and with
normal liver function, the liver rapidly and efficiently converts NAPQI to non-toxic
compounds; this reaction requires glutathione. Liver stores of glutathione are limited,
however, and at higher paracetamol doses, the levels of NAPQI exceed available levels of
glutathione, allowing NAPQI levels to rise and cause liver injury (Fig. 6.22). The
standard treatment for paracetamol overdose is n-acetylcysteine (NAC), given orally
or intravenously. NAC increases glutathione levels and increases the liver’s ability to
clear NAPQI. It provides complete protection from liver injury if given within 8 h of
paracetamol ingestion.

Antihistamines
Histamine is an important inflammatory mediator, synthesised from the amino acid
histidine by the enzyme histidine decarboxylase and broken down via two main
metabolic pathways catalysed by diamine oxidase (also called histaminase) and
histamine N-methyl transferase respectively (Fig. 6.23).
Histamine is implicated in a range of inflammatory and allergic disorders including
atopic dermatitis and allergic rhinitis (hay fever).

Histamine
Most body tissues synthesise histamine, which has several actions in regulating
inflammatory and immune functions. It acts via four types of histamine receptor: the H1,
H2, H3, and H4 receptors. The location and distribution of these receptors varies, which
determines the effect of histamine on a specific tissue. The main actions of histamine are
as an inflammatory mediator, a regulator of gastric acid secretion, and a
neurotransmitter in the brain.
 FIG. 6.22 Metabolism of paracetamol and the hepatotoxic
metabolite NAPQI. Modified from Ha CE and Bhagavan NV (2023)
Essentials of medical biochemistry, 3rd ed, Fig. 35.9. San Diego:
Academic Press.

Histamine and Inflammation

Tissues exposed to the external environment – the skin, GI tract, and respiratory
passageways – have large populations of mast cells and therefore high histamine levels.
The strategic placement ensures that any antigen exposure or injury to these external-
facing tissues is met with a rapid and protective inflammatory response, and it explains
why allergy usually involves respiratory, cutaneous, and/or GI symptoms. Histamine is
stored in mast cells with other pro-inflammatory substances and released into the local
environment when the mast cell is activated. Basophils are another important source of
histamine. Acting on H1 receptors in the smooth muscle of blood vessels and airways
and on secretory epithelia, histamine causes vasodilation, increased vascular
permeability and swelling, pain and itch, bronchoconstriction, and increased secretions.
Drugs that block the effects of histamine at H1 receptors, e.g. chlorphenamine and
fexofenadine, are called antihistamines and are commonly used to treat allergic
inflammation. H4 receptors were only discovered in 2001 and are found mainly on
inflammatory and immune cells including lymphocytes and eosinophils, the latter of
which is strongly associated with allergy. There is increasing evidence that much of
histamine’s pro-inflammatory actions are mediated by acting on H4 receptors, and so
they are the subject of current research in the hope that H4 antagonists may offer a new
group of anti-inflammatory and immunomodulatory drugs.

FIG. 6.23 Synthesis and breakdown of histamine. Modified from

Meisenberg G and Simmons WH (2012) Principles of medical
 biochemistry, 3rd ed, Fig. 16.23. Philadelphia: Saunders.

Histamine in Allergy
In allergy (immediate or type I hypersensitivity), exposure to a usually harmless antigen
stimulates an excessive and inappropriate immune response. Signs and symptoms
depend on the site of exposure to antigen and on the degree of the immune response.
Local responses, e.g. following an insect bite, include redness, swelling, itch, and pain at
the site. Inhaled allergens, e.g. in hay fever, cause swelling and increased nasal
secretions, sometimes also involving the eyes and ears. This causes runny nose, nasal
congestion, sneezing, and red, itchy eyes characteristic of the disorder. If the bronchial
tree is involved, there is bronchoconstriction and increased secretions, causing wheeze
and cough, as in asthma. Ingested substances in food allergy cause abdominal cramping,
nausea, vomiting, and diarrhoea. In the most severe form, anaphylaxis, widespread
release of histamine gives blood levels high enough to cause systemic and life-
threatening bronchoconstriction and upper airway swelling. In addition, systemic
vasodilation and loss of blood volume because of histamine-induced increased vascular
permeability reduces blood pressure and leads to profound shock, and there is usually a
widespread skin rash, urticaria, or other skin symptoms.

Histamine and Gastric Acid Secretion

Histamine release from histaminocytes in the stomach triggers gastric acid release from
parietal cells. Parietal cells possess H2 receptors, and drugs used to block this action of
histamine and to treat conditions associated with excess stomach acid are called H2
receptor antagonists. They include cimetidine and famotidine (see also Ch. 10).

Histamine as a Neurotransmitter
Histamine is a neurotransmitter in the brain, acting on H1, H2, and H3 receptors. It is
released in vomiting pathways linking the inner ear and the brain, triggering nausea and
vomiting induced by motion sickness and vertigo (see Fig. 10.13). It is also released by
a collection of nerves running from the hypothalamus to the cortex and the reticular
activating system, which are involved in regulation of the sleep-wake cycle. These nerves
are active during waking hours and the histamine they release maintains alertness, and
at night their activity stops to allow sleep. Antihistamines that cross the blood–brain
barrier are commonly used as anti-emetics (e.g. cinnarizine and cyclizine) and/or
sedatives (e.g. promethazine).
Antihistamines
Antihistamines antagonise the action of histamine at H1 receptors and are widely used
as anti-inflammatories, especially in allergic inflammation, as anti-emetics, and as
sedatives. Research in the first decades of the twentieth century demonstrated and
explained the role of histamine in allergy and anaphylaxis, and the first antihistamines
were introduced in the 1930s. Most antihistamines are available as oral preparations,
and some are available for topical application to the skin, eye, or ear. They are not useful
in the emergency treatment of anaphylaxis, because histamine is not the only mediator
involved.

First-Generation Antihistamines
Examples: chlorphenamine, cyclizine, cyproheptadine, diphenhydramine, promethazine
Diphenhydramine and chlorphenamine, which are still widely used today,
became available in the 1930s. These and other older drugs are sometimes referred to as
first-generation or sedating antihistamines because they cross the blood–brain barrier
and sedate, impair memory and cognitive function, and can decrease sleep quality.
Promethazine is particularly sedative. Additionally, they are associated with a range
of adverse effects because they block other receptor types including muscarinic
receptors and so can have significant antimuscarinic adverse effects, including urinary
retention, dry mouth, constipation, and tachycardia. First-generation antihistamines
can interfere with cardiac conductivity and cause arrhythmias, including QT
prolongation and torsades de pointes, and can cause hypotension. In general, these
agents are best avoided in older people because newer drugs are considered to be safer
and superior choices. Most have fairly long half-lives: the half-life of chlorphenamine
can vary between 12 and 40 h depending on the individual’s ability to metabolise it.
Cyclizine is used as an anti-emetic.

Second- and Third-Generation Antihistamines

Examples: cetirizine, fexofenadine, loratadine
Newer drugs, the so-called second- and third-generation antihistamines, were
developed to reduce adverse effects associated with older agents. In most circumstances,
and particularly in older people, they are preferred to the first-generation agents in the
treatment of allergic and inflammatory conditions because they have fewer side-effects
and are considered safer. Their ability to cross the blood–brain barrier is much more
limited than the first-generation agents, although some cause some sedation:
loratadine and fexofenadine are two of the least sedating agents but may still impair
co-ordination, judgement, and reaction speed in some individuals. Fexofenadine is a
third-generation agent: it is the active metabolite of an earlier second-generation drug,
terfenadine, which was withdrawn from the market because of cardiotoxicity. As a
group, they generally have a faster onset of action than the first-generation drugs. Most
have a duration of action of between 3 and 6 h and are deactivated in the liver.
Loratadine is an exception; it is converted to an active metabolite that has a plasma
half-life of around 20 h, and this drug can be given only once daily.

REFERENCES
1. Bannister K, Dickenson A.H. The plasticity of descending controls in pain:
translational probing. J. Physiol. 2017;595(13):4159–4166.
2. Melzack R, Wall P.D. Pain mechanisms: a new
theory. Science. 1965;150(3699):971–979.
3. Praveen Rao P.N, Knaus E. Evolution of nonsteroidal anti-inflammatory drugs
(NSAIDs): cyclooxygenase (COX) inhibition and beyond. J. Pharm. Pharm.
Sci. 2008;11(2):81s–110s.
4. Steed C. The anatomy and physiology of pain. Surgery. 2016;34(2):55–59.
5. Trang T, Al-Hasani R, Salvemini D, et al. Pain and poppies: the good, the bad and
the ugly of opioid analgesics. J. Neurosci. 2015;35(41):13879–13888.
6. Valentino R.J, Volkow N.D. Untangling the complexity of opioid receptor
function. Neuropsychopharmacology. 2018;43:2514–2520.

Resources
Church M.K, Church D.S. Pharmacology of antihistamines. Indian J.
Dermatol. 2013;58(3):219–224.
Emanuel M.B. Histamine and the antiallergic antihistamines: a history of their
discoveries. Clin. Exp. Allergy. 1999;29(S3):1–11.
Laight D. Accounting for cardiovascular risk when prescribing
NSAIDs. Prescriber. 2018:15–20.
Thangam E.B, Jemima E.A, Singh H, et al. The role of histamine and histamine
receptors in mast-cell mediated allergy and inflammation: the hunt for new
therapeutic targets. Front. Immunol. 2018;9:1873.
7: Drugs and Cardiovascular Function

Introduction

The Myocardium
Contractility of the Myocardium
The Cardiac Conducting System
Autonomic Control of the Cardiovascular System
Sympathetic Activity and Cardiovascular
System Function
Parasympathetic Activity and Cardiovascular
System Function
Drugs and the Heart
Drugs That Affect Cardiac Contractility
Sympathetic Agonists
Sympathetic Antagonists

Calcium-Channel Antagonists
Digoxin
Phosphodiesterase Inhibitors
Cardiac Arrhythmias
The Cardiac Action Potential
The Aetiology of Cardiac Arrhythmias
Anti-Arrhythmic Drugs
Class I Agents

Class II Agents
 Class III Agents
Class IV Drugs
Anti-Arrhythmic Drugs Not Covered in the
Vaughan Williams System
Drugs and Blood Vessels
Blood Vessel Anatomy and Blood Vessel Diameter

Control of Systemic Blood Pressure

Vasodilators
Vasodilators and the Sympathetic Nervous
System
Nitrates
Ca2+-Channel Antagonists
K+-Channel Openers
Drugs and the Renin–Angiotensin–Aldosterone System
Angiotensin-Converting Enzyme Inhibitors
Angiotensin-Receptor Antagonists
Renin Antagonist
Endothelin-Receptor Antagonists

Ischaemic Heart Disease

Ischaemic Heart Disease and Myocardial Infarction
Drugs Used to Treat Ischaemic Heart Disease
Vasodilators
β-Blockers
Statins
Antithrombotic Drugs
Haemostasis

Platelets and Clotting

 The Blood-Clotting Cascade
Natural Anticoagulants
Anticoagulants
Vitamin K Antagonists
Heparin
Direct Thrombin Inhibitors

Factor Xa Inhibitors
Antiplatelet Drugs
Aspirin
Adenosine-Receptor Antagonists
Dipyridamole
Fibrinolytic Drugs
The Fibrinolytic System
Haemostatic Drugs

F OCUS ON

Focus on: Drug Treatment of Heart Failure p. 134

Focus on: The Vaughan Williams Classification of Anti-Arrhythmic drugs p.
137
Focus on: Hypertension p. 145

Introduction
Worldwide, cardiovascular disease, including coronary heart disease and stroke, is the
most common non-communicable disease. The morbidity, mortality, and economic cost
imposed on healthcare systems by this disease burden is enormous. In this chapter, the
main groups of drugs used to treat some important cardiovascular disorders are
described and related in the Focus sections to their use in specific conditions. Although
the material here is divided for convenience into drugs acting on the heart and drugs
acting on blood vessels, cardiovascular physiology is an integrated balance of both
cardiac and blood vessel activity, and many drugs discussed below affect the function of
both.

FIG. 7.1 The layers of the heart wall. Modified from Waugh A and
Grant A (2020) Ross & Wilson anatomy and physiology in health
and illness, 14th ed, Fig 5.9A. Oxford: Elsevier.

The Myocardium
The layers of the heart wall are shown in Fig. 7.1. The heart chambers, and the valves
that control flow through the heart and into the aorta and pulmonary arteries, are lined
with a single-cell thick endothelium. This provides a smooth, glossy surface to facilitate
low-friction, non-turbulent blood flow. The outer layer, the pericardium, is a protective
double membrane enclosing the pericardial sac, which contains pericardial fluid to
lubricate the beating of the heart. The middle layer, the myocardium or heart muscle, is
the thickest layer and is composed of branched cardiac myocytes which are structurally
and functionally different from smooth and skeletal muscle cells.

Blood Supply to the Myocardium

The myocardium receives about 5% of the cardiac output via the coronary arteries,
which open from the aorta just above the aortic valve where the aorta arises from the left
ventricle. The oxygen needs of the myocardium are high: at resting heart rates,
myocardial oxygen consumption is 8 mL of oxygen per minute per 100 g of tissue. This
rises to 70 mL of oxygen per minute per 100 g during strenuous exercise. For
comparison, the brain consumes 3 mL of oxygen per minute per 100 g tissue, and
contracting skeletal muscle uses 50 mL of oxygen per minute per 100 g of tissue.

Contractility of the Myocardium

As with other muscle types, the myocardium needs calcium (Ca2+) for contraction. Fig.
7.2 shows the mechanism by which stimulation of the cardiac myocyte, e.g. by
sympathetic nerve activity or by sympathomimetic drugs, increases Ca2+ levels in the
cell. Sympathetic nerves release noradrenaline at the axon terminal, which binds to
postsynaptic β1-adrenoceptors and activates a pathway that generates cyclic AMP
(cAMP). cAMP opens Ca2+ channels in the myocyte membrane, allowing Ca2+ to enter
the cell from the extracellular fluid. This triggers release of much larger quantities of
Ca2+ from the sarcoplasmic reticulum, the organelle that stores the cell’s Ca2+.
Intracellular Ca2+ levels rise rapidly, which activates the actin–myosin proteins that
generate contraction. Certain drugs, e.g. digoxin, increase Ca2+ levels and cell
contraction by mechanisms other than cAMP stimulation (see Fig. 7.8). Drugs that
increase Ca2+ levels in the myocyte increase the contractility of the heart, and drugs that
reduce them reduce cardiac contractility.
 FIG. 7.2 The importance of calcium in initiating cardiac myocyte
contraction.Sympathetic stimulation increases cyclic AMP levels in
the cell, which opens calcium channels in the cell membrane. Rising
calcium levels trigger release of more calcium from intracellular
stores and activate actin and myosin.

The Relationship Between Cardiac Output, Preload, and Afterload

Key Definitions

• Cardiac output (CO):

the volume of blood one ventricle ejects in 1 minute

• Stroke volume (SV):

the amount of blood ejected by the ventricle in a single contraction

 • Preload:

the degree of stretch in the ventricular wall just before it contracts

• Afterload:

the resistance against which the ventricle must push to eject blood into the
circulation

• End-diastolic volume:

the volume of blood in the ventricle immediately before it contracts

Cardiac output is calculated by the following equation:

where HR is heart rate and SV is stroke volume. Factors, including drugs, that
increase or decrease either Heart rate or SV consequently affect cardiac output, although
when functioning normally, the cardiovascular system (CVS) makes appropriate
adjustments to maintain cardiac output if one parameter changes. For example, in a
warm environment, peripheral blood vessels dilate to increase heat loss through the
skin, which reduces systemic blood pressure (BP). To maintain blood flow to the tissues,
sympathetic stimulation increases heart rate to compensate and maintain cardiac
output. Cardiac output is an important determinant of BP. Falling cardiac output tends
to reduce BP, and rising cardiac output tends to increase it.
Preload is the degree of stretch in the ventricular wall just before it contracts and is
mainly determined by the volume of blood in the ventricle, called the end-diastolic
volume (EDV, Fig. 7.3). The higher the EDV, the more stretched the ventricular wall
and the higher the preload. The EDV in turn is determined by the venous return. The
more blood returning to the ventricle through the venous system, the fuller the ventricle
is and the more work it must do to eject it. In the healthy ventricle, increasing EDV
actually increases the force of contraction because the increased blood volume stretches
the myocardium, and as with other muscle tissue, a degree of stretch increases the force
of muscular contraction. This ensures that the myocardium adjusts its contractility to
match the amount of work it must do to eject the blood from the heart chambers. Drugs
that reduce preload, e.g. β-blockers, reduce cardiac workload but can reduce cardiac
output.
Afterload is the pressure against which the ventricle must push to eject blood into the
arterial system (Fig. 7.3). This increases when arterial BP is high, either because of high
circulating blood volume or because there is increased vasoconstriction in the peripheral
arterial networks. Drugs that reduce afterload, e.g. vasodilators, reduce cardiac
workload and increase cardiac output.

The Cardiac Conducting System

The heart possesses the property of autorhythmicity, meaning that it generates its own
action potentials and is not dependent on external signals to trigger contractions. The
main pacemaker is the sinoatrial (SA) node, located in the upper wall of the right
atrium. Heart rhythms originating here are called sinus rhythms. The SA node is a group
of electrically active but unstable cells, which depolarise spontaneously and regularly,
generating the impulses that spread through the heart muscle along a network of
specialised conducting fibres to trigger each heartbeat (Fig. 7.4). Depolarisation is
highly dependent on the opening of Ca2+ channels in the SA nodal cells, allowing Ca2+
from the extracellular fluid to enter and intracellular Ca2+ levels to rise. This explains
why Ca2+-channel blockers reduce HR when in sinus rhythm. The intrinsic discharge
rate of the SA node is around 120 bpm, but the resting heart rate is usually much slower
than this because the vagus nerve (cranial nerve X), a parasympathetic nerve, exerts a
continuous inhibitory influence. This is called vagal tone, and this action explains why
some drugs that block the action of the parasympathetic nervous system, including
drugs with antimuscarinic side-effects, increase heart rate. Increased sympathetic
activity and the action of a range of hormones, e.g. thyroxine and adrenaline,
increase the rate of SA nodal firing and increase heart rate.
FIG. 7.3 Preload and afterload. Modified from Irwin S and Tecklin
SJ (2005) Cardiopulmonary physical therapy: a guide to practice,
4th ed. St. Louis: Mosby.
 FIG. 7.4 The conducting system of the heart. Modified from
Waugh A and Grant A (2020) Ross & Wilson anatomy and
physiology in health and illness, 14th ed, Fig 5.9A. Oxford: Elsevier.

Travelling along a specialised network of conducting fibres within the myocardium,

each impulse from the SA node spreads through the atria and via the atrioventricular
(AV) node and bundle branches to the Purkinje fibres in the ventricles. This produces
co-ordinated and synchronous contraction, starting in the atria and spreading to the
ventricles. Impulse conduction slows as it travels through the AV node, to allow the atria
to finish emptying into the ventricles before ventricular contraction begins.

Secondary Pacemakers
The SA node is the primary pacemaker in the heart because it spontaneously discharges
faster than any other area of the conduction system. However, if the SA node fails or if
the conduction pathway carrying its impulses to the AV node are blocked or damaged,
the AV node can take its place, discharging much more slowly (40–60 times per
minute). This gives the heart a backup pacemaker, which preserves life, although an
heart rate so slow greatly limits exercise tolerance. Like the SA node, the AV node is
supplied by the vagus nerve (parasympathetic input), which slows conduction between
atria and ventricles; sympathetic stimulation increases the rate and frequency of AV
conduction. As with the SA node, AV node depolarisation requires increased Ca2+ levels
in its cells. This is achieved by the opening of Ca2+ channels in the nodal cell plasma
membranes, allowing Ca2+ to enter from the extracellular fluid, and so Ca2+-channel
blockers, which prevent Ca2+ entry, effectively delay AV conduction speeds.
Sometimes, an area of tissue somewhere in the heart may develop abnormal
pacemaker activity and, by generating its own action potentials, it can disrupt normal
conduction pathways and interfere with normal cardiac contraction. The abnormal
tissue is called an ectopic focus, and ectopic beats are a common cause of arrhythmia.

Autonomic Control of the Cardiovascular System

The autonomic nervous system (ANS) regulates physiological processes not under
conscious control and is described on p. 45. Autonomic input to the heart and blood
vessels is a very important contributor to cardiovascular function, and several important
drugs exert their clinical effect either by enhancing or inhibiting it. Fig. 7.5 (see also
Figs. 4.4A and B) summarises the autonomic nerve supply to the heart and blood
vessels, identifying the receptor subtypes present at each site and the neurotransmitters
released at each synapse. Both sympathetic and parasympathetic pathways from the
central nervous system (CNS) to the heart and blood vessels contain two nerves, which
synapse at a ganglion. The neurotransmitter released at both sympathetic and
parasympathetic ganglia is acetylcholine (ACh) acting on nicotinic receptors on the post-
synaptic neurone. Post-synaptic neurones in the sympathetic pathways release
noradrenaline at their target organs, but the receptor subtypes differ between the heart
and blood vessels: the heart has β1-adrenergic receptors, and blood vessels have mainly
⍺1 adrenergic receptors, although some also have β2-receptors. Post-synaptic
parasympathetic neurones release ACh at the target tissue, which acts on muscarinic
receptors.
 FIG. 7.5 Summary of the autonomic nerve supply to the heart and
blood vessels, showing receptor types and
neurotransmitters.Sympathetic supply in red, parasympathetic
supply in blue. Most blood vessels have no parasympathetic blood
supply.

Most blood vessels have only sympathetic supply, which usually causes
vasoconstriction (e.g. in the gastrointestinal tract and the skin). In some blood vessel
beds, however, for example the coronary arteries, sympathetic activity causes
vasodilation to supply the myocardium in times of stress.

Sympathetic Activity and Cardiovascular System Function

Sympathetic activity increases in times of stress (flight or fight). Increased activity in
sympathetic nerve fibres supplying the SA node increases the heart rate (positive
chronotropy), and nerve fibres supplying the myocardium increase the strength of
contraction (positive inotropy) via release of noradrenaline acting on β1-receptors.
Sympathetic stimulation of blood vessels via their ⍺1 receptors usually causes
vasoconstriction. Sympathetic activity stimulates the renin–angiotensin–aldosterone
system (RAAS, see Fig. 7.13), causing general vasoconstriction and water and sodium
retention. This in turn increases circulating blood volume and increases BP.
 The hormone adrenaline, which is closely related to noradrenaline (see Fig. 4.12),
is released from the adrenal cortex and has exactly the same activity on adrenergic
receptors as noradrenaline. Drugs that stimulate adrenergic receptors are called
sympathomimetics.

Parasympathetic Activity and Cardiovascular System Function

Parasympathetic activity predominates over sympathetic activity when at rest (rest and
digest). Increased activity in parasympathetic nerve fibres supplying the SA node slows
the heart rate (negative chronotropy) and, in parasympathetic nerve fibres supplying the
myocardium reduce the strength of contraction (negative inotropy), via release of ACh
acting on muscarinic receptors. Most blood vessels have no parasympathetic blood
supply, but those that do, including salivary and digestive glands, dilate in response to
parasympathetic stimulation.

Drugs and the Heart

Key Definitions

• Positive/negative inotrope:

a drug that increases/decreases the strength of cardiac contractions

• Positive/negative chronotrope:

a drug that increases/decreases heart rate

Drugs That Affect Cardiac Contractility

Drugs with positive inotropic and/or positive chronotropic effects can improve heart
function in a range of conditions including heart failure, shock, and some
cardiomyopathies. Drugs that reduce cardiac contractility are used to reduce the
workload and oxygen consumption of the heart in conditions such as angina.
Drugs with positive chronotropic and/or inotropic activity may act by increasing Ca2+
levels in the myocyte by one of a few mechanisms. Conversely, drugs with negative
inotropic and/or chronotropic activity are often associated with reduced intracellular
Ca2+.

Sympathetic Agonists
Examples: adrenaline, dobutamine
Sympathomimetics that stimulate cardiac β1-receptors have positive inotropic and
chronotropic effects. β1-receptors in the cardiac myocyte membrane are linked to
biochemical pathways in the cell that generate cAMP, which activates a range of
processes that facilitate contraction, including opening Ca2+ channels in the cell
membrane. The Ca2+ that enters the cell stimulates further Ca2+ release from the
sarcoplasmic reticulum, activating the intracellular contractile mechanism (Fig. 7.6).
Sympathomimetics also cause vasoconstriction, partly by a direct action on ⍺1 receptors
on blood vessels, but also via the vasoconstrictor action of angiotensin II, released by
activation of the RAAS (see Fig. 7.13). This increases BP, which is further enhanced by
RAAS-induced fluid retention and increased circulating blood volume.
Adrenaline acts at both ⍺- and β-receptors and so affects the heart and blood
vessels, and is used in acute cardiac emergencies including cardiac arrest, as well as in
anaphylaxis. Dobutamine is more active on β-receptors than ⍺-receptors, so it has
more effect on the heart than the vasculature and is used to support heart function in a
range of situations including cardiogenic shock.
β2-agonists, used as bronchodilators in asthma and other obstructive airways
disorders, are discussed on p. 164.

Pharmacokinetics
Sympathomimetics should either be avoided completely or used very carefully with
other drugs that increase sympathetic neurotransmitter levels, including amitriptyline
and doxepin, because their common action of increasing sympathetic activity increases
preload and afterload, placing additional strain on the heart. Adrenaline is used by
injection or by infusion. When given intravenously, it is rapidly removed from the
bloodstream and taken up into sympathetic nerves, so it has a rapid onset of action but
its duration of action is short. It is mainly metabolised in the liver and its breakdown
products are excreted in the urine. It is a powerful vasoconstrictor because it also
activates ⍺1 receptors in blood vessels, which helps to slow its absorption and extend its
duration of action when given intramuscularly. Dobutamine has a very short half-life
of around 2 minutes and is given by intravenous infusion.

Adverse Effects
Sympathomimetics increase the risk of cardiac arrhythmias and can cause tachycardia
and hypertension. They increase the workload and the oxygen requirements of the heart
and can precipitate angina in people with pre-existing cardiac ischaemia. Other adverse
effects related to their sympathetic action include palpitations, cold fingers and toes
(Raynaud’s phenomenon), hyperglycaemia, and tremor.

FIG. 7.6 The action of β1-agonists on cardiac myocytes.The β-

receptor is linked to pathways that increase cyclic AMP levels, which
in turn increases intracellular calcium levels and activates actin and
myosin contractile filaments.

Sympathetic Antagonists
A wide range of drugs is available to block sympathetic effects at both ⍺- and β-
receptors.

⍺-Adrenergic Antagonists (⍺-Blockers)

Prazosin and doxazocin (see below) are selective ⍺1-blockers, and effectively block
sympathetic-mediated vasoconstriction, causing widespread vasodilation and a rapid
fall in BP. Some adrenoreceptor antagonists, e.g. labetalol and carvedilol (see below),
block both ⍺- and β-receptors.

β-Adrenergic Receptor Antagonists (β-Blockers)

β-blockers reduce heart rate, cardiac contractility, and cause vasodilation by reducing
the influence of the sympathetic nervous system on the heart and blood vessels. They
also inhibit sympathetic activation of the RAAS. They are used in hypertension, angina,
and some arrhythmias. The family of β-blockers includes agents that non-selectively
block two or more β-receptor subtypes, e.g. propranolol, which blocks β1-, β2-, and β3-
receptors, as well as drugs with a degree of selectivity for particular subtypes, e.g.
atenolol, which is relatively selective for β1-receptors. It is important when choosing a
β-blocker for use in cardiac conditions to be aware that non-selective agents block both
β1- and β2-receptors, widening the potential range of adverse effects. Agents that
selectively block β1-receptors are referred to as cardioselective. Some β-blockers, e.g.
labetalol and carvedilol, also block ⍺1-receptors on blood vessels and so can cause
vasodilation, which may be beneficial, for example in hypertension. It is important to
note that although subtype-selective agents are preferentially active on one subtype,
they also affect other subtypes, usually in a dose-dependent manner; for example,
cardioselective agents such as atenolol may also cause bronchoconstriction by blocking
β2-receptors in the airways, especially at higher doses (Fig. 7.7).

β-Blockers and Blood Glucose Control

β-blockers can interfere with regulation of blood glucose levels. Sympathetic stimulation
increases blood glucose, because in a fight-or-flight situation, key body tissues such as
the heart and skeletal muscle need a good energy supply. Sympathetic stimulation of β2-
receptors in the pancreas inhibits insulin release, which allows blood glucose levels to
rise. β-receptor blockade can therefore cause hypoglycaemic episodes and particular
care must be taken in diabetes. In addition, β-blockers can mask the signs of an
impending hypoglycaemic episode, which can be troublesome for some diabetics.
Falling blood glucose levels reflexively activate the sympathetic nervous system,
producing a range of symptoms including increased heart rate, tremor, irritability, and
sweating, signalling potential hypoglycaemia. This early warning system is blunted or
absent in the presence of β-blockers.
 FIG. 7.7 The effects of β-receptor blockade on the heart and
airways.

Hypoglycaemia secondary to β-blockers can be treated with glucagon (p. 85). β-

blockers can also cause hyperglycaemia, mainly in type 2 diabetes, probably because
they block insulin release from the pancreas.

β-Blockers and Bronchoconstriction

Non-selective β-blockers block not only cardiac β1-receptors, but also the β2-receptors
found in the airways, which cause bronchodilation. Blockade here can cause significant
airflow restriction in susceptible people, including asthmatics (Fig. 7.7).

β-Blockers and the Renin–Angiotensin–Aldosterone System

The sympathetic nervous system activates the RAAS (see Fig. 7.13), causing systemic
vasoconstriction and increasing renin release and sodium and water retention. This
increases circulating blood volume and increases BP. β-blockers blunt the effects of the
RAAS, an important contribution to their overall antihypertensive effect.

Pharmacokinetics
Some β-blockers, including propranolol, pindolol, and labetalol, are more fat-
soluble than water-soluble, and so enter liver cells and are metabolised. Others, like
atenolol and sotalol, are more water-soluble, and so are less well metabolised in the
liver and depend upon renal function to clear them from the bloodstream. The half-lives
of β-blockers is generally short, between 2 and 12 hours, and there are sustained-release
preparations available to extend the duration of action of each dose.
Adverse Effects
Many of the main adverse effects of β-blockers relate to reduced sympathetic nervous
system activity. There may be hypotension and bradycardia. β-blocker-induced
bradycardia can be treated with glucagon, which increases Ca2+ levels in cardiac
myocytes by increasing cAMP levels and has positive inotropic and chronotropic effects.
β-blockers depress myocardial contractility and so should be used very carefully in heart
failure. They interfere with cardiac conduction and can cause arrhythmias and should be
used cautiously if at all in heart block. They can cause cold hands and feet because they
block β2-receptors on blood vessels, which normally mediate vasodilation and maintain
blood flow. This may be less common when cardioselective β1-antagonists are used than
with non-selective agents. They interfere with lipid and glucose metabolism and can
cause weight gain and fatigue. The more lipid-soluble drugs, e.g. propranolol and
metoprolol, cross the blood–brain barrier and cause CNS side-effects, including vivid
dreams, nightmares, and other sleep disturbances. This is less common with the more
water-soluble agents like atenolol.

Non-selective β-blockers
Examples: propranolol, sotalol, pindolol, oxprenolol
Some non-selective β-blockers, including pindolol and oxprenolol, weakly
stimulate β-receptors when they bind; this gives them a degree of sympathomimetic
activity. Although the ability of a β-blocker to mildly stimulate β-receptors may seem
counterproductive, it does mean that the side-effects of these drugs can be attenuated;
bradycardia and cold extremities, for example, can be less marked. Propranolol has an
additional action in the heart: it has an anaesthetic-like action on the sinoatrial node,
which may be important when used to treat cardiac arrhythmias.

Cardioselective β-Blockers
Examples: atenolol, bisoprolol, metoprolol
Cardioselective (β1-selective) agents may cause fewer β2-blockade related side-effects,
including cold extremities. However, they are more likely to prevent the hypoglycaemia-
induced tachycardia that warns many people with diabetes, particularly type 1, of falling
blood glucose levels.

Calcium Channel Antagonists

Also called Ca2+-channel blockers, these drugs block Ca2+ channels in cardiac myocytes
and in smooth muscle cells, which prevents the rise in intracellular Ca2+ essential for
contraction (Fig. 7.2). Ca2+-channel blockers fall into two main groups, according to
their relative selectivity for cardiac muscle or for vascular smooth muscle. Agents acting
preferentially on vascular smooth muscle are the dihydropyridines and include
nifedipine, felodipine, and amlodipine, used in hypertension and angina. By
relaxing vascular smooth muscle, these drugs cause systemic vasodilation, reducing BP,
cardiac workload, and cardiac output consumption. They dilate the coronary arteries,
improving blood flow to the heart.
Cardioselective Ca2+-channel blockers include verapamil and diltiazem, used to
treat cardiac arrhythmias, angina, and hypertension. They slow the heart rate, slow the
speed of impulse transmission through the heart’s conducting system, and cause
vasodilation. cardiac output falls because of the fall in heart rate and reduced cardiac
contractility, and because of this and the vasodilator effect of these drugs, BP falls.

Pharmacokinetics
Amlodipine has a long half-life of 30–50 hours because it is slowly absorbed and
poorly metabolised. Felodipine has a half-life of 11–16 hours because it is heavily
plasma protein-bound. Most drugs in this group, however, have relatively short half-
lives (nifedipine, 2 hours; verapamil, 4 hours), and sustained-release preparations
are available to maintain therapeutic plasma levels. Most are extensively metabolised in
the liver, and enzyme inducers such as rifampicin and St. John’s wort can increase
their metabolism and reduce their effectiveness. On the other hand, enzyme inhibitors
like ketoconazole and grapefruit juice can reduce metabolism of the Ca2+ antagonist
and elevate blood concentrations to potentially toxic levels. The Ca2+-channel blockers
themselves interfere with the metabolism of a large number of other drugs.

Adverse Effects
Most Ca2+-channel blockers, except amlodipine, reduce cardiac contractility and can
precipitate or worsen heart failure. Verapamil is the most likely to do this. There may
be bradycardia and poor exercise tolerance because the heart cannot respond adequately
to the demands of exercise. Relaxation of GI smooth muscle causes gastric acid reflux
and constipation. Vasodilation causes headache, facial flushing, and pooling of blood,
especially in leg veins. This in turn causes oedema of the feet and ankles.

Digoxin
Cardiac glycosides, including digoxin and digitoxin, are a group of plant-derived
organic compounds related to steroids. Digoxin, the main agent in clinical use, was
originally extracted from the purple foxglove (Digitalis purpurea) and is still extracted
from plants of the foxglove family because this is cheaper than manufacturing it. It is
used mainly in heart failure and in some atrial arrhythmias. The doctor credited with
first demonstrating its clinical effectiveness in heart failure was William Withering, who
in 1795 published an account of his use of foxglove extracts in a range of patients,
including those with dropsy (oedema), a common consequence of heart failure.
Digoxin blocks the Na+/K+ pump in the cell membrane. This pump maintains the
ionic gradient across the membrane so that it remains electrically excitable. It
continually pumps potassium ions into the cell in exchange for Na+ ions. By blocking the
Na+/K+ pump, digoxin increases Na+ levels in the cell (Fig. 7.8). This excess Na+ is
pumped out of the cell using a pump which exports Na+ and imports Ca2+. This
therefore increases intracellular Ca2+ levels, which increases myocyte contractility and
the strength of cardiac contraction. Digoxin improves ventricular contractility and
improves heart function in heart failure.

FIG. 7.8 The mechanism of action of digoxin.

 Digoxin stimulates the vagal nerve, increasing parasympathetic activity in the heart:
this action slows electrical discharge from the SA node and reduces the speed of impulse
transmission through the AV node. This slows the heart down, so that although digoxin
has a positive inotropic effect, it is a negative chronotrope. This reduces the heart’s
workload and oxygen consumption, useful in the failing heart and when treating
arrhythmias featuring tachycardia, such as atrial fibrillation.

Pharmacokinetics
Digoxin is given orally and is generally well absorbed. Some antibiotics, including
erythromycin and gentamicin, destroy microbes in the GI tract that normally
deactivate oral digoxin and can significantly increase absorption and blood levels.
Digoxin is very water-soluble, and so is poorly metabolised in the liver and has a long
half-life of about 36 hours. Clearance therefore depends on renal elimination, and care
must be taken in people with reduced kidney function. It has a narrow therapeutic
index, and even small increases in plasma levels can precipitate toxicity.

Adverse Effects
Digoxin toxicity is potentially life-threatening and can develop even when plasma levels
are within the therapeutic range. Although digoxin is used to treat certain atrial
arrhythmias, it can cause a range of abnormal rhythms, including ventricular ectopic
beats, because by interfering with the Na+/K+ pump, it increases the excitability of the
myocyte membrane. It may slow down AV nodal conduction enough to cause heart
block, and cause bradycardia because of its inhibition of the SA node. One important
interaction is with diuretics, which may cause excessive K+ excretion and
hypokalaemia and are often co-prescribed with digoxin in heart failure. Hypokalaemia
increases the risk of digoxin-induced arrhythmias, so it is important to ensure K+ levels
remain within the normal range, giving K+ supplements if necessary. Digoxin also has a
range of non-cardiac side-effects, including nausea and vomiting, mainly due to
stimulation of the chemosensitive trigger zone. Other neurological effects include
dizziness, fatigue, and a yellowing of vision, the latter because of inhibition of the
Na+/K+ pump in the light-sensitive cones of the retina.

Phosphodiesterase Inhibitors
Examples: enoximone, milrinone
Phosphodiesterase (PDE) is the enzyme that breaks down cAMP (see Fig. 3.7). When
its action is inhibited, cAMP levels in the cardiac myocyte rise, Ca2+ levels increase, and
contractility improves, without increasing heart rate. PDE inhibitors improve heart
function in heart failure but can trigger potentially life-threatening ventricular
arrhythmias, seen in more than 1 in 10 patients. They are given by infusion. Milrinone
has a plasma half-life of 2 hours and depends on good kidney function for clearance
because it is not metabolised in the liver. Enoximone has a longer half-life of 8 hours
and undergoes hepatic metabolism, so should be used carefully in people with liver
impairment. Both agents cause vasodilation and possibly hypotension.

F oc us on: Drug Treatment of Heart F ailure

Heart failure is a syndrome that occurs when the heart becomes unable to meet the
needs of the body. This may be due to a disorder or disease of the heart itself that
impairs its pumping efficiency or due to a non-cardiac condition that places
additional demands on it, e.g. thyrotoxicosis or lung fibrosis. Heart failure usually
involves the ventricles, and more commonly the left because its workload is greater.
The main causes of heart failure are listed in Box 7.1.
Pathophysiology of Heart Failure
When a ventricle begins to fail, forward movement of blood becomes sluggish,
reducing blood flow through body tissues and creating back pressure in the failing
chamber and the blood vessels feeding blood into it. Left ventricular failure reduces
output of blood via the aorta to body organs, leading to systemic hypoxia. As blood
accumulates in the left ventricle, pressure rises, eventually backing up through the left
atrium and into the pulmonary veins. This increases pressure in the pulmonary
circulation, with pulmonary congestion and oedema. Right ventricular failure reduces
blood flow into the pulmonary circulation, and as blood backs up through the right
atrium, it causes congestion in the venous circulation.
Once the heart begins to fail, it usually initiates a self-perpetuating circle of events
that accelerates progressive deterioration of its function. The failing heart pumps out
less blood with each contraction, leading to a reduced cardiac output, falling BP, and
diminished perfusion of vital organs including the kidneys. This stimulates
compensatory mechanisms via the sympathetic nervous system in an attempt to
restore cardiac output, summarised in Fig. 7.9. Reduced renal blood flow activates
the RAAS (Fig. 7.13), leading ultimately to the release of angiotensin II, which causes
widespread vasoconstriction and stimulates water and Na+ retention. Both
mechanisms help to support BP, but at the expense of increasing preload and
afterload, imposing higher demands on the already failing heart. Sympathetic
stimulation releases adrenaline and increases activity in sympathetic nerve supply
to the heart, causing tachycardia and increasing the force of contraction. This
measure increases the performance of the heart in the early stages of failure, but these
additional demands increase its oxygen requirements and accelerate its deterioration.

B ox 7. 1 The M ain Causes of Heart F ailure

Myocardial infarction, usually due to coronary artery atherosclerosis

Hypertension
Valvular disease, including stenosis
Cardiac myopathy
Restrictive pericarditis
Arrhythmias
Non-cardiac disease, e.g. hyperthyroidism, chronic anaemia, pulmonary
embolism, pregnancy

Drug treatment of heart failure aims to interrupt and delay the progress of the
vicious cycle of deteriorating cardiac function. This includes reducing the workload of
the heart by blocking excessive sympathetic nervous system activity, reducing preload
and afterload, improving coronary artery blood flow to increase oxygen and glucose
supply, and supporting cardiac function with drugs that improve contractility without
increasing oxygen demands. The main drug groups used in the treatment of heart
failure are summarised in Fig. 7.10.

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme inhibitors (ACEIs) are key drugs in heart failure
because they:

• reduce circulating blood volume, reducing preload

• cause vasodilation, reducing venous return and reducing afterload
• reduce sympathetic nervous system activity.

Their pharmacology is described below. For people who cannot tolerate ACEIs,
angiotensin-receptor antagonists (ARAs) can be used; they have a similar range of
effects and their pharmacology is also described below.
Diuretics
Diuretics, e.g. bendrofluazide, furosemide, and spironolactone, are widely
used in heart failure because they promote water and electrolyte loss in the urine,
reducing oedema, pulmonary congestion, and circulating blood volume. By reducing
the volume load of the heart, the efficiency of heart contraction can be improved. Care
must be taken not to over-reduce circulating blood volume, because this reduces
cardiac output, causes hypotension, and may trigger kidney injury if renal blood flow
falls too low. The pharmacology of diuretics is discussed in Chapter 10.

FIG. 7.9 The cycle of deterioration in heart failure.RAAS, Renin-

angiotensin-aldosterone system.
 FIG. 7.10 The main drug treatment options in heart
failure.ACEIs, Angiotensin converting enzyme inhibitors; ARAs,
angiotensin receptor antagonists; PDEIs, phosphodiesterase 5
inhibitors.

Vasodilators
Vasodilators are useful in heart failure because they:

• dilate coronary arteries, improving blood supply to the myocardium

• dilate the systemic veins, reducing venous return and preload
• dilate the arterial system, reducing afterload.

The pharmacology of the main vasodilators is described below.

Digoxin
Digoxin is useful in heart failure because it slows the heart down, reducing its
workload and its oxygen needs. Slowing the heart rate gives the heart chambers time
to fill adequately and so improves contraction efficiency. It is particularly useful when
heart failure is complicated by atrial arrhythmia, because of its anti-arrhythmic
activity.
β-Blockers
These drugs block the sympathetic input to the heart, slow the heart rate, reduce
contractility, and reduce oxygen requirements. They must be used carefully, because
they depress myocardial function and may worsen heart failure; however, in low
doses they improve symptoms and reduce mortality.

Cardiac Arrhythmias
A cardiac arrhythmia is a disturbance of rate or rhythm. Some arrhythmias are very
common and do not interfere significantly with the efficiency of the heart’s pumping
action. At the other end of the spectrum, some arrhythmias are immediately life-
terminating. Arrhythmias are described according to their anatomical origin: ventricular
arrhythmias arise from the ventricles, and supraventricular arrhythmias arise either
from the atria or the AV node.

The Cardiac Action Potential

Initiation and spread of action potentials through the healthy heart are described above
(Fig. 7.4). Normal heart rhythm generated by SA nodal activity is called sinus rhythm.
In a similar way to nerve and muscle tissues elsewhere, electrical activity of the
pacemaker cells, conducting tissue, and the myocytes is generated by the movement of
electrically charged ions, specifically Na+, K+, and Ca2+, across the cell membrane,
which in turn is controlled by the opening and closing of ion channels.

Ion Movements and the Cardiac Action Potential

At rest, the distribution of ions across the myocyte membrane is not equal. Na+ ions are
concentrated outside the cell and K+ ions are concentrated inside, and this unequal
distribution is maintained by the continuous operation of the Na+/K+ pump. This
unequal distribution means that the interior of the cell is more electrically negative than
the outside, and the resting membrane potential sits at between -70 mV and -80 mV
(Phase 4, Fig. 7.11).
When the myocyte is stimulated, Na+ channels in its plasma membrane open, and
Na+ floods into the cell down its concentration gradient. The inside of the cell is now
more electrically positive than the outside, and the membrane potential is now +20 mV.
This is called phase 0 and represents depolarisation, which triggers contraction. The
myocyte is now electrically unexcitable, and unlike skeletal muscle, it is important that it
remains electrically unexcitable for a period of time so that the action potential
travelling along conduction pathways cannot travel backwards (retrograde conduction),
which would generate arrhythmias and interfere with the synchronised pumping action
of the heart. Phase 0 is therefore followed by a brief period of repolarisation (phase 1)
and an extended plateau phase (phase 2) of sustained depolarisation, during which the
myocyte remains unexcitable (refractory). The plateau phase persists for about 0.2
seconds and is caused by opening of Ca2+ channels, allowing entry of Ca2+ ions, keeping
the inside of the cell electrically positive. The Ca2+ channels then close and K+ channels
open, allowing K+ ions to rush out of the cell down their concentration gradient, which
repolarises it and returns the membrane potential to its resting value (phase 3). The
interior of the cell is now left with high levels of Na+ and less K+ but the Na+/K+ pump,
which is in continuous operation, rapidly restores this to its original state by pumping
out Na+ and importing K+. Drugs that block Na+ channels, e.g. lidocaine, and K+
channels, e.g. amiodarone, disrupt and delay these electrical changes, and are useful
anti-arrhythmic agents.
In the SA and AV nodes, although the key elements of depolarisation, plateau, and
repolarisation are present, the action potential is a different shape (see Fig. 7.13B) and
the ion that causes depolarisation is Ca2+. Ca2+-channel blockers therefore reduce
the speed of action potential conduction through the AV node and reduce the firing rate
of the SA node.
 FIG. 7.11 Representative action potential from a ventricular
myocyte, showing the four phases and relating them to the
pharmacological action of the four classes (I–IV) of anti-arrhythmic
drugs. Modified from Brown MJ, Sharma P, Mir FA, et al. (2019)
Clinical pharmacology, 12th ed, Fig. 25.1. Edinburgh: Elsevier.

Understanding the physiology of the cardiac action potential explains the mechanism
of action of the main anti-arrhythmic drugs, especially as the classification of anti-
arrhythmic agents relates to their physiological effects on the movement of specific ions
during different phases (Fig. 7.11).

The Aetiology of Cardiac Arrhythmias

The two main mechanisms responsible for arrhythmias are the establishment of re-
entrant circuits and the appearance of ectopic foci within the myocardium.

Re-Entrant Rhythms
These are common causes of arrhythmias and arise when an action potential is allowed
to establish a self-perpetuating circuit. In the healthy heart, the impulses travel together
throughout each section of tissue and cannot spread backwards or to adjacent areas
because of the long refractory period following the wavefront. Impulses that do meet
along adjacent pathways extinguish each other (Fig. 7.12A). Re-entrant circuits develop
when two parts of the myocardium are conducting at different speeds, one slower than
the other. As the slower impulse travels down its pathway, it can then excite adjacent
areas of the myocardium that have conducted at normal speed and have repolarised and
become excitable again (Fig. 7.12B). This sends impulses backwards up the normally
conducting tissue, establishing a self-perpetuating re-entrant circuit (Fig. 7.12C). Re-
entrant rhythms are common causes of tachyarrhythmias, i.e. arrhythmias associated
with fast heart rates, including atrial fibrillation and flutter and ventricular tachycardia
following myocardial infarction.

Ectopic Arrhythmias
If an area of heart muscle acquires increased automaticity, it can begin to generate
action potentials independently of normal sinus rhythm, interfering with normal
conduction pathways and co-ordinated myocardial contraction (Fig. 7.12D).

Anti-Arrhythmic Drugs
Because they interfere with electrical activity in the heart, anti-arrhythmic drugs may
themselves generate arrhythmias. By slowing the generation and transmission of
impulses in normal pathways, they may allow an ectopic focus to become dominant, or
may allow a re-entrant circuit to become established (Fig. 7.12). The risks of anti-
arrhythmic drug-induced arrhythmias is increased in people with pre-existing heart
disease, e.g. ischaemic heart disease. In addition, people with increased sympathetic
drive are at higher risk because sympathomimetics are themselves arrhythmogenic; for
example, sympathetic drive to the heart is increased in heart failure in an attempt to
maintain cardiac output. Some anti-arrhythmic drugs, e.g. sotalol, disopyramide,
and digoxin, are particularly associated with the production of arrhythmias.
 FIG. 7.12 The genesis of cardiac arrhythmias.A. Normal
conduction pathways. B–C. Re-entrant rhythms. D. Ectopic focus.

F oc us on: The Vaughan Williams Classific ation of Anti-

Arrhythmic Drugs
The standard classification of anti-arrhythmic drugs was drawn up by Miles Vaughan
Williams in 1970. The four classes reflect the main electrophysiological targets of each
group of drugs, but newer drugs do not always fall tidily into this classification
system, and some drugs have activity in more than one class.
Class I
These agents all block Na+ channels and block the influx of Na+ that depolarises the
cell (phase 0), similar to the mechanism of action of local anaesthetics (p. 69). They
all therefore slow the rate of depolarisation. There are three subgroups, classified
according to the drug binds to and dissociates from the channel, which in turn
determines the duration of the channel block.

Class Ia: quinidine, procainamide, disopyramide

Class Ib: lidocaine
Class Ic: flecainide, propafenone

Fig. 7.13A shows a typical action potential from a ventricular cell treated with a
class Ic agent, showing the shallower slope of depolarisation caused by the reduced
rate of Na+ entry into the cell. Class Ia and Ic agents are used in both supraventricular
and ventricular arrhythmias, and class Ib drugs are only effective in ventricular
arrhythmias.
Class II
Examples: propranolol, atenolol, metoprolol
Class II agents are the β-blockers, which inhibit the effect of the sympathetic
nervous system on the heart. Adrenaline and other sympathomimetics can cause
arrhythmias by stimulating both SA and AV nodal discharge, by initiating ectopic
beats and by increasing the excitability of the myocardium, and a range of
arrhythmias are at least partly due to excessive sympathetic stimulation, including
atrial fibrillation and post-MI. β-blockers delay AV nodal conduction and control
ventricular tachycardias originating from the atria and suppress discharge from
ectopic foci. Fig. 7.13B shows the effect of β-blockade on an action potential in an AV
nodal cell: the action potential is both delayed and prolonged. Class II agents are used
in both supraventricular and ventricular arrhythmias.

Class III
Examples: amiodarone, sotalol
These agents are K+-channel blockers, and so they inhibit phase 3 of the action
potential and slow repolarisation of the cardiac cells. In so doing, they delay the
restoration of the ion balance across the myocyte membrane and extend its refractory
period. Fig. 7.13C shows the effect of a class III agent on the action potential in a
ventricular myocyte. They are used in both supraventricular and ventricular
arrhythmias.
Class IV
Examples: verapamil, diltiazem
Class IV agents are the Ca2+-channel blockers. They have particular activity on the
Ca2+ channels that open to depolarise cells in the SA and AV nodes, and so reduce the
rate of SA nodal firing and slow impulse transmission through the AV node. For this
reason, they are most useful in treating arrhythmias originating in these parts of the
heart and are not effective in ventricular arrhythmias. Fig. 7.13D shows the effect of
Ca2+-channel blockers on an action potential in an AV nodal cell: depolarisation is
slow because depolarisation in AV and SA nodal cells is due to Ca2+ influx, not Na+
influx, and repolarisation is delayed.
 FIG. 7.13 The main effects of each of the Vaughan Williams
classes of anti-arrhythmic drugs on the ventricular action potential
(A and C) and on the action potential in atrioventricular nodal cells
(B and D). Modified from Waller DG and Sampson A (2018)
Medical pharmacology and therapeutics, 5th ed, Fig. 8.3. Oxford:
Elsevier.

Class I Agents
Although all class I agents block Na+ channels and so slow depolarisation in heart cells,
this class is subdivided because some have additional channel-blocking activity, and
some have more extended block than others.

Disopyramide (Ia)
Disopyramide blocks K+ channels (class III activity) as well as Na+ channels, so it not
only delays depolarisation, it slows repolarisation too and extends the action potential
and the refractory period. Along with quinidine, another class Ia drug, it is falling out
of use because of its serious side-effects.

Pharmacokinetics
Disopyramide is given orally and has a half-life of about 6 hours. It is partly metabolised
in the liver, producing a metabolite with marked antimuscarinic activity.
Adverse Effects
Antimuscarinic side-effects (reduced saliva production, bradycardia, constipation,
blurred vision) can be very troublesome. Disopyramide has a significant negative
inotropic action: it can cause or worsen heart failure and produce problematic
hypotension. It is strongly arrhythmogenic.

Lidocaine (Ib)
Lidocaine blocks Na+ channels in a use-dependent manner (see also Local anaesthetics,
p. 69). This means that it is most effective in electrically excitable cells when they are
most active and their Na+ channels are open for most of the time. Lidocaine therefore
blocks rapidly discharging, arrhythmogenic heart cells preferentially to normal tissue.

Pharmacokinetics
Lidocaine is given intravenously because if given orally, it is almost completely cleared
by the liver in first-pass metabolism. It is extensively metabolised in the liver, and some
of its metabolites are active. IV administration allows drug delivery to be rapidly titrated
against its clinical effects. Its plasma half-life is around 2 hours, but this can be longer in
liver or renal failure.

Adverse Effects
Lidocaine depresses nerve activity in the CNS and at high doses may cause drowsiness,
confusion, and convulsions.

Flecainide (Ic)
Flecainide is given orally or intravenously. Although it is used in both ventricular and
supraventricular arrhythmias, it is particularly effective in converting atrial fibrillation
to sinus rhythm.

Pharmacokinetics
Flecainide is slowly but completely absorbed following oral administration. Its plasma
half-life is around 12 hours, and there are extended-release preparations, so its action is
long-lasting.

Adverse Effects
Flecainide is contra-indicated in people who have had a myocardial infarction or have
heart failure, in whom the drug significantly increases the risk of fatal ventricular
arrhythmias. Common side-effects include oedema, dyspnoea, and dizziness.

Class II Agents
The general pharmacology of β-blockers is described on p. 47. A number of β-blockers,
including propranolol and atenolol, are used to treat arrhythmias.

Class III Agents

Sotalol
Sotalol is a β-blocker with additional class III activity: that is, it blocks K+ channels
which open to allow the cardiac myocyte to repolarise in phase 3 of the action potential.
It has significant arrhythmogenic action of its own, and so is usually only used in certain
serious arrhythmias, e.g. ventricular tachycardia.

Amiodarone
Amiodarone is widely used in a range of arrhythmias. Although its main action is by
blocking K+ channels and so is categorised as a class III drug, it has activity in all four
classifications. It blocks Na+ channels (class I), has β-blocker activity (class II), and
blocks Ca2+ channels (class IV). It can be given orally or intravenously.

Pharmacodynamics
Amiodarone is highly lipid-soluble and is extensively taken up from the blood and
stored in many body tissues. Its half-life is very long, between 7 and 8 weeks. Because its
half-life is so long, treatment is usually initiated with a large loading dose to bring
plasma levels up quickly. It is metabolised in the liver.

Adverse Effects
The incidence of side-effects with amiodarone is very high: up to 15% of patients report
side-effects in the first year of treatment, rising to 50% with longer-term use. Skin
reactions and nausea are common. Amiodarone contains about 37% iodine by weight,
and so can interfere with thyroid function, causing either hyperthyroid or hypothyroid
states. Assessing thyroid function before beginning treatment is essential. Cardiac side-
effects include arrhythmias and bradycardia. In 10% of patients, corneal deposits of the
drug cause visual symptoms including halos and photophobia. There may be irreversible
pulmonary toxicity, which carries a mortality rate of up to 10%. Neurotoxic side-effects
include peripheral neuropathy and altered taste and smell. Hepatic function should be
monitored because amiodarone can cause liver impairment.
Dronedarone
Like amiodarone, dronedarone has activity in all four Vaughan Williams classes. It
may be preferred to amiodarone because it is better tolerated and patients may be more
likely to comply with treatment.

Pharmacokinetics
Dronedarone was designed to be much less fat-soluble than amiodarone in the
expectation that its distribution throughout body tissues would be less extensive and it
contains no iodine, so it has no thyroid toxicity. It has a much shorter half-life than
amiodarone and is less arrhythmogenic.

Adverse Effects
Dronedarone shares many of amiodarone’s side-effects including pulmonary toxicity
and liver toxicity. It should not be used in heart failure because it increases mortality,
and it can cause heart failure in people with no prior history. GI symptoms, e.g.
vomiting, diarrhoea, nausea, and taste disturbances, are common.

Class IV Drugs
The general pharmacology of Ca2+-channel blockers is described on p. 132.

Anti-Arrhythmic Drugs Not Covered in the Vaughan Williams System

Adenosine
Adenosine is a small but important molecular mediator widespread in body fluids and
has a range of biological effects. It forms the core of ATP, the cell’s energy storage
molecule. Adenosine is pro-inflammatory and theophylline, an adenosine-receptor
antagonist, is used in asthma (see p. 165). In the heart, adenosine inhibits transmission
in both the SA and AV nodes and is used to terminate supraventricular tachycardia.

Pharmacokinetics
Adenosine has a very short plasma half-life (less than 10 seconds) and its duration of
action is less than a minute, so is given by rapid bolus injection.

Adverse Effects
These are common but short-lived because adenosine is so rapidly cleared from the
bloodstream. There may be bradycardia and AV block. Adenosine is a vasodilator, so
facial flushing and headache may occur. It should not be used in asthma because it can
cause bronchospasm.

Digoxin
The pharmacology of digoxin is described above. It blocks AV nodal conduction and so
is used to reduce transmission of impulses to the ventricles in atrial tachycardias,
including atrial fibrillation and atrial flutter. Because it increases Ca2+ levels in
myocardial cells, it increases excitability and can cause arrhythmias.

Drugs and Blood Vessels

The health of blood vessels has an important impact on cardiovascular function. The
ability of the arterial system to adjust vessel diameter is a major determinant of
afterload, and so contributes significantly to the workload of the heart. Damage to blood
vessel walls, for example by atheroma, can reduce blood flow to the organs they supply
and is an important cause of stroke, ischaemic heart disease (IHD), and peripheral
vascular disease. The ability of the vascular system to respond appropriately to neural
and hormonal control mechanisms is a key element in maintaining BP within normal
parameters and in adjusting blood flow to meet changing tissue needs, e.g. in exercising
muscle.

Blood Vessel Anatomy and Blood Vessel Diameter

Arteries and veins have the same three layers of tissue: an outer protective layer (the
tunica externa) and an inner lining, the endothelium or tunica intima, which is
continuous with the endocardium lining the heart and is smooth to optimise non-
turbulent blood flow (Fig. 7.14). The middle layer, the tunica media, varies
considerably in composition depending on the vessel. In large arteries, it contains a
great deal of elastic tissue to absorb the pressure wave from the heart and propel the
blood forward by elastic recoil. The large arteries divide into extensive networks of small
arterioles whose middle layers are very rich in smooth muscle. Contraction and
relaxation of this smooth muscle constricts and dilates the vessels, adjusting flow and
pressure. Because they contain so much smooth muscle and are so numerous, the
muscular arterioles are the most important blood vessel in the control of systemic BP,
and for this reason they are sometimes called resistance vessels. Their diameter is
controlled by the autonomic nervous system, although unlike most body tissues, most
blood vessels do not have both sympathetic and parasympathetic supply: most arteriolar
beds have only sympathetic nerve fibres, and sympathetic stimulation usually causes
vasoconstriction.
The Biological Activity of the Endothelium
The endothelium is a single-cell layer of flattened cells lining blood vessels. It is actively
involved in regulation of clotting, recruitment of white blood cells in tissue injury and
inflammation, and the control of blood vessel diameter. It produces several agents that
relax or contract the smooth muscle in the blood vessel wall, causing vasodilation or
vasoconstriction, as well as regulating the coagulability of the blood and the ‘stickiness’
of the endothelium, which increases in inflammation to allow white blood cells to adhere
and migrate through into the tissues. Some of the most important are listed in Table
7.1, and many are important targets for drug action. Nitric oxide (NO) is an important
vasodilator, and the nitrate vasodilators, e.g. glyceryl trinitrate (GTN), increase NO
levels in blood vessel walls, relax vascular smooth muscle, increase blood flow, and
reduce pressure. NO has antiplatelet activity and inhibits blood clotting; there is also
evidence that it reduces inflammation and the development of atherosclerotic changes
in the vascular wall. Atherosclerosis is an important contributor to blood vessel disease
and is discussed on p. 147. Some prostaglandins, notably prostaglandin I2
(prostacyclin), are vasodilators and antithrombogenic. Important vasoconstrictors
derived from the endothelium include endothelin and angiotensin II (see below),
and key drugs used in a range of cardiovascular conditions act by antagonising their
action or preventing their synthesis: for example, bosentan is an endothelin-receptor
antagonist, and losartan is an angiotensin receptor antagonist.

FIG. 7.14 The structure of arteries, veins, and capillaries. From

Naish J and Court DS (2019) Medical sciences, 3rd ed, Fig. 11.29.
 Edinburgh: Elsevier.

Table 7.1

Endothelium-Derived Mediators
Mediator Function Relevant Drugs
Nitric oxide Vasodilator; anticlotting; anti- Nitrate vasodilators increase
inflammatory nitric oxide levels
Prostacyclin Vasodilator and anticlotting Non-steroidal anti-
prostaglandin inflammatory drugs reduce
production (Fig. 6.18)
Endothelin Vasoconstrictor Bosantan blocks endothelin
receptors
Angiotensin II Produced by the enzyme Angiotensin-converting
angiotensin-converting enzyme inhibitors inhibit
enzyme acting on angiotensin production; angiotensin-
I in pulmonary endothelium; receptor antagonists block
vasoconstrictor its action

Control of Systemic Blood Pressure

BP is determined by two main factors: cardiac output and total peripheral resistance
(TPR), according to the following equation:

Cardiac output, the volume of blood ejected from each ventricle per minute, is
discussed above. TPR is determined by the degree of constriction in the arterial bed,
especially the resistance arterioles. The greater the degree of constriction in arterioles,
the higher the resistance to blood flow and the higher the BP. Vasodilation, on the other
hand, opens up the vascular bed and BP falls. Moment-to-moment control of BP is
controlled mainly by the ANS regulating heart rate, cardiac contractility, and peripheral
resistance.
Total blood volume is an additional factor influencing BP. It is usually maintained
within a narrow range, and in health varies little. Excess fluid is excreted, mainly by the
kidney, and if the body water content falls, homeostatic mechanisms conserve fluid, for
example by reducing urine volume, until intake can replace it. This is a slower, more
sustained mechanism in BP regulation because changes in total body water usually take
longer to become significant. The RAAS is fundamental to this process.

The Renin–Angiotensin–Aldosterone System

The RAAS operates closely with the sympathetic nervous system to regulate fluid
balance, peripheral resistance, and BP. The outcomes of RAAS activity include increased
Na+ and water retention by the kidney, increased circulating blood volume, a
generalised vasoconstriction, and a rise in BP.
The sequence of events involved in activation of the RAAS are shown in Fig. 7.15. The
first step is release of the enzyme renin into the bloodstream from the kidney, which is
triggered by three main factors:

• reduced blood flow through the renal blood vessels

• increased Na+ levels in body fluids
• sympathetic stimulation of the kidney, which is triggered by central mechanisms
detecting any fall in systemic BP. β-blockers inhibit this loop and help to
reduce BP by blocking this sympathetically mediated activation of the RAAS.

In the bloodstream, renin converts an inactive protein called angiotensinogen to

angiotensin I. Angiotensin I itself has little biological activity, but when it passes
through the pulmonary capillaries in the lungs, it is converted to angiotensin II. The
enzyme that catalyses this conversion is called angiotensin-converting enzyme (ACE), an
important drug target in the treatment of hypertension and some kidney disorders by
the group of drugs called ACEIs. Angiotensin II is a powerful vasoconstrictor and
increases peripheral resistance. It also stimulates release of the mineralocorticoid
steroid hormone aldosterone from the adrenal cortex. Aldosterone stimulates Na+ and
water reabsorption and promotes K+ excretion in the renal tubules, increasing Na+ and
water load, blood volume, and BP. Certain diuretics, e.g. spironolactone, are
aldosterone antagonists, used to increase Na+ and water excretion in hypertension,
heart failure, and other conditions associated with oedema (see also Chapter 9).

Vasodilators

Key Definitions

Vasodilator:
 an agent that relaxes smooth muscle in arteries and veins

Venodilator:

an agent whose vasodilator action is more pronounced in veins than arteries

Vasodilators relax vascular smooth muscle, increasing blood flow through the vessel.
They are used to reduce BP in hypertension and to reduce afterload in heart failure.
Dilation of systemic vessels improves blood supply to tissues, including the heart in
angina and systemic vessels in peripheral vascular disease and Raynaud’s disease. Most
vasodilators act on both arteries and veins, and so reduce pressure throughout the
vascular system. Exceptions include the nitrate vasodilators, which act preferentially
on veins, and hydralazine, which dilates arteries. Venodilators like nitrates are useful
mainly in heart failure, because by opening venous capacity, more blood remains in the
venous system and less is returned to the heart, reducing preload and relieving cardiac
effort. Arterial dilators are more useful in hypertension, although they reduce BP, which
can trigger reflexive sympathetic tachycardia.

FIG. 7.15 The renin–angiotensin–aldosterone system. Adapted

from Raven JPH, Raven P, Chew SL (2023) The endocrine system,
3rd ed, Fig. 6.10. Oxford; Elsevier.

Vasodilators and the Sympathetic Nervous System

Sympathetic nerves supplying blood vessels release noradrenaline, which acts on ⍺1-
receptors and usually causes vasoconstriction; ⍺1-receptors are the most common
adrenergic receptor in blood vessels. ⍺1-receptor blockade therefore causes vasodilation.
Some blood vessel beds also have β2-receptors, which cause vasodilation. β-blockers can
cause vascular side-effects by blocking these receptors: for example, propranolol
causes cold hands and feet, because it blocks the vasodilator action of the sympathetic
nervous system on β2-receptors in these vascular beds and reduces blood flow.

⍺1-Blockers
Examples: prazosin, doxazocin
⍺1-receptor blockade causes vasodilation in arteries and veins, which decreases
afterload, preload, and BP, and these drugs are used in hypertension. They are also used
to treat urinary retention associated with benign prostatic hyperplasia because they
relax the smooth muscle of the bladder neck and improve urine flow. Prazosin has also
been used to improve sleep patterns in post-traumatic stress disorder. Its half-life is
only 3 hours, whereas doxazocin’s half-life is about 12 hours. Hypotension, especially
early in treatment and in older people, is common.

Nitrates
Examples: Glyceryl trinitrate, isosorbide dinitrate
Nitrates have been used as vasodilators since the 1850s to treat hypertension and
angina. Nitroglycerine, the original nitrate, is highly unstable (it is a key component of
explosives), and early workers studying this new class of compound included Alfred
Nobel, who gave his name to the most famous prize in science, and whose first invention
was a detonator to control nitroglycerine explosions. Early work to produce a stable and
convenient form of nitroglycerine included incorporating it into chocolate, which was
nibbled at the onset of anginal pain. Nitrates increase levels of nitric oxide in smooth
muscle in blood vessel walls, producing vasodilation, reducing BP, and increasing blood
flow. Nitric oxide is the main endogenously produced vasodilator, and so has a key role
in the control of systemic vascular resistance. It lowers free Ca2+ levels inside the muscle
cell by increasing Ca2+ uptake into the storage membranes inside the cell and by
blocking Ca2+ uptake by the cell from extracellular fluids. This reduces the amount of
Ca2+ available to activate the actin–myosin contractile proteins and relaxes the muscle.
Nitrate vasodilators cause venous dilation, which reduces venous return and preload,
and arterial dilation, which reduces afterload, relieving the workload of the heart. They
dilate coronary arteries, improving blood and oxygen supply to the heart, and improve
blood flow, particularly to the ischaemic areas of the myocardium.

Glyceryl Trinitrate
GTN is an important drug in the treatment of angina. Given as a sublingual spray or a
tablet tucked under the tongue, it relieves anginal pain within minutes. Tablets lose their
pharmacological activity within 8 weeks of opening their container because GTN is
volatile and evaporates with time, but the spray formulation is stable for up to three
years. It may also be given by infusion or via a skin patch.

Pharmacokinetics
GTN cannot be given orally because it is completely eliminated from the bloodstream by
first-pass metabolism in the liver. Its plasma half-life is between 1 and 4 minutes, and it
is effective over a period of half an hour or so. Tolerance to the vasodilator effect of the
drug develops with extended administration, i.e. with infusion or with patches, and
withdrawal of the drug is needed for it to regain its effectiveness. The cause of the
tolerance is not understood, but it limits sustained use of nitrate vasodilators especially
in chronic angina. The usual management strategy is to build in a nitrate-free period
every 24 hours, usually overnight, to restore the drug’s effectiveness.

Adverse Effects
Because it is such a powerful vasodilator, GTN dilates meningeal blood vessels and
causes headaches, which can be severe. Other side-effects due to excessive vasodilation
include facial flushing and hypotension.

Isosorbide Dinitrate
This nitrate vasodilator can be taken orally, and in addition is available in slow-release
form to prolong therapeutic plasma levels. Tolerance to its vasodilator effects develops
quickly, and it is usually taken in the morning, so that its levels are low overnight and
the tolerance is reversed.

Ca2+-Channel Antagonists
Smooth muscle needs an increase in intracellular Ca2+ levels to activate contraction.
This rise is triggered by Ca2+ influx through Ca2+ channels in the smooth muscle cell
membrane. In the presence of a Ca2+-channel antagonist, e.g. nifedipine or
amlodipine, Ca2+ entry is prevented and vascular smooth muscle is relaxed. This
causes vasodilation and reduces BP. The pharmacology of Ca2+-channel blockers is
described in more detail on p. 132.

K+-Channel Openers
Some vasodilators relax vascular smooth muscle by opening K+ channels in the muscle
cell membrane and allowing extra K+ to enter. This reduces the membrane potential
(makes it more negative or hyperpolarises it, see Fig. 7.11), pulling it further away from
the activation threshold, and the muscle cell relaxes.

Minoxidil
Minoxidil is primarily an arterial dilator. It is well absorbed when given orally and is
metabolised in the liver. Its half-life is about 4 hours, but its vasodilator effect is potent
and long-lasting, which triggers reflex sympathetic compensatory mechanisms. As a
result, there is tachycardia and activation of the RAAS with Na+ and water retention,
which usually require additional treatment with a β-blocker and a diuretic, respectively.
Minoxidil is therefore not a first-line agent and is used to treat severe hypertension that
does not respond satisfactorily to other drugs. One of its metabolites stimulates hair
growth, and hirsutism is an unwanted effect, particularly in women, although the drug is
used topically to treat male-pattern baldness.
 FIG. 7.16 The beneficial effects of angiotensin-converting enzyme
inhibitors and angiotensin-receptor antagonists in cardiovascular
disease.HR, Heart rate.

Nicorandil
This vasodilator is given orally to treat angina. It is classed as a K+-channel opener, but
its vasodilator activity is partly due to its action in increasing NO levels in vascular
smooth muscle. It dilates both healthy and diseased coronary arteries, improving blood
flow to the myocardium, and causes systemic vasodilation, reducing both preload and
afterload. It has a short plasma half-life (1 hour), and its main side-effects are similar to
those of the nitrates, including headache, hypotension, lethargy, and fatigue. It may also
cause GI side-effects, including vomiting.

Drugs and the Renin–Angiotensin–Aldosterone System

The RAAS has a central role in the control of peripheral resistance and blood volume
and is the target of several important drugs used to treat hypertension and IHD.
Angiotensin-Converting Enzyme Inhibitors
Examples: captopril, ramipril, lisinopril
The first ACEI, captopril, was developed in the 1970s as the product of rational drug
design. The structure of the active site of ACE was known, and the drug development
programme that produced captopril exploited this understanding to predict which
chemical modifications to their test compounds would produce an effective inhibitor.
ACEIs are used to treat hypertension, heart failure, and diabetic nephropathy, as well as
to improve prognosis following MI. Because activation of the RAAS affects
cardiovascular function in several ways (Fig. 7.16), ACEIs and angiotensin receptor
antagonists (discussed below) have more than one mechanism of action. By blocking the
production of angiotensin II, they cause vasodilation, mainly of arterioles, although they
act also on the venous system; this is the main reason for their very effective
antihypertensive activity. Reducing angiotensin II levels also reduces angiotensin II-
stimulated aldosterone release, which in turn reduces water and Na+ absorption by the
kidney and reduces circulating blood volume. This contributes to the hypotensive effect,
as well as reducing cardiac workload. Because angiotensin II stimulates the sympathetic
nervous system, inhibiting its production reduces sympathetic tone in the CVS, reducing
heart rate and causing vasodilation. In addition, angiotensin II stimulates the
proliferation of smooth muscle cells, and is believed to be one of the factors that
promote thickening of blood vessel walls in hypertension and the hypertrophy of cardiac
ventricular muscle in heart failure. These structural changes are called remodelling and
are compensatory responses of the muscle to increased BP. Initially they help to
maintain cardiovascular function but ultimately worsen the situation. Thickened blood
vessel walls stretch less and exacerbate rising BP, and hypertrophic cardiac muscle
demands more oxygen and interferes with effective pumping. Blocking this action of
angiotensin II is likely to help prevent remodelling and to preserve normal
cardiovascular structure and function in chronic cardiovascular disease.
ACEIs also have an important place in the treatment of diabetic nephropathy and
diabetes-related hypertension. Diabetes mellitus is strongly associated with renal
vascular disease, which in turn accelerates the development of hypertension. This
further damages the renal vasculature and promotes a cycle of deteriorating kidney
function and worsening hypertension. Angiotensin II is a key player in this because its
vasoconstrictor action increases BP in the glomerular capillaries and alters the structure
of the glomerular filter, making it more permeable and contributing to the proteinuria
and structural glomerular damage seen in diabetic people developing kidney
impairment. ACEIs and ARAs help to break this vicious circle by blocking the effect of
angiotensin II in the glomeruli and are significantly renoprotective in diabetic
nephropathy.
ACEIs must be used carefully in people with known renovascular disease because they
can cause a dramatic and dangerous fall in glomerular filtration rate (GFR). The afferent
arteriole bringing blood into the glomerular capillaries is wider than the efferent
arteriole, bringing more blood into the glomerulus than there is room for it to leave,
raising pressure in the capillaries and driving filtration across the glomerular membrane
(Fig. 7.17A). When afferent arteriolar blood flow falls because of, for example,
atherosclerosis, the kidney uses angiotensin II to constrict the efferent arteriole and
keep filtration pressure high in the glomerulus to maintain GFR (Fig. 7.17B). By
blocking angiotensin II production, ACEIs prevent the kidney from making this
compensatory adjustment, the efferent arteriole widens, and filtration pressure falls in
the glomerular capillaries (Fig. 7.17C).

Pharmacokinetics
All ACEIs are given orally. Some, e.g. ramipril and enalapril, are pro-drugs, and rely
upon activation in the liver. Half-lives vary considerably; captopril’s half-life is only 2
hours, but enalapril has a half-life of 35 hours, and its active metabolite enalaprilat is
10 hours. Lisinopril is given as an active drug and needs only once daily
administration because it has a half-life of 12 hours. Caution is needed when co-
administered with a diuretic, especially when initiating ACEI treatment, because this
can result in a sudden and potentially dangerous fall in BP.

Adverse Effects
ACEIs are contra-indicated in pregnancy because they damage the developing fetal
kidney. They can cause a range of side-effects, including allergy, electrolyte imbalances,
and significant liver impairment: liver function should be monitored and the drug
discontinued if there is evidence of liver problems. In up to 35% of patients, a dry,
troublesome cough develops, more commonly in women, which can be bothersome
enough to lead to the patient wishing to discontinue treatment. ACEI-induced cough is
not dose-related and can arise at any time after initiation of treatment. It is attributed to
the accumulation of the irritant inflammatory mediator bradykinin in the airways (Fig.
7.18). In addition to producing angiotensin II, ACE also deactivates bradykinin.
Inhibition of ACE activity allows bradykinin levels to rise, causing cough. This adverse
effect disappears when the drug is withdrawn. Increased levels of bradykinin may also
be the reason why ACEIs can cause urticaria and angioedema (sudden swelling in the
deeper layers of the skin). Although these side-effects are much rarer than cough,
angioedema is sometimes severe enough to cause dangerous tracheal obstruction.

Angiotensin-Receptor Antagonists
Examples: losartan, valsartan
Angiotensin II acts on two different receptor types, AT1 and AT2, and from a clinical
point of view the AT1 receptor is the more important because this is the subtype involved
in the main cardiovascular actions of angiotensin II. Drugs that block the AT1 receptor
therefore have a very similar range of pharmacological activity to the ACEIs, although
they do not cause cough (because ACE is still produced and is still available to break
down bradykinin). Losartan was the first orally active drug in this group, and although
its half-life is short (2 hours), metabolism produces an active metabolite with a half-life
of 10 hours, and losartan can be given once daily. As with ACEIs, ARAs should be used
carefully in people with renovascular disease and not in pregnancy.

FIG. 7.17 The role of angiotensin in maintaining glomerular

filtration rate in renal artery disease.A. The healthy glomerulus: the
afferent arteriole is wider than the efferent, maintaining filtration
pressure. B. Renovascular disease: the afferent arteriole is narrowed
by e.g. atherosclerosis, so to maintain filtration pressure, the efferent
arteriole is constricted by angiotensin II. C. Angiotensin-converting
enzyme inhibitors (ACEIs) and angiotensin-receptor antagonists
(ARAs) block this compensatory adjustment, and filtration pressure
falls.
 FIG. 7.18 Mechanism of action of angiotensin-converting enzyme
inhibitor (ACEI)–induced cough.

Renin Antagonist
The only renin antagonist currently available is aliskiren, licensed for the treatment of
hypertension. It binds to renin and prevents it from converting angiotensin I to
angiotensin II. Angiotensin II levels therefore fall and its effects are significantly
reduced. Aliskiren is given orally, and because of its long half-life (24–40 hours), it is
only given once daily and takes up to two weeks to achieve effective steady state plasma
levels. As with captopril, aliskiren was a product of rational drug design and effectively
reduces BP when used as monotherapy. Used alone, it is generally well tolerated,
although it can cause diarrhoea and hypokalaemia. However, effective control of
hypertension frequently requires concurrent use of two or more drugs, and issues have
been identified when aliskiren is combined with ARAs or ACEIs in patients with
diabetes, cardiovascular disease, or renal disease. In these patients, the rates of serious
side-effects including renal dysfunction and hypotension are high and these drugs
should therefore not be used in combination.

Endothelin-Receptor Antagonists
Endothelin is a powerful vasoconstrictor released by the endothelial lining of blood
vessels and vascular smooth muscle as part of the normal regulation of blood vessel
tone. It acts on two receptor types, ETA and ETB, and it probably causes prolonged, local
vasoconstriction, increases BP, and activates inflammatory mediators mainly through
ETA receptors. It also stimulates proliferation and fibrosis in the blood vessel wall and in
the heart, which may contribute to the remodelling damage seen in the heart and blood
vessels in cardiovascular disease and is likely to be involved in the pathogenesis of
atherosclerosis. Despite endothelin’s well-understood multifunctional role in
cardiovascular pathophysiology, endothelin antagonists have so far only proved useful
in pulmonary arterial hypertension and in treating finger ulcers in systemic sclerosis. In
pulmonary arterial hypertension, endothelin levels are consistently raised, and
endothelin-receptor antagonists improve exercise tolerance, reduce mean pulmonary
artery pressure, and delay the progression of the disease.

Bosentan
Bosentan was the first endothelin antagonist discovered, licensed in 2001, and it blocks
both ETA and ETB receptors equally. It is used to treat pulmonary arterial hypertension,
is given orally, has a half-life of around 5 hours, and is cleared by the liver and the
kidney. It is teratogenic, so is contra-indicated in pregnancy, and can cause liver
impairment, so hepatic monitoring is important and it should be avoided in all but the
mildest degrees of pre-existing liver disease. It commonly causes GI side-effects, and
because it is an enzyme inducer, it can increase the clearance rates of a range of other
drugs including warfarin, opioids, and Ca2+-channel blockers.

F oc us on: Hypertension
Hypertension is a common disorder in which sustained high BP damages the heart
and the arterial system. It is a major risk factor for cardiovascular disease and greatly
increases the risk of stroke, myocardial infarction, heart failure, cardiac arrhythmia,
and kidney disease. It is a major factor in the development of atherosclerosis (see
below) which itself is both a cause and a manifestation of cardiovascular disease. Most
cases are primary (essential) hypertension, sustained high BP with no directly
identifiable cause. Risk factors for essential hypertension include increasing age, male
sex, overweight, obesity, heredity, high salt intake, high alcohol intake, sedentary
lifestyle, and low birthweight. Fewer than 10% are directly related to another
condition; this is secondary hypertension and causes include pregnancy, renal
disease, and a range of endocrine disorders including diabetes.
Regulation of BP in health is a complex process, and a range of factors contribute,
including normal RAAS activity, normal endothelial function, cardiac function,
balanced sympathetic/parasympathetic activity, insulin resistance, and balanced
activity of a large range of hormones, cytokines, and other mediators. There is also
evidence for an inflammatory and immunological component, and it has been shown
that in hypertension, activated immune cells infiltrate the kidney and blood vessels,
both key organs in BP regulation. There is increasing evidence that much of the end-
organ damage seen in hypertension––in the kidneys, the brain, the blood vessels, and
the heart––is due to ongoing inflammation. Research into precisely which immune
cells and which inflammatory mechanisms are involved is ongoing and may lead to
novel treatments for hypertension in the future: this would be particularly useful for
the substantial subset of hypertensive people for whom conventional antihypertensive
treatment does not work.

FIG. 7.19 The mechanism of action of the main drugs used to

treat hypertension.ACEIs, Angiotensin converting enzyme
inhibitors; ARAs, angiotensin receptor antagonists; CO, cardiac
output; HR, heart rate; RAAS, renin-angiotensin-aldosterone
system; SV, stroke volume; TPR, total peripheral resistance.

Considering the multiple processes contributing to BP regulation, it is not

surprising that the pathophysiology of essential hypertension is complex. In an ideal
scenario, a single drug would be effective in reducing BP to target levels, but often
more than one agent is needed. Current treatment options for hypertension usually
centre around one or more of the parameters controlling BP as described above: SV,
HR, or TPR (Fig. 7.19).
Angiotensin-Converting Enzyme Inhibitors/Angiotensin-Receptor
Antagonists
These agents are usually first-line treatment in younger people with hypertension and
in diabetes at any age because they slow the development of diabetic nephropathy.
They reduce peripheral resistance through their vasodilator action, and they reduce
blood volume and cardiac output because they increase water and Na+ excretion.
Thiazide Diuretics
This class of diuretic is usually the preferred choice in hypertension because they have
a moderate but sustained effect on Na+ and water excretion. They may be the
preferred initial option in older people and those with any degree of heart failure
because they reduce oedema and circulating blood volume, which helps to reduce
cardiac workload. In longer-term use, diuretics also have a vasodilator action. The
mechanism of action of this is not known, but it is likely to contribute significantly to
their hypotensive effect, especially in longer-term treatment. Diuretics are considered
in more detail in Chapter 9.
Calcium-Channel Blockers
These are usually first-line treatment in older non-diabetic people with hypertension.
Their vasodilator action, mainly in the arterial system, reduces peripheral resistance.
These drugs may also reduce cardiac contractility and slow the heart, also helping to
reduce BP.
Second-Line Agents
If monotherapy is inadequate, other first-line drugs can be added (although ACEIs
and ARAs should never be co-prescribed). If this fails, other antihypertensive agents
may be added to the regimen. This may bring clinical benefit, because two or more
low-dose drugs used together can reduce side-effects compared with high-dose
monotherapy. Spironolactone, a K+-sparing diuretic (p. 177), is of proven
usefulness in hypertension resistant to standard treatments. It is an aldosterone
antagonist and increases Na+ and water excretion, suggesting that Na+ retention is an
important factor in resistant hypertension. β-blockers are generally not given unless
there are additional indications for their use, because they are less effective than the
drug groups listed above and have significant adverse effects, including in diabetes.
Other possible options may include α-blockers and aliskiren.
Adjuvant Drugs
Statins (p. 148) are commonly used in hypertension to reduce blood lipid levels and
the risk of a cardiovascular event. Low-dose aspirin (p. 121) reduces the risk of
thrombosis-related cardiovascular events in at-risk patients.

Ischaemic Heart Disease

The left ventricle pumps oxygenated blood into the aorta for distribution to all body
tissues. The coronary arteries supply the myocardium. Coronary artery disease (also
called ischaemic heart disease (IHD)), restricts myocardial oxygen supply because blood
flow through the narrowed coronary arteries is inadequate to meet the heart’s needs.
IHD is the leading cause of death worldwide and is usually caused by atherosclerotic
changes in the coronary artery wall.

Atherosclerosis
Atherosclerosis is a chronic inflammatory condition of blood vessels that causes
deposition of semi-liquid fatty material within the blood vessel wall and damages and
roughens the endothelium. The initial changes take the form of a fatty streak on the
endothelium, which enlarges and develops over a period of time to form a mature lesion,
called an atherosclerotic plaque, which progressively obstructs the vessel lumen as it
expands. The fatty streak is initiated by deposition of a form of cholesterol called low-
density lipoprotein (LDL) cholesterol in the arterial wall, which triggers ongoing
inflammation that drives ongoing injury. The main pathological features are shown in
Fig. 7.20A, and Fig. 7.20B is a photomicrograph of a coronary artery showing the
gross appearance of an atherosclerotic plaque. The plaque core is a semi-fluid
accumulation of fatty material, including cholesterol and other lipids, and infiltrated
with inflammatory cells including lymphocytes. Characteristic of these plaques are foam
cells, macrophages that have consumed large quantities of fat, which appear under the
microscope as dense foamy bubbles in the cytoplasm. Smooth muscle cells grow into the
core, and collagen and other fibrous material is deposited in the plaque. As the plaque
grows, the blood vessel lumen becomes progressively narrower and blood flow is
obstructed. The whole plaque is covered with a rough fibrous cap, which lacks the
smooth surface of healthy endothelium and increases the risk of thrombus formation.
The most advanced plaques become calcified and stiff, which makes them more likely to
rupture. If the plaque splits, exposing its fatty contents to the bloodstream, a blood clot
forms over the area of rupture, because the lipid-rich core is highly thrombogenic. This
causes sudden and immediate obstruction of the artery and is the commonest cause of
acute myocardial infarction and sudden coronary death. Fragments of this clot can also
travel in the bloodstream and lodge elsewhere, e.g. in the pulmonary circulation, which
causes a pulmonary embolism.

Risk Factors for Atherosclerosis

Some risk factors are non-modifiable, e.g. age, male sex, and heredity. Modifiable risk
factors include smoking, hypertension, hyperlipidaemia, poorly controlled diabetes, and
systemic inflammation. Not all blood lipids promote atheroma formation. LDL
cholesterol and very-low-density lipoprotein (VLDL) cholesterol, together called non-
high-density lipoprotein cholesterol, are strongly associated with atheroma, whereas
high-density lipoprotein (HDL) cholesterol transfers cholesterol to the liver for removal
from the bloodstream, an anti-atherogenic effect, and reduces the risk of
atherosclerosis. Reducing LDL cholesterol blood levels is a standard therapeutic
approach, and is proven to reduce cardiovascular events because it reduces deposition of
these lipids in arterial walls, but it is also recognised that the total cholesterol:HDL
cholesterol ratio is an important indicator of cardiovascular risk. Ideally this ratio
should be as low as possible, and values above 6 are considered high.

Ischaemic Heart Disease and Myocardial Infarction

In the early stages of IHD, with mild to moderate coronary artery obstruction, blood
flow generally meets the heart’s needs at rest or in gentle exercise, but more demanding
exercise increases its oxygen needs beyond what can be supplied through the narrowed
coronary arteries. The myocardium becomes ischaemic, metabolism shifts from aerobic
pathways to anaerobic pathways, and lactate (the physiological form of lactic acid) starts
to accumulate. This causes the characteristic pain of angina. When blood flow is below
the critical minimum needed for cell survival even at rest, the muscle cells begin to die.
This is infarction, and if a large enough portion of the myocardium is involved, the
effective beating action of the heart cannot continue and sudden death may follow.
 FIG. 7.20 Atherosclerosis.A. The main features of an
atherosclerotic plaque. B. Photomicrograph of a diseased coronary
artery. The artery lumen (A) is reduced and the fibrous cap (f) and
lipid core (x) are clearly shown. The coronary vein (V) is
adjacent. Modified from Cross S (2019) Underwood’s pathology: a
clinical approach, 7th ed, Fig. 13.4. Oxford: Elsevier.

Drugs Used to Treat Ischaemic Heart Disease

A range of lifestyle changes underpins the management of people with IHD, but the aim
of drug treatment is to reduce the heart’s workload, improve its oxygen supply, improve
exercise tolerance, and extend life. Drugs that reduce the heart rate improve coronary
artery flow, because during cardiac systole the coronary arteries are compressed by the
contracting myocardium. During diastole, however, when the heart muscle relaxes, they
open up again. Reducing heart rate increases the length of time spent in diastole and
therefore improves coronary artery flow. Drugs that reduce blood lipids, particularly
LDL cholesterol, reduce the risk of a first or subsequent coronary event.

Vasodilators
The pharmacology of the main vasodilators is discussed above, but their usefulness in
IHD and angina is threefold:

• they dilate systemic arteries, which reduces afterload and cardiac workload.
• they dilate the coronary arteries, increasing myocardial blood flow.
• they are venodilators, which pool the blood in systemic veins and reduce venous
flow to the heart, reducing preload and cardiac workload.

Ca2+-channel blockers, e.g. amlodipine, diltiazem, and nifedipine, as well as

nitrates and K+-channel agonists, e.g. nicorandil, may all be used.

β-Blockers
The pharmacology of β-blockers is described above. In IHD, they slow the heart and
therefore improve coronary artery blood flow by increasing time spent in diastole and
reduce contractility and oxygen consumption. This in turn reduces BP, further relieving
cardiac effort and alleviating the pain of angina. Cardioselective agents include
atenolol, bisoprolol, and metoprolol. Some β-blockers, e.g. pindolol and
carvedilol, also produce a degree of vasodilation, which reduces afterload and reduces
cardiac work. The drugs vasodilate via different mechanisms: pindolol weakly stimulates
β-receptors in blood vessels, and carvedilol blocks vascular ⍺-receptors.

Statins
Examples: simvastatin, atorvastatin, pravastatin
Statins were introduced in the 1980s and inhibit the liver enzyme
hydroxymethylglutaryl co-enzyme A (HMG co-A) reductase. This enzyme catalyses a
crucial step in cholesterol synthesis, so in the presence of a statin, hepatic cholesterol
production is inhibited. This in turn reduces circulating levels of non-HDL (‘bad’)
cholesterol. Statins are used in both primary and secondary prevention of cardiovascular
events like myocardial infarction and stroke: that is, in people who have never had a
cardiovascular event, and in people who have had one or more such event. They protect
against cardiovascular events even in people whose blood lipid profile is normal and are
recommended for use in type 1 diabetes even in the absence of other cardiovascular risk
factors. In addition to their effect on blood lipids, statins have additional biological
activities, including improving the health of vascular endothelium, stabilising
atherosclerotic plaques, and reducing the systemic inflammatory response, all of which
may contribute to cardiovascular protection. Statins are also used to treat primary
hyperlipidaemias and hypercholesterolemia.

Pharmacokinetics
Statins are given orally and most undergo significant first-pass metabolism. Half-lives
vary considerably between these drugs. Simvastatin and pravastatin have short half-
lives of 1–2 hours and are best taken at night because cholesterol synthesis is highest at
night. Atorvastatin has a much longer half-life of more than 30 hours.

Adverse Effects
Statins are generally well tolerated, even at high doses. Muscle pain is commonly
reported, but actual muscle damage caused by statins is rare. This may be due to statin-
induced leakage of Ca2+ from the endoplasmic reticulum within muscle cells, which may
damage the cell. People with pre-existing muscle conditions are more susceptible than
those with no such history, and exercise has been shown to reduce its incidence. Statins
may also cause liver damage, although there is evidence that certain statins may protect
against liver cancer and protect liver function in patients with pre-existing liver disease.
They may trigger diabetes in patients with predisposing factors, who should be
monitored. They are contra-indicated in pregnancy because fetal abnormalities have
been reported.

Additional Lipid-Modifying Drugs

Fenofibrate may be used with statins if blood lipid profiles remain unsatisfactory with
statins alone. Fenofibrate reduces blood fatty acid levels by activating fatty-acid
transporters in the liver, which increases their removal from the bloodstream. It may
also decrease LDL cholesterol levels and increase HDL cholesterol, but this is variable.
Fenofibrate has a long half-life of 20 hours and is given once daily. It is a pro-drug,
activated by hepatic metabolism, and mainly eliminated in the urine. Ezetimibe blocks
cholesterol uptake in the small intestine by inhibiting the cholesterol transporter in the
duodenal epithelium and reduces absorption of dietary cholesterol by about half. It has
a synergistic action when combined with statins, enhancing statin-induced
improvement in blood lipid profile, and also further reducing the systemic inflammation
seen in atherosclerosis as well as reducing the likelihood of cardiovascular events.

AntiThrombotic Drugs
Treatment with antithrombotic drugs reduces the risk of clots forming at the plaque site.
Low-dose aspirin inhibits platelet activation via blockade of platelet thromboxane A2
production (p. 152). Clopidogrel (p. 152) reduces clotting risk by irreversibly
preventing platelet aggregation. Anticoagulant therapy may also be used in for example
acutely developing coronary syndromes, in which the risk of thrombosis is significantly
elevated. Antithrombotic drugs are discussed in more detail below.

Haemostasis
Haemostasis, or blood clotting, is the physiological mechanism that converts fluid blood
to a firm, semi-solid thrombus. In health, blood remains fluid unless and until clotting is
needed to stop blood loss, but inappropriate blood clotting is an important
pathophysiological complication in a range of conditions, including myocardial
infarction, some cardiac arrhythmias including atrial fibrillation, atherosclerotic
vascular disease, serious infections and sepsis, pulmonary embolism, and stroke. There
is a range of rare, inherited disorders that increase blood coagulability, but more
common factors that increase the risk of thrombosis include pregnancy, varicose veins,
smoking, surgery, and malignant disease. Antithrombotic drugs are used when the risks
associated with clotting outweigh the risks associated with haemorrhage.

Key Definitions

• Antithrombotic:

a drug that by any mechanism prevents the formation or enlargement of blood clots

• Anticoagulant:

a drug that prevents blood clotting by inhibiting one or more clotting factors

• Antiplatelet:

a drug that prevents blood clotting by inhibiting platelet activity

• Fibrinolytic:

a drug that dissolves an existing blood clot

Platelets and Clotting

Platelets, produced in the red bone marrow, are small cell fragments packed with
clotting factors including serotonin and ADP. Platelets also contain the enzyme cyclo-
oxygenase (COX, see also p. 119). Healthy blood vessel endothelium constantly produces
anticoagulant substances including prostacyclin and nitric oxide to prevent
inappropriate clotting. However, injury to a blood vessel stimulates the endothelial cells
to produce adhesion factors, to which platelets stick. Once the platelet is attached to the
endothelium, it is activated, becomes sticky, and other platelets stick to it. Ongoing
blood clotting is a good example of a positive feedback process, accelerating clot growth
and expansion. Platelet adhesion molecules produced by an activated platelet include
receptors for fibrinogen, and fibrinogen sticking to platelets via these receptors
produces a progressively expanding fibrous network which permanently traps platelets
and red blood cells. Over the few minutes following injury, platelets therefore rapidly
accumulate and are activated, releasing their clotting factors and activating the blood-
clotting cascade. Antiplatelet drugs like aspirin and clopidogrel block blood clotting
by inhibiting platelet activity.

The Blood-Clotting Cascade

A blood clot forms because of the serial activation of a number of clotting factors
circulating in the bloodstream. Most clotting factors are enzymes produced in the liver,
and to avoid inappropriate clotting they circulate as inactive precursors which are only
activated when needed. The final event in thrombus formation is called the final
common pathway, in which Factor X (FX) activates prothrombin activator which in turn
activates the enzyme thrombin. Thrombin converts fibrinogen to fibrin (Fig. 7.21).
Fibrin forms the sturdy framework of the clot, in which red blood cells and platelets are
trapped as it grows. Some anticoagulant drugs, e.g. dabigatran, directly inhibit
thrombin and block fibrin production.

FIG. 7.21 The clotting cascade.Both the extrinsic and intrinsic

pathways lead ultimately to activation of Factor X and activation of
the final common pathway.
 The final common pathway is activated by two related pathways, the intrinsic and
extrinsic pathways (Fig. 7.21), which are usually activated simultaneously. Both require
Ca2+ and both contribute to activating FX. The intrinsic pathway is initiated when
inactive clotting factor XII (FXII) in the bloodstream comes into contact with collagen
exposed at the blood vessel wall injury site. This activates FXII, which, in co-operation
with a platelet-derived factor and clotting factors VIII and IX, produces a substance
called FX activator complex. FX activator complex activates FX, which then activates the
final common pathway. The other pathway, the extrinsic pathway, is activated when
damaged tissues release a substance called tissue factor, also called thromboplastin.
Tissue factor, in co-operation with clotting factors III and VII, produces a substance
called tissue factor complex, which then activates FX and the final common pathway.
Some anticoagulant drugs, including apixaban, directly inhibit activated FX.
Vitamin K is required for synthesis of several clotting factors, including factors II
(prothrombin), VII, IX, and X. Warfarin and phenindione are examples of
anticoagulant drugs that antagonise vitamin K.

Natural AntiCoagulants
Physiological regulation of the clotting cascade involves a few natural anticoagulants
which control clotting and normally prevent inappropriate clotting, and which also
terminate it once the bleeding episode is resolved. As mentioned above, healthy
endothelium produces anticoagulants, important contributors to the prevention of
inappropriate clotting. These include antithrombin, an inhibitor of both thrombin and
activated FX. The body produces a powerful stimulant of antithrombin activity,
heparin, which is essential to physiological suppression of the clotting process, and
which is in widespread use as an anticoagulant.

AntiCoagulants
Blood flow is slower in veins than arteries, predisposing to thrombosis, and clots that
form here have time to develop and are rich in fibrin. Because most anticoagulants
directly or indirectly reduce thrombin activation and therefore fibrin production, they
prevent thrombus development more effectively in the venous circulation than in the
arterial circulation, where clots contain higher proportions of platelets than fibrin. The
main side-effect of anticoagulant therapy is haemorrhage, and anticoagulants should
therefore be used with great care, if at all, in patients with bleeding disorders and in
those at increased risk of haemorrhage, e.g. peptic ulcer disease or hypertension.
Vitamin K Antagonists
Examples: warfarin sodium, phenindione
Vitamin K is a co-factor in one key step in the synthesis of clotting factors II, VII, IX,
and X. Co-factors are essential participants in a wide range of biochemical reactions,
and the body needs only tiny quantities because they are constantly recycled. The
vitamin K molecule is deactivated each time it is used to make a molecule of clotting
factor and must be converted back to its biologically active form in order to be used
again. Vitamin K antagonists block its reactivation, and so the vitamin remains in its
deactivated form and clotting factor synthesis stops (Fig. 7.22). Their anticoagulant
effect may take several days to develop, because although clotting factor production is
halted, the factors already present in the blood will initially ensure normal clotting.

Warfarin
Warfarin belongs to the coumarin group of anticoagulants. The first coumarin to be
discovered, dicoumarin, was isolated in 1940 from a fungus that infected cattle fodder
and was causing the animals to die from internal bleeding. Warfarin, derived from
coumarin, was originally developed as a rat poison, but found a place in clinical
medicine in the mid-1950s as a therapeutic anticoagulant. Although warfarin is an
effective anticoagulant, its use is in decline because of the development of newer, safer
agents including thrombin inhibitors and Factor X inhibitors.

Pharmacokinetics
Unlike heparin, the only available anticoagulant at the time the coumarins were being
developed, warfarin is given orally. It is well absorbed and very highly bound to plasma
proteins, so it has a long half-life of up to 48 hours. A single dose takes effect in 14–16
hours and lasts for four to five days, and at the end of a course of warfarin it takes two or
three days for clotting times to return to normal, reflecting the time required to produce
adequate levels of new clotting factors. Warfarin crosses the placenta and is both
teratogenic and haemorrhagic in the developing baby, so should be avoided where
possible in pregnancy. Warfarin is associated with a range of drug interactions. Its
antithrombotic effect is additive to that of other anticlotting drugs, e.g. aspirin,
increasing bleeding times, and great care must be taken if these drugs are used together.
Its action is potentiated by a range of drugs, e.g. amiodarone and a range of
antimicrobials, which inhibit the liver enzymes that metabolise warfarin. Its action is
reduced by enzyme inducers such as alcohol and phenytoin, which enhance the liver
enzymes that metabolise warfarin and accelerate its clearance from the bloodstream.
 FIG. 7.22 The mechanism of action of the vitamin-K
antagonists. Modified from Padmanabhan S (2014) Handbook of
pharmacogenomics and stratified medicine, Fig. 24.1. San Diego:
Academic Press.

Adverse Effects
The main side-effect is haemorrhage and bleeding times should be routinely monitored.
If bleeding times are excessively long with ongoing bleeding or significant risk of
dangerous haemorrhage, vitamin K (phytomenadione) can be given intravenously
to restore clotting factor production; it takes up to 6 hours for full effect. Alternatively,
blood clotting can be immediately restored to normal by infusion of functional clotting
factors.

Heparin
Examples: dalteparin, enoxaparin (low-molecular-weight (LMW) heparins),
unfractionated heparin
Heparin is the oldest anticoagulant in regular clinical use and is on the World Health
Organisation list of essential medicines. It was discovered in 1918 by a medical student
called L. Emmett Holt, who named it heparin because he was working with liver
extracts, although it is also produced by a range of other tissues including mast cells and
lung and blood vessel endothelium. Chemically, heparin belongs to a family of complex
sugars called glycosaminoglycans (GAGs), which are joined together to form much
larger molecules, the size of which depends on the number of individual GAG molecules
used. Heparin can therefore exist in a range of different molecular weights.
Unfractionated heparin is extracted from a range of animal sources and contains
heparin molecules with a range of molecular weights between 3000 and 30 000 kDa.
LMW heparins are separated from unfractionated heparin and contain molecules with
MW less than 7000 kDa. The molecular weight of the heparin units affects the
pharmacokinetics of the preparation, including absorption.
Heparin exerts its anticoagulant effect by binding to antithrombin. Antithrombin is
one of the key natural brakes on clotting and blocks thrombin and FX activity. Heparin
binds to antithrombin and greatly enhances its activity, further reducing the action of
thrombin, fibrin production, and clot development (Fig. 7.23).
 FIG. 7.23 The action of heparin.

Pharmacokinetics
Heparin must be given by injection because heparin molecules are too large and heavily
charged to be absorbed across the wall of the GI tract. It is used intravenously or
subcutaneously, but not intramuscularly because of the risk of haematoma formation.
LMW heparin is usually given subcutaneously and is well absorbed from injection sites.
Its anticoagulant effect is generally predictable when the dose is calculated in relation to
body weight, and routine blood clotting monitoring is usually not required. It does not
bind significantly to plasma proteins and is cleared from the bloodstream by the liver
and the kidneys. Its half-life is longer than unfractionated heparin, and so requires less
frequent administration.
Unfractionated heparin’s absorption is more variable and less predictable than that of
LMW heparin and, depending on dose, its half-life ranges from 30 minutes to 3 hours.

Adverse Effects
Heparin has a narrow therapeutic index. Its main side-effect is haemorrhage, which is
potentially fatal. Bleeding caused by excess unfractionated heparin can be rapidly
reversed by IV administration of protamine sulphate, which binds to heparin in the
bloodstream and deactivates it. Protamine sulphate is much less effective in stopping
haemorrhage induced by LMW heparin, because it binds to it less strongly.
Another potentially lethal side-effect of heparin develops as the result of an
autoimmune reaction against platelets in the presence of heparin. In about 1 in 50
patients, the interaction between heparin and platelets stimulates the production of
antiplatelet antibodies that activate platelets and trigger thrombosis. In addition, the
widespread activation of platelets leads to their clearance from the circulation and
thrombocytopenia. In this situation, heparin must be discontinued and an alternative
anticoagulant, such as danaparoid or a direct thrombin inhibitor, used instead.

Danaparoid
This is a heparin-like agent (a heparinoid) made up of a number of different GAGs
related to heparin. As with heparin, its anticoagulant effect is due to activation of
antithrombin. It has a low MW of 5500 kDa and is completely absorbed from
subcutaneous administration.

Direct Thrombin Inhibitors

Examples: argatroban, dabigatran, bivalirudin
Thrombin is the enzyme that releases fibrin from fibrinogen (Fig. 7.21). Drugs that
bind to and inhibit thrombin therefore block the terminal stage in the final common
pathway. Without sticky fibrin to form the clot framework, clot formation is disrupted.

Dabigatran
This anticoagulant was licensed in 2008 and was the first new anticoagulant in over 50
years. One important advantage claimed by its manufacturer is that unlike warfarin,
the standard agent in use at the time, monitoring blood levels is unnecessary.
Dabigatran is given orally as an inactive pro-drug, dabigatran etexilate, which is
converted to the active form in the liver. Its onset of action is rapid, and its half-life is
short, about 40 minutes. Life-threatening dabigatran-induced bleeding can be reversed
with idarucizumab, an antibody which binds with high specificity and high affinity to
dabigatran and prevents it from binding to thrombin. Renal function should be assessed
before treatment is begun, because the drug is cleared mainly by the kidney, and
monitoring renal function is particularly important in elderly people, who are most at
risk of life-threatening bleeds with this drug.

Bivalirudin
The use of leeches in ancient medical practice to bleed patients has been revived in
modern medicine in a limited number of clinical situations. Leech saliva contains a
powerful anticoagulant called hirudin, so that when the leech bites its target for a
blood meal, the blood remains fluid to allow the leech to feed. Leeches are sometimes
used in plastic surgery or other situations to prevent clotting and maintain blood flow to
a tissue. Hirudin is a directly acting thrombin inhibitor, and bivalirudin is a stable,
synthetic hirudin analogue with a short half-life of around 25 minutes.

Factor Xa Inhibitors
Examples: apixaban, fondaparinux, rivaroxaban
Activation of FX is the first step in the final common pathway (Fig. 7.21). Inhibiting
activated FX (FXa) therefore blocks clotting initiated by both the extrinsic and intrinsic
pathways. Routine monitoring of bleeding times is not needed, because their clinical
effect correlates very well with dose and so is predictable.

Pharmacokinetics
These agents are given orally and are incompletely absorbed from the GI tract. Their
half-lives are around 12 hours, but the onset of anticoagulant action is quick. They are
only partially metabolised, and much of the administered drug is excreted unchanged in
the faeces and urine.

Adverse Effects
Haemorrhage and anaemia are common but less so than with warfarin. Rivaroxaban
can cause nausea.

AntiPlatelet Drugs
Antiplatelet drugs are most useful in conditions where there is inflammatory endothelial
damage, primarily atherosclerosis, which triggers platelet activation. The endothelium
of arteries is exposed to considerably more shear stress than veins because blood flow
and pressure is much higher in the arterial than the venous system, and so arterial
endothelial damage is more common than venous endothelial damage. Clots that form
in arteries are therefore rich in platelets, and antiplatelet drugs are more effective in
preventing arterial thrombosis than venous thrombosis.

Aspirin
Although aspirin has traditionally been a standard anti-inflammatory drug, its
antiplatelet action has led to its widespread use to reduce thrombotic events in
cardiovascular disease, as well as in primary prevention of thromboembolism in people
without overt disease but with significant risk factors. Aspirin inhibits platelet activation
by irreversibly inhibiting platelet COX, the enzyme that produces prostaglandins.
Platelets synthesise a prostaglandin called thromboxane A2 (TXA2), which activates the
platelet and causes local vasoconstriction by contracting vascular smooth muscle. TXA2
is therefore a pro-clotting substance, and by inhibiting platelet COX and preventing
TXA2 production, aspirin suppresses blood clotting and increases bleeding times (see
also p. 152).
Low-dose aspirin, i.e. aspirin concentrations significantly lower than required for an
anti-inflammatory effect, achieves effective antithrombotic action. The standard
maintenance antiplatelet dose is 75 mg aspirin daily, compared to up to 2.4 g daily as an
analgesic/anti-inflammatory. This is mainly because aspirin irreversibly destroys
platelet COX, permanently abolishing its clotting action, so that restoring full platelet
activity requires the synthesis of brand-new platelets. After a single dose of aspirin,
platelet TXA2 generation recovers slowly, at the rate of about 10% per 24 hours, as new
platelets are released into the bloodstream from the bone marrow to replace the defunct
ones.

Pharmacokinetics
Aspirin (acetylsalicylic acid) has a short plasma half-life of about 20 minutes and is
broken down by plasma esterases to release the active ingredient, salicylic acid, which
diffuses passively into platelets.

Adverse Effects
Because prostaglandins have a wide range of physiological functions in healthy tissues,
COX inhibitors have a range of unpleasant side-effects. The low dose used in
cardiovascular prevention means that it is usually well tolerated, but it may still cause,
for example, GI irritation and should be avoided in people with active peptic ulcer
disease or a history of the same. Haemorrhage and allergy are also common side-effects.
The side-effects of COX inhibitors are discussed in more detail on p. 120.

Adenosine-Receptor Antagonists
Examples: clopidogrel, ticagrelor, prasugrel
ADP is an important pro-clotting factor released by platelets. ADP promotes and
accelerates platelet activation by acting on the P2Y12 receptor found on the platelet
membrane. The more platelets are activated, the more ADP is released to activate more
platelets, a very good example of a positive feedback system. Adenosine-receptor
antagonists bind to the platelet P2Y12 receptors and block them, preventing adenosine
from attaching and activating the platelet (Fig. 7.24). Precursors of the current group of
agents were identified in the 1970s as ADP antagonists only by chance, because
researchers were actually screening for anti-inflammatory drugs, and further work
produced clopidogrel in 1998. Adenosine-receptor antagonists are often used with
aspirin in a range of thromboembolic disorders including ischaemic heart disease and
acute coronary syndromes because the antiplatelet effects of the combination are
additive.

Pharmacokinetics
Clopidogrel and prasugrel are pro-drugs and require activation in the liver. Both
bind irreversibly to the platelet ADP receptors, and so their action is long-lasting even
though clopidogrel’s active metabolite has a half-life of only around half an hour.
Adenosine-receptor inhibitors are given orally, sometimes with an initial loading dose to
ensure rapid onset of action.

Adverse Effects
Care should be taken when co-prescribing with other drugs that have an antiplatelet
effect: this list includes non-steroidal anti-inflammatory drugs as well as perhaps less
obvious agents such as fluoxetine and sertraline (p. 58). Clopidogrel and
ticagrelor commonly cause GI upset and skin reactions. All agents in this group can
cause haemorrhage.

Dipyridamole
Dipyridamole is used orally, sometimes with aspirin and sometimes as a modified-
release formulation. Its mechanism of action is not entirely clear, and it may inhibit
platelets in several ways: for example, it has been shown to inhibit TXA2 synthesis, and
it enhances the antiplatelet action of prostacyclin.
 FIG. 7.24 The antiplatelet action of the adenosine-receptor
antagonists.

Fibrinolytic Drugs
Examples: streptokinase, alteplase, tenecteplase
Clot-dissolving (fibrinolytic) drugs are used to break down a formed clot and restore
blood flow through an occluded vessel. Rapidly restoring blood flow through an artery
following thrombosis, e.g. in a cerebral or a coronary artery, can make the difference
between life and death for a patient, or the difference between significant disability and
complete recovery. Fibrinolytics are used in a range of situations, including deep venous
thrombosis, pulmonary embolism, myocardial infarction, or blocked in-situ cannulas or
stents. The main hazard with using these drugs is haemorrhage. Fibrinolytic drugs are
more effective the younger the clot, because as a clot matures, its fibrin content steadily
increases and it becomes denser, more compact, and less susceptible to drug action.
Treatment outcomes are therefore significantly better when drug infusion is begun as
soon as possible after the onset of symptoms.

The Fibrinolytic System

Following clotting, controlled dissolution of a blood clot (fibrinolysis) is an essential step
in tissue healing and restoring blood flow. The key enzyme responsible for dissolving the
blood clot is plasmin, which is converted from its inactive form plasminogen by two
enzymes: thrombin and plasminogen activator (tPA). Plasmin digests fibrin and breaks
the clot up (Fig. 7.25). It may seem counter-intuitive that thrombin, a key accelerator of
clotting, also promotes fibrinolysis, but this is one of the key checks and balances in
regulation of clotting and helps to ensure that the clotting cascade does not run away
with itself.

Streptokinase
Streptokinase was discovered by chance in 1933 when it was observed that streptococcal
bacteria dissolved blood clotted in test tubes used for an unrelated experiment. The
active enzyme was isolated and named streptokinase as a nod to its microbial origin. It
is now known that streptokinase activates plasminogen, i.e. it acts like naturally
occurring tPA to release clot-dissolving plasmin, but its mechanism of action was not
worked out until the 1940s, when plasmin and plasminogen themselves were isolated.
To clear a blocked coronary artery in myocardial infarction, it is recommended that
treatment starts within 12 hours of the onset of symptoms, but the earlier the better,
because early treatment correlates directly with reduced mortality and improved cardiac
function post-infarction.
 FIG. 7.25 The mechanism of action of fibrinolytic drugs.

Pharmacokinetics
Streptokinase is a highly efficient and fast-acting thrombolytic with a half-life of around
25–30 minutes and is given by IV infusion.

Side-Effects
Allergy is common, probably because streptokinase is derived from bacterial sources. In
addition, streptokinase can trigger an immunological response with the generation of
anti-streptokinase antibodies. These antibodies can persist for years and will neutralise
streptokinase if given again. Because of this, streptokinase is only used on one occasion
and if thrombolysis in the same patient is required in the future, a different agent is
chosen. A range of cardiovascular adverse effects, including cardiac arrest, hypotension,
heart failure, and cardiac ischaemia, are all common.

Alteplase and Tenecteplase

Alteplase and tenecteplase are human tPA produced by recombinant DNA technology,
and therefore do not have the antigenicity associated with streptokinase. Both are given
intravenously and metabolised in the liver. Alteplase has a shorter half-life (less than 5
minutes) and must be given by infusion, followed up with maintenance anticoagulant
therapy to prevent re-occlusion of the artery with a new clot. Tenecteplase has higher
affinity for fibrin than alteplase and a longer half-life (23 minutes), so it is given as a
single bolus.

Haemostatic Drugs
Haemostatic drugs promote clotting and stop haemorrhage. Purified clotting factor
preparations are available for the treatment of conditions associated with deficiency; for
example, purified factor XIII is used to treat haemophilia A.

Tranexamic Acid
Tranexamic acid is a synthetic antifibrinolytic used in general surgery and in trauma to
reduce the risk and extent of bleeding and the need for transfusions. It is used to reduce
blood loss in women with very heavy menstrual periods, to stop prolonged nosebleeds,
and to control prolonged bleeding following dental surgery. It works by stopping
plasminogen activation, and so reduces plasmin production and protects the developing
fibrin clot (Fig. 7.25). It is also used to treat hereditary angioneurotic oedema (HAE), a
rare condition caused by a deficiency of a key inhibiting enzyme that restrains the action
of several enzyme cascades, including complement and clotting. Although not licensed
in all countries, there is some evidence that tranexamic acid can reduce the severity of
the attacks of swelling that characterise HAE.
It is given orally or intravenously, and is generally well tolerated, although there is a
risk of seizures with higher doses. It is a small molecule and is excreted unchanged in
the urine, so care must be taken if kidney function is reduced. Its half-life is around 2
hours, but this is extended in renal impairment.

References
1. Awtry E.H, Loscalzo J. Aspirin. Circulation. 2000;101(10):1206–1218.
2. Echt D.S, Ruskin J.N. Use of flecainide for the treatment of atrial fibrillation. Am.
J. Cardiol. 2020;125(7):1123–1133.
3. Lei M, Wu L, Terrar D.A, et al. Systematic review: modernised classification of
cardiac antiarrhythmic drugs. Circulation. 2018;138(17):1879–1896.
4. Marsh N, Marsh A. A short history of nitroglycerine and nitric oxide in
pharmacology and physiology. Clin. Exp. Pharmacol. Physiol. 2000;27(4):313–
319.
 5. Norlander A.E, Madhur M.S, Harrison D.C. The immunology of hypertension. J.
Exp. Med. 2018;215(1):21–33.
6. Ruggenenti P, Cravedi P, Remuzzi G. The RAAS in the pathogenesis and
treatment of diabetic nephropathy. Nat. Rev. Nephrol. 2010;6(6):319–330.
7. Sirtori C.R. The pharmacology of statins. Pharmacol. Res. 2014;88:3–11.

Online Resources
Florek J.B, Lucas A, Girzadas D. Amiodarone. In: StatPearls [Internet]. Treasure
Island: StatPearls Publishing; 2023 Available
from:. https://www.ncbi.nlm.nih.gov/books/NBK482154/.
Ornelas A, Zacharias-Millward N, Menter D.G, et al. Beyond COX-1: the effects of
aspirin on platelet biology and potential mechanisms of
chemoprevention. Cancer Metastasis Rev. 2017;36(2):289–303.
8: Drugs and the Respiratory System

CHAPTE R OU TLINE

Introduction
The Respiratory System
The Structure of the Respiratory
Passageways
Drug-Induced Pulmonary Toxicity
Drugs and Pulmonary Defence Mechanisms
Ciliated Epithelium
Mucus
Cough
Obstructive Airways Disease
Asthma
Bronchodilators
Anti-Inflammatory Drugs
Chronic Obstructive Pulmonary Disease

F OCUS ON

Focus on: Drug Delivery via Inhalation in Respiratory Disorders p. 158

Focus on: Tailored Genetic Therapy in Cystic Fibrosis p. 161
Focus on: The Stepwise Principles of Asthma Treatment p. 169

Introduction
The respiratory system, conventionally divided into upper and lower parts, brings
atmospheric air into the lungs, from which it extracts oxygen and into which it excretes
waste carbon dioxide. The epithelia lining the respiratory passageways and the alveoli
are constantly exposed to the external environment via this inhaled air, so that
respiratory infections are very common, especially if normal respiratory defence
mechanisms are compromised in some way. Antimicrobial agents are described in
Chapter 11.

The Respiratory System

The main respiratory structures and organs of the upper and lower respiratory tracts are
shown in Fig. 8.1A. Air inhaled through the nose or mouth travels through the trachea,
which splits into the right and left primary bronchi to direct air into the right or left
lung, respectively. Within each lung, the primary bronchus divides into secondary
bronchi, which through progressive and extensive branching produce 30,000 tiny
terminal bronchi which direct air into a total of around 450 million microscopic air sacs
called alveoli (Fig. 8.1B). Alveolar walls are only one epithelial cell thick, and each
alveolus is wrapped in a dense network of capillaries, the walls of which are also only
one cell thick. Because the membrane formed between the fused alveolar and capillary
walls is so thin, gas exchange is rapid and efficient; oxygen is absorbed by diffusion from
the alveolar air into the bloodstream and carbon dioxide diffuses from the bloodstream
into the alveoli, to be excreted in exhaled air.

The Structure of The Respiratory Passageways

The respiratory passageways are lined with epithelium, which varies in structure
depending on the location. The epithelium lining the pharynx is stratified, because this
part of the system is shared with the gastrointestinal (GI) system; the upper layers of
cells can be safely rubbed off by swallowed food and drink because they are constantly
being replaced with cells from the lower layers. The trachea and the larger airways are
lined with ciliated epithelium (see Fig. 8.5) and contain numerous goblet cells for
mucus production. The sticky mucus blanket lining the upper airways traps inhaled
particles and is constantly moved towards the mouth by the beating action of the cilia.
This so-called mucociliary escalator (see below) is an important pulmonary defence
mechanism. The epithelium of the alveoli is composed of thin, flattened squamous cells
to allow rapid gas exchange.
The walls of the larger airways are supported with embedded rings or plates of
cartilage, preventing them from partial or complete collapse when air pressures change,
and the lungs expand and recoil during normal respiration. The smaller airways and the
alveoli have no cartilage, but they are kept open by the elastic fibres of the lung, which
exert constant tension on their walls and prevent them from collapse.

Smooth Muscle of the Respiratory Passageways

Under the control of the autonomic nervous system, smooth muscle within the walls of
the respiratory passageways regulates airway diameter and so controls air flow in the
lung. Sympathetic fibres supplying the muscle release noradrenaline, which acts on
β2-adrenoceptors on the muscle cells (see Fig. 4.5) and relaxes it, opening the airways
and increasing airflow. Parasympathetic fibres release acetylcholine, which acts on M3
muscarinic receptors on the bronchial smooth muscle (see Fig. 4.8) to contract it,
causing bronchoconstriction and reducing air flow. There is very little smooth muscle in
the larger airways and, in any case, there is a substantial amount of cartilage in their
walls, holding them open and preventing obstruction. However, the walls of the small-
to medium-sized airways contain substantial amounts of smooth muscle, allowing
significant adjustment to their diameter and permitting the lungs to direct air flow to
areas of the lung receiving good blood supply.

Drug-Induced Pulmonary Toxicity

The lungs have a generous blood supply because they receive the entire output of the
right ventricle, and so receive high concentrations of circulating drugs. Over 600 drugs
in all fields of medicine and some recreational drugs have been associated with
pulmonary toxicity, which is generally an idiosyncratic adverse effect and not usually
dose-related. Risk factors include increasing age, genetic predisposition, and pre-
existing lung disease or damage. Any respiratory structure or tissue may be involved,
including the supporting elastic tissue of the lung, the pulmonary vasculature, the
pleura, the muscles of respiration, the airways, or the alveoli. Fig. 8.2 shows the
histology of bleomycin-induced lung damage compared to healthy tissue. The healthy
lung tissue shows thin-walled, interconnected alveolar spaces. The damaged lung is
infiltrated with inflammatory cells, and the alveolar epithelium is thickened with loss of
normal alveolar architecture. Drug-mediated lung damage may be due to a range of
pathological changes (Table 8.1), and toxicity may be acute or chronic. Stopping the
drug may reverse the changes, but in some cases the lung damage is permanent.

Drugs and Pulmonary Defence Mechanisms

The total surface area in the alveoli exposed to inhaled air, with all its suspended
contaminants and micro-organisms, is thought to be around 70 m2. One of the main
functions of the upper respiratory tract is, therefore, to clean this air and protect the
lungs from damage and infection.

Ciliated Epithelium
The trachea and large airways are lined with ciliated columnar epithelium (Fig. 8.5).
Cilia are present on the epithelial lining deep into the respiratory tree, to the level of the
terminal bronchioles. They are thread-like motile structures anchored in the epithelial
cell membrane. Through a co-ordinated beating action, they clear mucus and other
secretions, along with particles trapped on their sticky surface, from the respiratory
passageways and carry them towards the throat for swallowing. This is called the
mucociliary escalator.

FIG. 8.1 The main structures and organs of the respiratory

system.A. The upper and lower respiratory tracts. B. Progressive
divisions of the bronchial tree and the alveoli. Modified from (A)
Thibodeau G and Patton K (2016) Anatomy and physiology, 9th ed.
St Louis: Mosby and (B) www.Netter.com: Illustrations 155
(bronchus, acinus) and 191 (circulation). Elsevier.
 FIG. 8.2 Histology of lung tissue.A: Healthy alveoli. B: Bleomycin-
induced lung damage. Modified from Miller DL (2016) Mechanisms
for induction of pulmonary capillary hemorrhage by diagnostic
ultrasound: review and consideration of acoustical radiation surface
pressure. Ultrasound in Medicine & Biology, 42(12), pp. 2743-2757.

Table 8.1

Some Examples of Drugs that Cause Pulmonary Toxicity

Toxic Effect Drug(s)
Inflammation and fibrosis of the Amiodarone; azathioprine; bleomycin;
lung substance chlorambucil; methotrexate; oxygen;
nitrofurantoin; phenytoin; statins;
sulphasalazine
Capillary leak syndrome: the Cocaine; cyclophosphamide; diamorphine;
pulmonary capillaries become iodine-containing radiographic contrast
increasingly permeable, agents; methotrexate
causing pulmonary oedema
Hypersensitivity (allergy) β-blockers; methotrexate; nitrofurantoin
Bronchospasm Aspirin and other non-steroidal anti-
inflammatory drugs; amiodarone;
amphotericin B; β-blockers;
dipyridamole; nitrofurantoin;
penicillamine
Pleural injury Amiodarone; bleomycin; carmustine;
 cyclophosphamide; methotrexate;
nitrofurantoin; phenytoin

Mucus
Mucus is produced by goblet cells present in the columnar epithelial lining of the upper
airways and forms a thin blanket overlying the cilia. Mucus is a viscous water-based gel
containing mucins, which are complex sugar/protein molecules, and particles present in
inspired air adhere to mucus layer and are trapped. The consistency of mucus is
normally thin enough to allow the ciliary escalator to transport it without difficulty and
clear it efficiently from the respiratory passageways; however, in respiratory infection or
irritation, mucus production increases, and the mucus often becomes thicker and
stickier. This makes the job of the ciliary escalator more difficult and increases the need
to cough to help clearance.
In some situations, mucus viscosity significantly affects clearance. The
parasympathetic nervous system promotes secretion of a fluid mucus that is easily
moved by ciliary action. Antimuscarinic drugs such as hyoscine are used to reduce the
volume of respiratory secretions, e.g. before surgery. However, they thicken the mucus,
which hampers normal clearance and can cause mucus pooling, airway obstruction, and
increased risk of infection. In some respiratory conditions, such as cystic fibrosis,
continual production of thick mucus leads eventually to failure of ciliary action.

Mucolytics and Expectorants

Mucolytics are agents that liquefy mucus and facilitate its clearance from the airways.
Simple measures such as steam inhalation, which may be used with menthol or
eucalyptus, hydrate and soften mucus and can be helpful. Drugs such as
acetylcysteine and carbocisteine disrupt the binding of the mucins within mucus,
increasing its water content and thinning it. In addition, there is evidence that
acetylcysteine reduces mucus production and may have some

F oc us on: Drug Delivery Via Inhalation in Respiratory

Disorders
Drugs given to treat airway disorders are often administered by inhalation. This route
delivers the drug directly to the target tissue, achieving high pulmonary drug
concentrations and a rapid onset of action. The dose delivered can therefore be
reduced compared to the systemic dose, reducing the incidence and severity of
adverse effects.
 Drugs for inhalation are formulated specially for this delivery route. Drug
formulations include dry powder preparations, aerosols, or suspensions, which are
then administered using an appropriate inhaler device. It is important to choose an
appropriate device to meet the patient’s needs. Table 8.2 summarises key features of
the main inhaler devices available.
Less than 10% of an inhaled dose of drug reaches the smaller airways. Most is
deposited in the inhaler device and in the mouth, throat, and upper airways, from
where it is cleared by the mucociliary escalator and swallowed. The swallowed drug is
absorbed into the bloodstream from the gastrointestinal tract and liver; in addition,
some drug is absorbed across the bronchial walls. In this way, a proportion of an
inhaled dose reaches the systemic circulation (Fig. 8.3). This may contribute to the
drug’s clinical effect but may also cause systemic side-effects. The likelihood of this
happening increases with the drug dose, dosing frequency, and the chemical
characteristics of the drug. For example, if the drug is very fat-soluble, it will be
readily absorbed into the blood, or if it is very potent then even small circulating
quantities may cause side-effects. It is desirable that inhaled drugs given for a local
effect (e.g. bronchodilators in asthma) that reach the circulation should be rapidly
cleared, for example by liver metabolism, to minimise systemic side-effects.
Factors Affecting Inhaled Drug Access to the Airways
Whereas a dose of drug given orally or by parenteral routes can be accurately
calculated, drug delivery by inhalation cannot be easily quantified because the
amount of drug reaching the airways depends upon a range of factors. One of these is
the action of the mucociliary escalator. Healthy mucociliary function efficiently but
variably clears inhaled particles, including drug molecules, and it is not possible to
measure this in individual patients. Another is the drug formulation, which is
important because the size of the drug particle determines how far it may travel into
the respiratory tree, which in turn determines which clearance mechanisms
contribute (Fig. 8.4). Large particles (10 μm or more in diameter) are heavy and do
not travel far when inhaled: they land on the membranes of the mouth, throat, and
large airways and are swallowed or cleared by mucociliary action. However, if the
particles are very small (1 μm or less), they are so light that they remain suspended in
the air and are breathed back out again, never reaching their target tissue. Drug
deposition in the small airways is optimal when the drug particle size falls in the range
2–5 μm, and this can be maximised if the patient holds their breath for several
seconds after inhalation; this gives the drug particles more time to fall by gravity and
adhere to the airway epithelium. Drug particles depositing in the alveoli can be
removed and destroyed by alveolar macrophages.

Table 8.2

Key Features of Inhaler Devices

Inhaler
Comments Disadvantages
Device
Manuall A pre-calculated dose of aerosolised drug is Requires good co-
y driven from the inhaler under pressure ordination of
activ by a propellant substance when the inhalation and
ated inhaler is manually activated. inhaler activation,
press which is difficult in
urise many people
d including children
mete and the elderly
red Requires adequate
dose inspiratory effort,
inhal potentially a
er problem in
children and the
elderly and when
airway obstruction
is present
Breath- As above, but drug release is triggered by Requires good inspiratory
activ inhalation. effort; difficult in
ated children, frail elderly,
press and when airflow is
urise obstructed
d
mete
red
dose
inhal
er
Spacer This is a plastic chamber attached to the Spacers are bulky,
devic inhaler mouthpiece. Released drug inconvenient, and
es disperses into the air in the spacer and cannot be used with
is breathed in over a period of time. It is breath-activated
very useful for children and those inhalers because
unable to effectively use metered dose sufficiently high airflow
inhalers alone. rates cannot be
achieved on inhalation.
Dry The drug is delivered as particles into the Requires good inspiratory
powd airway. effort and the ability to
er hold the breath for at
inhal least 10 seconds
ers following activation
Nebulis The drug is delivered into the airways as a Equipment is bulky and
ers fine mist, produced by bubbling may not be available
pressurised air or oxygen through a outside of healthcare
solution of the drug. High doses can be settings.
delivered rapidly and comfortably in
acute attacks.
FIG. 8.3 Routes of access into the systemic circulation following
drug inhalation.
 FIG. 8.4 Drug penetration into the airways depends upon
particle size.Large particles deposit in the upper tract. The optimal
size for deposition in the small airways is 2–5 μm in
diameter. Modified from Tekade RK (2020) Drug delivery systems,
Fig. 11.8. St. Louis: Academic Press.

A range of inhalation devices is available, but effective drug delivery with all of
them depends very much on patient technique. If inhalation of drug triggers
coughing, most will be immediately expelled and therefore ineffective. If the patient’s
respiratory effort is poor, e.g. in children or frail elderly people, less drug reaches the
target airways. In addition, drug penetration into the respiratory tree is reduced if the
airways are narrowed by inflammation or bronchoconstriction; this means that
during exacerbations of the disease, inhaled drugs may be considerably less effective
than normal.
Alternative Routes to Inhalation
During exacerbations, drugs can be given orally or intravenously to ensure that high
concentrations reach the lung tissues via the bloodstream. This of course means that
the risk and incidence of side-effects are increased.

anti-inflammatory action. An expectorant is an agent that helps the movement of

material, including mucus, out of the airways. Traditional expectorants include squill
and guaifenesin, which may be added to proprietary cough preparations, but there is
no evidence that they have any benefit.

Dornase Alfa
Dornase alfa is a synthetic form of human deoxyribonuclease, the enzyme that breaks
down DNA in the body. It is given by nebuliser in cystic fibrosis. The thick mucus
produced in this condition is rich in neutrophils, because of the repeated infections, and
when these cells break down, they release their DNA along with other cellular
constituents. The very long DNA molecules are highly viscous, and dornase alfa snips
them up into much smaller segments, thinning the mucus and facilitating clearance.
Fig, 8.6A shows sputum from a patient with cystic fibrosis stained for DNA. The
elongated DNA molecules are clearly seen. Fig. 8.6B shows the effect of dornase alfa:
the DNA polymers have been effectively degraded, greatly reducing the viscosity of the
sputum.

Mannitol
Inhaled mannitol powder is thought to liquefy mucus by generating an osmotic gradient
between the mucus layer and the epithelial cells lining the airway. Mannitol is not
absorbed and increases the osmolarity of the mucus. This osmotic gradient pulls water
from the airway tissues into the mucus, hydrating it. This is also the basis of its activity
as an osmotic diuretic (p. 174) and in reducing cerebral oedema by pulling water from
brain tissue into the bloodstream. It can cause airway irritation, cough, haemoptysis,
and sore throat.
FIG. 8.5 The epithelial lining of the trachea and large
 airways. From Waugh A and Grant A (2018) Ross & Wilson anatomy
and physiology in health and illness, 13th ed, Fig 10.12. Oxford:
Elsevier.

FIG. 8.6 The effect of dornase alfa on cystic fibrosis sputum

stained for DNA.A. In untreated sputum, the elongated DNA
molecules are clearly seen. B. Dornase alfa digests and degrades the
DNA polymers, reducing mucus viscosity. From Gardenhire DS
(2012) Rau’s respiratory care pharmacology, 8th ed, Fig. 9.9. St.
Louis: Mosby.

Ivacaftor
Ivacaftor was licenced in 2012 for use in cystic fibrosis (see Focus on: Tailored
Genetic Therapy in Cystic Fibrosis box).

F oc us on: Tailored G enetic Therapy in Cystic F ibrosis

Cystic fibrosis (CF) is the most common inherited autosomal recessive disease in
Caucasians. Because the faulty gene causing this disorder is recessive, an affected
individual must inherit a faulty gene from both parents for the disease to manifest;
people with one faulty gene and one normal gene are clinically healthy but can pass
the gene to their children (they are carriers). CF is caused by a faulty ion channel in
the membranes of secretory epithelial cells, including the lungs, pancreas, and
genitourinary tract. This channel, called the cystic fibrosis transmembrane
conductance regulator (CFTR), allows the cell to export chloride ions through its
plasma membrane, pulling water with them and hydrating respiratory and
gastrointestinal secretions. Fig. 8.7 shows the production of CFTR proteins and their
role in chloride ion secretion. The code for the protein is transcribed from the CFTR
gene into a molecule of mRNA, which is then read by a ribosome in the cytoplasm to
synthesise the CFTR protein. It travels to the cell surface and is inserted into the
membrane; this process is called trafficking. When the CFTR channel function is
abnormal or inadequate, chloride secretion is decreased or absent, reducing water
transport out of the cell. This dehydrates and thickens secretions. The lungs are
normal at birth, but the viscous secretions are rapidly colonised with a range of micro-
organisms, and repeated infections cause inflammation and progressive destruction
of the lung tissue. Respiratory failure is usually the cause of death. Fig. 8.8
summarises the pathophysiology of CF. Treatment plans include physiotherapy to
mobilise thick secretions and help airway clearance, aggressive antibiotic
management of infections, oral replacement of digestive enzymes, and exercise plans
to optimise physical fitness. Even so, CF remains a life-limiting disease, and
development of new therapies is a key research focus.
FIG. 8.7 The production and function of cystic fibrosis
transmembrane conductance regulator protein.
 FIG. 8.8 The pathophysiology of cystic fibrosis. Modified from
Broaddus VC, Ernst JD, King TE Jr, et al. (2022) Murray & Nadel’s
textbook of respiratory medicine, 7th ed, Fig. 67.4. St. Louis:
Elsevier.

The gene that codes for the CFTR channel is found on chromosome 7, and it is a
large gene, increasing the number of possible mutations that may occur within its
genetic sequence. In fact, there are around 2000 different mutations in this gene,
each of which changes the code in a different way and so produces a wide range of
abnormal amino-acid sequences in the final CFTR protein. Different mutations
interfere with channel production or function at different stages in the process, and
this opens the possibility of designing drugs to specifically target individual channel
abnormalities: a pharmacogenetic approach. The most common mutation in
American and northern European patients is called the F508del mutation and
involves the loss of only one amino acid from the CFTR protein, but even this slight
change means that the protein cannot fold into the correct shape, and the cell destroys
it instead of trafficking it to the cell surface. Nearly 90% of patients with CF have at
least one copy of this common mutation. Other mutations produce channels that
cannot open correctly or do not stay open long enough, or lead to reduced production
of the CFTR protein.
CFTR Modulators
These new agents are low-molecular-weight molecules which target a specific defect
in the CFTR channel and improve its function. Re-establishing correct chloride flow
rehydrates mucus, improves pulmonary clearance, and reduces the likelihood of
obstruction in other systems including the gastrointestinal tract. Identifying the
specific mutation in the patient’s CFTR gene identifies the nature of the defect in the
CFTR protein, and an appropriate CFTR regulator can be prescribed to improve
channel function.
There are three types of CFTR modulators: potentiators, correctors, and amplifiers.
Not all are available in all countries.

• Potentiators, e.g. ivacaftor, increase the length of time that the CFTR channel
remains open, allowing movement of additional chloride.
• Correctors, e.g. lumacaftor and elexacaftor (the latter not currently available
in the UK), allow the CFTR protein to assume the right shape for it to be
trafficked to the cell surface and incorporated into the cell membrane, increasing
the number of channels at the cell surface.
• Amplifiers increase production of CFTR protein and are currently in development.

Understanding the genetic basis of the faulty protein allows tailored therapy to be
offered to patients with certain mutations. For instance, ivacaftor alone is not
effective in patients with the common F508del mutation, because this mutation
results in unstable CFTR protein that is quickly broken down and so little reaches the
cell surface to benefit from the action of ivacaftor. However, using ivacaftor and
lumacaftor together can significantly improve pulmonary function, because
lumacaftor increases the amount of CFTR protein reaching the cell surface, and
ivacaftor keeps the new channels open for longer.
Pharmacokinetics and Adverse Effects
The currently available CFTR modulators are given orally and may be given in
combination: ivacaftor and lumacaftor are used together in the UK and other
combinations are used in other countries. Ivacaftor has a half-life of around 12
hours following oral administration, and its absorption is enhanced if taken with fat-
containing foods. Regular monitoring of liver enzyme levels is recommended because
it can increase liver transaminase levels. It is metabolised by the cytochrome (CYP) 3A
family of liver enzymes, and so interacts with drugs that induce or inhibit these
enzymes. For example, a range of antimicrobials including the azole antifungals
and macrolide antibiotics, which are CYP3A inhibitors, can significantly increase
ivacaftor blood levels.

Cough
Coughing is an essential reflex mechanism for clearing the airways of accumulated
mucus, accidentally inhaled materials, or other obstructions. It is controlled by the
cough centre in the brain stem. Irritation of the respiratory epithelium triggers sensory
impulses that travel to the cough centre via the vagus nerve. The cough centre responds
by activating the respiratory and abdominal muscles to produce the sequence of events
of cough. There is an initial deep inspiration, to bring enough air into the lungs for an
effective cough. The vocal cords in the larynx are then pulled together (closing the
glottis), and the abdominal muscles, diaphragm, and intercostal muscles contract
sharply. This generates a rapid rise in intrathoracic pressure. Then the glottis opens, and
the high intrathoracic pressure generates fast, high-volume airflow out of the airways. A
persistent cough should always be investigated, and the cause identified and treated
where possible.

Antitussives
Antitussives are drugs that suppresses cough and are used to relieve the discomfort and
disturbance caused by persistent dry cough. The cough reflex is suppressed by central
nervous system (CNS) depressants, including alcohol and sedating antihistamines.
This can be clinically helpful, e.g. to treat a dry cough that disturbs sleep, but the
potential for compromising the airway in vulnerable individuals by interfering with this
important protective reflex should always be considered. General anaesthetics
depress cough and can compromise the airway during induction of and recovery from
anaesthesia unless the airway is carefully protected. Antitussives are not used when the
cough is productive, because they predispose to mucus accumulation in the airways and
increase the risk of obstruction and infection.

Opioids
Opioids (Ch. 6) are the most effective antitussive medications currently available and
suppress cough at sub-analgesic doses. They act on μ (mu) receptors in the cough centre
in the brainstem and reduce their sensitivity. Weak opioids such as codeine and
pholcodine have fewer side-effects and are less likely to cause dependence than more
powerful opioids like morphine. However, morphine and diamorphine are used in
palliative care in patients with lung cancer, in whom a persistent, exhausting, and
distressing cough is a frequent symptom. Side-effects include constipation and
respiratory depression. Opioids also thicken sputum and depress ciliary action, and so
care is needed, for example, in chronic obstructive pulmonary disease (COPD).

Obstructive Airways Disease

Obstructive airways disease is a general term encompassing mainly asthma and COPD.
In both these conditions, there are chronic inflammatory changes in the airways which
cause varying degrees of airflow limitation, although the aetiology and progression of
the disorders are different.

Asthma
Asthma is characterised by reversible airway obstruction, with periods of good lung
function interspersed with episodes of deteriorating function, airway narrowing, and
airflow obstruction. It is frequently associated with allergy, which stimulates mast cells
and basophils in the airway to release a range of inflammatory mediators and cytokines,
including leukotrienes, platelet-activating factor, and interleukins (ILs). Fig. 8.9 shows
the main inflammatory mediators and cytokines involved, and also shows the targets of
the main drugs used in asthma. The smooth muscle tissue in the bronchial walls is
thickened and hyperreactive and responds inappropriately with exaggerated
bronchoconstriction to a range of triggers. The smaller airways, whose walls contain a
lot of smooth muscle and have no cartilage to keep them open, are disproportionately
affected. Bronchodilators, including β2-agonists, leukotriene-receptor
antagonists, and theophylline help reverse bronchoconstriction and improve
airflow.
Inflammation is a key feature, and the airway wall is swollen and infiltrated with a
range of inflammatory and immune cells including macrophages, mast cells,
eosinophils, and T-lymphocytes. Activated T-lymphocytes release a wide range of pro-
inflammatory cytokines, including Interleukins. The ongoing inflammatory response
damages the epithelium, causing patchy desquamation and exposing the basement
membrane, which contributes to the ongoing airway hypersensitivity. Goblet cells are
hypertrophic, and mucus production increases. Loss of the ciliated epithelium decreases
mucus clearance, so mucus accumulates and plugs airways. With time, the chronic
inflammation leads to structural changes and permanent remodelling of the airway wall.
Glucocorticoids are the mainstay of anti-inflammatory treatment in asthma. Fig.
8.10 shows the main pathological features of an asthmatic airway compared with
normal.
FIG. 8.9 The main inflammatory mediators and cytokines involved
in asthmatic airway inflammation.The sites of action of the main
drugs used to treat asthma are also shown. Modified from Abbas AK,
Lichtman AH, and Pillai S (2021) Cellular and molecular
immunology SAE, 10th ed, Fig. 20.10. New Delhi: Elsevier.
 The cause of asthma is not known, although it is likely to be multifactorial. There is
often an inherited component with a strong familial tendency. Allergy is a common and
important component in asthma, and asthma often co-exists with other allergic
conditions such as hay fever and eczema.

Bronchodilators
These drugs reduce airflow obstruction by relaxing bronchial smooth muscle and
opening the airways. They are usually used to relieve symptoms, although sometimes
they are useful prophylactically, for example, before exercise if exercise is a trigger
factor. Because of this, they are sometimes called relievers or rescue agents.

b2-Agonists
Examples: salbutamol, terbutaline, salmeterol
The use of sympathetic drugs to improve symptoms in asthma dates to 3000 BC,
when physicians in ancient China used extracts of the plant Ephedra equisetina to treat
dyspnoea. The active agent, epinephrine (adrenaline), was isolated in 1897, and the
first β-agonist drug, isoprenaline, was synthesised in 1940. It was used in the
treatment of asthma, but it is not selective for β2-receptors and has significant activity
on β1-receptors too, including those in the heart (see Fig. 4.5). This meant that even
when used in the relatively small doses needed by inhalation to improve asthma
symptoms, enough was absorbed into the systemic circulation to cause unwanted
cardiovascular side-effects including hypertension and arrhythmias. The discovery of β1
and β2 subtypes and their distribution in the respiratory and cardiovascular systems led
to the development of drugs relatively selective for β2-receptors, which cause
bronchodilation with minimal activity on the heart. The first β2-selective agonist,
salbutamol, is 29 times more active on the β2-receptor than the β1-receptor and was
introduced in the late 1960s. Since then, a range of similar agents have been produced
including the longer-acting agents formoterol and salmeterol. β2-agonists bind to
and activate sympathetic β2-receptors on smooth muscle cells in the airway wall. They
mimic the action of the sympathetic nervous system, which prepares the body for stress
or activity, and relax bronchial smooth muscle by reducing calcium entry into the
smooth muscle cells. Because calcium is essential for activation of the contractile
proteins in the muscle cell, this leads to bronchodilation, increases air flow, and
maximises oxygen intake. In addition, they improve ciliary function and have an anti-
inflammatory action. β2-agonists and glucocorticoids have a synergistic effect (see later
and Fig. 8.11).
Pharmacokinetics
β2-agonists are given by inhalation for occasional use in well-controlled asthma and may
also be given orally or by intramuscular or intravenous injection if required. Short-
acting agents, e.g. salbutamol and terbutaline, usually take effect within 5 minutes of
inhalation, and their duration of action is usually between 4 and 6 hours. Salmeterol
has a duration of action of around 12 hours, so is useful for managing night-time
symptoms and takes up to half an hour to begin working. Formoterol’s duration of
action can be up to 24 hours, and its onset of action is within 2–3 minutes. Overuse of
these drugs, however, downregulates β2-receptor numbers and reduces their
effectiveness.
Long-acting agents have been associated with increased mortality rates in severe
asthma; the reasons for this are unclear. Current advice is that they should only be used
in conjunction with an anti-inflammatory steroid and should only be added into therapy
if adequate control is not achieved with shorter-acting agents. Patients taking these
agents should be reviewed regularly and the drug withdrawn if no clinical benefit is
observed.

FIG. 8.10 The normal and asthmatic airway.A. Structural features

of the healthy airway. B. Pathological changes in asthma. From
Waugh A and Grant A (2018) Ross & Wilson anatomy and
physiology in health and illness, 13th ed, Fig 10.12. Oxford: Elsevier.
 FIG. 8.11 Positive synergism between glucocorticoids and β2-
agonists in the asthmatic airway.

Adverse Effects
Significant systemic side-effects can occur if circulating drug levels are high enough,
including from high doses of inhaled drug. At higher doses, β2-agonists also activate β1-
receptors: i.e. their selectivity at the subtypes of the β-receptor is dose-dependent. This
includes cardiac β1-receptors, leading to tachycardia, palpitations, hypertension, and
arrhythmias. A fine tremor can occur, due to stimulation of β2-receptors on skeletal
muscle. They can cause hypokalaemia by shifting potassium from the blood into cells via
an action on the sodium–potassium pump in the cell membrane. Hypokalaemia in turn
can cause potentially fatal cardiac arrhythmias, and care should be taken in people who
are at risk of hypokalaemia, including concurrent use of theophylline in severe
asthma. Because they reduce blood potassium levels, these drugs are also used to treat
hyperkalaemia. They may cause hyperthyroidism because sympathetic stimulation
increases release of thyroid hormone from the thyroid gland. They increase blood
glucose levels, because sympathetic stimulation increases glycogen breakdown in the
liver, releasing glucose into the bloodstream, which may interfere with blood glucose
control in diabetes.

Theophylline
Theophylline is a methylxanthine, a family of chemicals that includes caffeine; strong
coffee was recommended in 1786 for asthma in a letter written by William Withering (of
digoxin fame, p. 133). As a group, xanthines have bronchodilator, diuretic, and anti-
inflammatory properties, although their exact mechanism of action is unclear. They act
at several targets in human cells and probably produce their pharmacological action via
more than one pathway. One potential mechanism of action is via their blockade of
adenosine receptors on airway smooth muscle cells. Adenosine triggers
bronchoconstriction, so antagonism at their receptor may account at least in part for the
bronchodilator action of the xanthines. In addition, they inhibit one form of the enzyme
phosphodiesterase (PDE), which breaks down cyclic AMP (cAMP) inside cells, including
smooth muscle cells. This increases cAMP levels and relaxes bronchial smooth muscle,
inducing bronchodilation. Other types of PDE inhibitors are used to treat heart disease
(p. 133). They may also have a central effect and stimulate the respiratory centre in the
brainstem. Finally, the anti-inflammatory effect of xanthines may be due to their ability
to increase the activity of anti-inflammatory genes and suppress the activity of
inflammatory cells. Xanthines are usually used to manage acute, severe exacerbations of
asthma.

Pharmacokinetics
Theophylline is given orally. It is well but unpredictably absorbed from the GI tract,
giving fluctuating plasma levels which could increase the risk of side-effects; modified
release preparations are preferred, which are absorbed at a steadier rate and help to
stabilise plasma levels over extended periods. Aminophylline is a preparation of
theophylline and ethylendiamine. Ethylenediamine has no pharmacological activity,
but it makes theophylline much more soluble in water, giving a formulation suitable for
intravenous injection. Once in the body, it releases theophylline, which is responsible for
its pharmacological effects. The plasma half-life of theophylline is 4–8 hours, and it is
heavily plasma protein-bound.

Adverse Effects
Theophylline has a wide range of potentially serious side-effects because it affects such a
wide range of cellular targets important in a range of body tissues. It has a narrow
therapeutic index, and side-effects become increasingly common at plasma levels at the
upper end of the therapeutic range and above. Therapeutic drug monitoring is helpful in
managing dosing. Adverse effects include cardiac arrhythmias, probably due to
adenosine antagonism and seizures due to CNS stimulation, both of which can be fatal.
Gastric acid secretion is increased and so is GI motility, with GI pain, gastro-
oesophageal reflux, diarrhoea, and increased risk of peptic ulcers. Hypokalaemia can
occur, especially when theophylline is used with β2-agonists. Theophylline is
metabolised in the liver, and its effects are decreased in the presence of enzyme
inducers, including smoking, alcohol, phenytoin, and St. John’s wort. Enzyme
inhibitors can reduce theophylline clearance and increase circulating levels: these
include isoniazid, interferons, and carbamazepine.

Antimuscarinic Bronchodilators
Examples: aclidinium, ipratropium, tiotropium
The parasympathetic nervous system causes bronchoconstriction via the action of
acetylcholine on M3 receptors in bronchial smooth muscle (see Fig. 4.8). Drugs that
block M3 receptors therefore cause bronchodilation and are used to relieve
bronchospasm in obstructive airway disease, including asthma and COPD.

Pharmacokinetics
Ipratropium is given by inhalation in maintenance treatment of asthma and in the
management of acute asthma. Its peak action occurs 30–60 minutes after
administration, and it is effective for 3–6 hours. It is also given intranasally to reduce
rhinorrhoea, for example, in hay fever. It is a large, highly charged molecule, so is poorly
absorbed into the bloodstream, and so is generally not associated with systemic side-
effects, although care must be taken not to contaminate the eye directly because of the
risk of glaucoma (see below). Longer-acting agents include aclidinium (duration of
action, 8 hours) and tiotropium (64 hours).

Adverse Effects
Antimuscarinic drugs can cause a range of systemic antimuscarinic side-effects (see p.
51) by blocking muscarinic receptors throughout the body and antagonising the ‘rest and
digest’ functions of the parasympathetic nervous system. Care is needed in people with
glaucoma or at risk of glaucoma because these drugs can increase intraocular pressure
(see Fig. 4.11). Antimuscarinic agents can also block the effects of the parasympathetic
nervous system on the heart and predispose to tachycardia and arrhythmias: the risk is
increased if antimuscarinics are used in conjunction with β-agonists.

Anti-Inflammatory Drugs
Preventing or reversing the inflammatory changes associated with the asthmatic airway
alleviates the signs and symptoms of the disorder and improves airway function. They
should be used on a regular basis even when the asthma is not troublesome to suppress
airway inflammation, and so they are sometimes referred to as preventers.

Glucocorticoids
Examples: budesonide, beclometasone, fluticasone
Glucocorticoids are the mainstay of anti-inflammatory treatment in asthma. They are
superior to other anti-inflammatory medications in the management of recurrent and
chronic disease and prevent or reduce the rate of asthma exacerbations. They block the
activity and proliferation of inflammatory cells in the airway wall and prevent the
production of a wide range of inflammatory mediators and cytokines. Their mechanism
of action is discussed on p. 111. Because they can cause a wide range of potentially severe
side-effects, they should be used at the lowest effective dose and given systemically only
when required to manage severe disease and for as short a period as possible.
Glucocorticoids and β2-agonists demonstrate therapeutic synergism when used
together in asthma. Glucocorticoids increase the number and efficacy of β2-receptors in
the airways, and therefore improve the bronchodilator response to β2-receptor agonists.
β2-agonists in turn have an anti-inflammatory action and enhance the airway response
to glucocorticoids (Fig. 8.11).

Pharmacokinetics
Maintenance glucocorticoid therapy is delivered by inhalation wherever possible to
minimise side-effects. However, because steroid molecules are small and fat-soluble,
they are readily absorbed across the airway wall and can reach physiologically active
levels in the bloodstream if used in high doses to manage severe asthma or used
excessively. For this reason, it is desirable that they are quickly cleared from the
circulation by hepatic metabolism. Bioavailability and half-lives of the commonly used
steroids vary significantly. Fluticasone, budesonide, mometasone, and
ciclesonide are quickly removed from the bloodstream by first-pass metabolism, and
any swallowed drug from an inhaled dose is rapidly cleared. Beclometasone is
metabolised much more slowly and so has a longer plasma half-life. Liver impairment
can therefore increase circulating levels of any inhaled glucocorticoid. Water-soluble
drugs, for example budesonide, dissolve in the watery mucus lining the airways and
are more efficiently cleared by the mucociliary escalator. More lipid-soluble drugs,
including fluticasone and beclomethasone, enter the airway tissues and remain
there for extended periods, extending the duration of their activity.

Adverse Effects
Local side-effects from deposition of inhaled glucocorticoid in the mouth and throat
include hoarseness from the build-up of drug on the vocal cords, and oral thrush
because glucocorticoids suppress local immune defences. It is good practice to rinse the
mouth and/or brush the teeth after inhalation. If the drug reaches physiologically active
levels in the circulation, either because of high inhaled doses or oral/parenteral use in
severe disease, any of the wide range of side-effects may be seen, including growth
suppression in children, osteoporosis, cataract, and adrenal suppression (Cushing’s
syndrome, see Fig. 6.16).

Cromones
Cromones (nedocromil sodium and sodium cromoglicate) are add-on options in
the treatment of asthma and are used as antiallergy medications in some other
situations, e.g. food allergy. They are not helpful in acute asthma, but they may benefit
some patients, particularly children, in maintenance therapy. Their anti-inflammatory
action is less effective than glucocorticoids, and their mechanism of action is not fully
understood. They stabilise mast cells and reduce mast cell release of inflammatory
mediators including histamine, which may be their main mechanism of action in
allergy treatment. They also suppress the activity of a range of inflammatory cells
including neutrophils, eosinophils, and macrophages and reduce the release of a range
of inflammatory mediators and cytokines. Nedocromil sodium is given only by
inhaler, because it is a large, electrically charged molecule not absorbed across the wall
of the GI tract, but sodium cromoglicate can be given orally or by inhaler.

Leukotriene Receptor Antagonists

Leukotrienes are synthesised by the enzyme lipoxygenase from arachidonic acid, an
important constituent of the cell membrane, which is released from the cell membrane if
the cell is injured or exposed to a range of potentially damaging stimuli. Leukotrienes
are closely related to the prostaglandins (p. 167); their biosynthesis and main activities
are summarised in Fig. 8.12. They contribute to the pathophysiological changes in
asthma via a range of actions: they recruit and activate inflammatory cells including
mast cells, neutrophils, and macrophages; they increase vascular permeability and cause
oedema in the airway wall; they constrict bronchial smooth muscle; they stimulate
mucus production; and they damage the epithelial lining of the airway, which in turn
increases airway sensitivity and destroys the cilia. Drugs that either block leukotriene
synthesis (lipoxygenase inhibitors) or block their receptors (leukotriene-receptor
antagonists) are used as second-line drugs in conjunction with steroids and
bronchodilators to optimise asthma control.

Lipoxygenase Inhibitors
These agents are not available in the UK but are used in other countries including the
US and India. Zileuton was the first agent approved for the treatment of asthma and is
given orally. Its most significant side-effect is elevation of liver enzymes.

Leukotriene Receptor Antagonists

Examples: montelukast, zafirlukast
These agents do not prevent leukotriene synthesis, but block leukotrienes from
attaching to and activating their receptors on airway tissues (Fig. 8.12). Used regularly
as adjunct therapy with glucocorticoids, they can improve airway function and reduce
symptoms, and seem to be particularly useful in children and in exercise-induced
bronchoconstriction. They are taken by mouth and are generally well tolerated.
Common side-effects include GI upset and headache. Rarely, they have been associated
with Churg–Strauss syndrome, an autoimmune response in which intense systemic
vasculitis can cause widespread damage to a range of body tissues including the nervous
system and the heart. Withdrawal or reduction of glucocorticoid treatment may increase
the risk.

Immunosuppressants
The use of monoclonal antibodies against the cells and mediators involved in the
pathophysiology of asthma is the most recent development in asthma treatment. They
are used under specialist care in severe asthma only because suppression of the immune
and inflammatory responses can cause serious side-effects.

Omalizumab
Omalizumab is an antibody to IgE, the immunoglobulin associated with allergy. In
severe allergic asthma, IgE triggers and promotes airway inflammation. By binding to
IgE in the blood and in body tissues, omalizumab prevents it from binding to mast cells
and triggering histamine release and the resultant allergic response. It is therefore used
in severe persistent allergic asthma, as well as certain other allergic conditions. It is
given by subcutaneous injection and the dose is calculated according to the patient’s IgE
levels and bodyweight. It is generally better tolerated than other biologics, although it
can cause a range of side-effects including skin reactions and has been associated with
Churg–Strauss syndrome (see above).
FIG. 8.12 Biosynthesis and activity of the leukotrienes.

FIG. 8.13 The mechanism of action of benralizumab.IL-5,

 Interleukin-5.

Benralizumab
IL-5 is an important inflammatory mediator in asthma. It is released by T-lymphocytes
in the asthmatic airway and binds to its receptors on other inflammatory cells including
eosinophils, which are of particular importance in allergic asthma. IL-5 promotes
eosinophil maturation, activity, and survival, and therefore enhances the allergic
inflammatory reaction. Benralizumab is an antibody to the IL-5 receptor. By blocking
IL-5 receptors on eosinophil cell membranes, benralizumab reduces eosinophil activity
and survival, depletes eosinophil numbers, and suppresses allergic inflammation (Fig.
8.13). Because eosinophils are an important part of the body’s defence against
helminthic infections, it is important to treat any such infection before beginning
benralizumab treatment in asthma.

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is associated with persistent and
progressive airflow obstruction and is usually caused by tobacco smoking, although
chronic exposure to lung irritants such as air pollution may also be responsible. It is
usually understood to comprise chronic bronchitis and emphysema, which is
irreversible destruction of alveoli and their supporting tissue, leaving large non-
functional spaces in the lung. The chronic irritation caused by exposure to cigarette
smoke sets up a progressive inflammatory response, with infiltration and activation of
inflammatory cells and the release of inflammatory mediators and cytokines.
Neutrophils in the inflammatory exudate release proteases, which digest and destroy the
protein structure of lung tissue, including the elastic fibres that allow the lungs to recoil
during expiration. This means the lungs gradually expand and the total lung capacity
increases, although the lung’s ability to exchange gases is progressively lost because of
alveolar destruction. The airway walls become swollen, and mucus glands hypertrophy
and produce increased quantities of mucus. The ciliated epithelium lining the airways is
progressively destroyed by the ongoing inflammation, and so mucus is retained in the
airways, leading to plugging and regular infections. Prompt and aggressive antibiotic
treatment of infection is important to minimise airway damage.

Bronchodilators
β2-agonists and antimuscarinic agents (see above) may both help relieve
bronchospasm, especially in acute exacerbations, although in general they are less
helpful in COPD than in asthma.

Glucocorticoids
Generally, the inflammatory changes in COPD airways respond poorly to inhaled
steroids, and if these drugs are tried in a patient, the response should be monitored and
the drug withdrawn if they do not help.

Phosphodiesterase Inhibitors
Roflumilast is a PDE inhibitor specific for PDE4, the form of the enzyme found in the
lung. PDE breaks down the important intracellular messenger cAMP. Inhibition of the
enzyme

F oc us on: The Stepw ise Princ iples of Asthma Treatment

Asthma management aims to minimise symptoms, prevent or minimise acute flare-
ups, and optimise physical and psychological health. Current guidelines follow a
stepwise approach to drug treatment, with patients maintained on the lowest doses of
as few drugs as possible to give optimal control with minimal side-effects, but with the
flexibility to step up or step down treatment as needed. There are slight differences
between guidelines depending on the issuing body, but the fundamental principles
remain consistent. Guidelines are available for different age groups, and it is
important to follow the correct algorithm depending on the age of the patient. Fig.
8.14 shows the 2019 British Thoracic Society/Scottish Intercollegiate Guidelines
Network (BTS/SIGN) algorithm for the stepwise treatment of asthma in adults. In
very mild or intermittent asthma, or in suspected asthma, a short-acting
bronchodilator, usually a β2-agonist, should be prescribed. Inhaled glucocorticoids
may be trialled to see if they make a difference. If there are nocturnal symptoms, or if
there are daytime symptoms occurring more than three times a week or if the
bronchodilator needs to be used more than three times a week, a regular
glucocorticoid inhaler should be added. If control is still not achieved, and the
prescriber is confident that the existing treatment regime is being adhered to, the next
addition is a long-acting bronchodilator. From there, the next step is an increase in
glucocorticoid dose or adding in second-line agents, e.g. a leukotriene-receptor
antagonist. In more severe disease, specialist management should be sought; this may
include regular oral steroids or the addition of biologics such as omalizumab.
 FIG. 8.14 British Thoracic Society/Scottish Intercollegiate
Guidelines Network guidelines for the management of asthma
(2019).ICS, Inhaled corticosteroid; MART: maintenance and
reliever therapy, formulations containing both a glucocorticoid and
a bronchodilator; LABA, long-acting β2-agonist; LAMA, long-
acting muscarinic antagonist; LTRA, leukotriene-receptor
antagonist. From British Thoracic Society and Scottish
Intercollegiate Guidelines Network’s ‘British Guideline on the
Management of Asthma’ (2019), with permission.

increases cAMP levels in lung tissues, and this has a range of anti-inflammatory actions,
including preventing neutrophil accumulation of neutrophils and eosinophils in the
airway wall, reducing the inflammatory action of the inflammatory cells present, and
improving the survival of the ciliated epithelium lining the airway. Roflumilast is given
orally and is a pro-drug, converted to its active form by liver enzymes. This means that
any change in liver enzyme activity, either by other drugs that induce or inhibit them or
in liver impairment can affect its action. It should be avoided in moderate to severe liver
impairment and with inducers including rifampicin and a range of anticonvulsants.
References
1. Borghardt J.M, Kloft C, Sharma A. Inhaled therapy in respiratory disease: the
complex interplay of pulmonary kinetic processes. Can. Respir. J. J. Can. Thorac.
Soc. 2018;2018:2732017.
2. Chauhan B.F, Ducharme F.M. Anti-leukotriene agents compared to inhaled
corticosteroids in the management of recurrent and/or chronic asthma in adults
and children. Cochrane Database Syst. Rev. 2012;2014(5):CD002314.
3. Derichs N. Targeting a genetic defect: cystic fibrosis transmembrane conductance
regulator modulators in cystic fibrosis. Eur. Respir. Rev. 2013;22(127):58–65.
4. Hatipoglu M.K, Hickey A.J, Garcia-Contreras L. Pharmacokinetics and
pharmacodynamics of high doses of inhaled dry powder drugs. Int. J.
Pharm. 2018;549(1–2):306–316.
5. Matera M.G, Rinaldi B, Calzetta L, et al. Pharmacokinetics and
pharmacodynamics of inhaled corticosteroids for asthma treatment. Pulm.
Pharmacol. Therapeut. 2019;58:101828.
6. O’Reilly R, Elphick H.E. Development, clinical utility and place of ivacaftor in the
treatment of cystic fibrosis. Drug Des. Dev. Ther. 2013;7:929–937.

Online resources
Camus P. Pneumtox online Available
at:. https://www.pneumotox.com/drug/index/, 2024.
Condren M.E, Bradshaw M.D. Ivacaftor: a novel gene-based therapeutic approach
for cystic fibrosis. J. Pediatr. Pharmacol. Therapeut. 2013;18(1):8–13 Available
at: http://doi.org/10.5863%2F1551-6776-18.1.8.
Scottish Intercollegiate Guidelines Network, . British guideline on the management
of asthma Available at:. https://www.sign.ac.uk/sign-158-british-
guideline-on-the-management-of-asthma, 2024.
9: Renal and Genitourinary Drugs

CHAPTE R OU TLINE

Introduction to the Urinary System

Structure and Function of the Kidney
The Nephron

Urine Formation
Diuretics
Osmotic Diuretics
Loop Diuretics
Thiazide Diuretics
Potassium-Sparing Diuretics
Carbonic Anhydrase Inhibitors
Male Sexual Function
Erectile Dysfunction
Phosphodiesterase Inhibitors
Alprostadil

Introduction to the Urinary System

The main organs of the urinary system are the kidneys and the bladder. The kidneys
control the composition and volume of body fluids by regulating excretion of wastes,
water, electrolytes, and other substances: this includes drugs and their metabolites, and
impaired renal function can cause drug toxicity. Unwanted and excess substances leave
the kidneys as urine, which travels to the bladder through the ureters to be stored until
it is convenient to excrete it, at which time it passes to the exterior via the urethra.
Additional roles of the kidney include production of erythropoietin, the hormone that
regulates red blood cell production, and activation of vitamin D. Because it controls the
body’s fluid load, the kidney also plays a key role in blood pressure regulation and
releases renin, the enzyme which activates the renin–angiotensin–aldosterone system
(RAAS, see also Fig. 7.15).

Structure and Function of the Kidney

The kidney is a bean-shaped organ enclosed in a robust protective capsule. Internally
there are three distinct regions: a dark outer layer called the cortex, an inner layer called
the medulla, and a cavity called the renal pelvis, into which urine drains and which
opens into the ureter (Fig. 9.1). The functional unit of the kidney is called the nephron,
and each kidney contains around 1.5 million nephrons.

The Nephron
Each nephron is essentially a long, folded tubule, with an expanded end called the
glomerular capsule and the other end opening into a network of drainage tubes called
collecting ducts (CDs), which drain urine towards the renal pelvis. Fig. 9.2 shows the
structure of a typical nephron.

The Regions of the Nephron

The glomerular capsules are located in the cortex. Each capsule contains a tuft of
glomerular capillaries supplied by an afferent arteriole, and water and low-molecular-
weight substances are filtered out of the blood here, forming a fluid called filtrate.
Filtrate flows from the capsule into the first part of the tubule, called the proximal
convoluted tubule (PCT), which leads into the loop of the nephron (loop of Henle). The
loop forms a hairpin bend dipping into the medulla before returning to the cortex and
forming the final section, the distal convoluted tubule (DCT). The distal convoluted
tubule in turn empties into the collecting ducts, which drain urine into the renal pelvis.

Filtration in the Glomerulus

Filtration through the glomerular capillary walls is driven by the hydrostatic (blood)
pressure generated by the difference in diameter of the afferent and efferent arterioles.
The afferent arteriole is wider than the efferent arteriole, and so blood pressure in the
glomerular capillaries is around 55 mmHg (compare with standard capillary pressure,
which is only around 25 mmHg). This higher-than-average blood pressure in the
glomerular capillaries drives filtration out of the blood and into the glomerular capsule.
Low-molecular-weight molecules including water, ions, glucose, urea, and other
substances are filtered out of the blood and enter the glomerular capsule. Higher
molecular-weight substances, including plasma proteins and some drugs, are too large
to pass through the pores in the glomerular filter and remain in the bloodstream (Fig.
9.3).

Glomerular Filtration Rate

This is the volume of filtrate produced every minute, and in health, is an impressive 125
mL/min, equivalent to 180 L every 24-hour period, or around 78 times the total plasma
volume every day.
 FIG. 9.1 The internal structure of the kidney. Modified from Patton
K and Thibodeau G (2020) Structure & function of the body, 16th ed,
Fig. 18.2. St. Louis: Elsevier.

Urine Formation

Key Points
Three processes contribute to the formation of urine (Fig. 9.4).

• Filtration: Water and small molecules are filtered out of the glomerular capillaries
into the glomerular capsule, forming filtrate.
• Reabsorption: As the filtrate passes through the nephron, water, organic
nutrients, electrolytes, and other key substances are reabsorbed from the filtrate
back into the bloodstream.
• Secretion: Unwanted materials, including drugs, hydrogen ions, and other waste
products, are actively pumped out of the bloodstream and into the filtrate for
excretion.

Fig. 9.5 shows the main sites of sodium (Na+), chloride (Cl-), and potassium (K+)
reabsorption in the nephron, and also indicates the region of the nephron where the
main diuretics exert their effect.

Reabsorption and Secretion in the Different Regions of the Nephron

The efferent arteriole opens into a second network of capillaries that wrap around the
nephron for efficient reabsorption from the filtrate into the blood. Additionally,
unwanted substances including excess hydrogen (H+) ions, creatinine, and molecules
too large to be filtered in the glomerulus can be actively secreted out of the blood into
the filtrate for excretion.
Reabsorption of materials from the filtrate occurs along the length of the nephron, the
walls of which contain a number of pumps and transport mechanisms. As electrolytes
and other solutes, for example glucose and Na+ ions, travel from the filtrate back into
the bloodstream, this creates an osmotic gradient between these fluids: that is, the
bloodstream becomes more concentrated than the filtrate. As a result, water travels
passively from the filtrate and is reabsorbed into the bloodstream. The quantity of
solutes reabsorbed is therefore a major determinant of water reabsorption by the
nephron. Na+ reabsorption in particular is an important factor in water reabsorption:
the more Na+ reabsorbed into the blood, the more water is reabsorbed, reducing urine
volume.
Around 99% of the filtrate is reabsorbed into the blood as it travels through the
nephron, and the end product, urine, contains waste and unwanted substances
concentrated in a relatively small volume of water.

Reabsorption and Secretion in the Proximal Convoluted Tubule

The PCT is equipped with a range of carrier mechanisms for active reabsorption, and to
increase available surface area for this, it is lined with simple epithelium with a brush
border of microvilli. Sixty to seventy percent of the filtrate volume is reabsorbed into the
peritubular capillaries here, including Na+, K+, bicarbonate, and Cl- ions. Ninety-nine
percent of organic nutrients, including glucose, amino acids, and free fatty acids, are
actively reabsorbed in the PCT; water follows passively by osmosis. The PCT is also an
important site for secretion of unwanted materials that are too large to be filtered in the
glomerulus, including diuretics and other drugs, and of the waste products, uric acid
and ammonium compounds. H+ ions are also secreted here in exchange for Na+: as H+
ions are pumped into the filtrate, Na+ ions are reabsorbed (Fig. 9.5.1).

Reabsorption in the Loop of the Nephron

Filtrate entering the loop is at the same osmotic pressure as (isotonic to) the filtrate
formed in the glomerular capsule. The descending limb is permeable to water, so water
is reabsorbed here, concentrating the filtrate. However, the ascending limb is
impermeable to water but possesses a co-transporter complex called the Na+/K+/2Cl-
co-transporter (Fig. 9.5.2) which reabsorbs these three ions. Loop diuretics such as
furosemide act here. As the filtrate travels through the ascending limb, it therefore
becomes progressively more dilute, because electrolytes are reabsorbed but water
cannot follow.

Reabsorption and Secretion in the Distal Convoluted Tubule

Only about 10% of the volume of the original filtrate arrives in the DCT, because 90%
has already been reabsorbed. The walls of the DCT contain pumps and channels that
reabsorb Na+ and Cl- (Fig. 9.5.3); water follows passively by osmosis. These pumps
exchange Na+ for K+, so as Na+ is retained, K+ is lost and vice versa. Thiazide diuretics,
such as bendrofluazide, act here. The mineralocorticoid hormone aldosterone
increases the number of pumps and channels here, increasing Na+ and water
reabsorption and enhancing K+ loss. The DCT is also the main site of calcium (Ca2+)
reabsorption; parathyroid hormone acts here to increase Ca2+ reabsorption (see Fig.
9.9) and decreases Ca2+ loss in the urine. Secretion of H+ ions, K+ ions, and some drugs
also takes place here.

FIG. 9.2 The structure of a typical nephron. Modified from

Thibodeau G and Patton K (2019) Anatomy and physiology, 10th ed,
 St Louis: Mosby; and Applegate E (2011) The anatomy and
physiology learning system, 4th ed. Philadelphia: Elsevier.

FIG. 9.3 Glomerular filtration. Modified from Waugh A and Grant

A (2020) Ross & Wilson anatomy and physiology in health and
illness, 14th ed, Fig. 13.9. Oxford: Elsevier.

Reabsorption in the Collecting Duct

Aldosterone increases the number of Na+ pumps and channels in the walls of the CD,
increasing reabsorption of Na+ and water. Anti-diuretic hormone (ADH) increases
the number of aquaporins (water channels) in the walls of the CD, increasing water
reabsorption and reducing urine volume. Amiloride and spironolactone act here.

Diuretics
Diuretics increase urine production and promote the loss of water and electrolytes,
mainly Na+, from the body. Most work by a direct action on tubular Na+ transport
mechanisms and increase the Na+ content of the filtrate, increasing its osmolarity,
which in turn reduces water reabsorption and increases urine volume. In addition,
diuretics may affect renal handling of other electrolytes because many of the transport
mechanisms in the renal tubule exchange or co-transport more than one ion. Diuretic
therapy can therefore lead to excessive or deficient levels of other electrolytes, most
significantly K+, Cl-, and Ca2+.
FIG. 9.4 Filtration, reabsorption, and secretion in urine
formation.The green arrow represents filtration from the glomerular
capillaries. The turquoise arrows represent reabsorption of
substances from the filtrate into the bloodstream. The purple arrows
represent secretion of unwanted substances from the bloodstream
into the filtrate. Modified from Patton KT, Bell FB, Thompson T,
et al. (2022) Anatomy & physiology, 11th ed, Fig. 42.17. St. Louis:
 Elsevier.

Most diuretics must be present in the filtrate in order to work because most target a
Na+-transport mechanism on the epithelium lining the tubule. However, most are
heavily plasma protein-bound, and so are too large to be filtered in the glomerulus and
can only reach the filtrate by active secretion into the tubule by transporters in the PCT
(Fig. 9.6). These transporters secrete a range of substances into the filtrate and have a
finite working capacity. This means that once the diuretic drug plasma concentration is
high enough to saturate these transporters, no additional drug will reach the filtrate, and
increasing the drug dose will have no further therapeutic effect. It also means that if
there is another drug in the bloodstream which is also secreted into the filtrate using the
same transporters, the two drugs will compete at the transporter and reduced levels of
the diuretic may reach the filtrate. This can reduce diuretic action.
Diuretics are useful in cardiovascular disease to reduce circulating blood volume and
blood pressure and are used to reduce fluid load in situations associated with oedema or
fluid retention, like raised intracranial pressure, pulmonary oedema, liver disease, and
nephrotic syndrome. However, in conditions that reduce renal blood flow, e.g. heart
failure, drug delivery to the kidney is reduced and this can reduce drug effectiveness.

Osmotic Diuretics
Example: mannitol
Osmotic diuretics do not directly interfere with renal ion transport mechanisms, but
their presence in body fluids increases the osmotic pressure of that fluid and so
influences water movement between body compartments. The sugar mannitol is the
prototype agent in this group, but other substances with similar actions include urea
and isosorbide. High levels of other solutes in the urine, e.g. glucose, also produce an
osmotic diuresis.
FIG. 9.5 The main regions of the nephron where sodium, chloride,
and potassium are reabsorbed, and the sites of action of the main
groups of diuretic drugs. Modified from Ritter JM, Flower RJ,
Henderson G, et al. (2020) Rang & Dale’s pharmacology, 9th ed, Fig.
30.4. Oxford: Elsevier.
FIG. 9.6 Secretion of diuretics into the filtrate in the proximal
convoluted tubule.Diuretics are heavily plasma protein-bound and so
do not filter out of the blood in the glomerulus. Transporter
mechanisms in the wall of the proximal convoluted tubule actively
extract them from the bloodstream and pump them into the filtrate.
Once in the filtrate, they inhibit their target sodium-transport
mechanism.
 FIG. 9.7 The mechanism of action of mannitol: osmotic diuresis.1.
Mannitol in the bloodstream pulls water out of the tissues. 2.
Increased blood volume increases filtration rates in the glomerulus.
3. Mannitol is filtered but not reabsorbed. 4. Mannitol increases the
osmotic pressure of the filtrate and pulls water from the bloodstream
into the nephron.

Mannitol is given intravenously to reduce intracranial pressure, relieve cerebral

oedema, and reduce intraocular pressure. It does not leave the bloodstream, so it
increases the osmotic pressure of the blood, which pulls fluid from the tissues into the
circulation and therefore reduces oedema. This increases blood volume and blood flow
to the kidney, increasing glomerular filtration and the amount of filtered Na+, which
itself may increase urine volume. Mannitol is filtered in the glomerulus but is not
reabsorbed, so it remains in the filtrate, increasing its osmotic pressure. This generates
an osmotic gradient between the tubule filtrate and the fluid outside the tubule and
reduces water reabsorption, increasing urine volume (Fig. 9.7). Its plasma half-life is
around 2 hours, although this is extended if renal function is poor.

Adverse Effects
Initially, because mannitol in the blood draws fluid from the tissues into the circulation
and increases circulating blood volume, it can precipitate heart failure. Once diuresis
commences, however, there can be hypovolaemia and hypotension, and pre-existing
heart failure may be exacerbated by depleting circulating blood volume. Cardiovascular
function should therefore be assessed before beginning treatment.

Loop Diuretics
Examples: bumetanide, ethacrynic acid, furosemide, torasemide
Loop diuretics are the most potent diuretics available because they inhibit the
Na+/K+/Cl- co-transport complex in the ascending limb of the loop of the nephron (Fig.
9.8), which normally reabsorbs around 25% of the filtrate’s Na+ content. This complex
pumps Na+, K+, and Cl- from the filtrate into the epithelial cells of the nephron, and the
ions are then pumped out the other side of the cells into the bloodstream, taking water
with them. Loop diuretics bind to the Cl--transporting unit of the complex but are too
large to travel through the transporter, and so they block it. This increases Na+ and Cl-
loss in the urine, which increases its osmolarity and reduces water reabsorption. Loop
diuretics have vasodilator activity, which may be helpful in certain circumstances: for
example, in heart failure because it reduces afterload, and in hypertension because it
reduces blood pressure. In general, however, loop diuretics are not the optimal choice in
hypertension because their duration of action is too short and the diuresis they produce
is excessive. They are usually the diuretic of choice to relieve pulmonary oedema and
fluid retention secondary to heart failure and in renal disease.
 FIG. 9.8 The sodium/potassium/chloride co-transporter complex
of the ascending limb of the loop of the nephron. Modified from
Shanbhag TV, Shenoy S, and Nayak V (2021) Pharmacology for
dentistry, 4th ed, Fig. 5.3. New Delhi: Elsevier India.

Pharmacokinetics
Bumetanide and torasemide are better and more reliably absorbed when given
orally than furosemide, and all can be given intravenously if rapid diuresis is needed;
intravenous administration gives peak effect within half an hour. Furosemide’s
plasma half-life is 1.5–2 hours, and with oral administration its effects last around 6
hours; about 50% is metabolised in the kidney, and the remainder is excreted
unchanged. Bumetanide has a plasma half-life of 1 hour and is metabolised by the
liver and kidney. Torasemide has a half-life of 3–4 hours and is mainly metabolised in
the liver. Loop diuretics are tightly bound to plasma albumin and so are not filtered in
the glomerulus, but reach the filtrate by secretion in the PCT; if this is compromised by
poor renal function, diuretic action can be reduced. Several drugs, including non-
steroidal anti-inflammatory drugs and some antimicrobials, inhibit the
transporters that secrete loop diuretics into the filtrate and so impair their actions.

Adverse Effects
As with any diuretic, there may be urinary frequency and urgency, nocturia, and
incontinence. Hypokalaemia is a common occurrence, because blocking Na+
reabsorption in the loop means that the filtrate arriving in the DCT contains high Na+
levels; this stimulates renin release, which in turn stimulates aldosterone secretion from
the adrenal cortex (the RAAS, see Fig. 7.15). This increases activity of the DCT’s Na+/K+
pumps, which reabsorb Na+ in exchange for K+, and K+ is lost in the urine.
Hypokalaemia is potentially dangerous because it can predispose to cardiac
arrhythmias. Diuretic-induced hypokalaemia increases the arrhythmogenic action of
certain anti-arrhythmic drugs, e.g. digoxin, a clinically important interaction. Other
electrolyte imbalances include hyponatraemia and hypomagnesaemia. Ca2+ excretion is
increased, and loop diuretics may be used to bring plasma Ca2+ down in
hypercalcaemia. Uric acid secretion is impaired, and blood uric acid levels rise. The loop
diuretics, especially furosemide, can produce dose-related ototoxicity, giving deafness,
tinnitus, and vertigo, because they affect the delicate hair cells of the inner ear
responsible for hearing and balance; function usually returns to normal when the drug
is withdrawn.
Excessive water and Na+ loss can reduce the circulating blood volume and cause
hypotension. If renal blood flow falls, renal function can be impaired.

Thiazide Diuretics
Examples: chlorothiazide, bendrofluazide, hydrochlorothiazide; chlortalidone,
indapamide, and metolazone have thiazide-like activity but are not structurally related
to thiazides.
The original drug in this group, chlorothiazide, was first introduced to the market
in 1957, and the agent most commonly used today, bendrofluazide, was introduced in
1960. Thiazides are used mainly in hypertension and heart failure. They are heavily
plasma protein-bound, and so are not filtered in the glomerulus and reach the filtrate
via active secretion in the PCT (Fig. 9.6). Thiazides inhibit the Na+ pump in the DCT,
reducing Na+ reabsorption and therefore increasing Na+ and water excretion. This has a
knock-on effect on Ca2+ excretion. Blocking Na+ reabsorption in the tubular epithelial
cell reduces Na+ levels in the cell. This activates a Na+/Ca2+ transporter in the
basolateral membrane which exchanges Na+ for Ca2+. When activated, this transporter
imports Na+ into the cell in exchange for Ca2+, which is transported into the
bloodstream (Fig. 9.9). Thiazide-induced reduction in Na+ reabsorption therefore
reduces urinary Ca2+ and increases circulating blood Ca2+ levels: this is why thiazides
are sometimes used to reduce Ca2+ excretion (and therefore urinary Ca2+ concentration)
in people prone to urinary stones. Elevating blood Ca2+ can also be helpful in people at
risk of osteoporosis. In long-term use, they have a vasodilator effect, which contributes
significantly to their therapeutic use in hypertension.

Pharmacokinetics
Thiazides are less potent than loop diuretics and have a slower onset of action, but their
duration of action is longer. For example, bendrofluazide has a plasma half-life of 3–4
hours but is active over 12–24 hours.

Adverse Effects
As with any diuretic, there may be urinary frequency and urgency, nocturia, and
incontinence. There is a significant risk of hypokalaemia because the filtrate arriving in
the distal section of the DCT and the CDs contains high Na+ levels; this stimulates the
RAAS as described for the loop diuretics above, which increases Na+ reabsorption at the
expense of K+, which is lost in the urine. Electrolyte imbalances including hypokalaemia
and hyponatraemia are more frequent with thiazides than loop diuretics because
thiazides have a considerably longer duration of action. In higher doses, thiazides can
cause erectile dysfunction, which is reversible on stopping the drug; sometimes reducing
the dose can resolve the problem. They compete with uric acid for the transporter which
secretes them into the tubule, so they increase blood levels of uric acid; for this reason,
they should be used with caution in people with, or at risk of, gout.
Thiazides impair glucose tolerance and can cause hyperglycaemia, thought to be
secondary to thiazide-induced hypokalaemia. Low blood K+ levels reduce the ability of
pancreatic β-cells to release insulin in response to falling blood glucose levels. As a
result, blood glucose rises. Thiazides should therefore be used with care in diabetes.
 FIG. 9.9 Thiazides increase sodium loss in the urine and calcium
retention.1. Thiazides inhibit the sodium/chloride pump in the distal
tubule, increasing the loss of these ions and water in the urine. 2.
Falling sodium concentrations in the cell activate a sodium-calcium
pump on the basolateral membrane, which imports sodium from the
blood in exchange for calcium. Blood calcium levels therefore
rise. Modified from Hemmings H and Egan T (2013) Pharmacology
and physiology for anesthesia, Fig. 34.8. Philadelphia: Saunders.

Potassium-Sparing Diuretics
Examples: amiloride, eplerenone, spironolactone, triamterene
K+-sparing diuretics act at the distal portion of the DCT and CD, the walls of which
contain pumps and channels that reabsorb Na+ and Cl- in exchange for K+. They are
weak diuretics because most electrolyte reabsorption has already taken place: the DCT
and CD are the sites of any final adjustments to Na+ reabsorption, and relatively small
quantities of Na+ are reabsorbed here. However, they may be usefully combined with a
loop or thiazide diuretic to reduce the risk of hypokalaemia. Although all the K+-sparing
diuretics block this mechanism, preventing Na+ reabsorption and so retaining K+, their
mechanisms of action are slightly different.
 Spironolactone and eplerenone are aldosterone antagonists. Aldosterone, the
main mineralocorticoid from the adrenal cortex, binds to DNA in the tubular cell and
increases production of Na+ pumps and channels in the DCT and CD and so enhances
Na+ reabsorption, with water following passively (Fig. 9.10A). Spironolactone prevents
aldosterone from binding to its receptor and so reduces Na+ pump and channel pump
production. With fewer pumps and channels available, less Na+ is reabsorbed,
increasing Na+ and water loss in the urine (Fig. 9.10B). Because Na+ reabsorption
increases K+ loss, the diuresis and increased Na+ loss seen with spironolactone is
accompanied by K+ retention.
Amiloride and triamterene bind directly to Na+ channels in the DCT and CD,
preventing Na+ reabsorption, increasing urinary Na+ and water loss, and retaining K+.

Pharmacokinetics
These drugs are given orally and are generally well absorbed with the exception of
amiloride, whose oral bioavailability is only around 50%, and less if there is food in the
gastrointestinal (GI) tract. Spironolactone is a pro-drug and is metabolised in the wall
of the GI tract and the liver to the active metabolite canrenone (Fig. 9.10B), which
has a longer half-life than spironolactone (16 hours to spironolactone’s 90 minutes).
Both triamterene and amiloride are secreted into the tubule in the PCT. As with
steroid drugs in general, spironolactone and eplerenone can take several days to
achieve full therapeutic effect; triamterene and amiloride, on the other hand, have a
rapid onset of action.
 FIG. 9.10 The mechanism of action of spironolactone.A. The
steroid hormone aldosterone enters the distal convoluted
tubule/collecting duct cells and binds to its receptor in the
cytoplasm. The hormone–receptor complex then binds to DNA and
stimulates production of sodium pump protein. This increases
sodium reabsorption and reduces sodium and water loss in the urine.
B. Spironolactone (as its active metabolite canrenone) binds to and
blocks aldosterone receptors. This prevents sodium pump synthesis.
Sodium and water loss in the urine therefore increases but without
additional potassium loss.

Adverse Effects
These drugs can cause hyperkalaemia, and care is needed if there is already a
predisposition to raised K+ levels, for example in renal failure or with co-administration
of β-blockers, angiotensin-converting enzyme inhibitors, or angiotensin-
receptor antagonists, all of which can increase plasma K+. The aldosterone-receptor
antagonists are structurally related to steroids (otherwise they would not be able to bind
to steroid receptors) and can block steroid receptors elsewhere in the body, including
oestrogen, progesterone, and testosterone receptors. Spironolactone is more likely
than eplenerone to cause such side-effects; it may cause gynaecomastia, menstrual
irregularities, and testicular atrophy. Due to its anti-androgen effect, spironolactone
can be used to treat hirsutism in women with polycystic ovary disease and male pattern
baldness.

Carbonic Anhydrase Inhibitors

Examples: acetazolamide
The enzyme carbonic anhydrase is found in the cells along the length of the nephron
but is present in particularly high concentrations in the PCT, which is therefore the main
site of action of these agents. Inside the tubule cell, carbonic anhydrase catalyses the
conversion of carbon dioxide and water into carbonic acid, which then rapidly
dissociates into a H+ ion and a bicarbonate ion. The H+ ions produced are then
exchanged for Na+ ions across the wall of the tubule: H+ ions are secreted into the
filtrate and Na+ ions reabsorbed (Fig. 9.11). Blocking the enzyme therefore reduces the
availability of H+ ions for exchange, and less Na+ can be reabsorbed. This Na+ is then
lost in the urine, taking water with it. Along with increased Na+ loss, bicarbonate ion
excretion is also increased, producing an alkaline urine and a mild acidosis. This mild
acidosis stimulates respiration and is the basis for the use of acetazolamide in altitude
sickness: by increasing respiratory effort, it helps to counteract the hypoxia caused by
the reduced oxygen content of the atmosphere at altitude.
However, the diuretic action of carbonic anhydrase inhibitors is weak and short-lived.
One reason for this is that the H+/Na+ exchange mechanism in the PCT accounts for a
relatively small proportion of total tubular Na+ reabsorption, so the impact of inhibiting
it is fairly minor. In addition, the PCT cells respond to the inhibition of carbonic
anhydrase by simply producing more enzyme, restoring its activity. With more effective
diuretics available, the use of acetazolamide is now generally restricted to reducing
intraocular pressure in people with glaucoma, as well as its more specialised use in
altitude sickness as explained above.

Male Sexual Function

To achieve penetration in sexual intercourse, the penis must become rigid (erect). The
internal structure of the penis is shown in Fig. 9.12. In section, the penis is seen to be
constructed from three columns of tissue running the length of the organ. The corpus
spongiosum encloses the urethra. The two corpora cavernosa (singular: corpus
cavernosum) run laterally to each other. Each is supplied by a deep artery of the penis,
and they are rich in sinusoids, spaces that fill with blood during erection.
Parasympathetic stimulation of these arteries during sexual excitement causes
vasodilation, increasing blood flow, engorging the sinusoids, and stiffening the penis.

FIG. 9.11 The mechanism of action of carbonic anhydrase

inhibitors. Modified from Hemmings H and Egan T (2013)
Pharmacology and physiology for anesthesia, Fig. 34.8. Philadelphia:
Saunders.
FIG. 9.12 Cross-section showing the internal structure of the
penis. From Waugh A and Grant A (2020) Ross & Wilson anatomy
and physiology in health and illness, 14th ed, Fig. 13.9. Oxford:
Elsevier.
 FIG. 9.13 Mechanism of action of sildenafil. Modified from Ritter
JM, Flower RJ, Henderson G, et al. (2012) Rang & Dale’s
pharmacology, 7th ed, Fig. 34.6. Oxford: Elsevier.

Erectile Dysfunction
The inability to achieve or maintain an erection sufficient for sexual intercourse (erectile
dysfunction) is common, and prevalence increases with age. There is often a
psychological component, but a range of conditions that may interfere with vascular or
neurological function may be responsible. There is a strong correlation between erectile
dysfunction and cardiovascular disease, including ischaemic heart disease, stroke, and
hypertension. Other recognised risk factors include obesity, diabetes mellitus,
neurological disease such as multiple sclerosis, testosterone deficiency, and benign
prostatic hypertrophy. A wide range of drugs, including recreational substances such as
alcohol and marijuana, can cause erectile dysfunction: the most common include
benzodiazepines, selective serotonin re-uptake inhibitors, thiazide
diuretics, β-blockers, and tricyclic antidepressants.

Phosphodiesterase Inhibitors
Examples: avanafil, sildenafil, tadalafil
The phosphodiesterases (PDEs) are a family of enzymes which break down the
important intracellular signalling molecules cyclic AMP (cAMP) and cyclic guanosine
monophosphate (cGMP) (p.33). Sexual arousal increases the levels of nitric oxide in the
tissues of the penis, which activates guanylyl cyclase and increases cGMP production.
cGMP relaxes the smooth muscle in the erectile tissue of the corpora cavernosa and the
arteries that supply them, increasing blood flow into the penis and facilitating
engorgement and erection. PDE5 breaks cGMP down, reducing cGMP levels and so
reducing engorgement. Sildenafil and the other drugs in this category inhibit PDE5,
increasing cGMP levels, which increases blood flow into the penis and promotes and
prolongs erection (Fig. 9.13). Sildenafil and tadalafil are also used in pulmonary
hypertension: by relaxing pulmonary artery smooth muscle, these drugs reduce
pulmonary artery pressure.
In conjunction with non-pharmacological measures (e.g. reducing alcohol
consumption, stopping smoking, and weight loss if indicated), PDE inhibitors are the
mainstay of erectile dysfunction management.

Pharmacokinetics
Sildenafil is rapidly absorbed from the GI tract and has a duration of action of 3–5
hours, so a single dose must be taken within a relatively short timeframe in advance of
anticipated sexual activity. Tadalafil has a longer duration of action (17–24 hours) and
can be taken as a regular daily dose to allow for spontaneous activity and/or when
sexual activity is regular. PDE5 inhibitors are primarily metabolised by CYP3A4 enzymes
in the liver, which metabolise a range of other drugs. As a result, enzyme inhibitors such
as the azole antifungals (e.g. ketoconazole), Ca2+-channel blockers (e.g.
verapamil), grapefruit juice, and macrolide antibiotics (e.g. erythromycin) are
likely to increase PDE5 inhibitor levels and precipitate toxicity, and enzyme inducers
including some anticonvulsants (e.g. carbamazepine and phenytoin) and St.
John’s wort increase the clearance of PDE5 inhibitors and decrease their effectiveness.
Adverse Effects
Although the PDE5 inhibitors are relatively selective for this form of the enzyme, they
may also inhibit other members of the PDE family in other tissues, giving a range of
side-effects. PDE5 inhibitors relax vascular smooth muscle and can cause systemic
vasodilation, reducing blood pressure and affecting systemic haemodynamics. They
should therefore be used with care, if at all, in individuals with cardiovascular disease or
compromise, including hypotension, heart failure, a history of heart attack or stroke, or
ischaemic heart disease. In addition, they have clinically important interactions with
other hypotensive agents, including nitrates and α-blockers and can cause a
potentially dangerous fall in blood pressure. Rarely, priapism (sustained and painful
erection) occurs. By an action on PDE6 in the rods and cones of the retina, these drugs
can cause vision problems; this is more likely with high-dose sildenafil than with the
other PDE5 inhibitors.

Alprostadil
Natural prostaglandins (PGs) have very short half-lives, usually too brief to be clinically
useful, and so stable synthetic analogues are often more suitable. PGE is an important
vasodilator in normal physiological regulation of cardiovascular function, and the
synthetic PGE1 analogue alprostadil is used to relax penile arterial smooth muscle and
increase penile engorgement in the diagnosis and treatment of erectile dysfunction,
usually as a second-line treatment if a PDE5 inhibitor cannot be used because of side-
effects or a contra-indicating factor. Alprostadil can be applied topically to the penis tip,
given as an intra-urethral pellet, or injected directly into the corpus cavernosum. The
main side-effects include painful erection, and if enough drug escapes into the
circulation, there may be headache and dizziness from systemic vasodilation.

References
1. Koeppen B, Stanton B. Renal physiology. 6th ed. Elsevier: Oxford; 2018.

Online resources
Arumugham V.B, Shahin M.H. Therapeutic uses of diuretic agents. In: StatPearls
[Internet]. Treasure Island: StatPearls Publishing; 2021 Available
from:. https://www.ncbi.nlm.nih.gov/books/NBK557838/.
Ellison D.H. Clinical pharmacology in diuretic use. Clin. J. Am. Soc.
Nephrol. 2019;14(8):1248–1257 Available
at:. https://cjasn.asnjournals.org/content/14/8/1248.
10: Drugs and the Gastrointestinal
Tract

The Structure and Function of the Gastrointestinal System

The Main Gastrointestinal Organs

Nervous Control of the Gastrointestinal Tract

Drugs and Gastric Function
Gastric Acid Secretion
Drugs That Regulate Gastric pH
Antacids
Proton-Pump Inhibitors
H2-Receptor Antagonists
Misoprostol
Drugs and Disorders of Gastrointestinal Motility
Drugs That Reduce Gastrointestinal Tone and/or
Motility
Opioids
Antimuscarinic Agents
Smooth-Muscle Relaxants
Drugs That Increase Gastrointestinal Motility
Laxatives
Opioid Receptor Antagonists
Pro-Kinetic Drugs
Antiemetics
 The Physiology of Vomiting
Dopamine Antagonists
5-HT3 Antagonists
Neurokinin-Receptor Antagonists
Antihistamines
Antimuscarinic Agents

Nabilone
Other Drugs With Anti-Emetic Activity

F OCUS ON

Focus on: Drugs Used in Peptic Ulcer Treatment p. 188

The Structure and Function of the Gastrointestinal

System
The gastrointestinal (GI) tract is essentially a long tube, open at both ends, adapted for
the ingestion, digestion, and absorption of fluids and nutrients, and the excretion of
unwanted solid materials. Foodstuffs and fluids enter the tract at the mouth and are
subjected to both mechanical and chemical change as they pass through the tract, with
wastes excreted via the anus. Mechanical digestion includes the grinding and crushing
action of the teeth in chewing, as well as the mixing and churning that takes place in the
stomach, and chemical digestion is carried out by a range of enzymes which are added to
the contents of the tract at various stages. Several important organs associated with the
tract, including the liver, pancreas, and gallbladder, release hormones and enzymes that
regulate and contribute to healthy GI function. GI side-effects are associated with a wide
range of drugs. For example, antibiotics alter GI flora and motility, and may cause
diarrhoea, nausea and vomiting, and more seriously, antibiotic-induced colitis, caused
by overgrowth of Clostridium difficile. A wide range of drugs affect autonomic nervous
system function either adversely or as their main therapeutic action and alter motility
and secretory activity of the tract: for example, first-generation antihistamines
have antimuscarinic side-effects and commonly cause dry mouth due to reduced salivary
secretion and constipation by inhibiting tract motility. Drugs that irritate the tract, e.g.
non-steroidal anti-inflammatory drugs (NSAIDs), can cause ulceration, bleeding,
or perforation. GI side-effects may be more severe if, as is commonly the case, the
medication is taken orally, but because the tract receives a generous blood supply, drugs
given parenterally can still affect its function. It follows that impaired GI function may
affect absorption and excretion of drugs taken orally; this is discussed in more details in
Chapter 2.

The Main Gastrointestinal Organs

The main organs of the GI tract are shown in Fig. 10.1. Foodstuffs enter the tract via
the mouth, where chewing begins the process of mechanical digestion and mixes them
with saliva. Saliva lubricates the food and contains amylase, a digestive enzyme that
begins to digest any carbohydrate present. From the mouth, food is propelled by
peristaltic waves sweeping down the muscular oesophagus to the stomach. The highly
acidic gastric juices have significant antimicrobial action, but also stop the action of
salivary amylase. The only significant chemical digestion in the stomach is performed by
pepsin, secreted by chief cells in the gastric lining and which begins protein digestion.
The stomach walls contain three layers of smooth muscle whose fibres run in different
directions to each other: regular, rhythmical, and co-ordinated contraction of these
layers mixes and churns the stomach contents, producing a liquid called chyme. The
next section of the tract, the small intestine, has three segments, the duodenum, the
jejunum, and the ileum, and is around 7 m (22 feet) long in total. Most digestion and
absorption take place here. Digestive enzymes are secreted into the small intestine by
intestinal glands and the epithelial cells lining the tract, and fluids containing digestive
enzymes from the pancreas and the gallbladder are emptied into the duodenum. These
include lipases, which digest fats, proteases which digest proteins, and maltases,
sucrases, lactases, and amylases which digest carbohydrates. The pancreatic juices and
bile from the gallbladder are very alkaline, which rapidly increases the pH of the acidic
chyme arriving in the duodenum from the stomach and protects the duodenum from
acid damage.
 FIG. 10.1 The main organs of the gastrointestinal tract. From
Patton K and Thibodeau G (2020) Structure & function of the body,
16th ed, Fig. 16.1. St. Louis: Elsevier.

The small intestine is coiled within the abdominal cavity, anchored to the posterior
abdominal wall by folds of the peritoneum, and opens into the large intestine (the colon)
at the ileocaecal valve. The colon arches over the small intestine and opens into the
rectum. The opening from the rectum to the exterior, the anus, is normally under
voluntary control in the adult and ensures faecal continence.

Nervous Control of the Gastrointestinal Tract

Healthy GI function depends upon the muscle found in the wall of the tract all the way
from the mouth to the anus. Except for the tongue and the muscle of the throat and
external anal sphincter, which are composed of voluntary muscle, the tract walls contain
smooth muscle. This regulates forward propulsion of the tract contents by peristalsis, as
well as mixing and churning activity in the stomach and intestines. GI smooth muscle is
under the overall control of the autonomic nervous system, but much of its activity is
controlled locally by reflexes, local hormones, and changing conditions: for example,
histamine stimulates gastric acid secretion, and stretching of the walls of the intestine
stimulates peristalsis. The walls of the intestines contain two dense networks of nerves
(plexuses), together called the enteric nervous system (Fig. 10.2). The myenteric plexus
is sandwiched between the two layers of smooth muscle in the tract wall, and its main
function is regulation of intestinal motility. The submucosal plexus lies between the
mucosal lining of the tract and the smooth muscle layer, and its main functions are
regulation of blood flow and control of the quantity and composition of secretions. The
enteric nervous system is innervated by the autonomic nervous system, but also
contains much shorter neurones internal to the plexus giving reflexive local control
independent of autonomic control: for example, these are the neurones which stimulate
contraction when the wall of the tract is stretched, and which adjust the volume and
composition of secretions in response to different foodstuffs travelling through.

FIG. 10.2 The enteric nervous system. Modified from Costanzo L

(2022) Costanzo physiology, 7th ed, Fig. 8.1. Philadelphia: Elsevier.
 FIG. 10.3 The main neurotransmitters and hormones affecting
gastrointestinal motility and secretion.

Neurotransmitters in the Gastrointestinal Tract

A wide range of neurotransmitters are released by nerves supplying the glands and
smooth muscle of the GI tract and regulate its function (Fig. 10.3). Acetylcholine
(ACh), released by parasympathetic nerves and acting on muscarinic receptors, is the
main stimulator of GI motility and secretion, including gastric emptying and intestinal
peristalsis. On the other hand, noradrenaline from sympathetic nerves shuts the tract
down; in a fight-or-flight situation, digesting a meal is not a priority. Enkephalins,
members of the endogenous opioid family, act on mu (μ) receptors on myenteric nerves,
inhibiting contraction and secretion. This is the reason why morphine and other
opioids have a powerful constipating action. Ninety-five percent of the body’s
serotonin (5-hydroxytryptamine, 5-HT) is found in the GI tract, where it stimulates
motility and secretion by acting on 5-HT4 receptors. Serotonin also activates sensory
neurones, sending sensory impulses such as pain, nausea, and stretch from the GI tract
to the brain, primarily by acting on 5-HT3 receptors on these afferent nerves. The
development of drugs with selective action on these subtypes has been of significant
clinical use: 5-HT4-receptor agonists such as prucalopride are used to treat
constipation, whereas 5-HT3-receptor antagonists, e.g. ondansetron, inhibit sensory
impulses travelling to the vomiting centre (VC) in the brain and are effective anti-
emetics. Substance P is a powerful stimulant of intestinal contraction and stimulates
neurokinin 1 (NK1) receptors on sensory fibres, sending impulses from the GI tract to
the brain, including to the VC. Aprepitant, an NK1 antagonist, is an effective anti-
emetic. Dopamine (DA) inhibits GI motility and is an important neurotransmitter in
vomiting pathways: dopamine antagonists such as metoclopramide are widely used
to manage nausea and vomiting.

Drugs and Gastric Function

Swallowed food and drink arrive in the stomach, which acts as a reservoir, storing the
food and regulating its delivery into the small intestine. Food can stay in the stomach for
extended periods, depending on the quantity and composition of the meal and on gastric
motility. In this time, it is well churned and mixed with gastric juices, and the liquid
chyme is squirted into the duodenum through the pyloric sphincter.

Gastric acid Secretion

The gastric mucosa contains parietal cells, which secrete hydrochloric acid (HCl) into
the stomach, keeping gastric pH very low, usually between 1 and 2. This highly acidic
environment contributes to the breakdown of hard-to-digest materials such as plant cell
walls and connective tissue in meat, and kills or damages most microbes.
The parietal cell does not synthesise HCl within its own intracellular fluid, because
this would destroy the cell. Instead, it pumps chloride ions (Cl-) and hydrogen ions (H+)
separately into the stomach lumen. The mechanisms by which it does this are shown in
Figure 10.4. Within the parietal cell, H+ ions are generated when carbonic acid
(H2CO3), which is very unstable, breaks down into H+ and a bicarbonate ion (HCO3-).
This H+ is then pumped into the stomach by an ATPase pump called the proton pump,
which exchanges the H+ for potassium (K+). Proton-pump inhibitors (PPIs) like
omeprazole are first-line treatments in managing conditions associated with excessive
acidity. Cl- is pumped into the parietal cell from the blood by a pump which swaps Cl-
for HCO3- produced when H2CO3 breaks down. K+ imported into the parietal cell by the
proton pump is then pumped back out into the gastric fluids, co-transported with Cl-. In
this way, [H+] and [Cl-] are kept much higher in stomach fluids than in other body
tissues and fluids: [H+] is three million times more concentrated in gastric juice than in
blood. Conditions associated with excessive acidity or failure of the normal physiological
measures in place to protect the stomach and duodenum from the corrosive stomach
juices are common and include peptic ulceration and gastro-oesophageal reflux disease
(GORD).

Mechanisms Protecting the Gastric Mucosa

The tissues of the stomach wall use a range of measures to protect themselves from their
own corrosive juices. Mucous glands produce a protective layer of mucus, which is
resistant to the corrosive action of both gastric acid and the protein-digesting activity of
gastric pepsin: it forms an effective barrier lining the stomach and prevents direct
contact between the gastric epithelium and stomach contents. In addition, HCO3-
produced by the gastric epithelium is pumped into the mucus lining; this keeps the
mucus alkaline and helps to neutralise any acid diffusing into the mucus layer. Gastric
blood flow is high, helping to wash away any H+ ions which manage to diffuse through
the mucus layer into the stomach wall. Prostaglandins, particularly PGE2 and PGI2
(prostacyclin), are important cytoprotective agents in the stomach and are continuously
produced in gastric tissues, mainly by cyclo-oxygenase (COX-1, see Ch. 6). They are
important vasodilators, ensuring a good blood flow especially in gastric inflammation;
they stimulate HCO3- and mucus production and act directly on parietal cells to inhibit
acid production by the proton pump (Fig. 10.5). NSAIDs block COX and inhibit
gastric prostaglandin production, the basis of their gastric irritant effect. Synthetic
prostaglandins used to treat acid-related conditions include misoprostol.
 FIG. 10.4 The proton pump and parietal cell secretion of H+ and
Cl- ions into the stomach. Modified from Ritter JM, Flower RJ,
Henderson G, et al. (2020) Rang & Dale’s pharmacology, 9th ed, Fig.
31.1. Oxford: Elsevier.

Stimulants of Gastric Acid Secretion

There are three main physiological stimulants of gastric acid secretion (Fig. 10.5).

Histamine
Histamine is released by enterochromaffin-like (ECL) cells in the gastric mucosa. It is an
important stimulant of gastric acid secretion and binds to H2 receptors on parietal cells,
which in turn activates the proton pump and increases acid secretion. H2-receptor
blockers, e.g. cimetidine, are widely available to treat conditions associated with
excess acid.
Acetylcholine
ACh released by parasympathetic nerves supplying the stomach acts on M3 receptors on
parietal cells, activating the proton pump and increasing acid secretion. This promotes
digestive function when the body is resting, and parasympathetic activity (‘rest and
digest’) predominates over sympathetic (‘fight or flight’). Antimuscarinic drugs, e.g.
hyoscine and atropine, block M3 receptors and reduce gastric acid secretion as part of
their more widespread inhibitory effects on digestive function.

Gastrin
The hormone gastrin is released into the bloodstream by G cells in stomach glands in
response to stretching of the stomach wall and the presence of protein-rich foods in the
stomach. It does not directly stimulate parietal cells: instead, it binds to receptors on
ECL cells and increases histamine production, which in turn activates the proton pump.

Drugs that Regulate Gastric pH

Conditions associated with excess stomach acid are common and range from the
occasional episode of heartburn after a rich or heavy meal to the continual misery of
chronic peptic ulceration associated with, for example, Helicobacter pylori infection
(see Focus on: Treatment of Peptic Ulcers box) or long-term use of NSAIDs.
 FIG. 10.5 The main agents stimulating gastric acid secretion by the
parietal cell, and some drugs that block them.ACh, Acetylcholine;
PGE2, prostaglandin E2 Modified from Waller DG, Sampson A, and
Hitchings A (2022) Medical pharmacology and therapeutics, 6th ed,
Fig. 33.1. Oxford: Elsevier.

Antacids
Antacids are weak bases, usually prepared as liquid formulations or chewable tablets,
which neutralise gastric acid. They are freely available over the counter and are widely
used on a non-prescription basis to self-manage upper GI tract disorders. The rise in
gastric pH also inhibits pepsin, which works best at pH 2–3.5. Antacids contain calcium,
magnesium, or aluminium salts, which react with and neutralise HCl, increasing gastric
pH. For example, calcium carbonate (CaCO3) reacts with HCl to form H2CO3 and
neutral calcium chloride (CaCl2) according to the following reaction:

H2CO3 quickly breaks down into water (H2O) and carbon dioxide (CO2) gas, which
causes the belching associated with CaCO3 use.
Antacids are best taken with food because gastric emptying is much faster on an
empty stomach, shortening the duration of action of the drug. Sometimes the thickening
agent alginic acid is used with an antacid to increase the viscosity of the gastric fluids
and help retain the drug in the stomach, and/or simeticone, an anti-foaming agent.

Adverse Effects
Taken occasionally and according to manufacturer’s instructions, antacids are generally
well tolerated. There may be significant absorption of calcium, magnesium, or
aluminium which can cause problems particularly in people with impaired renal
function who cannot clear the excess. Magnesium salts can cause diarrhoea and
aluminium salts can constipate, but using a combination can help minimise any
disruption to bowel function. Some antacid preparations contain significant amounts of
sodium and should be avoided in people on salt-restricted diets.
Antacids may increase or decrease absorption of a wide range of co-administered
drugs by several mechanisms (Fig. 10.6). Antacids may chelate other drugs in the GI
tract; that is, the metal ions in the antacid bind to them and form insoluble complexes,
reducing their bioavailability: for example, tetracycline, digoxin, and quinolone
antibiotics are chelated by antacids, significantly reducing absorption. Some drugs,
e.g. itraconazole, are formulated to be released from the drug preparation in the acid
environment of the stomach, and increasing gastric pH can reduce the amount of free
drug reaching the duodenum for absorption, reducing circulating drug levels and drug
efficacy. The coating of enteric-coated formulations is pH sensitive, formulated to
remain intact in the stomach and break down in the higher pH of the duodenum; if
gastric pH rises, this enteric coating may break down in the stomach, exposing acid-
sensitive drugs to gastric fluids and reducing the quantity of active drug reaching the
duodenum for absorption. On the other hand, the absorption of other drugs may be
facilitated by increasing gastric pH. Whenever possible, it is therefore generally advised
to separate administration times of antacids and other drugs.

Proton-Pump Inhibitors
Examples: esomeprazole, lansoprazole, omeprazole
The proton pump is the final common mechanism for all stimulants of gastric acid
production. The first PPI, omeprazole, was introduced in 1989 and is still in
widespread use today. Because these agents reduce gastric acid production irrespective
of the stimulus (histamine, alcohol, smoking, caffeine, etc.) and have proved to be well
tolerated and highly effective, they have become the mainstay of management in acid-
related disorders. Globally they are among the most widely consumed drugs and are
included on the World Health Organisation’s list of essential medicines. They are
usually given orally and are absorbed into gastric parietal cells from the bloodstream.
Here, they bind irreversibly to one of the subunits of the proton pump, permanently
deactivating it (Fig. 10.5). It can take the parietal cell up to 36 hours to synthesise a
new pump to replace it, and the irreversible nature of the binding means that the
biological effect of PPIs far exceeds the plasma half-life, and once daily dosing is
adequate. Both basal secretion and feeding-stimulated secretion are inhibited. The
effectiveness of PPIs improves with repeated administration and is maximal after 5 days
of daily dosing. This is because only around a third of proton pumps are activated when
a meal is eaten. Over the course of the next few days and meals eaten, more and more of
the inactive pumps are recruited in an attempt to maintain acid secretion; after about 5
days, all available pumps are blocked, and acid production is maximally reduced.
 FIG. 10.6 The main mechanisms of antacid-mediated drug
interactions.GI, gastrointestinal.

Pharmacokinetics
In general, these drugs have short plasma half-lives; omeprazole’s plasma half-life is
30–60 minutes, esomeprazole’s is between 60 and 90 minutes, and lansoprazole’s
is around 90 minutes. However, because they irreversibly inhibit the proton pump, their
acid-suppressant action is highly effective: a single dose reduces acid production by up
to 90% over a 24-hour period. They are acid-sensitive and oral preparations are enteric-
coated to protect the drug on its passage through the stomach. The increase in gastric
pH reduces absorption of azole antifungals including itraconazole (see also Antacids
above) and some other drugs whose solubility falls at higher pH values, including some
antiviral agents. They are highly plasma protein-bound and all are metabolised to
inactive products in the liver by cytochrome P450 enzymes. This can cause interactions
with other drugs also metabolised by members of this family, including selective
serotonin re-uptake inhibitors, whose plasma levels are increased when taken with
a PPI.

Adverse Effects
PPIs may cause a range of GI symptoms including nausea, vomiting, abdominal pain,
and diarrhoea. There is evidence linking PPI use to increased risk of GI infections, likely
due to improved microbial survival in the less hostile gastric environment. Additionally,
changing gastric pH affects the bowel microbiome, the populations of microbes
inhabiting the tract, which may help pathogenic species establish themselves. The rise in
gastric pH may reduce absorption of calcium and magnesium, and long-term use of PPIs
has been associated with increased risk of osteoporosis, fracture, and magnesium
deficiency. Compared to H2-receptor blockers, PPIs have been shown to slightly increase
the risk of gastric cancer, and the risk increases with dose and duration of treatment.
The reason for this is unclear and it is likely that more than one mechanism is involved.
One possible factor may relate to gastrin levels. When gastric pH rises, which would
normally happen after eating because food and fluids dilute stomach fluids, gastrin
secretion increases in response to aid digestion; gastrin also acts as a growth factor and
may stimulate hyperplasia in stomach tissues. PPI use may also mask the symptoms of a
pre-existing gastric cancer.

H2-Receptor Antagonists
Examples: cimetidine, famotidine, ranitidine
Histamine stimulates gastric acid secretion by stimulating H2 receptors on gastric
parietal cells and activating the proton pump (Fig. 10.5). James Black, a Scottish
pharmacologist, identified the subtype of histamine receptors found in the stomach and
named them H2 receptors because H1 receptors, which mediate the inflammatory and
allergic actions of histamine, had already been named. Standard antihistamines such as
chlorphenamine had been used to treat allergic inflammation since the early years of
the 20th century, but recognising that these drugs did not reduce histamine-induced
gastric acid secretion, Black reasoned that there must be more than one subtype of
histamine receptor and spent several years looking for an agent that would selectively
block histamine’s action on the stomach. The result was cimetidine, which blocked
histamine-induced gastric acid secretion but had no anti-inflammatory action, and
which came on the market in 1976. Black had already had significant research success in
the newly emerging field of receptor subtypes: he had also led the group that in the early
1960s produced the β2-selective antagonist propranolol (p. 131), a highly significant
step in the treatment of cardiovascular disease; he shared the 1988 Nobel Prize in
Physiology and Medicine for his contribution to pharmacological research.
The use of H2-receptor antagonists has steadily fallen since the development of PPIs,
but they are effective suppressants of both basal and stimulated gastric acid secretion:
they reduce 24-hour gastric acid secretion by around 70%. Ranitidine was withdrawn
from global markets in 2019/2020 following concerns that an impurity in its
formulation, called nitrosodimethylamine, a known human carcinogen, could be linked
to increased risk of cancer.
As with PPIs, regular use of histamine-receptor antagonists can mask the symptoms
of stomach cancer.

Pharmacokinetics
H2-receptor antagonists are taken orally and have short plasma half-lives, ranging from
1–3 hours. Famotidine is the most potent member of the group. Cimetidine is a
potent inhibitor of hepatic cytochrome P450 enzymes and can reduce the metabolism of
a range of other medications, including anticoagulants and tricyclic
antidepressants. H2-receptor antagonists are mainly eliminated unchanged by the
kidney and doses may need to be reduced in people with poor renal function.

Adverse Effects
H2-receptor antagonists are usually well tolerated. Common side-effects include GI
upsets such as diarrhoea or constipation and skin reactions, headache, and myalgia.
Rarely, they can cause acute liver injury. Cimetidine has weak anti-androgenic activity
and blocks testosterone receptors; this can cause gynaecomastia and impotence.

Misoprostol
Misoprostol is a stable synthetic analogue of PGE1 with gastroprotective actions and is
used to treat or prevent peptic ulcer disease: it is also given to prevent or minimise
NSAID-induced GI toxicity. Naturally produced gastric PGs are cytoprotective in the
stomach as described above (see also Fig. 10.3) but are too unstable to be useful: oral
misoprostol has a plasma half-life of around 40 minutes and is metabolised in the liver.
It stimulates GI smooth muscle and can cause abdominal cramps, diarrhoea, nausea,
and vomiting. It also stimulates uterine smooth muscle, causing uterine cramping and
potentially uterine rupture. For this reason, it should not be used in peptic ulcer disease
in pregnancy. It has an alternative therapeutic use in termination of pregnancy and
induction of labour.

F oc us on: Drugs Used in Peptic Ulc er Treatment

Peptic ulcers are caused by exposure of the gastric or duodenal tissues to acid. Risk
factors include increasing age, non-steroidal anti-inflammatory drug use,
smoking, alcohol intake, and Helicobacter pylori infection, which alone increases
the risk of peptic ulcer up to 10-fold. H. pylori infection is also a significant risk factor
in gastric carcinoma, the rates of which have fallen since eradication therapy became
standard practice in the management of peptic ulcers.
Triple/Quadruple Therapy
H. pylori is associated with 95% of duodenal ulcers and up to 80% of gastric ulcers,
and the discovery of the relationship between this bacterium and peptic ulcer disease
earned Barry J. Marshall and J. Robin Warren (Fig. 10.7) the Nobel Prize for
Medicine in 2005. The incidence of peptic ulceration has steadily decreased since this
association was recognised and antibiotic treatment introduced as part of the
treatment regime. H. pylori is a flagellated bacterium (Fig. 10.8) which burrows into
the gastric mucosa and survives in the acid conditions by producing ammonia, which
neutralises HCl, and in this way generates a protective pH neutral bubble around
itself. Although H. pylori infection is common, with up to half the population infected
by the age of 50, in most it causes no more than a mild gastritis with little or no
increase in gastric acid production. However, in up to 10% of people, it increases
gastric acid secretion and inhibits HCO3- production, predisposing to peptic ulcers.
Although treatment with proton-pump inhibitors (PPIs) and H2-receptor
antagonists alone can heal an ulcer even in the presence of infection, recurrence is
inevitable and cure depends on eradication of H. pylori. Currently, triple or quadruple
therapy is the standard treatment in H. pylori-positive people. In triple therapy, two
different antibiotics are used, usually for a period of up to 2 weeks, along with high-
dose PPI, usually with a cure rate of 80%–90%. Depending on antibiotic resistance, a
typical antibiotic regimen includes two from amoxicillin, metronidazole, and
clarithromycin. A tetracycline or other antibiotic may be substituted if these first-
line agents are ineffective. In quadruple therapy, bismuth (see below) is added.
FIG. 10.7 J. Robin Warren and Barry J. Marshall, co-discoverers
of the role of Helicobacter pylori in peptic ulcer disease and joint
winners of the 2005 Nobel Prize for this work. Photo courtesy of
Drs Warren and Marshall, University of Western Australia,
Adelaide, Australia.
 FIG. 10.8 A. Photomicrograph of Helicobacter pylori. B.
Schematic of H. pylori, showing its ability to produce an
ammonium cloud around itself due to urease production. From (A)
Photo by Christina Nilsson, Karolinska Institutet, and (B)
Shanbhag TV, Shenoy S, and Nayak V (2017) Pharmacology for
dentistry, 3rd ed, Fig. 8.6. New Delhi: Elsevier India.

Bismuth
Bismuth subsalicylate is an antacid with antimicrobial activity. Given orally, it breaks
down to release bismuth, which is toxic to a range of gastrointestinal pathogens
including Escherichia coli and Clostridium difficile but is thought to have minimal
effects on normal gut flora. It is available over the counter to treat the symptoms of
acid reflux and the relief of other gastrointestinal upsets including nausea, flatulence,
and diarrhoea. It is the fourth component of quadruple therapy in peptic ulcer
disease; it blocks the ability of H. pylori to attach to the gastric epithelium and
inhibits some of its key enzymes, including the urease it uses to synthesise its
protective ammonia cloud. At therapeutic doses, less than 1% of bismuth is absorbed,
but systemic side-effects include blackening of the tongue and faeces, encephalopathy
and deteriorating mental status, insomnia, and seizures. Bismuth is excreted very
slowly via the kidneys, so care is needed in renal impairment.
Sucralfate
Sucralfate is a complex of sucrose sulphate and aluminium hydroxide, which in the
acidic environment of the stomach forms a thick gel which coats the ulcer and forms a
physical barrier between it and the gastric juices. Because gel formation depends on
low pH, it is less effective if stomach acid has been neutralised or reduced by other
treatments, so dosing should be appropriately spaced out. In addition, it inhibits
pepsin and increases HCO3- secretion, reducing tissue damage and promoting
healing. Activated sucralfate possesses multiple negatively charged groups, which are
responsible for binding to the protein-rich exudate from the ulcer and essential for its
activity, but which may also bind a range of drugs including digoxin, tetracyclines,
phenytoin, and quinolone antibiotics and reduce their absorption. The most
common side-effect is constipation. Rarely, sucralfate may consolidate into a
hardened mass called a bezoar, which can obstruct the tract.

Drugs and Disorders of Gastrointestinal Motility

A wide range of neurotransmitters (Fig. 10.3) are released by GI nerves, offering a
number of potentially very useful targets for drug action in conditions involving either
hypermotility or hypomotility of the GI tract. Other drugs may affect GI motility by
interfering directly or indirectly with smooth muscle function.

Drugs that Reduce Gastrointestinal Tone and/or Motility

Increased GI motility and reduced intestinal transit time are usually due to enteric
infections or inflammatory conditions such as irritable bowel syndrome (IBS). GI spasm
is painful, and sustained increased motility can cause diarrhoea, defined as the passage
of three or more watery stools in a 24-hour period. As with increased motility, diarrhoea
is also associated with increased intestinal secretion. This potentially pours litres of fluid
into the tract in a 24-hour period, exceeding the capacity of the tract to reabsorb it, and
which if prolonged can cause life-threatening electrolyte loss and dehydration, especially
in children and frail people.

Opioids
Via their action on μ (mu) opioid receptors (MORs) on enteric nerves, opioids decrease
the motility of GI smooth muscle, delaying gastric emptying, inhibiting forward
peristaltic movement, and halting the propulsion of materials through the tract.
Constipation is a troublesome side-effect when opioid drugs such as morphine and
codeine are used as analgesics. Opioids increase intestinal transit time, allowing more
time for water absorption and reducing faecal volume.

Loperamide
Loperamide is a synthetic opioid widely available as a constituent of over-the-counter
antidiarrhoeal preparations: it has 50 times the antidiarrhoeal effect of codeine and is
more potent than diphenoxylate (see below). It is taken orally and subject to
significant first-pass metabolism, so its bioavailability is very low, usually in the order of
2%. At doses recommended for the treatment of diarrhoea, very little crosses the blood–
brain barrier, so loperamide lacks the central action associated with most opioid drugs.
It has a high affinity for MORs on nerves of the myenteric plexus and is absorbed
directly from the tract into the wall of the intestine: its onset of action is usually within
an hour and it is effective for up to 24 hours. In addition to its action on intestinal
smooth muscle, it increases absorption of water and electrolytes, although it reduces
absorption of nutrients such as glucose. Adverse effects include constipation and
nausea. At high doses, loperamide is sometimes used as a recreational agent to achieve
euphoria and relieve the unpleasant symptoms of opioid withdrawal; supra-therapeutic
doses have been associated with serious cardiac arrhythmias including QT prolongation,
torsades de pointes, and cardiac arrests. Naloxone is an effective reversal agent.

Diphenoxylate/Atropine
Diphenoxylate is an opioid with the expected antimotility action of this group of
drugs, but it crosses the blood-brain barrier in greater quantities than loperamide, so
its potential for abuse is higher. To discourage abuse, it is used with atropine, an
antimuscarinic agent: atropine itself has antimotility action because it blocks
parasympathetic activity in the tract, but it causes a range of other unpleasant
antimuscarinic side-effects, including dry mouth and eyes, nausea, and bloating. Even at
therapeutic doses, the atropine component of the preparation can cause antimuscarinic
side-effects including tachycardia and closed-angle glaucoma.

Racecadotril
This is a pro-drug and is metabolised in the liver to thiorphan. Thiorphan is not a
directly acting MOR agonist like loperamide or diphenoxylate, but it increases the
concentrations of endogenous opioids in the GI tract by blocking the enzyme that breaks
them down. In the tract, endogenous enkephalins, acting on MORs on enteric nerves,
contribute to the regulation of gut function. They are broken down by enkephalinase,
terminating their action. Thiorphan inhibits enkephalinase, prolonging enkephalin
action (Fig. 10.9). Its main therapeutic action in the treatment of diarrhoea seems to be
by reducing excessive intestinal secretory activity rather than reducing gut motility: this
drug does not reduce transit times, and constipation is therefore not one of its side-
effects. Another clinical advantage of not reducing gut motility is that in infection, the
drug does not increase retention time and so does not increase the length of time
infective products are in contact with the GI wall. Thiorphan acts quickly (within half an
hour), and because it does not cross the blood-brain barrier, it does not have central
side-effects. Racecadotril is available in many countries worldwide including India and
several European countries but not currently in the UK.

FIG. 10.9 The mechanism of action of racecadotril.MORS, μ opioid

receptors.
Antimuscarinic Agents
Examples: atropine, hyoscine butylbromide, propantheline
Because antimuscarinic drugs have widespread effects on multiple body systems by
blocking the action of ACh released by parasympathetic stimulation, their use as
antimotility agents is limited. However, antimuscarinic agents may be used for their
antispasmodic properties in the GI tract in GI infections, IBS, and other disorders
associated with smooth muscle spasm. They cause a range of predictable antimuscarinic
adverse effects including dry mouth, tachycardia, constipation, bronchoconstriction,
blurred vision, and urinary retention. Atropine and hyoscine are closely related
naturally occurring substances found in a range of poisonous plants including deadly
nightshade and henbane. Atropine crosses the blood-brain barrier and so has central
antimuscarinic side-effects such as sedation as well as peripheral antimuscarinic
activity. It is mainly used topically in ocular preparations and in pre-medication,
although it is combined with diphenoxylate (see above) to discourage inappropriate
use of this drug. Hyoscine butylbromide is the formulation of hyoscine usually used
to relieve smooth muscle spasm; it is a quaternary ammonium derivative, which reduces
its lipid solubility and means that it is poorly absorbed orally and does not cross the
blood-brain barrier. It therefore lacks central nervous system-depressant effects and
should not be confused with hyoscine hydrobromide, which does cross the blood-
brain barrier and is used mainly as an anti-emetic (see below). Hyoscine hydrobromide
is also used to reduce respiratory secretions in palliative care. Most of an oral dose is
excreted in the faeces because it is poorly absorbed, and the plasma half-life is 5 hours.

Smooth-Muscle Relaxants
Examples: alverine citrate, mebeverine, peppermint oil
Drugs that directly relax smooth muscle may be used in GI disorders associated with
spasm.

Alverine Citrate
Serotonergic nerves supplying the GI tract release serotonin (5-HT) which acts on 5-
HT1A receptors on GI smooth muscle to stimulate contraction and cause pain. Alverine
citrate blocks 5-HT1A receptors, and so relieves pain and spasm in GI disorders; it also
effectively relieves the pain of dysmenorrhoea. Side-effects include headache, dizziness,
and nausea.

Mebeverine
Mebeverine is a direct-acting smooth-muscle relaxant used mainly in IBS. It is taken
orally, but little reaches the circulation because it is extensively cleared by first-pass
metabolism in the liver. It is well tolerated with few significant side-effects. Its
mechanism of action is not clear, although it may have antimuscarinic activity. It blocks
sodium channels in the smooth muscle cell membrane and reduces calcium levels within
smooth muscle cells, both of which promote muscle relaxation and relieve intestinal
spasm. Side-effects include skin reactions and facial oedema.

Peppermint Oil
Peppermint oil is the essential oil obtained from the plant Mentha piperita and has been
used for hundreds of years in traditional medicine as an anti-inflammatory,
antispasmodic, and expectorant. It is commonly used to treat the symptoms of IBS. The
major constituent of peppermint oil is menthol, thought to be responsible for its
therapeutic action. Menthol blocks calcium channels in the smooth muscle cells of the
GI tract, reducing calcium influx and inhibiting contraction. In addition, peppermint oil
has antimicrobial, anti-inflammatory, and anaesthetic properties, all of which may
contribute to its therapeutic action. Capsules are enteric-coated to prevent their
dissolution in the stomach, because menthol relaxes the sphincter between the
oesophagus and the stomach and causes acid reflux.

Drugs that Increase Gastrointestinal Motility

The frequency of defaecation varies from individual to individual, but usually falls
somewhere between three times daily to once every 3 days. Several disorders impair the
co-ordinated contractile activity of the GI tract, leading to increased transit times,
constipation, and potentially obstruction. Hypomotility disorders of the tract include
achalasia (loss of oesophageal contractility) and GORD, but many systemic disorders
impacting on neurological or smooth muscle function, including multiple sclerosis,
Parkinson’s disease, diabetes, thyroid disease, and systemic lupus erythematosus, also
affect GI motility. GI motility is also reduced in pain.

Constipation
Constipation is the passage of stools less frequently than an individual’s normal pattern,
and the faeces is usually dry, hard, and difficult to expel. It is a common problem, and
while it may be a feature of a range of diseases as described above, it is often due to
lifestyle factors including insufficient physical exercise, a low-fibre diet, and inadequate
fluid intake. It may also be a side-effect of a wide range of drugs, including opioids,
antimuscarinic agents, and iron supplements. Because progesterone relaxes
smooth muscle, constipation is also common in pregnancy. Wherever appropriate,
lifestyle advice regarding dietary modifications, drinking more fluid, and taking regular
exercise should be the first approach to managing constipation.

Laxatives
Laxatives promote defaecation, usually either by softening or lubricating the stool or by
stimulating intestinal motility and are used to treat constipation. If laxative use is
required for short-term management, their use should be for as limited a time as
possible. Laxatives may also be used to cleanse the bowel in preparation for endoscopy,
surgery, or radiological procedures. They should not be used in GI obstruction.
Laxatives are classified into four main groups (Fig. 10.10).

Bulk-Forming Laxatives
Examples: bran, ispaghula husk, methylcellulose, sterculia
These are all bulky, indigestible plant extracts which retain fluid and soften and
expand faecal volume. This stretches the intestinal walls, which stimulates reflexive
contraction of its smooth muscle and propels its contents forward. It is important to
ensure an adequate fluid intake with these agents to avoid obstruction. They may take
2–3 days to work, but their action is gentle and they are generally well tolerated,
although they can cause bloating and flatulence.

Softening Laxatives
Examples: arachis oil, docusate sodium, liquid paraffin
These agents coat and soften the faeces, lubricating their passage through the tract.
Arachis oil is given as an enema and liquid paraffin is given orally; both can cause
unpleasant and itchy anal seepage. Accidental inhalation of liquid paraffin can cause
aspiration pneumonia. Docusate sodium can be given orally or rectally, and has an
additional direct stimulant effect on intestinal smooth muscle.

Stimulant Laxatives
Examples: bisacodyl, dantron, glycerol, senna, sodium picosulfate
Stimulant laxatives stimulate enteric nerves, which triggers contraction of intestinal
smooth muscle and stimulates water and electrolyte secretion into the tract, promoting
peristalsis. Because of this, they can cause painful abdominal cramps. Overuse
desensitises the enteric nerves and reduces the efficacy of the drugs, which can lead to
increased laxative consumption. This further desensitises the nerves, establishing a
vicious circle of laxative overuse and deteriorating bowel function, potentially causing
an atonic bowel. In general, stimulant laxatives exert their effects rapidly, usually within
12 hours.

FIG. 10.10 The four groups of laxative drugs. Modified from

Mariotti A, Johnson B, and Dowd FJ (2017) Pharmacology and
therapeutics for dentistry, 7th ed, Fig. 28.4. St. Louis: Mosby.

Dantron is used only in palliative care, because it is potentially carcinogenic and

causes skin irritation: it discolours the urine red, blue, or green. Co-danthrusate is
dantron formulated with docusate, and co-danthramer is dantron formulated with a
synthetic polymer called a poloxamer, which helps to attract water into the stool.
Glycerol is given as an enema and stimulates evacuation by irritating rectal nerves and
lubricating the rectal contents. Bisacodyl can be given orally or rectally. Senna is
given orally, and is broken down to the active agent rheinanthrone, which has the
dual action of stimulating enteric nerves and triggering peristalsis, and reducing water
absorption from the faeces, softening and expanding it. Sodium picosulfate is given
orally and is sometimes found as an ingredient in bowel cleansing preparations.

Osmotic Laxatives
Examples: lactulose, macrogol, salt solutions
These agents are concentrated preparations of substances which are not absorbed
from the intestines, creating an osmotic gradient between the contents of the tract and
the walls of the tract. This osmotic gradient draws fluid into the intestinal contents and
traps it there, expanding and softening faeces and stimulating peristalsis. Lactulose is
a semi-synthetic disaccharide which is converted in the colon to organic acids including
lactic acid, acetic acid, and formic acid, as well as methane gas, which can cause
flatulence. Macrogols are large-molecular-weight polymers of ethylene glycol and may
be combined with magnesium or phosphate salts in bowel cleansing preparations or
with a stimulant laxative such as sodium picosulfate. Macrogol 3350 (3350 is the
molecular weight) is taken orally and used both in constipation and to relieve faecal
impaction, and can cause abdominal pain and flatulence.

FIG. 10.11 The main mechanisms of action of pro-kinetic drugs.

Opioid-Receptor Antagonists
Examples: methylnaltrexone, naldemedine, naloxegol
Peripherally acting MOR antagonists are used to block MORs on enteric nerves to
prevent opioid-related constipation, generally when standard laxatives are inadequate.
The molecular structure of these drugs is based on the opioid reversal agent
naltrexone, but they are chemically modified to reduce lipid solubility and increase
electrical charge, which prevents them from crossing the blood-brain barrier and
blocking the analgesic and other centrally mediated actions of opioids.
Methylnaltrexone is given by injection, has a half-life of around 10 hours, and is
excreted largely unchanged in the urine and faeces. Naldemedine and naloxegel are
given orally and have half-lives in the order of 11 hours. Their most common side-effects
are GI-related, including abdominal pain, nausea, vomiting, and diarrhoea.

Pro-Kinetic Drugs
Pro-kinetic drugs increase the strength and frequency of GI smooth muscle contraction
and shorten transit times (Fig. 10.11).

Dopamine Receptor Antagonists

Examples: domperidone, metoclopramide
In the biosynthetic pathway which produces adrenaline, dopamine is converted to
noradrenaline, which in turn is converted to adrenaline (see Fig. 4.12). Dopamine
released by enteric nerves has sympathetic activity of its own, and like adrenaline and
noradrenaline, inhibits GI motility. The GI tract contains significant quantities of
dopamine, which acts on D2 receptors on the intestinal smooth muscle. D2-receptor
antagonists are widely used to increase oesophageal, gastric, and small intestinal
motility, as well as being effective anti-emetics (see below for more detailed discussion
of their pharmacology). They stimulate gastric emptying in conditions such as diabetic
gastroparesis and gastroesophageal reflux, and may be used to hasten the movement of
barium through the tract in a barium meal. In migraine, gastric emptying is significantly
delayed, which contributes to the associated nausea and vomiting, and the use of a D2
antagonist not only helps to relieve this but also speeds the passage of oral analgesia into
the duodenum for absorption. New D2-receptor antagonists currently in clinical trials
include trazpiroben.

Macrolide Antibiotics
Motilin is a hormone secreted by glandular cells mainly in the duodenum. It stimulates
gastric and intestinal motility via action on motilin receptors on GI smooth muscle: it is
most active in the stomach. The macrolide antibiotics, including erythromycin,
azithromycin, and clarithromycin, act as motilin-receptor agonists at doses lower
than required for their antibacterial action, although not all are used for this purpose
and the use may be off-licence: for example, erythromycin is unlicensed for this
indication in the UK but authorised in the US. Erythromycin is the standard agent used
for this purpose but is limited to short spells of treatment (less than 4 weeks), because
with continual exposure, motilin receptors are down-regulated, and the drug becomes
much less effective. In addition, the use of these important antibiotics for non-infective
conditions may contribute to the increasing of multi-drug-resistant microbes. Novel
motilin agonists are in development.

Serotonin Receptor Agonists

Examples: prucalopride, tegaserod
Serotonin stimulates peristalsis and secretion in the GI tract via an action on 5-HT4
receptors. Prucalopride is a 5-HT4-receptor agonist used to treat constipation that has
not responded to other treatments. It accelerates gastric emptying, stimulates
peristalsis, and decreases transit time. It has a long half-life, of around 20 hours, and is
mainly excreted unchanged by the kidney. It is well tolerated, but it can cause GI
disturbances including loss of appetite, abdominal pain, nausea, and vomiting. Rarely,
prucalopride can cause cardiovascular problems, because although the main serotonin-
receptor subtype in the heart is the 5-HT2 receptor, 5-HT4 receptors are also present.
Care should be taken in patients with known cardiovascular conditions, including
arrhythmias or ischaemic heart disease. Other 5-HT4 agonists which reached the market
included tegaserod and cisapride, now withdrawn from most health systems
worldwide because of cardiovascular side-effects.

Guanylate Cyclase-C Receptor Agonists

Example: linaclotide
Linaclotide is converted to its active metabolite within the GI tract. It is taken orally,
is not absorbed, and exerts its effect from the gut lumen. The enzyme guanylate cyclase
converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), an
important second messenger responsible for a wide range of cell signalling functions. In
intestinal epithelial cells, one of its actions is to activate cystic fibrosis transmembrane
conductance regulator (CFTR) channels, which secrete Cl- and HCO3- into the tract
(dysfunction of these CFTR channels is the pathophysiological abnormality in cystic
fibrosis). Linaclotide is a guanylate-cyclase agonist and increases cGMP levels, which in
turn increases the activity of CFTR channels in the intestinal cells (Fig. 10.12). This
efflux of ions creates an osmotic gradient, and water is pulled from the intestinal cells
into the lumen, expanding and softening the faeces and promoting its easy passage. It
also has an inhibitory action on sensory nerves in the intestines, reducing transmission
of pain signals to the brain. Linaclotide is used to treat constipation and pain in IBS.
Side-effects are mainly GI-related and include flatulence, bloating, and diarrhoea.

Future Possibilities
Ghrelin is a hormone released by the stomach, which stimulates appetite and GI
secretion and motility. Relamorelin is a ghrelin analogue that increases gastric
emptying and is currently in advanced clinical trials for the treatment of diabetic
gastroparesis.

Antiemetics
Vomiting (emesis) is an important protective reflex to rapidly expel actually or
potentially toxic substances from the stomach. Although the muscular propulsion that
forcibly ejects material comes mainly from the stomach and muscles that compress the
stomach, intestinal smooth muscle can also generate peristaltic contractions to reverse
the normal direction of tract flow and return contents back towards the stomach.
Nausea is the unpleasant sensation that vomiting is imminent, may or may not precede
vomiting, and may occur with autonomic symptoms such as pallor, sweating, and
dizziness.
 FIG. 10.12 The mechanism of action of linaclotide.CFTR, Cystic
fibrosis transmembrane conductance regulator; cGMP, cyclic
guanosine monophosphate; GTP, guanosine triphosphate.

The Physiology of Vomiting

The vomiting centre (VC) in the medulla oblongata is a loose collection of nerves which
controls the vomiting reflex. It receives sensory impulses from a range of structures both
within and outside of the CNS which can trigger emesis. Five main neurotransmitters
are involved in the pathways feeding input to the VC, all of which offer potential targets
for the action of anti-emetic drugs: histamine, acting on H1 receptors; ACh, acting on
muscarinic receptors; dopamine, acting on D2 receptors; serotonin (5-HT), acting on
5-HT3 receptors; and substance P, acting on NK1 receptors.
The key structures and their nerve pathways to the VC are shown on Fig. 10.13,
which also shows the main neurotransmitters and the receptors involved with each
pathway. The VC itself contains D2, 5-HT, muscarinic, and H1 receptors. Understanding
the pathogenesis of vomiting is therefore essential for choosing the best anti-emetic in
any given situation.

The Gastrointestinal Tract

Stretch receptors in the tract wall detect distension, like that caused by stasis in the tract
or by obstruction, and send parasympathetic afferent impulses via the vagus nerve to the
VC. Additionally, chemoreceptors in the tract respond to toxic or irritant substances:
this releases 5-HT and substance P, which also activate vagal afferents to the VC. Vagal
afferents from the GI tract also travel to the chemosensitive trigger zone (CTZ), which in
turn sends input to the VC (Fig. 10.14). These pathways are at least in part responsible
for vomiting caused by GI infection, obstruction, inflammation and radiotherapy. Drugs
which irritate or inflame the GI tract, e.g. NSAIDs and some cytotoxic agents, can
cause vomiting by this mechanism, as can drugs which inhibit GI motility and cause
distension, e.g. opioids. The nausea, vomiting, and constipation associated with
pregnancy is thought to be due to progesterone, which relaxes intestinal smooth
muscle, delays gastric emptying, and reduces peristalsis.

Higher Centres
Unpleasant, frightening, or emotional situations may all trigger vomiting because the
cortex, where these higher-order functions are housed, has input to the VC. Sights,
smells, and memories may all induce vomiting. Pain can also be a powerful stimulant of
vomiting. Raised intracranial pressure causes vomiting, although the reason for this is
not clear.

The Chemosensitive Trigger Zone

This is a group of neurones in the floor of the fourth cerebral ventricle. They are exposed
both to cerebrospinal fluid circulating within the ventricular system of the brain and to
blood-borne substances, because the CTZ lies outwith the blood-brain barrier. This
means that it detects potentially toxic substances both within the CNS and circulating in
the bloodstream. There are receptors here for 5-HT, dopamine, substance P, and
enkephalins. The CTZ may trigger vomiting in response to circulating toxins from GI
and other infections, and to drugs including digoxin, opioids, L-DOPA (which is
converted to dopamine, which acts directly on the D2 receptors of the CTZ), the D2
agonist apomorphine, and cytotoxic agents. In addition, disturbances of normal
acid–base balance, electrolyte imbalances, and metabolic abnormalities, for example
uraemia and diabetic ketoacidosis, directly stimulate the CTZ. Stimulation of the CTZ
directly stimulates the VC (Fig. 10.14).
FIG. 10.13 The vomiting centre and key associated
structures. Modified from Quigley EM, Hasler WL, Parkman HP
(2001) AGA technical review on nausea and vomiting.
Gastroenterology, 120, 263−286.
 FIG. 10.14 Vomiting pathways between the gastrointestinal tract,
vomiting centre, and chemosensitive trigger zone.5-HT, 5-
hydroxytryptamine; NK, neurokinin; SP, substance P.

The Vestibular Nuclei

The four vestibular nuclei are collections of nerves in the brainstem which receive and
integrate input from the balance mechanism of the middle ear, as well as from the eyes
and proprioceptors in the musculoskeletal system. The two main neurotransmitters
released here are histamine and ACh. Nausea and vomiting associated with motion
sickness, vertigo, and middle ear infections are due to stimulation of the VC from the
vestibular nuclei.

Dopamine Antagonists
Examples: domperidone, metoclopramide, phenothiazines
Dopamine, released in the VC and in the CTZ, is a powerful pro-emetic, and as
described above has direct actions on the GI tract, decreasing motility and increasing
transit time. Dopamine antagonists are therefore effective anti-emetics in a range of
conditions including drug-, pregnancy-, and radiotherapy-induced vomiting and post-
operative nausea and vomiting. However, because dopamine also has important
functions in the nigrostriatal pathway and the regulation of voluntary muscle
movement, dopamine antagonists that cross the blood-brain barrier can produce
extrapyramidal movement disorders similar to those seen in Parkinson’s disease (see
also p. 53), and these drugs should be avoided in people with this disorder. Basal
dopamine release in the tuberoinfundibular pathway suppresses prolactin production,
and dopamine antagonists can therefore increase prolactin levels even in non-lactating
people and cause galactorrhoea and gynaecomastia (Fig. 10.15).
 FIG. 10.15 Dopamine antagonists as anti-emetics.DA, Dopamine;
GI, gastrointestinal.

Domperidone
Unlike other D2 antagonists used to treat vomiting, domperidone does not readily cross
the blood-brain barrier and so it is fairly free of central side-effects, including movement
disorders and abnormal lactation, seen with the others in this group. It suppresses
vomiting via its action on D2 receptors in the CTZ; it also blocks D2 receptors in the GI
tract, which increases peristalsis and shortens gastric emptying times. For this reason, it
is also used as a pro-kinetic agent in hypomotility disorders including GORD (see
above). It is given orally and has a plasma half-life of around 7 hours.

Metoclopramide
Metoclopramide is related to the phenothiazines but is not used as an antipsychotic
agent. It does, however, cross the blood-brain barrier, so extrapyramidal movement
disorders and abnormal lactation are seen in its adverse effects profile. Its main action is
via blockade of D2 receptors, both in the CTZ and peripherally in the GI tract, but it also
stimulates 5-HT4 receptors and blocks muscarinic receptors in the intestines, which aids
motility and speeds up transit times. It is given orally or by injection, is well absorbed,
and has a plasma half-life of around 5 hours, which is increased if kidney function is
impaired. Intranasal preparations are available in some countries.

Phenothiazine Antipsychotic Drugs

Examples: chlorpromazine, droperidol, levomepromazine, prochlorperazine
 Phenothiazines are used as D2-receptor antagonists in the treatment of psychotic
disorders (p. 64), but they are effective anti-emetics at much lower doses (around a
third) of those used in psychiatry. They block D2 receptors in the CTZ, but they also have
antimuscarinic and antihistamine activity (antihistamines and phenothiazines are
structurally related). They are useful in controlling vomiting caused by most stimuli,
including vestibular disorders because of their antihistamine activity. However, even at
anti-emetic doses, adverse effects are common, including parkinsonian symptoms,
sedation, abnormal lactation, and gynaecomastia.

5-HT3 Antagonists
Examples: granisetron, ondansetron, palonosetron
5-HT3 receptors are found in the GI tract and in the CTZ. 5-HT3 antagonists are used
in post-operative nausea and vomiting, hyperemesis gravidarum, and drug-induced
vomiting including with chemotherapy. The first 5-HT3-receptor antagonist developed
as an anti-emetic, ondansetron, came on the market in the mid-1980s. It is given
orally, rectally, or by intravenous or intramuscular injection and has a plasma half-life of
3 hours. Palonosetron has a longer half-life of up to 40 hours. Unlike antihistamines
and phenothiazines, these drugs are non-sedating and are generally well tolerated;
common side-effects include headache and constipation, the latter due to blockade of 5-
HT3 receptors in the GI tract (Fig. 10.14). Rarely, they may cause arrhythmias
including QT interval prolongation.

Neurokinin-Receptor Antagonists
Examples: aprepitant, fosaprepitant, netupitant (used in combination with
palonosetron)
These drugs are anti-emetic because they block binding of substance P on NK1
receptors in the GI tract (Fig. 10.14), VC, and CTZ, inhibiting input into and activation
of the VC. They are used mainly to manage chemotherapy-induced vomiting and in
some countries are also licensed for post-operative nausea and vomiting.
Fosaprepitant is given intravenously and is converted to aprepitant in the liver;
aprepitant has a half-life of 9–13 hours.
In addition to their anti-emetic action in blocking NK1 receptors, neurokinin-receptor
antagonists enhance the anti-emetic effect of 5-HT3 antagonists. Netupitant has a long
half-life (around 90 hours) and is used in combination with the 5-HT3 antagonist
palonosetron to treat chemotherapy-induced nausea and vomiting (CINV),
particularly with regimens that include cisplatin, which is highly emetogenic. The
acute phase of CINV in the hours immediately following administration of the cytotoxic
drug is thought to be mainly due to 5-HT release in the GI tract, so both drugs
contribute therapeutically at this time. The delayed phase of CINV, which manifests 25–
120 hours after cytotoxic treatment, is thought to be mainly due to substance P acting on
NK1 receptors, and netupitant blocks this.
Adverse effects of these drugs include appetite suppression, constipation, and
abdominal discomfort.

Antihistamines
Examples: cinnarizine, cyclizine, doxylamine, promethazine
The most familiar use of antihistamines is in allergy (p. 122). The older
antihistamines, the so-called first-generation agents, have significant antimuscarinic
properties and cross the blood-brain barrier. They block H1 and muscarinic receptors in
the vestibular nuclei and muscarinic receptors in the VC itself. They relieve vomiting
from most causes, although they are particularly helpful in preventing and treating
nausea and vomiting associated with motion sickness and middle ear disorders such as
Ménière’s disease. The newer second- and third-generation antihistamines do not cross
the blood-brain barrier and do not prevent or relieve motion sickness. When treating
motion sickness, antihistamines are more effective as preventive treatment, taken in
advance, than stopping established nausea and vomiting. Cyclizine is also used in
palliative care, especially to counteract opioid-induced vomiting. It has a half-life of 20
hours.
Antihistamine anti-emetics block muscarinic receptors throughout the body and
cause a range of antimuscarinic side-effects, including dry mouth, tachycardia, closed-
angle glaucoma, and blurred vision. Sedation is a significant side-effect because
histamine is also an important transmitter in central pathways that maintain daytime
alertness (see also p. 124). Advice should always be given regarding likely drowsiness,
e.g. avoiding driving and cycling; alcohol should be avoided because it enhances
sedation.

Antimuscarinic Agents
Examples: hyoscine hydrobromide
Drugs with central antimuscarinic activity are anti-emetic because ACh stimulates
vomiting via an action on muscarinic receptors in the VC and the vestibular nuclei. As
discussed above, phenothiazines and first-generation antihistamines owe at least some
of their anti-emetic activity to their ability to block muscarinic receptors in vomiting
pathways. Hyoscine (scopolamine) and the closely related drug atropine are found in
a range of poisonous plants including deadly nightshade and henbane. Hyoscine was
first isolated in 1880; it is highly lipid-soluble, crosses the blood-brain barrier, and is a
potent CNS depressant. Two formulations are currently in use, the main difference
between them being their lipid solubility and therefore their ability to cross the BBB (see
also hyoscine butylbromide above). Hyoscine hydrobromide is used as an anti-
emetic because it crosses the blood-brain barrier and blocks muscarinic receptors in
central vomiting pathways. Other central antimuscarinic side-effects include sedation,
which may be beneficial in certain circumstances: for example, in the treatment of
motion sickness in children, in pre-medication, and in reducing respiratory secretions in
palliative care. Peripheral antimuscarinic side-effects include dry mouth, urinary
retention, and blurred vision. Its plasma half-life is around an hour, although this is
extended if the drug is given subcutaneously or by transdermal patch.

Nabilone
Nabilone is a synthetic cannabinoid closely related to tetrahydrocannabinol, the
main psychoactive substance in cannabis. Both the peripheral and central nervous
systems possess cannabinoid receptors and several endogenous substances, collectively
called the endocannabinoids, have been identified. This is a relatively new area of
study, but the known functions of endocannabinoids relate to anti-inflammatory activity
and modulation of pain. It is not certain why nabilone has anti-emetic activity, but it
may inhibit 5-HT release in the VC. It is well absorbed orally and has a plasma half-life
of around 2 hours. It is used to relieve CINV when standard anti-emetics have not been
effective. Adverse effects include sedation, confusion, sleep disruption, psychotic
symptoms, and GI upsets.

Other Drugs with Anti-Emetic Activity

Dexamethasone is a synthetic glucocorticoid used mainly as an anti-inflammatory
agent, but its anti-emetic properties are useful in a range of conditions including
palliative care and cancer treatment, and when combined with other anti-emetics, it
enhances their effectiveness. The glucocorticoids have such a wide range of physiological
actions that their principal mechanism of action in preventing and alleviating nausea
and vomiting has not been identified, although they may act through inhibiting the
action of endogenous opioids or via inhibition of 5-HT. Benzodiazepines have no
inherent anti-emetic activity of their own, but some drugs in this group, e.g.
lorazepam, are sometimes used as adjuvants in chemotherapy-induced and post-
operative nausea and vomiting, and in acute attacks of vertigo. They reduce the
incidence and severity of nausea and vomiting and can reduce the requirement for anti-
emetic treatment. Their beneficial action is believed to relate to their anxiolytic and
calming effects. Ginger has been used for centuries in folk medicines for the relief of
nausea and vomiting, including in pregnancy. There is evidence that, similar to the
setron drugs such as ondansetron, ginger blocks 5-HT3 receptors, which would
account for its anti-emetic action. Ginger and the setron drugs bind to different sites on
the 5-HT3 receptor rather than competing for the same site, and there is evidence that
ginger’s action is additive when used with standard anti-emetic drugs in post-operative
nausea and vomiting.

References
1. Abrahami D, McDonald E.G, Schnitzer M.E, et al. Proton pump inhibitors and
risk of gastric cancer: population-based cohort study. Gut. 2022;71(1):16–24.
2. Camilleri M, Atieh J. New developments in prokinetic therapy for gastric motility
disorders. Front. Pharmacol. 2021;12:711500 art. no.
3. Denholm D, Gallagher G. Physiology and pharmacology of nausea and
vomiting. Anaesth. Intensive Care Med. 2021;22(10):663–666.
4. Ogawa R, Echizen H. Clinically significant drug interactions with
antacids. Drugs. 2011;71(14):1839–1864.
5. Strand D.S, Kim D, Peura D. 25 years of proton pump inhibitors: a
comprehensive review. Gut. Liver. 2017;11(1):27–37.
11: Antimicrobial Drugs

CHAPTE R OU TLINE

The Biology of Microbes

The History of Microbiology
Microbial Adaptability

Antimicrobial Drugs and Selective Toxicity

Antibacterial Drugs
Antibacterial Resistance
Combination Therapy
General Adverse Effects of Antibiotic
Treatment
Antibiotics That Inhibit Protein Synthesis
Aminoglycosides
Chloramphenicol
Fusidic Acid
Macrolides
Oxazolidinones
Tetracyclines
Antibiotics That Interfere With Cell Wall Integrity
The β-Lactam Antibiotics
Bacitracin
Teicoplanin and Vancomycin
Antibiotics Acting on the Bacterial Cell Membrane
 Polymyxins
Antibiotics Acting on Bacterial DNA
Antibiotics Interfering With Folic Acid Metabolism
The Sulphonamides and Trimethoprim
AntiViral Drugs
Antiviral Resistance

Antiviral Drugs
Inhibitors of Viral Nucleic Acid Synthesis
Inhibitors of Viral Uncoating and Release
Inhibitors of Viral Protein Synthesis
Antifungal Drugs
Antifungals That Interfere With Cell Wall Integrity
Echinocandins
Antifungals That Interfere With Cell Membrane
Integrity
Nystatin
Amphotericin
Terbinafine

Azoles
Antifungals That Interfere With Cell Division
Griseofulvin
Flucytosine
Antiparasitical Drugs
Protozoal Infections
Antimalarial Drugs
Helminthic Infestation

Antihelminthic Drugs
 Arthropod (Insect) Infestations
Insecticides

F OCUS ON

Focus on: The Penicillins p. 209

Focus on: Mycobacterial and Anti-Tuberculosis Drugs p. 214
Focus on: Antiretroviral Drugs and HIV Therapy p. 219

The Biology of Microbes

The first living organisms on Earth were bacteria, appearing more than 3.8 billion years
ago, and viruses probably evolved shortly afterwards. All life on Earth evolved from
these ancient bacteria. The world in which the earliest human beings first appeared
about 300,000 years ago already contained an enormous range of microbes, and
throughout its existence, mankind has had to co-exist with, and defend itself against,
these tiny organisms. Most microbes co-exist peacefully with humankind, and some are
actively beneficial, including those used in producing wine, beer, or cheese and the
bacteria in our digestive tract that synthesise vitamins, which we absorb and use. The
industrial culture of microbes for the manufacture of biologically active substances,
including drugs, is an expanding area of technology.

Key Definitions

• Microbe/micro-organism:

These terms are used interchangeably to mean an organism so small that it can only
be seen with a microscope.

• Pathogen:

a microbe that causes disease

• Antimicrobial:

a general term for a drug that kills micro-organisms

 • Antibacterial:

a drug that kills one or more types of bacteria

The History of Microbiology

Infection, the growth and multiplication of micro-organisms within living cells and
tissues of another organism, has been a major cause of death and disability throughout
human history. Although the biology of micro-organisms could not begin to be
understood until they were first viewed under the earliest microscopes in the mid-17th
century, there is clear evidence dating back to earliest recorded human civilisation of
people trying to prevent, treat, and control infection. With no basis in scientific fact,
many practices were either useless or downright dangerous: bloodletting was
recommended for pneumonia as late as the 1940s, and for hundreds of years from the
14th century on, syphilitic infections were treated with highly toxic mercury. Bubonic
plague has caused regular epidemics globally over the past 1000 years and was much
feared because of its sudden onset and very high death rate. Until the advent of
antibiotics, doctors were powerless; common and entirely useless treatments included
drinking vinegar or eating treacle, and topical application of onion or chopped-up
snakes or pigeons. The causative organism of plague, Yersinia pestis, has been
identified, and provided treatment is started early enough, the disease is usually curable.
Some practices could have been genuinely useful, although the practitioners did not
understand why. The ancient Egyptians dressed wounds with mouldy bread; the idea
that fungi and other micro-organisms protect themselves by releasing substances that
kill other micro-organisms is very familiar to us today, and in fact the term ‘antibiotic’ in
its original definition means an antimicrobial agent derived from another micro-
organism. Honey was used in ancient Sumeria from 2000 BC to treat wounds. Honey
contains antimicrobial substances, and its high sugar content gives it a very high
osmolarity, which pulls water from microbial cells, dehydrating and killing them. Plant
extracts were also used: cinchona bark was used as a treatment for malaria, even though
quinine, its active principle, had not been identified.
The existence of invisible agents of infection was predicted in 1546 by an Italian
doctor, Hieronymus Frascatorius, who correctly deduced that transmission of tiny
particles between people accounted for the spread of infection. Proof of the presence of
these agents did not come for more than a century, until people began to use magnifying
lenses built into simple microscopes to examine objects from the natural world.
Pioneers of early microscopy included Robert Hooke (1635–1703) and Antonie van
Leeuwenhoek (1632–1723). Their lenses were crude but remarkably effective. Hooke
made beautiful and detailed drawings of a range of biological specimens, including
insects, plants, and fungi, and van Leeuwenhoek, working a few years later, extended
and expanded the newly discovered microscopic world, writing extensive and detailed
descriptions of his own observations. Van Leeuwenhoek is credited with the discovery of
bacteria; he put a drop of water mixed with pepper on his microscope stage because he
was interested in what gave pepper its fiery taste and was amazed to see huge numbers
of several different types of ‘animalcules’. He examined a wide range of materials,
including blood, sputum, and material scraped from his own teeth, finding these tiny
creatures in huge numbers in almost every medium he studied; they were clearly alive
because he could see them ‘swimming’ and ‘playing’. By the middle of the 19th century,
despite progressive development of the scientific process, rational and evidence-based
thinking, and recognition of the importance of observation and accurate
experimentation, the link between micro-organisms and human disease had not yet
been proven. Additionally, many scientists believed that micro-organisms arose
spontaneously in dead and dying tissues rather than having been transmitted in some
way.
Several important reports that helped to establish the principles of transmissibility of
infection appeared around this time. One key figure, Ignaz Semmelweiss (Fig. 11.1),
saved countless newly delivered mothers from the dreaded childbed fever. The physical
trauma associated with childbirth has always carried increased risk of infection, and in
the mid-1840s, 1 in 10 women died of post-natal infection, also called childbed or
puerperal fever. Semmelweiss, working in Vienna, noticed that women delivering in
midwife-led units were 10 times less likely to die than women delivering in units led by
obstetricians and medical students. He linked this to transmission of ‘putrid matter’
carried on their hands from autopsy rooms to the wards, and when he implemented a
policy requiring handwashing before patient contact, death rates fell dramatically. Louis
Pasteur (1822–1895) showed very clearly that microbial growth does not occur in
sterilised materials sealed inside sterilised containers, convincingly disproving the
theory of spontaneous generation; pasteurisation of foodstuffs is now used worldwide to
minimise microbial contamination and extend their shelf-life. The science of
microbiology, by now on a firm footing, expanded rapidly from the 1850s onwards,
driven by work done by notable scientists such as Robert Koch, whose significant
contributions included identification in 1822 of Mycobacterium tuberculosis as the
organism responsible for tuberculosis (TB), and isolating and growing it in pure
cultures. Joseph Lister, an Edinburgh surgeon, began to use antiseptics in handwashing
and in the cleaning of surgical instruments and materials, resulting in significant
reduction in the rates of post-operative infection in his patients.

FIG. 11.1 Dr. Ignaz Philipp Semmelweiss (1818–1865), pioneer of

antisepsis. From Gloviczki P (2014) The best vascular care for every
patient, every day. Journal of Vascular Surgery, 59 (3), pp. 843-856.
 Isolation, visualisation (with microscopes), and study of bacteria, protozoa, and fungi
formed the basis of early microbiological knowledge, but viruses, being much smaller,
were impossible to detect directly using technology available at the end of the 19th
century. However, their existence was deduced indirectly when it was shown in 1892
that extracts of diseased leaves from tobacco plants caused the same disease in healthy
plants, even after being passed through filters known to stop the passage of bacteria.
Direct viewing of viral particles had to wait until the development of the electron
microscope in 1931, which gave significantly higher magnification than the standard
light microscope. Fittingly, the first virus to be seen under the electron microscope was
the tobacco mosaic virus, the same virus whose existence was indirectly demonstrated in
the 1892 filter experiments (Fig. 11.2).

Microbial Adaptability
Microbes are the most varied and adaptable forms of life on Earth. Underlying their
evolutionary success throughout their billions of years of existence is their seemingly
inexhaustible ability to constantly adapt to changing environments. They survive and
flourish in the face of a wide range of intensely hostile conditions: in ice, around
volcanic craters, deep in the ocean, and in deserts. Some bacteria are even resistant to
radiation and survive for years in the inhospitable environment of space. Despite
reproducing asexually, i.e. each new daughter cell in theory should be an exact copy of
the parent cell, microbes constantly mutate and evolve, sometimes through random
genetic mutations, sometimes through errors in copying genetic material during cell
division, and sometimes in response to changing environmental conditions. The ability
of microbes to produce and survive quite significant degrees of genetic mutation means
that often not all microbes in a colony of apparently identical microbes are genetically
identical. This gives the colony, as a whole, a survival advantage. If a mutation in a
microbe’s genetic material improves its ability to survive and reproduce in its current
environment or in changing environmental conditions, it is more likely than its less
well-equipped neighbours to divide and proliferate, passing its beneficial mutation to its
daughter cells. In this way, if a colony is exposed to a toxin or other stressor, susceptible
microbes will perish, but better adapted ones survive to generate a new colony capable
of thriving in their new environment (Fig. 11.3). This adaptability is the basis for the
development of antimicrobial drug resistance.
 FIG. 11.2 Electron micrograph of tobacco mosaic virus. From
Williams RC and Fisher HW (1974) An electron micrographic atlas of
viruses. Charles C. Thomas, Springfield, Il, with permission.

Antimicrobial Drug Resistance

The ability of microbes to rapidly adapt to changing environmental conditions presents
major problems in treatment of infections. In response to exposure to an antimicrobial
agent, microbes can quickly develop mechanisms to protect themselves from the drug. A
microbe not killed or not prevented from dividing by an antimicrobial drug is said to be
resistant to that drug. Strains of microbes, particularly bacteria, that have developed
multi-drug resistance cause infections that cannot be effectively treated, a problem of
global proportions identified in 2019 by the World Health Organisation as one of the top
10 public health threats facing humanity. Without effective antimicrobial drugs,
common infections cannot be treated, a potential problem for even healthy individuals
but particularly for the vulnerable, e.g. the very young or older people. The risks
associated with post-operative infections are significantly magnified, and even trivial
procedures can become life-threatening. The dangers of childbirth increase, and
prevention and treatment of infection in immunocompromised people, i.e. in cancer
patients and in those receiving organ transplant, may become almost impossible.
Although the challenge presented by antimicrobial resistance threatens all populations
on Earth, impoverished countries with under-funded healthcare systems, poor
sanitation, lack of access to clean water, and unhygienic living conditions are
particularly vulnerable. Specific mechanisms by which each type of microbe develops
drug resistance are explained below.

Antimicrobial Stewardship
From the first half of the 20th century, clinical medicine has had access to an expanding
range of effective antimicrobial drugs, leading to a steady increase in global use. The
bulk of antimicrobial use, however, is not in human medicine, but in plant agriculture,
animal husbandry, food production, veterinary medicine, and a range of industrial
applications, and significant quantities of these drugs are washed into the natural
environment, including soil and water. This has led to widespread microbial exposure to
antimicrobial drugs, contributing to the consequent widespread emergence of multiple
resistant strains. This phenomenon was recognised relatively quickly in the
antimicrobial era, with warnings in the literature as early as the 1950s that antibiotic
efficacy was at serious risk. However, optimism that the continual production of new
drugs would offset the issue, as well as resistance from agriculture and industry to any
regulation of antibiotic use, has meant that the worldwide approach required to tackle
the issue has been slow and piecemeal.
 FIG. 11.3 Genetic mutations can give microbes a survival
advantage in changing environmental conditions.1. A microbe is
exposed to an environmental stressor, e.g. a natural toxin or an
antimicrobial drug. 2. One daughter cell develops or acquires a
mutated gene that protects against the stressor. 3. Daughter cells
produced from this line inherit the protective gene and are more
likely to survive and proliferate, producing a colony with a selective
survival advantage. 4. Daughter cells lacking the mutated protective
gene are much less likely to survive.

Much antimicrobial use, including prescribing in human medicine, is generally

accepted as inappropriate, unnecessary, and indiscriminate, and global agreements and
targets for limiting it have been put in place. Rational and directed use of antimicrobials
is called antimicrobial stewardship, which at the most fundamental level means that
every dose of an antimicrobial drug should be justified: the right antimicrobial at the
right dose by the correct route for the shortest time necessary. This approach, provided
it is followed across an entire organisation or healthcare system, should reduce overall
antimicrobial consumption, ensure that those antimicrobials that are used are likely to
be effective, and reduce the emergence of resistant strains.

Antimicrobial Drugs and Selective Toxicity

Antimicrobial drugs are inherently cytotoxic: they are used with the intention of killing
or fatally disabling the target microbe. The potential for host cell damage is high, and
avoiding or minimising damage to healthy cells is an integral consideration when
developing and using antimicrobials. The principle of selective toxicity depends on
identifying a biochemical process or structural feature present in the microbe but not in
human cells and finding or designing a drug that targets it. This should maximise
microbial toxicity while limiting damage to host cells. It is a significant challenge,
however, reflected in the limited number of new antimicrobials that have come to
market in the past 30 years.

Antibacterial Drugs
There are more antibacterial drugs in clinical use than any other category of
antimicrobial agents, because bacterial cells are sufficiently different in structure and
function to human cells to offer a range of potential drug targets. The term ‘antibiotic’ is
used throughout this section to mean any antibacterial drug, natural or synthetic, used
to treat bacterial infections.

Key Definitions: Bactericidal vs. Bacteriostatic

• Bactericidal refers to an antibiotic that kills bacteria.

• Bacteriostatic refers to an antibiotic that prevents the bacteria from dividing.

Although the definitions above are straightforward, the action of individual drugs can
be either bactericidal or bacteriostatic depending on drug dose, bacterial numbers, and
how favourable the growth medium is; most antibiotics can be either, depending on the
conditions. Clearing an infection is the result of a combined action of effective
antibacterial treatment and the efforts of the host’s own immune system; therefore,
treating infections in immunocompromised people is often harder than in individuals
with functional immunity. For this reason, bactericidal antibiotics may be preferred if
the patient has weakened immunity.

The Biology of Bacteria

Fig. 11.4 illustrates the key features of bacterial cells targeted by some important
antibiotics.

The Cell Wall and Cell Membrane

Bacteria possess a phospholipid cell membrane, similar in many respects to the human
cell membrane, and which is too fragile to protect the cell from its external environment.
Overlying the membrane and forming the outer coating of the cell is a rigid and robust
cell wall. An intact cell wall is essential for bacterial survival. Cell walls are not found in
human cells, and because they are made largely of peptidoglycans, molecules not found
in human biology, they offer an excellent selective target for antimicrobial drugs: the
penicillins and cephalosporins, among others, are lethal to bacteria because they
disrupt the cell wall. Peptidoglycan is formed of long, chain-like molecules which
extensively cross-link, giving the cell wall its strength. The cell wall varies in thickness
and composition between types of bacteria, which in turn alters the stains they take up
in the laboratory. Thick, peptidoglycan-rich cell walls take up crystal violet dye, staining
the bacterium deep blue when seen under the microscope. These organisms are said to
be Gram-positive, after the scientist who first made the observation (Fig. 11.5A). The
Gram stain is one of the most important laboratory techniques used to identify the
causative bacteria in infections. Gram-positive organisms include all staphylococci and
all streptococci. Gram-negative organisms do not retain the stain because they have
much less peptidoglycan and much thinner cell walls. However, because their cell wall is
so thin, they also have a complex lipid-rich outer membrane lying over it to protect it.
This outer membrane contains several pathologically important molecules, including
endotoxin (lipopolysaccharide, LPS) which stimulates host cell defence responses (Fig.
11.5B). Polymyxins bind to the LPS component of Gram-negative outer cell
membranes, disrupting membrane structure and increasing permeability. Antibiotic
resistance is more widespread in Gram-negative organisms because the complex outer
membrane contains a range of pumps, pores, and enzymes which can rapidly adapt to
exclude or destroy drugs in its local environment.
 FIG. 11.4 The main antibacterial drug targets, with examples of
drugs that attack each.

Key Definitions

• Broad-spectrum antibiotics are effective against a range of both Gram-positive

and Gram-negative bacteria. Narrow-spectrum antibiotics are effective only
against one type or the other.

Bacterial DNA and Protein Synthesis

The cytoplasm contains a range of specialised structures, including ribosomes for
protein synthesis. Human cells also synthesise proteins on ribosomes, but bacterial
ribosomes are smaller, providing a target for protein synthesis inhibitors including the
tetracyclines and chloramphenicol. Bacterial cells do not contain a nucleus, i.e.
they are prokaryotic, and their DNA is present as a single long strand rather than
separate chromosomes. Bacterial enzymes involved in DNA replication or in
transcription may be sufficiently different from their human equivalent to be drug
targets: for example, metronidazole inhibits replication of bacterial DNA.

Bacterial Metabolism
Like human cells, bacteria contain thousands of different enzymes to catalyse the wide
range of biochemical reactions required for life. Although microbial and human
biochemistry share similar pathways, it is possible to find metabolic processes present in
bacterial cells but not in human cells, including their handling of folic acid.
Trimethoprim and the sulphonamides are examples of antibiotics that interfere
with folic acid metabolism.

AntiBacterial Resistance
If a population of bacteria is exposed to an antibiotic, all susceptible cells will die, but
resistant cells will proliferate, so that eventually all bacteria in the population will be
resistant to that drug. Broad-spectrum antibiotic use induces the development of
resistance more effectively than narrow-spectrum antibiotics because it affects a wider
range of bacteria. Some bacteria develop resistance more readily than others: for
example, Staphylococcus aureus, a common bacterium often found living harmlessly on
skin and mucous membranes, but which causes a range of skin, wound, and other tissue
infections, rapidly develops resistance to nearly all known families of antibiotics.
Methicillin-resistant S. aureus (MRSA) infections are a major global problem,
particularly in healthcare settings and in vulnerable people, e.g. the very old and the
very young. Bacteria can develop or acquire protective genes against a drug, i.e. develop
resistance to that drug, in a range of ways. Once the bacterium possesses one or more
genes that protect it against a drug, it copies them, and in the ways described below, the
gene(s) can be spread through a rapidly dividing bacterial population in a matter of
hours (Fig. 11.6).

Transfer of Protective Genes From One Bacterium to Another

Bacteria can pass protective genes between themselves in a process called conjugation
(Fig. 11.7A). These genes are usually found on DNA fragments called plasmids, which
the bacteria copy and transfer into adjacent bacteria through a connecting tube called a
pilus (Fig. 11.7B). Plasmids can carry multiple resistance genes, giving resistance to
more than one drug, and are therefore a very important mechanism for spreading drug
resistance in a colony. In addition, bacteria can pick up plasmids released when bacteria
die and lyse.
FIG. 11.5 Gram-positive and Gram-negative organisms.A. Mixed
bacterial culture showing both Gram-positive and Gram-negative
bacteria. B. The structure of the cell wall and associated membranes
in Gram-positive and Gram-negative bacteria. Modified from (A) Lo
KK-W (2017) Inorganic and organometallic transition metal
complexes with biological molecules and living cells, Fig. 7.2. St.
Louis: Academic Press and (B) Tripathi P, Beaussart A, Andre G,
et al. (2012) Towards a nanoscale view of lactic acid bacteria.
Micron, 48, (12), pp. 1323–1330.
FIG. 11.6 Emergence of drug-resistant bacterial populations.

FIG. 11.7 Bacterial conjugation.A. Bacteria can pass genes that give
antibiotic resistance to each other, spreading resistance in a
population. B. False-coloured micrograph of bacteria, showing pilus
bridges between the large bacterium (bottom left) and its neighbour,
and the bacterium (middle right) and three of its
neighbours. Modified from (A) VanMeter KC, Hubert RJ, and
VanMeter WG (2010) Microbiology for the healthcare professional,
Fig. 25.2. St. Louis: Mosby and (B) Fitzgerald-Hayes M and
Reichsman F (2010) DNA and biotechnology, 3rd ed, Fig. 4.6. San
Diego: Academic Press.
Spontaneous Mutation
As mentioned before, bacteria are genetically unstable: that is, unlike human cells,
which have rapid and robust mechanisms for eliminating errors from their genetic
material, they tolerate significant mutations in their DNA. The mutations are random,
but because bacteria replicate so fast, they occur very frequently. Some will be beneficial
and will appear in all cells descending from the original (Fig. 11.3).

Mechanisms of Drug Resistance

Resistance genes can protect the bacterium against the drug in one of four main ways.

The Gene May Code for an Enzyme That Breaks Down the Drug
For example, when exposed to penicillin, bacteria with the gene that produces β-
lactamase survive because β-lactamase destroys the penicillin molecule.

The Gene May Change the Cell-Surface Receptor That Allows the Drug to
Bind to the Bacterium
For example, when exposed to penicillin, bacteria that do not make penicillin-binding
receptors survive, because penicillin cannot latch onto the bacterial cell surface and
penetrate it.

The Gene May Increase the Bacterium’s Ability to Excrete the Drug
For example, bacteria that produce pumps to excrete a drug survive, because they can
keep the drug levels in their cytoplasm too low to cause damage. Pseudomonas
aeruginosa, a microbe responsible for a wide range of clinically important infections
and which readily evolves into multi-drug resistance strains, quickly generates efflux
pumps to clear antibiotics from their internal environment.

The Gene May Change the Permeability of the Bacterial Cell Wall, Blocking
Drug Entry
For example, structural changes to pores in the bacterial cell membrane can allow the
bacterium to exclude particular drugs: this is a common mechanism and accounts for
resistance to a wide range of bacteria.

Combination Therapy
Using more than one antibiotic simultaneously (combination therapy) can be
advantageous in two main ways (Fig. 11.8).
Prevention of the Emergence of Drug-Resistant Bacteria
Combination therapy is used in hard-to-treat, serious, and chronic infections such as
TB, or to eradicate gastric Helicobacter pylori infection, which is strongly associated
with peptic ulcer disease (p. 188). It is also used in immunocompromised or vulnerable
individuals, whose own defence mechanisms are unable to contribute significantly to
clearing the infection. The principle is that by using more than one drug, a larger
proportion of bacteria are cleared as fast as possible at the beginning of treatment,
increasing the chances that the host immune system can eradicate the remainder (Fig.
11.8A). There are however risks to this approach, including the increased incidence of
side-effects from multiple drugs, and the likelihood that if treatment is not successful
and the infection is not cleared, surviving organisms will be multi-drug resistant.

Antibiotic Synergism
In some situations, antibiotics work synergistically, and their combined antibacterial
effect is greater than the sum of their individual action. Fig. 11.8B shows a hypothetical
example, where antibiotics A and B individually have a 35% kill rate for a particular
infection, but because of synergism, when combined, their total kill rate is 80%. For
example, trimethoprim and the sulphonamides work synergistically because
although they both interfere with bacterial folate use, they inhibit different steps in the
biochemical pathway. Ampicillin and gentamicin work synergistically when treating
enterococcal infections, e.g. infective endocarditis, because ampicillin increases bacterial
uptake of gentamicin (although this synergy does not work for all aminoglycosides, such
as amikacin).
 FIG. 11.8 The value of combination therapy in treatment of
complex or chronic infections.

General Adverse Effects of Antibiotic Treatment

Some adverse effects of antibiotic treatment are common to many antibiotics.

Superinfection
There are about the same number of bacteria living in or on the healthy individual as
there are cells in the body: a huge number, running into the tens of trillions. The
umbrella term given to these organisms is the human microbiome, and the importance
to human health of this symbiotic relationship is becoming increasingly clear. One
benefit of the healthy microbiome is that by colonising both internal and external body
surfaces, they prevent other, potentially pathogenic organisms from establishing
themselves. Introducing an antibiotic into the body, especially if broad-spectrum, kills
not only the target pathogen, but also normal body flora, and can allow pathogens to
colonise and proliferate. This is called super-infection. A common example is
candidiasis (thrush), caused by the yeast Candida albicans.

Gastrointestinal Adverse Effects

These are common, affecting about 10% of people, and are more common in broad-
spectrum therapy. They include diarrhoea, nausea, vomiting, abdominal bloating, and
discomfort, and are believed to be due to loss of normal gut flora. There is probably
more than one reason why eliminating normal gut flora disturbs gastrointestinal (GI)
function. Some superinfecting organisms (see above) probably have direct pathogenic
activity in the tract. Antibiotic-associated colitis, sometimes called pseudomembranous
colitis or Clostridium difficile colitis, is caused by overgrowth of C. difficile. The toxin
produced by this organism causes severe inflammation and bleeding of the colon, with
watery, profuse diarrhoea; bloody stool; and possible dehydration and electrolyte
imbalance. In addition, the normal gut flora helps to digest large-molecular-weight
carbohydrates, and if this is impaired because the normal gut organisms have been
killed, the undigested carbohydrates have an osmotic effect, retaining water in the gut
contents and contributing to watery diarrhoea. In addition, the normal microbiome
helps to regulate GI motility: when it is lost, motility is increased.

Allergy
Allergies, often manifested as skin reactions, are common, especially with certain groups
of drugs including the penicillins and cephalosporins. Many antibiotic-triggered
allergies are due to a type I hypersensitivity reaction, with histamine release and rapid
onset of symptoms, including itchy, raised blisters (urticaria). Other antibiotic-related
allergies are due to a type IV (delayed type) hypersensitivity reaction and may not
appear until up to 2 weeks after the antibiotic has been started, often after the course is
finished. This is sometimes called post-antibiotic rash and is more common in children.
The immunology of drug-related allergy is described in more detail on p. 37.

Antibiotics that Inhibit Protein Synthesis

Proteins are composed of amino acids and are the fundamental building blocks of living
cells. As in human biology, microbial DNA codes for the production of proteins needed
for the bacterial cell to carry out all functions essential to life. The sections of functional
code within the DNA––the genes––are used as templates to make molecules of
messenger RNA (mRNA) in a process called transcription. Each mRNA molecule
therefore carries the code for a specific protein, and travels into the cytoplasm and
attaches to ribosomes within the bacterial cell, where its code is translated into the final
protein. This is a complex, multi-stage process, and many protein synthesis inhibitors
are currently used as antibacterials, each of which blocks the process at different steps
(Fig. 11.9).

The Stages of Bacterial Protein Synthesis

The bacterial ribosome is composed of two protein units, a larger one (the 50S subunit)
and the smaller one (the 30S subunit). The actual process of protein synthesis, by
adding new amino acids to the growing protein chain, takes place on the 30S unit
because this is where the mRNA and amino acid binding sites are. Protein synthesis is
described in four stages (Fig. 11.9).

Initiation
In initiation (Fig. 11.9A), an mRNA molecule, containing the code for the new protein,
binds to the 30S subunit so that its code can be read and a new protein molecule
assembled. The first amino acid to be added is usually an N-formylmethionine residue
and is called the initiating amino acid. This amino acid is not found in human proteins.
It binds to what is called the P site. The next amino acid slots into an adjacent binding
site, called the A site, and the two amino acids are joined together with a peptide bond
(Fig. 11.9B and C).

Elongation
As soon as the two amino acids in the A and P sites are linked with a peptide bond, the
ribosome slides along the mRNA molecule to the next coding section. The A site is now
free for the next amino acid; a third amino acid is therefore added according to the
mRNA code, joined to the second with a peptide bond, and the ribosome shifts along
again. This is called elongation (Fig. 11.9D). The new protein emerges from the
ribosome through an exit tunnel, pushed out as new amino acids are added via the A
site. This proceeds until the ribosome has read the entire code along the mRNA
molecule and the new protein is complete.

Termination
Once the ribosome has finished reading the mRNA code, the new protein is released.
The mRNA itself, its job done, is degraded by enzymes in the cytoplasm.

Key Point: Selective Toxicity of Protein Synthesis Inhibitors

Although the basic process of protein synthesis is the same in both human and
bacterial cells and both have ribosomes for protein synthesis, bacterial ribosomes are
smaller than human ones. This structural difference offers a selective target for the
action of protein-inhibitor antibacterial drugs.
 FIG. 11.9 The stages of protein synthesis and examples of drugs
that inhibit different steps.

Aminoglycosides
Examples: streptomycin (the first), gentamicin, tobramycin, neomycin, amikacin
Streptomycin was isolated in 1944 from the soil bacterium Actinomyces griseus. Its
use now is almost exclusively in TB treatment, and gentamicin is the most frequently
used aminoglycoside. Aminoglycosides bind irreversibly to the 30S ribosomal subunit,
preventing new amino acids from accessing the A binding site (Fig. 11.9B). The new
protein is forced to terminate while only partially complete and is therefore non-
functional. Anaerobic organisms are not susceptible to aminoglycoside action because
the uptake mechanism needed to absorb the drug into the microbe is oxygen-dependent
and not present in anaerobes. They are broad-spectrum agents, with higher activity
against Gram-positive than Gram-negative organisms, and are usually reserved for
serious infections such as sepsis because they have highly unpleasant side-effects.
Pharmacokinetics
Aminoglycosides are large, highly charged molecules and so are not absorbed across the
wall of the GI tract; they are usually given by intravenous or intramuscular injection.
Tobramycin is also available for nebulisation in respiratory infections. Neomycin is
too toxic for systemic use, but it is used for topical infections; because it is not absorbed,
it is given orally to sterilise the GI tract before surgery. Aminoglycosides have relatively
short half-lives of 2–3 hours and cross the placenta but not the blood–brain barrier.
They are not metabolised, mainly because they are too large and electrically charged to
enter liver cells, so their clearance depends largely upon renal excretion. Active drug can
accumulate very quickly in the renal tubules if kidney function is impaired, and
renotoxicity is one of these drugs’ most dangerous side-effects.

Adverse Effects
Aminoglycosides have significant side-effects, which are generally dose-related, and
therapeutic drug monitoring is recommended to guide dosing. Renal toxicity is
described above, and kidney function must be monitored and the drug stopped at the
first sign of impairment. Ototoxicity, leading to permanent hearing loss, occurs in up to
one-third of patients. The drugs accumulate in the fluids in the cochlea of the inner ear,
where they may persist for extended periods of time and permanently damage the
sensitive hair cells responsible for hearing. High-pitched sounds are lost first, and
progressive hearing impairment can occur over several months following drug
administration because of the slow clearance from inner ear fluids. Neomycin is
particularly toxic to the hearing apparatus of the inner ear and so is not used
systemically. There may also be toxicity to the vestibular system, causing dizziness and
problems with balance. Gentamicin and streptomycin are more vestibulotoxic than
cochleotoxic. Aminoglycosides should not be used in myasthenia gravis, and care should
be taken with neuromuscular blockade in surgery, because they block acetylcholine
release at the neuromuscular junction and can cause paralysis, including of the
respiratory muscles.

Chloramphenicol
Chloramphenicol was isolated in 1947 from the bacterium Streptomyces venezuelae. It
binds to the 50S subunit of the ribosome and prevents peptide bond formation between
amino acids in the growing protein (Fig. 11.9C). Microbial resistance is usually due to
the acquisition of a gene that codes for an enzyme that breaks down the drug.
Pharmacokinetics
The plasma half-life of chloramphenicol is 2–3 hours. It is broad-spectrum and active
against a wide range of Gram-positive and Gram-negative bacteria. It is well absorbed
orally, but because of its significant toxicity, systemic use is limited to life-threatening
infections that do not respond to other, safer agents. Topically, it is widely and safely
used to treat bacterial conjunctivitis. Chloramphenicol is an enzyme inhibitor and
reduces metabolism of a range of other drugs, including phenytoin (p. 73) and the
coumarin anticoagulants (p. 150).

Adverse Effects
The most dangerous side-effect of chloramphenicol is irreversible bone-marrow
suppression, which occurs in 1 in 10,000 people and is always fatal. In newborn babies,
it can cause ‘grey baby syndrome’, which carries a 40% fatality rate. The characteristic
ashen colour of affected babies is due to progressive circulatory collapse caused by
chloramphenicol interfering with the ability of myocardial cells to use oxygen to produce
energy. The younger the baby, the greater the risk, probably due to liver immaturity and
a reduced capacity to metabolise the drug.

Fusidic Acid
Fusidic acid was first isolated from the fungus Fusidium coccineum and prevents the
new protein from sliding along the ribosome to free up the A site for an incoming amino
acid (Fig. 11.9D). It is bacteriostatic and narrow-spectrum, effective only in
staphylococcal infections. Because resistance develops rapidly, it is used in combination
with other agents when treating systemic infections. It is chemically related to steroids,
so is very fat-soluble and distributes very well through all body tissues (including bone
and joints), crosses the placenta, and appears in breast milk.

Pharmacokinetics
It is narrow-spectrum, and its plasma half-life is 10–14 hours. It is well but
unpredictably absorbed from the GI tract and is better absorbed from tablet
formulations than from suspensions. It is used topically for a range of staphylococcal
skin and eye infections and can be given intravenously if required.

Adverse Effects
Topical preparations can cause local irritation, including skin rashes and eye dryness
and discomfort. Side-effects from oral administration include GI upset, dizziness and
drowsiness, and impaired liver function.

Macrolides
Examples: erythromycin, clarithromycin, azithromycin
Erythromycin was first isolated from the soil bacterium Streptomyces erythraeus in
1950. It is a first-generation macrolide, and a range of second-generation agents
including clarithromycin and azithromycin were developed from erythromycin to
produce drugs more stable in stomach acid. They have broad-spectrum activity and are
effective in a wide range of important infections, but widespread use led to widespread
bacterial resistance, and in recent decades research effort has focussed on development
of novel macrolides. Third-generation agents entered the market in the 1990s but have
largely been withdrawn because of serious side-effects; fourth-generation agents are
currently in clinical trials. Macrolides block the exit tunnel in the ribosome through
which the new protein emerges (Fig. 11.9D). As a group, they are more active against
Gram-positive bacteria than Gram-negative because they are bulky molecules which do
not easily penetrate the complex outer cell membrane of Gram-negative bacteria (Fig.
11.5). Different members of the group have different activity profiles; for instance,
azithromycin is more active than erythromycin against Haemophilus influenzae.

Pharmacokinetics
Erythromycin is degraded by stomach acid, poorly absorbed across the gut wall
especially in the presence of food, and normally almost completely metabolised in the
liver. Azithromycin and clarithromycin are acid-stable and better absorbed.
Erythromycin and clarithromycin are both enzyme inhibitors, and so decrease the
activity of metabolising enzymes in the liver; this interaction can increase the plasma
concentrations of a wide range of other drugs.

Adverse Effects
Erythromycin can interfere with liver function, giving abnormal liver enzyme levels
and sometimes cholestatic jaundice. Both erythromycin and clarithromycin block
potassium channels in cardiac muscle, and high doses can cause arrhythmias, including
QT prolongation.

Oxazolidinones
The two antibiotics in this group, linezolid and tedizolid, released in 2000 and 2014,
respectively, are synthetic drugs most active against Gram-positive bacteria, including
MRSA. Tedizolid is more potent with a wider range of activity than linezolid and has
a longer half-life, meaning that it needs to be given only once daily. These drugs bind to
the P binding site on the ribosome (Fig. 11.9A) and prevent initiation of protein
synthesis. Currently, microbial resistance is not a major problem but is increasing,
mainly due to bacterial alterations in ribosome structure, preventing the drugs from
binding. They are well absorbed orally and can be given intravenously. Both agents can
cause GI upsets, headache, and rash. Linezolid can cause irreversible optic neuritis and
potentially dangerous blood disorders, including low blood platelet levels; patients
should be advised to report any visual symptoms, and full blood counts performed
regularly.

Tetracyclines
Examples: tetracycline, doxycycline, minocycline, oxytetracycline
Tetracyclines are produced by soil-dwelling bacteria of the Actinomycetes species.
They were first discovered in 1948 and widely used in the years following their
introduction because they are broad-spectrum agents effective in a very wide range of
infections. However, although development of second- and third-generation
tetracyclines produced newer and more effective drugs, widespread resistance has
limited their usefulness. Resistance is spread mainly by plasmids (Fig. 11.7), which
often carry genes for resistance to other antibiotics as well as tetracyclines, increasing
multi-drug resistance. These drugs work by blocking access of new amino acids to the A
site on the ribosome, preventing elongation of the new protein (Fig. 11.9A).

Pharmacokinetics
Following oral administration, many tetracyclines are irregularly and unpredictably
absorbed, although doxycycline and minocycline are slowly but completely
absorbed. All tetracyclines form insoluble complexes with iron, calcium, magnesium,
and aluminium, significantly inhibiting absorption. Dairy products, iron supplements,
and antacids, which frequently contain aluminium, calcium, or magnesium salts,
should therefore be avoided.

Adverse Effects
Tetracyclines can cause photosensitivity, super-infections, and GI disturbances. They
bind to calcium, are taken up into bones and teeth, and can permanently stain growing
teeth. The presence of the drug in developing bone and tooth tissue can also interfere
with its normal structure, leading to weakening or deformity. Tetracyclines are therefore
contra-indicated in pregnancy or breast-feeding women and not given to children. In
common with several other drugs, tetracyclines can cause drug-induced autoimmunity.
The drug binds to specific proteins, including collagen, in any of a range of tissues,
including skin and liver, and triggers an immune response against that tissue.
Minocycline is the most strongly implicated, with clear causative links to systemic
lupus erythematosus-like syndromes and autoimmune hepatitis.

Antibiotics that Interfere with Cell Wall Integrity

Key Point: Selective Toxicity of Antibiotics Targeting Bacterial Cell Walls

Cell wall synthesis and/or structure is an excellent selective target for antibiotics
because human cells do not use the peptidoglycans needed by bacteria for cell wall
synthesis.

Cell Wall Structure

Individual peptidoglycan chains are cross-linked firmly together with peptide bonds,
giving the cell wall a rigid mesh-like structure, enclosing the bacterium in a robust
protective wrapping (Fig. 11.10). Without these stabilising bonds, the peptidoglycan
layers lose strength and structure, and the cell wall is disrupted, losing its ability to
protect the bacterium from its external environment. The enzyme responsible for
synthesising the peptide bonds is called transpeptidase.
FIG. 11.10 The mechanism of action of the β-lactam antibiotics.A.
Normal cell wall peptidoglycan structure, showing peptide bonds
holding the peptidoglycan chains together. B. If peptide bond
formation is prevented, the peptidoglycan structure is weakened and
the cell wall loses its integrity. β-lactam antibiotics inhibit the
transpeptidase enzyme that produces peptide bond links.
The β-Lactam Antibiotics
The β-lactam antibiotics include the penicillins, the cephalosporins, and the
carbapenems.
The β-lactam ring is a simple four-membered ring built from three carbon atoms and
a nitrogen atom, and antibiotics containing this structure are called β-lactam antibiotics.
Fig. 11.11A shows the core chemical structure of penicillin, containing its β-lactam ring.
The β-lactam ring inhibits transpeptidase and so is essential for drug activity. In the
presence of a β-lactam antibiotic, the cell wall structure is disrupted and loses its
integrity, leading to bacterial cell death (Fig. 11.10).

Resistance to β-Lactam Antibiotics

The main mechanism by which bacteria develop resistance to β-lactam antibiotics is by
producing an enzyme called β-lactamase that destroys the β-lactam ring (Fig. 11.11B).
With the ring destroyed, the antibiotic loses its ability to inhibit cell wall synthesis. β-
lactamase inhibitors in clinical use are designed to bind to and inhibit the activity of
bacterial β-lactamase, thus preserving the antibiotic and prolonging its activity (Fig.
11.11C). Clavulanic acid is used with amoxycillin (co-amoxiclav) and avibactam
and tazobactam with some cephalosporins.
 FIG. 11.11 A. The core chemical structure of the penicillins,
showing the β-lactam ring. R is a variable side group and is different
in each penicillin derivative. B. Bacteria produce β-lactamase to
destroy the β-lactam ring. C. β-lactamase inhibitors are given with β-
lactam antibiotics to protect the drug from destruction by β-
lactamase.

F oc us on: The Penic illins

Examples: benzyl penicillin, amoxicillin, ampicillin, flucloxacillin
The discoverer of penicillin, the Scotsman Alexander Fleming, made his historically
famous observations in 1928. On returning from holiday, he noticed that some of his
staphylococcus culture plates had become contaminated with a fungus called
Penicillium notatum, and that surrounding the fungal colonies were large, clear areas
where bacteria were unable to grow. He reasoned that the fungus was producing a
substance toxic to the bacteria. His findings were published and picked up by a team
of scientists led by Howard Florey and Ernst Chain working in Oxford, who diverted
their research efforts into identifying and purifying the fungal antibacterial agent. At
the beginning of World War II, realising the impact an effective antibiotic would have
in treating the infections caused by battlefield injuries, the team relocated to the
United States where penicillin production was refined and begun on an industrial
scale. Over the remaining years of the war, it saved thousands of lives (Fig. 11.12).
Fleming, Florey, and Chain were jointly awarded the Nobel Prize for Medicine in
1945, recognising the massive impact of their work in human health. Today’s
penicillin family of antibiotics include the original, benzyl penicillin (penicillin
G), and about 15 further agents produced by chemically modifying the core penicillin
molecule.
 FIG. 11.12 Advertisement for penicillin, Life magazine,
1944. From Science Museum London, CC BY 4.0

Modifications and Altered Activity

Modifying the chemical structure of the basic penicillin core by adding different side
chains (position R in Fig. 11.11A) has produced different classes of penicillins with
different spectra of activity. This has yielded broad-spectrum drugs effective against
Gram-negative and Gram-positive organisms. They include the aminopenicillins (e.g.
amoxycillin and ampicillin, developed in the 1960s) and the newer
carboxypenicillins (e.g. carbenicillin) and piperazine penicillins (e.g. piperacillin).
β-lactamase-Resistant Penicillins
These are prepared by adding additional chemical groups to the β-lactam ring, which
shield it from bacterial β-lactamase and allow the drug to remain active even in the
presence of bacteria producing this enzyme. There is a trade-off, however, in terms of
antibacterial activity: by tucking the β-lactam ring deeper into the drug molecule, its
ability to inhibit cell wall synthesis is also reduced, so penicillins modified in this way
lose efficacy. Examples of β-lactamase-resistant penicillins include methicillin,
flucloxacillin, and temocillin.
Pharmacokinetics
Although benzyl penicillin is highly potent, it is almost completely destroyed in the
acidic juices of the stomach and so must be given parenterally. It is also narrow-
spectrum, with little activity against Gram-negative bacteria, and bacteria quickly
develop resistance via β-lactamase production. Phenoxymethylpenicillin
(penicillin V) was developed in 1948, and although it is less active than benzyl
penicillin and is narrow-spectrum, it survives the acid environment of the stomach
and can be given orally. Most penicillins can be given orally, although absorption
varies from drug to drug: ampicillin is poorly absorbed whereas amoxycillin and
flucloxacillin are well absorbed. Most penicillins do not enter liver cells and so liver
metabolism is limited, and the drugs are largely excreted unchanged by the kidney.
The kidney clears penicillin rapidly from the bloodstream, so plasma half-lives are
generally short; the half-life of benzyl penicillin is only about 30 minutes, and the
half-life of amoxycillin is 1 hour. Renal impairment can therefore significantly
extend plasma half-lives. In general, penicillins are well distributed, although they do
not cross the blood–brain barrier in appreciable quantities unless the meninges are
inflamed. Penicillin must not be given intrathecally because of the risk of convulsions.
Adverse Effects
Penicillins can cause any of the range of antibiotic-related adverse effects (see above),
including GI upsets, super-infection, and allergy. Penicillin allergy can be severe.
About 10% of people report a reaction to penicillin, although it is estimated that fewer
than 1% of these people have a true allergy. The most severe form of allergy,
anaphylaxis, is a type I hypersensitivity reaction, with massive release of histamine
and other inflammatory mediators into the bloodstream. This causes urticaria and GI
changes, and potentially life-threatening bronchoconstriction, vasodilation,
hypotension, and cardiovascular collapse.

Cephalosporins
Examples: cephalexin, cefuroxime, cefotaxime
The first cephalosporin, cephalosporin C, was identified in 1953 from the fungus
Cephalosporium, grown from sewage. It contained a β-lactam ring, but unlike the
penicillins, which by this time were in widespread use and had caused widespread
resistance, it was less susceptible to β-lactamase. Thousands of semi-synthetic
derivatives have been produced, leading to the introduction of several generations of
cephalosporin antibiotics, each giving improved activity against Gram-negative
infections and increased stability to β-lactamase. The newest agents have good activity
against both Gram-negative and Gram-positive organisms and do not lose activity when
exposed to bacterial β-lactamase.

Pharmacokinetics
Absorption in this group is variable: some can only be given intramuscularly or
intravenously because they are not absorbed across the wall of the GI tract (e.g.
ceftriaxone), whereas some, e.g. cephalexin, can be given orally. They distribute
well, including into the cerebrospinal fluid, especially the newer agents. As with the
penicillins, they are not significantly metabolised in the liver and rely on renal excretion
for clearance from the body.

Adverse Effects
Like their close cousins the penicillins, the cephalosporins are generally well tolerated.
There is penicillin cross-allergy, so a penicillin-allergic individual has an increased risk
of cephalosporin allergy too. Antibiotic-associated colitis (see above) is more common
with the cephalosporins than most other antibiotics.

Carbapenems
Examples: imipenem, meropenem
These β-lactam antibiotics were developed in the 1980s from thienamycin,
produced by a bacterium of the Streptomyces family.

Pharmacokinetics
Carbapenems are not absorbed across the wall of the GI tract and so must be given
intravenously. Imipenem, the original, is an effective broad-spectrum drug resistant to
β-lactamase but is rapidly deactivated by enzymes in the kidney. It is therefore given
with an inhibitor of these enzymes, cilastatin, to preserve it from renal metabolism and
prolong its activity. Carbapenem half-lives range from 1–5 hours. They are not
metabolised significantly in the liver and are therefore cleared from the body mainly by
the kidneys.

Adverse Effects
GI side-effects are very common. These drugs can also cause neurotoxicity (especially
imipenem) and renal toxicity.

Bacitracin
Bacitracin is produced by the bacterium Bacillus subtilis. It interferes with cell wall
synthesis by blocking the biochemical pathway that transports peptidoglycan molecules
into the growing cell wall structure. It is toxic in systemic use, including nephrotoxicity
and allergy, and is not licensed for use in all countries. Topical preparations are
available in some countries to treat eye and skin infections.

Teicoplanin and Vancomycin

These two glycopeptide drugs are structurally similar and possess similar activity
spectra. They are both more active against Gram-positive than Gram-negative bacteria
because they cannot penetrate the complex outer membrane of Gram-negative
organisms and are particularly active against staphylococcal species including MRSA.
Generally, they are reserved for serious infections that do not respond to other
antibiotics. Both drugs work by inhibiting the linking of peptidoglycans in cell wall
synthesis: the cell wall is therefore weakened and loses its protective function. They are
not absorbed after oral administration, so are given by intramuscular or intravenous
injection for systemic infection; however, given orally they clear GI infection, including
C. difficile. Teicoplanin has a long half-life of up to 100 hours while vancomycin’s is
much shorter (4–11 hours), and renal impairment significantly increases both. This is
compounded by the fact that both can cause nephrotoxicity, vancomycin more so than
teicoplanin. Both drugs cause a range of side-effects including blood abnormalities,
nausea, and allergy (there is cross-allergy between the two drugs).

Antibiotics Acting on the Bacterial Cell Membrane

Polymyxins
Examples: colistimethate sodium
Polymyxins are highly active against Gram-negative organisms because they bind
avidly to LPS on their protective outer cell membrane (Fig. 11.5). This disrupts the
membrane integrity, and it loses its barrier function. It also allows the polymyxin
molecules to travel through the bacterial cell wall to deeper structures, where they cause
further damage, increase membrane permeability and lead to lysis of the cell. They are
not active against Gram-positive bacteria.

Pharmacokinetics
Colistimethate is not absorbed across the wall of the GI tract because it is highly charged
and is given intravenously for systemic infections. It is also used by nebuliser for
respiratory tract infection, usually in cystic fibrosis in children, and can be given orally
to clear the bowel of Gram-negative organisms prior to surgery. It is not significantly
metabolised and is excreted unchanged by the kidney. Care is therefore needed in
reduced renal function, which may significantly extend the normal half-life of 2–3
hours.

Adverse Effects
Polymyxins can cause a range of unpleasant side-effects, including neurological and
renal toxicity.

Antibiotics Acting on Bacterial DNA

Key Point: Selective Toxicity of Antibiotics Targeting DNA Synthesis

This group of drugs has no one target in common because DNA synthesis is common
to both mammalian and bacterial cells. Individual selective targets are described for
individual drugs below.
 FIG. 11.13 The steps in DNA replication. Modified from HESI
(2021) Admission assessment exam review, 5th ed, Fig. 5.11. St.
Louis: Elsevier.

Several important antibiotics interfere with DNA structure, replication, or

transcription. Because the basic structure of DNA is the same in human and bacterial
cells, identifying a selective target that damages the infecting microbe and not host cells
is challenging.
DNA Replication
To divide and produce two daughter cells, bacteria first replicate their DNA, a copy for
each daughter cell. Fig. 11.13 shows the main steps, the enzymes responsible for
catalysing each step, and the antibiotics that target the process. The molecule must first
be uncoiled, an action facilitated by an enzyme called DNA gyrase, and the two bases
forming each rung separated, performed by an enzyme called DNA helicase. Using the
two halves of the original molecule as templates, an enzyme called DNA polymerase
attaches new bases in sequence to each half-ladder unit and links them together,
restoring the original ladder structure, and then an enzyme called topoisomerase coils
the DNA back up. The process ends up with two identical DNA molecules, one for each
daughter cell.

Metronidazole
Metronidazole is a pro-drug. It diffuses passively into cells, including host cells and
microbes. Some protozoa and some anaerobic bacteria, e.g. C. difficile and H. pylori,
possess an enzyme that converts metronidazole to a very reactive and toxic metabolite.
This metabolite binds to DNA and breaks it up (Fig. 11.14). This is a bactericidal action,
because the damaged DNA can neither be used to make new proteins nor can it be
copied to allow the microbe to divide. Aerobic cells, including human cells, lack this
enzyme and so do not produce the toxic metabolite. It also means, of course, that
aerobic microbes are resistant to metronidazole. Metronidazole is broad-spectrum and
used to treat a range of anaerobic infections, including vaginal, pelvic, and intestinal
infections, but formerly susceptible organisms are steadily developing resistance, mainly
due to reducing their uptake of the drug. Tinidazole is in the same class and has a
similar spectrum of action to metronidazole.
 FIG. 11.14 Activation of metronidazole in anaerobic organisms.

Pharmacokinetics
Metronidazole is available in a range of formulations and is usually given orally,
intravenously, rectally, or vaginally. It is well absorbed when given orally, with a
bioavailability of over 90%. It distributes into the CSF, crosses the placenta, and appears
in breast milk. It is not highly plasma protein-bound and has a half-life of 6–9 hours.
Most is metabolised in the liver and the metabolites excreted in the urine, so doses may
need to be reduced in reduced liver function.

Adverse Effects
Metronidazole can give an unpleasant metallic taste in the mouth, muscle pain, and GI
upsets. Current advice is to avoid alcohol while taking this drug because a disulfiram-
like reaction has been reported, although the validity of this is increasingly being
questioned because the evidence is weak.

Nitrofurantoin
Nitrofurantoin is a synthetic agent and a pro-drug. Susceptible bacteria possess enzymes
that convert it to toxic metabolites that interfere with certain key biochemical processes,
including synthesis of DNA, RNA, and protein. Cells lacking these enzymes, including
animal cells, do not produce the toxic metabolites. The drug can cause serious side-
effects and so is not used as a first-line agent. Nitrofurantoin is concentrated in the urine
in its active form because it is actively secreted into renal tubules, and so is used in
urinary tract infection. It is highly effective against Escherichia coli, which is responsible
for 80% of uncomplicated urinary tract infections, and resistance rarely develops. It
must, however, be used with caution or avoided altogether, in renal impairment,
because the drug can quickly accumulate and cause toxicity, including peripheral
neuropathy.

Pharmacokinetics
The half-life is short, less than 1 hour, and nitrofurantoin is very heavily plasma protein-
bound (up to 90%). Up to half of a dose is excreted unchanged in the urine. It is well
absorbed orally, especially if taken with food.

Adverse Effects
Mild GI side-effects are common, but nitrofurantoin can cause a range of serious
adverse effects, including acute pulmonary disease and bone marrow failure.

Quinolones (Fluoroquinolones)
Examples: ciprofloxacin, levofloxacin, ofloxacin
These broad-spectrum synthetic antibiotics are used in a wide range of infections,
including serious respiratory and enteric infections. They inhibit DNA gyrase and
topoisomerase (Fig. 11.13) and so prevent correct coiling and uncoiling of bacterial
DNA, in turn preventing DNA replication and bacterial cell division. Resistance is
usually due to the bacteria altering their binding site for the drug, or due to production
of efflux pumps which pump the drug out of the bacterial cell. The original drugs in this
group, including nalidixic acid, are narrow-spectrum, but incorporation of a fluoride
atom into the quinolone molecule produced fluoroquinolones, which are more potent
and broad-spectrum.

Pharmacokinetics
The quinolones are usually given orally or intravenously and distribute well throughout
body tissues. Levofloxacin is available for nebulisation, e.g. to treat chronic
respiratory infection in cystic fibrosis. Foodstuffs, iron preparations, and antacids in
the GI tract reduce absorption. Some of the drugs in this class, e.g. ciprofloxacin, are
enzyme inhibitors, decreasing the metabolising activity of cytochrome P450 in the liver
and inhibiting the metabolism of some other drugs, including warfarin.

Adverse Effects
Fluoroquinolones are generally well tolerated, but their more severe side-effects include
tendinitis, with possible rupture, especially in older people and most often affecting the
Achilles tendon. Central nervous system effects include headache, dizziness, and, rarely,
convulsions. They can also cause GI upsets, skin rashes, and cardiac arrhythmias.

Antibiotics Interfering with Folic Acid Metabolism

Key Point: Selective Toxicity of Antibiotics Targeting Folic acid

Metabolism
There are two main targets here. The first is that, unlike human cells, bacteria must
synthesise their own folic acid, and so possess a synthetic pathway not found in
human cells. In addition, the enzymes needed to metabolise folic acid differ slightly in
human and bacterial cells, offering another target.

The Sulphonamides and Trimethoprim

These antibiotics interfere with folic acid metabolism. Folic acid (dihydrofolic acid) is an
essential precursor in protein and DNA synthesis in both human and bacterial cells;
however, there are important differences in the folic acid pathway between them,
generating selective targets for antimicrobial action. Sulphonamides, the first
antimicrobial drugs, were developed in the 1930s by the German doctor Gerhard
Domagk, who won the Nobel Prize for this ground-breaking work. The original agent,
prontosil, is no longer used because of toxicity, and sulphonamide use in general has
declined because of widespread bacterial resistance. It is interesting that the
sulphonamides are chemically closely related to a range of other clinically important
drugs, including the diuretic acetazolamide, the antidiabetic sulphonylureas, the
anti-inflammatory sulfasalazine, and loop and thiazide diuretics, because they are
all derived from the same family of sulphur-containing dyes. Cases of cross-allergy
between these groups of drugs have been reported.

The Folic Acid Pathway

A simplified representation of the folic acid pathway, and the sites of sulphonamide and
trimethoprim action, are shown in Fig. 11.15. Bacteria must synthesise their own
dihydrofolic acid because they have no way of absorbing it from their environment. They
use the enzyme dihydropteroate synthase to produce dihydrofolic acid from the
precursor molecule para-aminobenzoic acid (PABA). Human cells do not possess this
enzyme because mammalian biology has evolved to absorb pre-formed dihydrofolic acid
from the diet and cells do not need to make their own. Dihydropteroate synthase is
therefore an ideal selective target and is inhibited by sulphonamides. In both human
and bacterial cells, folic acid is converted to its active form, tetrahydrofolic acid, by the
enzyme dihydrofolate reductase, but the enzyme takes slightly different forms in the two
different cells. Trimethoprim inhibits bacterial dihydrofolate reductase far more
effectively than the human enzyme, and therefore prevents bacterial synthesis of amino
acids and nucleic acids. Because they block sequential steps in folic acid metabolism,
trimethoprim and sulphonamides act synergistically and are often used together; the
sulphonamide usually used is sulphamethoxazole and the combination drug is called
co-trimoxazole.

FIG. 11.15 The mechanism of action of sulphonamides and

trimethoprim. Modified from Waller DG, Sampson A, and Hitchings
A (2022) Medical pharmacology and therapeutics, 6th ed, Fig. 51.4.
Oxford: Elsevier.

Methotrexate (p. 237) inhibits the human form of dihydrofolate reductase.

Sulphonamides
Examples: sulphamethoxazole, sulfadiazine
Sulphonamides exert their antibacterial action because they are very closely related to
PABA (Fig. 11.15). This means that the enzyme dihydropteroate synthase mistakenly
binds to the drug instead of PABA, significantly reducing folic acid production. They are
broad-spectrum agents, used mainly in GI, respiratory, and urinary tract infections.
Microbial resistance is now very common amongst all groups of previously susceptible
bacteria, mainly because the bacteria begin producing variants of dihydropteroate
synthase. These enzyme variants are still capable of generating folic acid for the
bacterium, but their binding sites for the sulphonamide drugs are subtly changed to
prevent the drug from latching on.

Pharmacokinetics
The most common sulphonamide, sulphamethoxazole, has a plasma half-life of 10
hours and is mainly excreted in its unchanged form by the kidney. Care is therefore
needed in reduced renal function. It is well absorbed after oral administration and
distributes well, crossing the blood–brain barrier and the placenta.

Adverse Effects
Sulphonamides commonly cause allergic reactions, including potentially fatal
anaphylactic events. Serious hypersensitivity reactions include Stevens–Johnson
syndrome (see Fig. 3.13) and other serious skin reactions and can trigger or worsen
systemic lupus erythematosus. They can cause folic acid deficiency and so should be
used with caution in people predisposed to this, e.g. in alcohol dependency, pregnancy,
or malabsorption syndromes. Use is contra-indicated in the first trimester of pregnancy
because its antifolate action can cause developmental abnormalities in the fetus. Other
significant side-effects include bone marrow suppression, blood abnormalities, and
renal toxicity.

Trimethoprim
The clinical pharmacology of trimethoprim is very similar to that of the sulphonamides,
unsurprisingly so because of their closely related activities. Trimethoprim is also broad-
spectrum and is more frequently used as monotherapy than the sulphonamides. Rarely,
it can precipitate serious blood disorders, and patients on long-term therapy should be
monitored. Its half-life is between 8 and 10 hours, which can be prolonged in renal
impairment because a significant proportion of the drug is excreted in its unchanged
form.

F oc us on: M yc obac teria and Anti-Tuberc ulosis Drugs

Mycobacteria are slow-growing microbes characterised by a thick cell wall rich in
lipids called mycolic acids. Mycolic acids make the cell wall much less permeable to
laboratory stains, more resistant to damage by detergents and antiseptics, and more
resistant to most of the main families of antibiotics and to the body’s immune
defences. Effective treatment of mycobacterial infections is therefore restricted to a
small number of drugs, to which microbial resistance is an increasing problem.
Important diseases caused by mycobacteria include leprosy (Mycobacterium leprae)
and tuberculosis (TB) (Mycobacterium tuberculosis).
Tuberculosis
Globally, TB is the leading cause of death from a single infectious agent and World
Health Organisation data estimates that one-quarter of the world’s population in
2020 was infected with M. tuberculosis. Although infection rates are slowly declining,
the TB epidemic remains a massive worldwide healthcare challenge. M. tuberculosis
is an intracellular pathogen, spread by inhalation, and once in the airways is
phagocytosed by alveolar macrophages. Normally, macrophages destroy
phagocytosed microbes using their range of digestive enzymes and toxins, but M.
tuberculosis deactivates these mechanisms and survives and replicates within the
macrophage. Although initial infection involves the lungs (pulmonary TB), untreated
disease frequently becomes latent, walled-off but protected within lesions
(granulomas) formed in the lungs as the immune system, unable to eradicate the
infection, tries to contain it. Latent disease can be re-activated and spread to involve
most other body tissues, including the brain, skin, heart, and bone. TB treatment
regimens vary from country to country, but an extended period of treatment, usually
between 6 and 9 months, with multiple antimycobacterial agents is the norm. First-
line drugs include isoniazid, rifampicin, ethambutol, and pyrazinamide, used
in varying combinations because monotherapy with any one alone rapidly produces
resistant strains. Despite this, multi-drug resistance is becoming an increasing
problem. Fig. 11.16 shows the targets exploited by the main anti-tuberculous agents.
Isoniazid
This antibiotic is highly effective against M. tuberculosis and is an important first-line
drug in TB treatment. It is a pro-drug, activated inside mycobacteria to an inhibitor of
an enzyme that catalyses the production of mycolic acids in the mycobacterial cell
wall. This prevents normal cell wall synthesis, and without an intact cell wall, the
mycobacterium cannot survive or replicate.
Pharmacokinetics
Isoniazid is well absorbed from the gastrointestinal tract and has a half-life of 0.5–5
hours, depending on the individual’s ability to metabolise it. Most of a dose is
metabolised in the liver to a range of metabolites, including highly reactive free
radicals which can cause significant liver injury. Particular care is therefore needed in
liver impairment, including regular monitoring of hepatic function. Isoniazid is a
potent inhibitor of the cytochrome P450 family of hepatic metabolising enzymes and
increases circulating levels of a number of other drugs, including anticonvulsants.

FIG. 11.16 Mycobacterium tuberculosis: targets for drug

action. Modified from Bhat ZS, Rather MA, Maqbool M, et al.
(2018) Drug targets exploited in Mycobacterium tuberculosis:
pitfalls and promises on the horizon. Biomedicine &
Pharmacotherapy, 103, pp. 1733-1747.

Adverse Effects
Isoniazid is generally well tolerated. Liver impairment, renal impairment, and
ototoxicity are among the most serious side-effects. It can cause peripheral
neuropathy because it inhibits cellular use of vitamin B6 (pyridoxine), essential for a
wide range of important metabolic pathways including myelin synthesis. Co-
administration of vitamin B6 supplements prevents this and is important in people at
particular risk of nutritional deficiency, including in those who are alcohol-
dependent, in malnutrition, and in older people. It reduces the efficacy of L-DOPA in
the treatment of Parkinson’s disease because it inhibits the enzyme dopa
decarboxylase, which converts L-DOPA to dopamine (p. 54).
Rifamycins
This group of drugs includes rifampicin and rifabutin; rifampicin (rifampin) is the
main one used in TB. It is broad-spectrum, bactericidal, and particularly useful in
mycobacterial infections, including leprosy. It inactivates the bacterial enzyme RNA
polymerase so that the bacteria are unable to make RNA, including mRNA. Because
mRNA is the molecule used to transfer the genetic code from DNA to the ribosome for
protein synthesis, this prevents the microbe from producing essential proteins, and it
dies. It is used in short courses for a range of infections, including meningococcal
meningitis, but in TB it is given for up to 6 months.
Pharmacokinetics
Rifampicin is well absorbed when given orally and is taken up and concentrated
within macrophages and other immune cells, explaining its ability to target the
intracellular pathogen M. tuberculosis. It is a strong inducer of a range of liver
enzymes, and so it increases the rate at which a range of other drugs are cleared from
the plasma. Drugs affected include oestrogen (so rifampicin can cause contraceptive
failure), warfarin, phenytoin, and sulphonylureas. It is metabolised in the liver
and has a plasma half-life of around 3.5 hours. Care is needed in patients with
reduced liver function, in whom the drug can accumulate.
Adverse Effects
Rifampicin commonly causes nausea and vomiting. It distributes well, including into
the CSF, and can cause an orange discolouration of body fluids, including urine and
tears, which can stain soft contact lenses. It can cause blood disorders, and blood
counts should be monitored regularly in long-term therapy.
Ethambutol
Although the mechanism of action of this bacteriostatic agent is not known, it is
believed to block production of a substance called arabinogalactan, which
mycobacteria use in their cell wall. Because other types of microbes do not use these
pathways, the drug is only effective in mycobacteria. In the presence of ethambutol,
dividing bacteria cannot produce an intact cell wall and do not survive. It is given
orally and work is currently under way to develop a dry powder formulation for
inhalation. This would reduce the drug dose required and therefore limit systemic
toxicity. Some of the drug is metabolised in the liver, but about 50% is excreted
unchanged by the kidney. In people with normal renal function, its half-life is 3–4
hours, but because of the large contribution made by the kidney to clearing
unchanged drug from the plasma, renal impairment can significantly extend this. It
enters the CSF, so is effective in tuberculous meningitis. Its most significant side-
effect is a dose-dependent neuropathy of the optic nerve, leading to reduced visual
acuity and red–green colour blindness. Although some restoration of vision can occur
if the drug is stopped as soon as vision problems are detected, there is often residual
and permanent vision loss.
Pyrazinamide
Pyrazinamide is bacteriostatic and a pro-drug. It is taken up into infected
macrophages and enters the cell’s lysosomes, where the macrophage has enclosed the
mycobacteria in an effort to destroy them. The environment in these lysosomes is
acidic, which activates the drug. Once activated, the drug inhibits microbial synthesis
of important fatty acids, disrupting membranes within the cell. Energy production
takes place on internal membranes, so interfering with membrane structure interferes
with energy production and depletes the mycobacterium’s energy stores, without
which it cannot survive. Pyrazinamide is given orally and has a long half-life of 10
hours. It distributes well, including across the blood–brain barrier, so is effective in
treating tuberculous meningitis. About 70% of a dose of the drug is excreted
unchanged in the urine, so care must be taken in reduced renal function. It can cause
liver impairment, and liver function should be checked before commencing
treatment. Other side-effects include reduced appetite, skin reactions, and
development or worsening of gout.

Other Antimycobacterial Drugs

Several other antibiotics are used as second-line agents or in multi-drug-resistant TB.
Macrolides including azithromycin can be useful. Other agents include
cycloserine, amikacin, and streptomycin and some quinolones
Aminosalicylic Acid
This is a pro-drug converted to its active form after uptake by the mycobacterium. In
its active form, it closely resembles para-aminobenzoic acid, which is the precursor
converted to folate in the folic acid pathway (Fig. 11.15). It is therefore used in the
pathway instead of PABA and so reduces microbial production of folate. It is given
orally and can cause gastrointestinal disturbances and hypersensitivity reactions.
Bedaquiline
Bedaquiline is a synthetic antibiotic used in the treatment of multi-drug-resistant TB.
It is bactericidal because it inhibits mycobacterial ATP synthase, an enzyme essential
for ATP production. Inability to produce ATP leads to bacterial death. It is well
absorbed when given orally and is over 99% bound to plasma proteins. It distributes
widely through body tissues, including into respiratory secretions. It has a very long
half-life, averaging 5.5 months, probably because it binds to proteins in peripheral
tissues and is released very slowly from these sites. It is only partly metabolised in the
liver, and most of the drug is excreted unchanged in the faeces, with very little
excreted in the urine. Bedaquiline causes nausea, headache, myalgia, and changed
liver function and should be used with care in certain cardiac disorders including
heart failure and arrhythmias because it extends the QT interval.

AntiViral Drugs
Compared to antibiotics, there are relatively few antiviral drugs because viruses are
obligate intracellular parasites: that is, they enter host cells and insert viral DNA into the
host cell DNA. Directed by viral genes, host cell organelles and biochemical pathways
produce new viral proteins and nucleic acids, which the host cell then assembles into
new viral particles. Because each step in viral replication is performed by host cell
machinery, finding a selective drug target and avoiding poisoning the host cell is a
challenge. Many antiviral agents are significantly toxic and cause serious adverse effects,
especially in systemic use.

The Biology of Viruses

Viruses are much smaller than human cells and most bacterial cells. Because they are
not capable of independent life, viruses are not categorised as living cells: instead, they
are referred to as viral particles, and infect a wide range of host cells including animals,
plants, and even bacteria. Structurally, they are much simpler than living cells, and
comprise an outer shell, called a capsid, which contains only their genetic material and a
few essential viral enzymes: there are no organelles or other internal metabolic
structures. Some viruses carry their genetic material in the form of DNA (DNA viruses)
but others (RNA viruses) have only RNA. Clinically important DNA viruses include
herpesviruses, human papilloma virus, and hepatitis B virus. DNA viruses may increase
the risk of cancer in infected tissues because the act of inserting their viral DNA into the
host cell genome generates a mutation, the key event in carcinogenesis. Clinically
important RNA viruses include influenza virus, coronaviruses, rhinoviruses, and most
hepatitis viruses.

Replication of DNA Viruses

The main stages of the viral replication cycle for DNA viruses are shown in Fig. 11.17.
The virus latches on to the target cell membrane and enters the cytosol. Here, it uncoats:
its capsid breaks apart and releases the viral DNA, which enters the host cell nucleus
and is integrated into the host cell’s own genome. The host cell then transcribes the viral
DNA into viral RNA, which carries the code for viral proteins. Viral RNA travels out of
the nucleus to the host cell ribosomes, which translate the viral protein code into new
viral proteins. At the same time, host cell enzymes make copies of the viral DNA. As new
viral proteins and DNA are synthesised, they are assembled into new viral particles,
which are released from the host cell and infect adjacent cells.
RNA viruses cannot insert their RNA directly into the host cell genome because RNA
is single-stranded and DNA is double-stranded. Their RNA is used directly by host
ribosomes to produce new viral proteins.

Replication of Retroviruses
Retroviruses are a type of RNA virus and contain RNA, which they convert to DNA using
an enzyme called reverse transcriptase which they carry with them in their capsid. This
DNA can then be inserted into the host cell DNA. Because reverse transcriptase is a
uniquely viral enzyme, it is an ideal selective target for drug action. Clinically important
retroviruses include HIV, and their biology is discussed in the section on HIV treatment.

AntiViral Resistance
As with antibacterial agents, viral resistance to antiviral drugs is spreading,
compromising the treatment of a range of infections. Viruses mutate readily and, unlike
animal cells, can remain viable even following significant alterations in their genetic
material. This further complicates efforts to find effective antiviral drugs, as well as
effective vaccines: if the virus constantly mutates, it presents the equivalent of a moving
target. Some clinically important viruses, such as rhinoviruses, responsible for the
common cold, exist as many serotypes, i.e. variants of the virus, all possessing slightly
different surface proteins. This means that even if a drug (or a vaccine) is developed
against one serotype, it is not necessarily effective against others. It also explains why it
is possible to catch the common cold on multiple occasions: antibodies produced against
the serotype causing this week’s cold will not protect against a different serotype
prevalent in 2 weeks’ time.

FIG. 11.17 The replication cycle of a DNA virus. Modified from Ryu
W-S (2017) Molecular virology of human pathogenic viruses, Fig.
3.1. Boston: Academy Press.

Latency
Latency is associated mainly with viruses of the herpes family, which have evolved this
strategy to resist elimination from their host organism and presents a significant
challenge to effective antiviral therapy. Herpes viruses are DNA viruses that include
herpes simplex (cold sores, genital sores, eye and central nervous system infections),
varicella zoster (chickenpox and shingles), Epstein–Barr virus (infectious
mononucleosis and a range of malignancies including Hodgkin’s disease), and
cytomegalovirus (a range of infections including hepatitis, and stillbirth and congenital
abnormalities). In latency, the virus scales all metabolic activity down to a very low level
but retains all its genetic material and is capable of rapid re-activation. Concealed within
its host cell, the virus effectively evades immune mechanisms, and because it is
metabolically inactive, is unaffected by antiviral drugs.

Antiviral Drugs
Most antiviral drugs are only effective when the virus is replicating because they inhibit
the synthesis of viral nucleic acids. Other mechanisms of action include prevention of
the uncoating step and inhibition of viral protein synthesis. Because of the pared-down,
relatively simple nature of viral biology, there is a limited range of viral-specific enzymes
available as drug targets.

Inhibitors of Viral Nucleic Acid Synthesis

These drugs inhibit the production of viral nucleic acids: DNA and RNA. Nucleic acids
are built of units called nucleotides, which contain a base (adenine, cytosine, guanine, or
thymine) linked to a sugar unit (ribose in RNA and deoxyribose in DNA) which in turn is
linked to a phosphate group. A nucleoside refers to the base and sugar only (Fig.
11.18A). RNA is a single chain of nucleotides, and DNA is a double chain, linked by the
bases (Figure 11.18B). Nucleic acids are built by enzymes called polymerases: RNA
polymerase builds single-stranded RNA and DNA polymerase builds double-stranded
DNA.

Nucleoside Analogues
Examples: acyclovir, famciclovir, ganciclovir, ribavirin
These are sometimes called false nucleosides and are structurally very similar to the
nucleoside units assembled into new viral DNA. Acyclovir, famciclovir, ganciclovir,
and ribavirin all contain the normal base guanine (and so are sometimes referred to as
guanosine nucleosides), but instead of a normal sugar, they are attached to a different
chemical group which does not bind to incoming nucleotides. DNA polymerase mistakes
the drug molecule for the true nucleoside and inserts it into the growing nucleotide
chain. However, once the drug molecule is incorporated into a new nucleotide chain, no
further nucleotides can be added, and synthesis is terminated (Fig. 11.18C). Viral DNA
synthesis cannot be completed and so the production of new viral particles stops. These
drugs are most useful against herpesviruses, including cytomegalovirus. Ribavirin is
also used in hepatitis C and a range of respiratory infections.
 FIG. 11.18 The mechanism of action of nucleoside inhibitors.A.
Nucleoside and nucleotide structure. B. Nucleotides linked in a
section of DNA. C. Nucleoside analogues, e.g. acyclovir, ribavirin,
and ganciclovir, are so similar in structure to the true analogue that
the polymerase enzyme builds new nucleic acid using them instead
of the true nucleosides. They cannot attach to incoming nucleosides,
and so the chain synthesis is terminated.

Acyclovir (Aciclovir)
This was the first drug in this class to be developed and entered the market in the mid-
1970s. When used topically, it is remarkably free of side-effects even though it blocks
DNA synthesis. Its selective toxicity is based on the fact that it is thirty times more active
against viral DNA polymerase than human DNA polymerase. In addition, it is a pro-
drug: it is only activated in host cells that have been infected with a virus. The result is
that it has very little effect on healthy host cell DNA production but is highly effective
against viral DNA synthesis in infected cells. However, viral resistance is an increasing
problem, usually because the virus produces slight variants of its DNA polymerase not
affected by the drug. Acyclovir is used topically, e.g. to treat cold sores, but needs to be
applied early to achieve effect. It is also given intravenously and orally to treat systemic
infections, and distributes well throughout body fluids, including crossing the blood–
brain barrier. Its very high selectivity for viral DNA polymerase means that even with
systemic use, it is usually well tolerated and does not cause significant adverse effects,
although encephalopathy has been reported. In systemic use, a good fluid intake is
important, because the drug can crystallise out in renal tubules, leading to inflammation
and renal impairment.

Foscarnet
Foscarnet binds to the active site on viral DNA polymerase and blocks its ability to add
nucleotides to a growing nucleotide chain. It is 100 times more selective for the viral
enzyme than the human enzyme, and so effectively blocks viral DNA production at
concentrations much lower than are needed to affect the host cell. It is most effective in
herpesvirus infections and is usually used in cytomegalovirus infections that have not
responded to a nucleoside analogue such as ganciclovir. It is poorly absorbed from the
GI tract and is given by slow intravenous injection. It causes a range of side-effects,
including serum electrolyte changes, which in turn can cause neurological abnormalities
including paraesthesia and seizures.

Inhibitors of Viral Uncoating and Release

Examples: amantadine, zanamivir, oseltamivir
Amantadine was first developed in the 1960s as an antiviral agent effective against
influenza virus, but its use is currently very limited because of widespread viral
resistance, and it is used more frequently in Parkinson’s disease. It disrupts a key viral
protein essential for viral uncoating inside the host cell so that the influenza virus
cannot release its nucleic acid. Because this protein is unique to the virus, amantadine
usually causes few significant adverse effects. Zanamivir and oseltamivir, both active
against influenza virus, inhibit a viral enzyme called neuraminidase, which frees new
viral particles from the host cell. Inhibiting this enzyme means that even though viral
replication has proceeded within the host cell, the new viruses cannot be released and so
cannot infect adjacent healthy cells.

Inhibitors of Viral Protein Synthesis

Examples: darunavir, ombitasvir, ritonavir
Viral proteins produced on the host ribosome from the viral RNA are usually in the
form of large polypeptides which contain the functional viral protein interspersed with
non-functional sections. The functional proteins are snipped out of this larger chain by
specific viral proteases (Fig. 11.19). These viral proteases are the targets for protease-
inhibitor drugs. Because they are unique to virus biology, inhibiting these proteases does
not affect host cell protease activity. Protease inhibitors are used mainly in hepatitis C
and HIV treatment.

FIG. 11.19 The mechanism of action of viral protease

inhibitors.Viral RNA is translated on the host cell ribosomes to make
viral polypeptides. Viral proteases then cut the viral polypeptides up
to release the functional proteins. Protease inhibitors bind to and
block the viral proteases.

F oc us on: Antiretroviral Drugs and HIV (Human

Immunodefic ienc y Virus) Treatment
Acquired immunodeficiency syndrome (AIDS) first came to global attention in the
early 1980s, when clusters of rare opportunistic infections and cancers in otherwise
healthy, gay young men were identified in Los Angeles, California, and New York.
These opportunistic conditions arose because affected individuals became seriously
immunocompromised, and the causative agent, HIV, was identified in 1983. HIV is an
RNA virus and is classified as a retrovirus because in order to replicate, once in its
host cell it must convert its RNA into DNA. ‘Retro-’ in this context means ‘going
backwards’, because in living cells DNA is always the template for RNA, and RNA is
never converted into DNA. The DNA generated from the viral RNA is then inserted
into the host cell’s DNA and copies of viral nucleic acid and viral proteins are
produced according to the mechanism described in Fig. 11.17. This process presents
a useful selective drug target because retroviruses use an enzyme unique to viral
biology and not present in human cells to catalyse the conversion of RNA to DNA.
This enzyme is called reverse transcriptase, and the ‘reverse’ label here also reflects
the fact that it catalyses a reaction that goes in the opposite direction to normal
biological processes (Fig. 11.20). A range of drugs is now available to treat HIV
infection and has transformed the condition from a rapidly and almost uniformly
lethal disease to a chronic but controllable condition. No cure has yet been developed,
although life expectancy with modern treatment is near normal.
Nucleoside HIV Reverse-Transcriptase Inhibitors
Examples: zidovudine, abacavir, lamivudine, stavudine
Zidovudine, which had been trialled unsuccessfully in the 1960s as an anticancer
drug, became the first effective anti-HIV drug on the market and was licensed in the
USA in March 1987. It initially showed great promise in HIV treatment, but interest
waned when it became clear that when used alone, HIV rapidly developed resistance.
However, in combination therapy, which greatly reduces the incidence of resistance, it
is still widely used today. It works because it closely resembles the nucleotide
containing the base thymine and is used in error by the viral reverse transcriptase
when building new DNA from the viral RNA: it is therefore classed as a nucleoside
analogue or false nucleoside. When the drug is incorporated into the growing nucleic-
acid chain, it halts chain synthesis because it does not have a binding site for the next
nucleotide to latch on to (Fig. 11.18). Zidovudine cuts transmission from an infected
mother to child both through the placenta and in breast milk and delays the onset of
HIV-related conditions, including HIV dementia.
 FIG. 11.20 The action of reverse-transcriptase inhibitors.

Pharmacokinetics
Nucleoside HIV reverse-transcriptase inhibitors (NRTIs) are given orally. Zidovudine
is a pro-drug and is activated in the infected cell. It is well absorbed and distributes
widely, including across the placenta and into the CSF.
Adverse Effects
NRTIs as a group are very toxic and cause significant side-effects that can involve any
body organ, probably by interfering with host cell energy pathways in the
mitochondria. Adverse effects include reduced white blood cell counts, bone marrow
disorders, and liver impairment. Regular full blood counts are needed, and care is
needed in reduced renal function, because the drug may accumulate if renal excretion
is impaired. The side-effects can be severe enough to require withdrawal of treatment.
Non-Nucleoside HIV Reverse-Transcriptase Inhibitors
Examples: efavirenz, etravirine, Rilpivirine
Non-NRTIs (NNRTIs), like NRTIs, inhibit HIV reverse transcriptase and prevent
the conversion of viral RNA into DNA. Their mechanism of action is, however,
different. They do not resemble normal nucleotides and are not assembled into new
DNA strands; instead, they bind to the enzyme, changing the shape of its active site
and deactivating it. The final result is the same: production of new DNA from viral
RNA is halted, and without it the virus cannot replicate. NNRTIs are less toxic and
more potent than NRTIs.
Pharmacokinetics
As a group, the NNRTIs have long half-lives of 2 days or more. Efavirenz is given
orally despite unpredictable GI absorption, and distributes widely, including crossing
the blood–brain barrier and causing central side-effects such as insomnia.
Etravirene is well absorbed when given orally, although absorption is more effective
following a meal, and is useful in treating HIV infections resistant to other NNRTIs.
Adverse Effects
NNRTIs can cause a range of adverse effects including hypersensitivity reactions and
GI upsets. Etravirine increases the risk of myocardial infarction, likely because it
interferes with glucose metabolism, can induce diabetes, and increases blood lipids.
HIV Protease Inhibitors
Examples: atazanavir, ritonavir, darunavir, saquinavir
The mechanism of action of protease inhibitors is described above (Fig. 11.19).
Saquinavir, approved in 1995, was the first protease inhibitor licensed to treat HIV
infection. It is given with ritonavir because ritonavir inhibits the liver enzyme
CYP450, which breaks saquinavir down. In this way, ritonavir increases the half-life
and plasma levels of saquinavir, and for the same reason is often used in low
concentrations with other protease inhibitors.
Pharmacokinetics
Inhibiting metabolism of these agents with ritonavir extends their half-lives
sufficiently that most require only once-daily dosing.

Adverse Effects
The protease inhibitors cause a range of adverse effects, including peripheral
neuropathy, seizures, and hypersensitivity reactions including Stevens–Johnson
syndrome (Fig. 3.13).

Antifungal Drugs
Key Definitions

• Mycosis:
 an infection caused by a fungus

• Yeast:

a fungus that grows as individual cells, often in colonies

• Mould:

a fungus that grows as multicellular colonies in the form of long, thread-like hyphae

There may be as many as five million species of fungus on Earth, of which only a few
hundred cause human disease. Most fungal infections are superficial, involving the skin,
nails, or mucous membranes. Very few fungi are pathogenic enough to cause systemic
infection in otherwise healthy people, and in general, those with functionally effective
immune systems rarely develop systemic fungal infection, except in certain
circumstances, for example following broad-spectrum antibiotic treatment. In the
vulnerable, fungal infections can be life-threatening: for example, Cryptococcus
neoformans, a very common yeast, causes no problems in healthy individuals but
produces cryptococcal meningitis in immunocompromised people. In recent decades,
the rate of invasive fungal infections is rising, because the numbers of
immunocompromised people are rising: an ageing population, whose immunity is
naturally declining, along with rising rates of certain chronic disorders, e.g. cancers and
HIV infection, are significant contributors to this. Globally, the burden of fungal disease
is disproportionately borne by resource-limited populations, with poor living conditions
and limited diagnostic and treatment facilities.

The Biology of Fungi

Fungal cells are saprophytic, meaning they live on dead or decaying organic matter.
They are more similar to human cells than are bacterial cells, making it challenging to
find selective drug targets that damage the microbe but spare the host. As a result, many
antifungal drugs are highly toxic in systemic use. Like human cells, fungal cells are
eukaryotes, but unlike other eukaryotic cells, they possess a rigid outer cell wall to
protect themselves from their external environment (Fig. 11.21). This cell wall contains
substances not found in mammalian biology, including chitin and glucans.
Echinocandins, e.g. caspofungin, inhibit glucan synthesis, disrupting cell wall
integrity. Underlying the cell wall is the fungal cell membrane, which contains
ergosterol, a substance related to cholesterol but not found in mammalian cell
membranes. It offers a selective target for a range of antifungal drugs including
nystatin, amphotericin, terbinafine, and the azole antifungals, e.g. iconazole.
Within the nucleus lies the cell’s DNA, which must be copied prior to cell division. Each
of the two copies then migrates to opposite ends of the cell, guided by a system of
microtubules, in preparation for the cell to split into two daughter cells. Griseofulvin
interrupts this process, halting cell division.

Pathology of Fungal Infections

Fungi frequently involved in superficial infections include Trichophyton, Microsporum,
and Epidermophyton species, which may all cause ring-shaped, itchy, red skin lesions
called tinea or ringworm (bear in mind this is a fungal infection and nothing to do with
worms). Tinea infections are categorised according to location. The main groups are
tinea pedis (athletes’ foot, Fig. 11.22A), tinea cruris (jock itch, affecting the groin, Fig.
11.22B), tinea corporis affecting the body (Fig. 11.22C), tinea unguium affecting the
nails (Fig. 11.22D), and tinea capitis affecting the scalp, eyebrows, and eyelashes (Fig.
11.22E). Tinea species are all dermatophytes (skin-loving) and feed on the keratin
content of the upper epidermis. The other main organism causing superficial infection is
Candida, the yeast responsible for thrush infections.
FIG. 11.21 The main features of fungal cell biology that provide
useful drug targets. Modified from Waller DG, Sampson A, and
Hitchings A (2022) Medical pharmacology and therapeutics, 6th ed,
Fig. 51.5. Oxford: Elsevier.
FIG. 11.22 Tinea infections.A. Tinea pedis. B. Tinea cruris. C.
Tinea corporis. D. Tinea unguium. E. Tinea capitis. From (A) Salvo
SG (2009) Mosby’s pathology for massage therapists, 2nd ed, Fig.
4.15B. St. Louis: Mosby; (B) Habif T (2016) Clinical dermatology: a
color guide to diagnosis and therapy, 6th ed. St Louis: Elsevier; (C)
Micheletti R, James W, Elston D, et al. (2023) Andrews’ diseases of
the skin clinical atlas, 2nd ed, Fig. 2.62. Oxford: Elsevier; (D)
Terhorst-Molawi D (2020) BASICS dermatologie, 5th ed, Fig. 11.4.
Munich: Elsevier Urban-Fischer Germany; and (E) Paller A and
 Mancini A. (2021) Hurwitz clinical pediatric dermatology, 6th ed,
Fig. 17.4. St. Louis: Elsevier.

A much wider range of fungi can cause systemic infections, which may establish in a
range of body organs. Frequently affected is the respiratory system, because inhalation
of fungal spores is a common route of infection. Fungi can also access the internal
environment via wounds, or the GI or genitourinary tracts, and cause sepsis,
endocarditis, meningitis, arthritis, osteomyelitis, peritonitis, and pyelonephritis. Many
plant fungi produce toxins, which may be stable to food processing and storage
processes especially if not carried out to high-enough standards, and then consumed in
contaminated foods. For example, aflatoxins produced by Aspergillus species
contaminating cereals can cause hepatitis and liver cancer.

Antifungals that Interfere with Cell Wall Integrity

Without an intact cell wall, a fungal cell cannot resist the osmotic extremes of its
external environment and disintegrates and dies.

Echinocandins
Examples: caspofungin, micafungin, anidulafungin
These are semi-synthetic agents, based on antimicrobial substances produced
naturally by a range of fungi. The first of this family of drugs, caspofungin, was made
available in 2001. Their target is an enzyme that produces glucans, essential
components of fungal cell walls. Because glucans are not used in mammalian biology,
this pathway provides a selective drug target. Echinocandins are only active against
Candida and Aspergillus species.

Pharmacokinetics
As a group, the echinocandins have long half-lives: caspofungin’s half-life is up to 50
hours. They are heavily plasma protein-bound and although they distribute well
throughout tissues, very little enters the CSF. They are not absorbed across the wall of
the GI tract and must be given intravenously.

Adverse Effects
These drugs cause a range of side-effects but are generally well tolerated, better so than
other classes of systemic antifungals. They can trigger histamine release from mast
cells, which can cause bronchospasm, bradycardia, hypotension, itch, and angioedema.
Antifungals that Interfere with Cell Membrane Integrity
The cell membrane controls the entry and exit of substances in and out of the cell, and
damage leads to microbial cell death.

Nystatin
Nystatin, one of the WHO’s essential medicines, was isolated in 1950 from a soil-based
bacterium. Although it is broad-spectrum, it is highly toxic in systemic use so is mainly
used topically to clear Candida infections. It can be given orally to clear infections of the
GI tract, including oral thrush, because its molecules are large, bulky, and highly ionised
and so are not absorbed, avoiding systemic effects. Nystatin binds directly to ergosterol
and generates damaging oxidising free radicals, which punch holes in the membrane.
This immediately allows rapid and uncontrolled movement of fluid and other
substances in and out of the fungal cell, killing it. Resistance to nystatin is very rare,
because ergosterol is so fundamentally important to fungal cell membrane biology that
it is preserved throughout generations. However, reports of resistant isolates are
increasing.

Amphotericin
Amphotericin works like nystatin. It is however used systemically for a range of serious
fungal infections, including invasive candidiasis, aspergillosis, and cryptococcus
infections. It must be given intravenously and is very toxic because although its favoured
target is fungal ergosterol, it also binds to cholesterol in host cell membranes, giving
widespread adverse effects. Amphotericin is both nephrotoxic and hepatotoxic, and
kidney and liver function should be monitored during treatment. The drug should be
immediately stopped if liver function tests begin to show liver impairment.

Terbinafine
Terbinafine prevents ergosterol synthesis by inhibiting the enzyme that produces it.
Without an adequate supply of ergosterol, the fungal cell cannot grow and divide
because it cannot make a functionally intact cell membrane. Terbinafine is strongly
keratinophilic and accumulates in skin and nails, which are rich in this protein, and is
very useful in skin and nail infections. It is broad-spectrum and can be given orally or
topically. It is highly lipophilic, so distributes very well throughout body tissues, and is
generally well tolerated even in extended oral therapy for stubborn nail infections,
which can be up to 6 months’ duration. It can however cause severe hypersensitivity
reactions including Stevens–Johnson syndrome (see Fig. 3.13) and hepatotoxicity,
which requires discontinuation of the drug.

Azoles
Triazoles: fluconazole, itraconazole, voriconazole
Imidazoles: ketoconazole, clotrimazole, econazole
The triazoles and imidazoles are closely related synthetic antifungals used in a wide
range of infections. Clinically, the triazoles are all used systemically whereas the
imidazoles are generally used topically. Although ketoconazole was the first antifungal
azole licensed for oral use, it was withdrawn from systemic therapy in the UK in 2013
because of hepatotoxicity and is rarely used systemically elsewhere because there are
safer drugs available. As a group, the azoles act by blocking ergosterol synthesis. This
prevents the fungal cell from producing new cell membrane, so that it cannot grow or
divide.

Pharmacokinetics
Orally administered agents have long half-lives; for example, fluconazole has a half-
life of 25 hours and itraconazole’s half-life is 21 hours. Fluconazole is well absorbed
with a bioavailability of over 90%, distributes into the CSF, and is one of the least toxic
azoles. Itraconazole is erratically absorbed from the GI tract. Absorption of the liquid
formulation is better than the capsules and is even better when gastric pH is low. It is
therefore best taken on an empty stomach because food and drink in the stomach dilute
the contents and increase pH. The azoles are metabolised in the liver and itraconazole
is the only agent to have an active metabolite.

Adverse Effects
Systemic use can cause a range of potentially significant side-effects, including GI
disturbances, blood disorders, and skin reactions. Azole antifungals are also associated
with multiple drug interactions via a range of mechanisms. One important cause of
interactions is azole-mediated inhibition of the important metabolising liver enzyme
CYP3A4, which metabolises a wide range of drugs, including anticonvulsants, non-
steroidal anti-inflammatory drugs, immunosuppressants, benzodiazepines,
antidepressants, antivirals, anticoagulants, and many others. When co-
administered with an azole antifungal, increased plasma levels of these drugs should be
anticipated and managed appropriately. Even when applied topically, absorption
through the skin can lead to plasma levels high enough to cause systemic side-effects,
including these drug interactions. Because azoles are better absorbed when gastric pH is
low, co-administration with drugs that reduce stomach pH, e.g. proton-pump
inhibitors and antacids, reduces their absorption. Itraconazole should be used with
caution in patients with heart disease because it has a direct, negative inotropic effect on
the myocardium: that is, it reduces cardiac contractility, although the mechanism by
which it does this is uncertain. Posaconazole can cause drowsiness and impair motor
skills such as driving.

Antifungals that Interfere with Cell Division

Fungal cells divide much more slowly than bacteria, and because of this slow rate of
proliferation and because, like human cells, they are eukaryotes, there are few available
antifungals that target cell division.

Griseofulvin
Griseofulvin is produced naturally by Penicillium species and is thought to interfere with
the function of microtubules in the cell. Microtubules are hollow threads made of
protein, used to give internal structure, to aid in motility in motile cells, and to guide
and transport materials, granules, and organelles around within the cell. They form the
mitotic spindle when a cell is dividing, which acts as tramlines to direct chromosome
movement to each end of the cell. Disruption of these guiding pathways prevents mitosis
and blocks fungal cell division. Griseofulvin is given orally, although its absorption is
poor; fatty foods in the GI tract improve this. It has a high affinity for keratin and
accumulates in hair, nails, and skin, and is used in tinea infections. Its half-life can be up
to 21 hours and it should not be used in serious liver disease. It is teratogenic in animal
studies, and effective contraception should be practiced if sexually active people are
being treated with the drug. It is a potent inducer of liver cytochrome P450 enzymes and
may therefore reduce the effect of a wide range of other drugs, including oral
contraceptives and warfarin. It commonly causes GI side-effects and may cause
serious skin reactions and peripheral neuropathy.

Flucytosine
Flucytosine is a synthetic agent mainly active against Candida and Cryptococcus
species. Within the fungal cell, it is converted to 5-fluorouracil (5-FU, used in the
treatment of some cancers, see also p. 236). 5-FU binds to and inhibits the enzyme
thymidylate synthase, which builds RNA and DNA. Therefore, in the presence of the
drug, the fungal cell can neither produce new proteins nor copy its DNA for cell division
and does not survive. Resistance develops rapidly if it is used alone, and it is usually
paired with amphotericin to prevent this. It is usually given intravenously and
distributes well throughout body tissues, including into the CSF. Little is metabolised in
the liver, so most is excreted unchanged by the kidney and the dose must therefore be
reduced in patients with poor renal function. Flucytosine can inhibit blood cell
production, probably because it exerts its antiproliferative action in the rapidly dividing
tissues of the bone marrow, and blood counts should be made weekly.

Antiparasitical Drugs
All living creatures are susceptible to colonisation by parasites, organisms that establish
themselves within the body of the host and survive and proliferate at the host’s expense
without providing any benefit in the relationship. Viruses by definition are therefore
parasitic and are considered above. Parasites may enter the body via insect bites,
contamination of wounds, via the GI tract in contaminated food or water, or from
mother to child across the placenta. The main groups of organisms that parasitise
humans and cause disease include protozoa, helminths (worms), and arthropods
(insects).

Protozoal Infections
Protozoa, a diverse group of single-celled organisms that vary hugely in size, preferred
habitats, feeding habits, and methods of locomotion, include Plasmodium, Leishmania,
and Trichomonas species.

Antimalarial Drugs
Malaria is caused by five different species of Plasmodium, which spend part of their
lifecycle in the Anopheles mosquito and part in their human host. The WHO estimated
the total number of cases worldwide in 2019 was 219 million, 94% of which occurred in
Africa.

Chloroquine
Chloroquine has been used to treat malaria since the 1940s and is still used today,
although resistance is a growing problem. Plasmodium spends part of its life cycle in the
infected person’s erythrocytes, where they ingest haemoglobin, the haem portion of
which is toxic to the parasite. Normally, the parasite converts haem to non-toxic
metabolites, but chloroquine and the related agents, quinine and mefloquine inhibit
this. Accumulation of toxic haem poisons and kills the parasite. Mefloquine is given
orally, and quinine and chloroquine are given orally or intravenously. These drugs
cause GI upsets, and a range of more significant problems: for example, at higher doses,
chloroquine binds to melanin in the retina and damages the photoreceptors, leading
to permanent loss of vision. They interfere with cardiac conduction and should be used
with care in patients with known conduction disorders.

Primaquine
Although structurally related to chloroquine, primaquine interrupts the Plasmodium
life cycle at a different point. Prior to entering host erythrocytes, the parasite spends
time in the host liver, and while it is at this stage, primaquine poisons it by inhibiting its
mitochondrial ATP production. It is given by mouth, is well absorbed, and is usually well
tolerated although it can cause GI upsets. Care should be taken in patients who are
deficient in glucose-6-phosphate dehydrogenase, and all patients should be tested prior
to beginning treatment. This enzyme is important for protecting the plasma membrane
of red blood cells, and a degree of deficiency is relatively common in the general
population. Primaquine worsens the effects of this deficiency and can cause serious
haemolysis.

Helminthic Infestation
Helminths (worms) may be transmitted orally, from contaminated food, water, or soil,
or by invasion through the skin. Some helminths, e.g. tapeworms (Fig. 11.23) and
roundworms, live in the host’s GI tract, and others, e.g. Schistosoma species (flukes),
invade other body tissues, e.g. the eye or the liver. Helminthic infections are of global
importance: WHO 2020 data estimates that 24% of the world’s population are infested
with soil-transmitted helminths, most of which occur in tropical and sub-tropical areas.

Antihelminthic Drugs

Ivermectin
Ivermectin is given orally to treat a range of helminthic infestations and is also effective
against the scabies mite Sarcoptes scabei. It interferes with calcium entry into the
parasite’s nervous and muscle tissue, paralysing it and causing death. It does not enter
the CSF in humans, thought to be the main reason why it causes few side-effects.

Benzimidazoles
Examples: mebendazole, albendazole
These drugs inhibit motility in helminths by blocking their ability to take up glucose.
Starved of their main source of energy, the helminth is paralysed and dies.
Mebendazole is given orally, and little is absorbed across the wall of the GI tract. Most
of what is absorbed is destroyed by first-pass metabolism in the liver, so this drug has
little systemic toxicity in humans and is mainly used to treat infestations of the GI tract.

Arthropod (insect) Infestations

These include fleas, mites, ticks, and lice. These parasites may themselves carry
microbes that cause human disease, e.g. tick bites can transmit Lyme disease. Common
among these infections are head lice (Pediculus capitis), pubic lice (Pthirus pubis), body
lice (Pediculus corporis), and scabies mite (Sarcoptes scabei) and are usually
transmitted by direct person-to-person contact.

FIG. 11.23 Tapeworm. From VanMeter K and Hubert R (2022)

Microbiology for the healthcare professional, 3rd ed, Fig. 16.8. St.
Louis: Elsevier.

Insecticides
The two main agents used to treat these infestations are permethrin and malathion,
applied topically, usually as creams and lotions.
Permethrin
Permethrin is a neurotoxin, blocking nerve conduction in the insect’s nervous system. It
is poorly absorbed through the skin, so has no measurable effect on the host’s
neurological function, although it can cause local irritation at the site of application.
Resistant variants in insect populations have been reported.

Malathion
Malathion is an organophosphate insecticide, a neurotoxin that blocks the enzyme
acetylcholinesterase. This enzyme clears the neurotransmitter acetylcholine from nerve
endings, including at the neuromuscular junction (the synapse of a motor nerve at
skeletal muscle tissue). Acetylcholine therefore accumulates, and its action is
significantly prolonged causing lethal interference with normal neurological function.
When applied topically, some drug is absorbed across the skin, but it is rapidly
metabolised, and does not cause measurable change in host nervous system function.
Resistance has been reported, but less frequently than permethrin.

References
1. Bhat Z.S, Rather M.A, Maqbol M, et al. Drug targets exploited in Mycobacterium
tuberculosis: pitfalls and promises on the horizon. Biomed.
Pharmacother. 2018;103:1733–1747.
2. Dinos G.P. The macrolide antibiotic renaissance. Br. J.
Pharmacol. 2017;174(18):2967–2983.
3. Gest H. The discovery of microorganisms by Robert Hooke and Antoni van
Leeuwenhoek, Fellows of the Royal Society. Notes Rec. R. Soc. 2004;58(2):187–
201.
4. Lobanovska M, Pilla G. Penicillin’s discovery and antibiotic resistance: lessons
for the future. Yale J. Biol. Med. 2017;90(1):135–145.
5. Rehman K, Kamran S.H, Akash M.S.H. Toxicity of
antibiotics. In: Hashmi M.Z, ed. Antibiotics and Antimicrobial Resistance Genes
in the Environment. Oxford: Elsevier; 2020.
6. Rubinstein E, Lagace-
Wiens P. Quinolones. In: Cohen J, Powderly W.G, Opal S.M, eds. Infectious
Diseases. fourth ed. Oxford: Elsevier; 2017.
7. Wanger A, Chavez V, Huang R.S.P, et al. Antibiotics, antimicrobial resistance,
 antibiotic susceptibility testing and therapeutic drug monitoring for selected
drugs. In: Wanger A, Chavez V, Huang R.S.P, et al., eds. Microbiology and
Molecular Diagnosis in Pathology: A Comprehensive Review for Board
Preparation, Certification and Clinical Practice. Oxford: Elsevier; 2017.

Online resources
National Institute for Health and Care Excellence, . Antimicrobial stewardship:
systems and processes for effective antimicrobial medicine use: NICE guideline
[NG15] Available at:. https://www.nice.org.uk/guidance/ng15, 2015.
Preston S.L, Drusano G.L. Penicillins. Antimicrobe. 2017 Available
at:. http://www.antimicrobe.org/d24.asp.
Very good review of the pharmacology of the penicillins.
Reygart W.C. An overview of the antimicrobial resistance mechanisms of
bacteria. AIMS Microbiol. 2018;4(3):482–501 Available
at:. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604941/.
Uthayakumar A. Cutaneous adverse reactions to
antibiotics. DermNet. 2018 Available
at:. https://dermnetnz.org/topics/cutaneous-adverse-reactions-to-
antibiotics/.
Clear and well-illustrated guide to skin reactions caused by antibiotics.
World Health Organisation. Global Tuberculosis Report: Executive
Summary. 2020 Available at:. https://www.who.int/docs/default-
source/documents/tuberculosis/execsumm-11nov2020.pdf?
sfvrsn=e1d925f_4.
12: Cytotoxic Drugs

Introduction

DNA, the Cell Cycle, and Healthy Cell Division

The Cell Cycle
Apoptosis
The Biology of Cancer
Properties of Cancer Cells
The Genetics of Cancer
Approaches and Issues in Cytotoxic Therapy
Common Adverse Effects of Chemotherapy
Drug Resistance in Chemotherapy
Drugs that Interfere with One or More Stages of the Cell Cycle
Spindle Poisons
Drugs That Act on DNA
Nucleoside Analogues (False Nucleosides)
Topoisomerase Inhibitors
Folate Antagonists
DNA Alkylating Agents
Other Agents That Directly Damage DNA
Drugs That Inhibit Cyclin-Dependent Kinase
PARP Inhibitors
Cell Signalling Pathway Inhibitors

Protein Kinase Inhibitors

 Hedgehog Pathway Inhibitors
Hormone-Responsive Cancers
Antioestrogens
Aromatase Inhibitors
Antiandrogens
Glucocorticoids

Monoclonal Antibody Therapies

Adverse Effects
Mechanisms of Action of mAbs
Stimulation of Defensive/Immunological
Mechanisms
Blocking Cell-Surface Receptors for Growth
Factors
Binding to Chemical Factors Essential for
Cancer Cell Growth and Survival
Targeted Delivery of Other Cytotoxic
Treatments
Immunotherapy
Immune Checkpoint Inhibitors
Immune System Modulators
Treatment Vaccines
Miscellaneous Chemotherapy Drugs
Proteasome Inhibitors
Asparaginase
Retinoic Acid and Its Derivatives

Introduction
The literal meaning of ‘cytotoxic’ refers to an agent which damages or kills a living cell,
and in its widest sense includes adverse effects of drugs in physiological systems and
antimicrobial agents used to kill or halt division of pathogenic micro-organisms. Its
common use, however, has come to mean a drug used to treat cancer, and because
cancer is such a common disease, the study and development of cytotoxic drugs is one of
the most rapidly advancing areas in pharmaceutical research. Cancer is a disease that
predates the history of our species. The oldest known case of cancer is an osteosarcoma
in a toe bone of an earlier relative of Homo sapiens and is around 1.7 million years old
(Fig. 12.1). Ancient Egyptian mummified remains show lesions indicative of bone
cancer, and cases of what is clearly breast cancer are described in ancient Egyptian
writings. The word ‘cancer’ is believed to have been first coined by Hippocrates (460–
370 BC), the Greek physician sometimes also referred to as the father of medicine. It
derives from the Greek word for ‘crab’, and likely originates because of the finger-like
projections of abnormal tissue extending from a superficial breast tumour and which
distort the surface of the breast. Chemotherapy, the treatment of cancer with cytotoxic
agents, is the most recent of the three main therapeutic approaches, the others being
radiotherapy and surgery.
The prospect of using drugs to treat cancer first emerged in the 1940s. Following the
observation that the highly toxic chemical warfare agent sulphur mustard (mustard gas)
caused a drastic fall in white blood cell counts, it was trialled in the treatment of
lymphoma. In the 1950s, antifolates including methotrexate were used to treat
leukaemia and other cancers. Since those early days, as understanding of the genetic,
immunological, hormonal, and molecular basis of malignancy rapidly advanced, it has
become clear that cancer is a collection of at least 200 different types. Based on this, a
raft of new therapies has been developed, and the concept of targeted treatments has
become a standard approach in many cancers. Cytotoxic drugs are amongst the most
noxious therapeutic agents in clinical pharmacology because of their harmful actions on
healthy tissues. However, our expanding understanding of the biochemistry, genetics,
and molecular biology of cancer cells is driving the development of novel drugs which
selectively target some aspect of malignant cell biology, reducing toxicity and improving
the tolerability and efficacy of treatment regimens. Reflecting the ingenuity of the
researchers engaged in this work, a bewildering and expanding array of drugs with a
wide range of highly specific mechanisms of action is now available, many of which are
only helpful in a small number of cancers because of their targeted action. This chapter
does not aim to provide a comprehensive list of chemotherapeutic agents: indeed, with
the speed with which the field is advancing, it is likely that any such list would be
incomplete at publication anyway. However, it explains the scientific principles
underpinning the pharmacology of the main groups of anticancer drugs and discusses
important examples in more detail.
With improved diagnostics and treatment options, survival times and cure rates for
many cancers have improved dramatically, but globally cancer remains the second
leading cause of death.

Key Points
All tumours originate from a body cell whose DNA has suffered one or usually more
mutations, the consequence of which is to release the cell from normal growth
controls and allow it to replicate in a disorderly and unregulated fashion. The cell
population produced from this malignant transformation becomes progressively more
genetically unstable as the tumour expands, accumulating more and more mutations
and becoming more and more abnormal. Cancers can be classified according to their
tissue of origin:

• Carcinomas originate in epithelial tissues. Epithelial tissues cover and line body
organs and surfaces, e.g. the skin and the lining of the gastrointestinal tract, and
cell division rates are high. Multiple cell divisions increase the likelihood of
copying errors occurring in the cell’s DNA, leading to mutations appearing in the
cell line. Eighty to ninety percent of cancers are carcinomas.
• Sarcomas originate in connective tissues like bone, cartilage, fat, and muscle.
• Blastomas originate in precursor cells (blasts). These cancers are most common in
children.

DNA, the Cell Cycle, and Healthy Cell Division

Deoxyribonucleic acid (DNA) carries the genetic code that allows every nucleated cell to
produce the structural and functional proteins it needs to fulfill its role. It is the largest
molecule in the body: if all the DNA in a single typical body cell was extracted and laid
out to its full length, it would be around 2 m long, an incredible feat of packaging given
that most body cells are so tiny they can only be seen under a microscope. The cell’s
DNA is found in the cell nucleus but is only clearly visible in a cell preparing to divide,
when it condenses into visible sausage-like structures called chromosomes. Nucleated
body cells (except for sperm and ova) contain 46 chromosomes matched up into 23
pairs.
 FIG. 12.1 The oldest known case of cancer.Osteosarcoma in the toe
bone of an earlier relative of Homo sapiens: around 1.7 million years
old. Photo by P. Randolph-Quinney, Northumbria University;
Weblink 1. Reprinted with permission.

Ninety-eight percent of the DNA in a healthy human cell does not code for a protein
and is referred to as ‘non-coding’. Some of this DNA regulates gene expression, but most
of it has no known function. The sections of DNA that do carry the code for a protein are
called genes and are found at specific locations on a particular chromosome: for
example, the gene that codes for insulin is found on chromosome 11. The human
genome, the complete set of genes within the cell, contains between 20,000 and 25,000
genes.

DNA Structure
The DNA molecule is formed of two chains twisted around each other into a double helix
like a twisted ladder (Fig. 12.2). The ‘uprights’ of the ladder are formed of alternating
phosphate and sugar (deoxyribose) groups. Each sugar group has a base attached to it,
and the bases on one chain are bound to the bases on the other chain with hydrogen
bonds, stabilising the molecule and forming the ‘rungs’ of the ladder. Each sugar/base
group is collectively called a nucleoside (see Fig. 11.18), and the sugar/base/phosphate
unit is called a nucleotide (Fig. 12.2).
 There are only four bases in DNA, thymine, adenine, guanine, and cytosine, and they
display specific pairings. Thymine always binds to adenine and guanine to cytosine.
Therefore, knowing the base sequence on one DNA strand accurately identifies the base
sequence on the second strand. This is called complementary base pairing. The genetic
code is written in the base sequences. Mutations in the base sequence of genes generate
errors in the code and lead to the production of faulty, often non-functional protein.
Chemically speaking, adenine and guanine are purines, and thymine and cytosine are
pyrimidines. Pyrimidine analogues, e.g. fluorouracil (FU), and purine analogues, e.g.
mercaptopurine, are long-standing members of the chemotherapeutic drug armoury,
and act by substituting for the true base when a cell is producing new nucleic acids.
Nucleic acid containing the fake bases is non-functional.
 FIG. 12.2 The structure of DNA.DNA is formed from two chains of
alternating sugar and phosphate groups, linked in a ladder-like
structure by bases attached to the sugar units. The molecule is then
twisted into a double helix. From Thibodeau G and Patton K (2019)
Anatomy and physiology, 10th ed. St. Louis: Mosby.

DNA Replication
In body cells preparing for mitosis, the cell’s DNA is duplicated, the fundamental event
in the S phase of the cell cycle (Figs 12.3 and 12.5). DNA replication is a complex event
involving several important enzymes, some of which are important targets for cytotoxic
drugs. The DNA molecule is first uncoiled by DNA helicase, and the hydrogen bonds
between the bases of the two strands are broken. This gives two complementary single
strands of DNA, each of which is used to make a new double-stranded molecule: two
identical daughter molecules are therefore produced from the original parent molecule.
The enzyme which assembles the second strand on each original strand is called DNA
polymerase. DNA topoisomerase stabilises and repairs DNA during DNA replication,
and DNA ligase stitches newly synthesised segments of DNA together.
Because malignant cells usually divide more quickly than normal cells, DNA
replication is an established chemotherapeutic target. Anticancer drugs can interfere
with DNA synthesis in a number of ways. For example, cytotoxic anthracyclines such as
doxorubicin and idarubicin insert themselves between the base ‘rungs’ of DNA
(intercalation), damaging the molecule and preventing DNA replication.

mRNA and Protein Synthesis

To manufacture the protein product coded for by a gene, its code (the base sequence) is
used to produce a single-stranded nucleic acid called messenger ribonucleic acid
(mRNA). This is called transcription: the base sequence of the DNA is rewritten
(transcribed) into the base sequence of the mRNA molecule, which travels from the
nucleus into the cytosol and attaches to a ribosome, the organelle responsible for protein
synthesis. The ribosome reads the mRNA code and assembles the new protein
accordingly. This is called translation: the language of the base sequence code in DNA is
translated into the correct sequence of amino acids making up the new protein (Fig.
12.4).
RNA is structurally different from DNA in three main ways: it is single-stranded
instead of double-stranded, it contains the sugar ribose instead of the sugar deoxyribose,
and it contains uracil instead of thymine. Like thymine and cytosine, uracil is a
pyrimidine.

The Cell Cycle

A body cell undergoing cell division follows a tightly controlled series of steps called the
cell cycle (Fig. 12.5). At key checkpoints, the cell and its genetic material are examined
to ensure that they are healthy and that conditions are favourable before the cell can
proceed to the next stage in the cycle: for example, cell division is inhibited if
abnormalities are detected in the cell’s DNA or if the nutrient supply is inadequate.
These safeguards ensure that potentially dangerous mutations in DNA are not copied
and passed to the next generation of cells. If damage is detected in a cell’s DNA,
pathways are activated to initiate repair if possible; if not, the cell’s apoptosis (cell
suicide, see below) genes are activated and the cell is eliminated.
The M (mitosis) phase comprises the process of cell division, producing two
genetically identical daughter cells. During mitosis, the duplicated chromosomes
separate, and a copy of each chromosome travels to opposite ends of the cell, attached to
microtubules which direct chromosome movement. The vinca alkaloids, e.g.
vincristine, and the taxanes, e.g. paclitaxel, inhibit microtubule formation and arrest
the cancer cell in mitosis.
Following mitosis, the daughter cells enter G1 (the first gap phase), during which they
grow and produce new proteins. Depending on the requirements of the tissue, the cell
may now enter the S (synthesis) phase to prepare it to divide again, or it may be shunted
into what is called the G0 phase, in which it is fully functionally active but its ability to
divide is disabled. If the cell is destined to divide again immediately, the health of its
DNA is inspected at a checkpoint called the G1/S restriction point. If abnormalities are
detected in the cell, its progress in the cell cycle is halted here. If the cell is found to be
healthy, it passes into the S phase, during which the cell’s chromosomes are duplicated
in preparation for its next division. In the next stage, the G2 or second gap phase, the
cell continues to grow and copies its organelles in preparation for mitosis. In addition,
the microtubules, which will line the duplicated chromosomes up, separate them, and
pull them to each end of the cell during mitosis, are assembled. Before progressing to
the M phase, the cell’s health and the integrity of its DNA is checked again at what is
called the G2/M checkpoint. Damaged or abnormal cells are halted in their progression
through the cell cycle here and are not permitted to undergo mitosis.
 FIG. 12.3 The steps in DNA replication. Modified from HESI
(2021) Admission assessment exam review, 5th ed, Fig. 5.11. St.
Louis: Elsevier.

Cell cycle-checkpoint defects are characteristic of cancer cells, leading to repeated and
uncontrolled cell division. Each time a damaged cell is allowed to proceed round the cell
cycle and divide, the number of mutated cells increases, and because one mutation
predisposes the cell to developing others (genetic instability), it leads to an expanding
population of cells accumulating multiple mutations and increasing risk of malignant
transformation. Some of the most common genetic mutations leading to checkpoint
failure are discussed below; they are an important target in anticancer drug research.
Key enzymes called cyclin-dependent kinases (CDKs) drive the cell cycle; CDKs need
to bind to a regulatory protein called cyclin for activation. Both are potential targets in
cancer drug development.

Apoptosis
Apoptosis is programmed cell death, sometimes referred to as cell suicide. It is an
essential part of embryonic and fetal development, during which many more cells are
produced than are actually needed, and the extra cells are eliminated by apoptosis to
bring cell numbers down to within the desired range. Old, damaged, or mutated cells are
also disposed of this way, as are cells that have arrested during mitosis, including as a
result of chemotherapy. Apoptosis is therefore essential for growth and repair and in
maintaining healthy function of cell populations in adult life. The key enzymes that drive
apoptosis are called caspases. During apoptosis, the cell undergoes controlled but rapid
disintegration: typically, half an hour is all that is needed for a cell to destroy itself. As
the cell breaks up, macrophages rapidly scavenge the fragments to prevent the cellular
contents from stimulating an inflammatory response. Identifying drugs that selectively
stimulate apoptosis in cancer cells is an active area in anticancer drug development.
Fig. 12.6 shows advancing stages of apoptosis in a malignant pig kidney cell exposed to
the chemotherapeutic drug etoposide.
 FIG. 12.4 Transcription and translation: the role of DNA, RNA,
and ribosomes in protein synthesis. From Waugh A and Grant A
(2020) Ross & Wilson anatomy and physiology in health and illness,
14th ed, Fig. 17.5. Oxford: Elsevier.

The Biology of Cancer

In health, cell proliferation, tissue growth, and the regulation of apoptosis are tightly
controlled to safeguard against unrestrained, unwanted, or abnormal cell division. The
fundamental pathological event in all cancers is one or more non-lethal mutations in the
DNA of a body cell, which confer several important properties on the cell and allow it to
escape the mechanisms normally governing the cell cycle and cell division. These
properties give the cancer cell several survival advantages over its healthy counterparts.

Properties of Cancer Cells

Malignant transformation of a cell means that the cell has suffered one or more genetic
mutations that have converted it from a normal body cell to a cancer cell, with the
acquisition of properties (Fig. 12.7) that allow it to move unchecked through the cell
cycle, escaping the normal control points and dividing without restraint in a disorderly
manner.

Loss of Differentiation Features

Differentiation is the process by which cells acquire their specialised (differentiated)
characteristics, which allow them to carry out their particular function in the body. For
example, muscle cells need to produce contractile proteins, and phagocytes need to
produce quantities of degradative enzymes and other toxic substances to destroy their
targets. A key feature of malignant cells is the loss of these specialised functions, and
this is called dedifferentiation. Dedifferentiation correlates with malignancy; the more
malignant a cell is, the more likely that it has lost its ability to carry out its specialised
role. Drugs such as retinoids promote differentiation and are therefore anti-
tumorigenic.

Immortality and Evasion of Apoptosis

Healthy cells are limited to between 50–60 divisions, after which the cell either has its
ability to divide disabled, or its apoptosis pathways are activated. This ensures that old
and potentially damaged cells do not continue to divide, reducing the chance that they
develop malignant change. Malignant cells can continue replicating indefinitely and are
resistant to apoptosis. Activating apoptosis is an attractive potential target for new
chemotherapeutics. Although no agents have yet reached the market, some are in
clinical trials, including turmeric derivatives such as curcumin.
 FIG. 12.5 The cell cycle. From Grant A (2024) Ross & Wilson
pathophysiology, Fig. 3.4. Oxford: Elsevier.

Telomerase
At each end of a chromosome is a section of DNA which is there to protect the
chromosome end and prevent it from damage, a bit like the short plastic sleeves
protecting the ends of shoelaces. These protective caps are called telomeres. With each
cell division, the telomere gets shorter. When it becomes too short to protect the
chromosome end, cell division is arrested, and the cell may even have its apoptosis
genes activated. This limits the number of divisions that a cell can undergo and ensures
that older cells are shunted out of the cell cycle. Telomerase is the enzyme that builds
telomere DNA onto the ends of chromosomes. Healthy body cells do not produce this
enzyme, but cancer cells frequently do. This allows them to constantly repair the
telomere caps on their chromosomes, theoretically allowing them to continue dividing
indefinitely, producing expanding populations of malignant cells. Telomerase offers a
selective target for cancer drugs; however, although telomerase inhibition strips the
cancer cells of their immortality, it does not disrupt their ability to divide or exert direct
cytotoxic effects. Although research in this area is ongoing, it has so far produced limited
success and only one telomerase inhibitor, imetelstat, has so far reached the market.

Angiogenesis
When a tumour is very small, less than 2 mm in diameter, nutrients and oxygen can
reach its centre by simple diffusion. As the tumour grows, diffusion is inadequate to
supply its metabolic requirements, and it needs its own blood supply. Cancer cells
produce growth factors like vascular endothelial growth factor (VEGF) that stimulate
blood vessel growth (angiogenesis), developing a vascular network within the growing
tumour and supporting its expansion. Several anticancer drugs, including aflibercept
and sorafenib, inhibit angiogenesis.

Loss of Contact Inhibition

In health, cells dividing in a tissue observe social restrictions: once they have made
contact with adjacent cells, their cell cycle is arrested and they stop dividing. This keeps
the structure of the tissue orderly and cell numbers normal. Malignant cells lose this
property and continue to divide even when in direct contact with their neighbours,
producing excessive cell numbers and abnormal tissue architecture.

Motility
During periods of normal tissue growth, e.g. embryogenesis and wound healing, newly
divided cells may be motile, allowing them to migrate along pre-determined pathways to
their destination. This is a tightly regulated process, and once at its destination, the cell’s
motility is inhibited, and the cell takes up its position in the developing tissue. Cancer
cells display increased and unhindered motility which allows them to invade locally and
to cross basement membranes and other physiological barriers, permitting distant
spread. Inhibition of cancer cell motility is a potential target in cancer therapeutics and
several agents currently under investigation have shown promise in animal models.
 FIG. 12.6 The progression of apoptosis in a malignant pig kidney
cell exposed to etoposide. Courtesy L.M. Martins and K. Samejima,
Wellcome Trust Institute for Cell Biology, University of Edinburgh,
UK.

Altered Nutrient Requirements

Because cancer cells generally divide faster than healthy cells, their nutrient
requirements are high. Sometimes cancer cells can adapt their metabolism to use
additional or alternative substances for energy. This is advantageous for the cancer cell
in terms of improving its ability to grow and proliferate at the expense of non-cancerous
cells, but it may also present potential drug targets: if a cancer cell has become
dependent on a novel metabolic pathway not essential to healthy cells, it may be
vulnerable to drugs which interrupt or interfere with that pathway, while minimising
toxicity to normal tissues.

Genetic Instability
Genetic instability is the increased likelihood of further mutations when a mutated cell
divides: that is, once one mutation is present, that cell will accumulate more and more
mutations as it continues to divide. This is an important feature in cancer cells because
cancer requires more than one, often multiple, mutations to be present. This can be
exploited in chemotherapy because the more mutations accumulate, the likelier it is that
the cell will be tripped into apoptosis and destroy itself. Poly-ADP ribose polymerase
(PARP) inhibitors such as niraparib prevent a tumour cell from repairing DNA breaks
and so push it towards cell suicide.

The Genetics of Cancer

Two main groups of genes, proto-oncogenes and tumour-suppressor genes, are involved
in the regulation of cell division, differentiation, and apoptosis, ensuring that cell
proliferation is tightly controlled, halted when not required, and that old, defective, and
worn-out cells are destroyed by apoptosis. Proto-oncogenes stimulate cell proliferation,
and tumour-suppressor genes inhibit it. Mutations in one or more of these genes,
leading to failure of their function, are found in all cancers, and an understanding of the
genetic mechanisms underpinning specific cancers has allowed the development of an
increasing pool of targeted therapies.
 FIG. 12.7 Properties of malignant cells. Modified from Craft J,
Gordon C, Huether S, et al. (2023) Understanding pathophysiology
ANZ, 4th ed, Fig. 37.3. Sydney: Elsevier Australia.

Proto-Oncogenes
Proto-oncogenes are healthy genes important in embryonic development, in growth, in
healing and repair, and in replacement of cells that have reached the end of their useful
life. They code for proteins which stimulate cell division and differentiation, and which
inhibit apoptosis. Mutations in a healthy proto-oncogene can produce an abnormal
oncogene (Fig. 12.8), which produces excessive quantities of a growth-stimulating
protein, driving the cell through the cell cycle and allowing it to escape normal growth
checks and halt signals. This is a common feature in cancer, and oncogenes are an
important molecular target for the design of new cytotoxic drugs.
One example illustrating how understanding the molecular genetics of an oncogene
has translated into clinical therapeutics is the story of trastuzumab (Herceptin), which
came on the market in 1998. In the mid-1980s, researchers discovered an oncogene,
called HER2, which produces a protein called human epidermal growth factor receptor
(HER) 2. HER2 belongs to a family of cell-surface receptors called epidermal growth
factor receptors (EGFRs). Epidermal growth factor (EGF) is a common growth factor
which stimulates cell division in a range of cell types by binding to EGFRs. It was then
shown that the HER2 gene is overactive in a subset of women with breast cancer,
increasing HER2 protein expression on the cell surface and increasing the cells’
responsiveness to growth stimuli and promoting tumour growth. This type of breast
cancer was designated HER2-positive. Trastuzumab is a monoclonal antibody which
binds to and blocks the HER2 protein at the cell surface, blocking the incoming growth
stimuli and preventing the cell from dividing. Introduction of trastuzumab into the
treatment regimes for HER2-positive primary and metastatic breast cancers
significantly improves survival and reduces relapse rates: it has been a game-changing
medical advance for this cohort of patients. It has also since been shown that the HER2
oncogene is involved in other cancers including some stomach and oesophageal
malignancies, and trastuzumab is now also used in these cases (Fig. 12.9).

Tumour-Suppressor Genes
Genes that produce proteins with anti-proliferative properties are called tumour-
suppressor genes. These proteins act as brakes on the cell cycle, suppress cell division,
and induce apoptosis in old and damaged cells. Mutations in one or more tumour-
suppressor genes are commonly found in cancer cells. Important tumour-suppressor
genes include TP53, which is mutated in over half of human cancers. The protein it
codes for, p53, is essential for normal function of the G1/S restriction checkpoint in the
cell cycle. Mutation of the TP53 gene and loss of p53 allows damaged and abnormal cells
to progress through this checkpoint, proceed through the cell cycle, and divide. Other
tumour-suppressor genes directly linked to cancer include BRCA1 and BRCA2.
Mutations in the BRCA (Breast Cancer) genes increase the risk of a range of
malignancies, including breast, prostate, pancreatic, and ovarian cancers. The proteins
coded for by these genes are enzymes that ensure that damage to the cell’s DNA is
accurately repaired and so maintain DNA integrity. Loss of these enzymes leads to DNA
instability, which predisposes the cell to malignant transformation. An understanding of
the basic science underlying BRCA function led to the development of the PARP
inhibitors, like niraparib (see below).

FIG. 12.8 Mutation in a healthy proto-oncogene can produce a

tumour-promoting oncogene.

FIG. 12.9 The action of trastuzumab.A. Normal HER2 receptor

numbers. Breast cell growth and division control normal. B. HER2
receptor over-expression due to mutated EGFR gene. Cell exposed to
excessive growth stimulation. C. Trastuzumab blocks HER2
receptors, reducing the EGF growth stimulus. EGF, Epidermal
growth factor; EGFR, epidermal growth factor receptor; HER2,
human epidermal growth factor receptor 2. From Grant A (2024)
Ross & Wilson pathophysiology, Fig. 3.19. Oxford: Elsevier.

Approaches and Issues in Cytotoxic Therapy

The perfect anticancer drug would kill cancer cells without causing toxicity to healthy
body cells. In practice, cytotoxic drugs usually cause significant injury to healthy tissues,
which often limits the dose that can be administered. Ideally, the drug should target
some aspect of the malignant cell’s metabolism or structure that is not present in normal
body cells; but as all cancer cells originate from a body cell, finding such a target is a
challenging proposition and requires a detailed understanding of the biology of the
cancer cell in question. By definition, cancer cells have changed in some way compared
to the healthy body cell from which they originated, and identifying these changes may
expose vulnerabilities in the cancer cell which can be exploited by targeted drug design.
For example, they are likely to divide more quickly, they may express different cell-
surface markers, or respond differently to hormones or to growth factors. The
progression from the basic research done at the lab bench to a clinically useful drug
which extends and saves lives is the essential story in all areas of modern medical
pharmacology, but perhaps the successes achieved in the development of novel, targeted
anticancer agents is the most impressive illustration of this relationship.
Chemotherapy in cancer is often used in combination with other therapeutic
approaches including surgery and radiotherapy, and drugs are often used in
combination. In practice, because cancer treatment usually causes significant side-
effects, the risk-benefit balance must be carefully considered when considering
treatment options.
Staff administering cytotoxic agents must take steps to protect themselves. Pregnant
women should not handle them.

Common Adverse Effects of Chemotherapy

A range of adverse effects are seen with many cytotoxic agents because of potential
toxicity in multiple tissues and organs (Fig. 12.10). In addition, many are directly toxic
to the liver and kidney, causing hepatic and renal impairment.

Teratogenicity
Women of childbearing age are always counselled to avoid pregnancy during
chemotherapy because chemotherapeutic agents are almost always teratogenic in
animal studies. The anti-proliferative and growth-suppressive activity of most
chemotherapeutic agents confer significant risk of birth defects, especially in the first
trimester.

Nausea and Vomiting

Along with anorexia, these are common and debilitating side-effects of many cytotoxic
regimes. The physiology of vomiting is discussed in Chapter 10. Cytotoxic drugs in the
bloodstream may stimulate the chemosensitive trigger zone and trigger vomiting, or
they may stimulate the vomiting centre directly. Other agents may irritate sensory
nerves in the GI tract and stimulate the vomiting centre via vagal afferents. Using anti-
emetics to prevent or relieve these unpleasant symptoms is important.

Suppression of Rapidly Dividing Healthy Tissues

Healthy tissues with rapid cell turnover rates, including bone marrow, hair, skin, testis,
and the epithelial lining of the gastrointestinal (GI) tract, are particularly susceptible to
the anti-proliferative action of chemotherapy. Bone marrow suppression inhibits
production of red blood cells, platelets, and some white blood cells. This causes
anaemia, with tiredness, breathlessness, and palpitations. Thrombocytopenia (reduced
platelet count) increases the risk of bleeding, and leukopenia (reduced white cell count)
increases the risk of infection and suppresses healing. Cell renewal in the epithelial
lining of the GI tract is affected, leading to painful ulcerations, especially in the mouth,
and diarrhoea. Rapidly dividing cells in hair follicles are suppressed, giving alopecia.

FIG. 12.10 Common adverse effects of chemotherapy. Modified

from Herrmann J (2018) Clinical cardio-oncology, Fig. 1.5. St. Louis:
 Elsevier.

Future Malignancies
Many chemotherapy agents kill or eliminate cancer cells by damaging DNA so are
themselves carcinogenic. Their action also extends to healthy tissues, and even if the
cancer is cured, there is the likelihood that mutations in normal cells can persist and
themselves cause secondary cancers, usually haematological, sometimes years down the
line.

Reproductive Consequences
Cytotoxic drugs may eliminate or critically damage stem cells in the testes and
permanently damage the oocytes of the ovary, leading to reduced or lost fertility.
Freezing of sperm or ova in advance of chemotherapy may be an option in patients who
may want to have a family in the future.

Drug Resistance in Chemotherapy

Cancer cells, by definition, are genetically unstable. This means that the malignant cells
within a tumour are not all genetically identical because of random mutations within the
cancer cell population as they divide. Because of this, the sensitivity to cytotoxic drugs
across the tumour-cell population is likely to vary, sometimes quite significantly.
Treating the cancer with a particular drug may kill or irreversibly damage a significant
proportion of the tumour cells, but cells which are less sensitive to the drug may survive
and proliferate, producing a population of malignant cells resistant to the original
treatment. This is fundamentally similar to the development of antimicrobial resistance
in microbial populations (see Fig. 11.6). As with antimicrobial therapy, combination
treatment, i.e. the use of two or more cytotoxic agents simultaneously, can help to
reduce the emergence of drug-resistant cancer cells.

Drugs that Interfere with One or More Stages of the

Cell Cycle
The increased rate and unrestrained manner of cancer cell division compared to healthy
body cells makes cell division a useful target for anticancer drugs. However, many of
these drugs are also highly toxic to healthy cells, particularly those with high
proliferation rates, giving rise to some of the most common side-effects as described
above.
Spindle Poisons
Examples of vinca alkaloids: vincristine, vinblastine, vindesine
Examples of taxanes: paclitaxel, docetaxel, cabazitaxel
Other agents: eribulin
The spindle is the network of fibres (also called microtubules) radiating out from each
pole of the cell in a cell undergoing mitosis. Microtubules are built from proteins called
tubulins (Fig. 12.11A). The spindle lines the chromosomes up in the correct alignment
in the middle of the cell and then pulls the separating chromosomes to opposite ends of
the cell, so that when the cell divides, each daughter cell has a full set of chromosomes.
Spindle poisons arrest the cell cycle in the M phase and are used in a wide range of
malignancies. They are usually given by injection or infusion because of poor oral
absorption, although vinorelbine can be given orally. Eribulin is used in advanced
breast cancer: it inhibits microtubule elongation and aggregates tubulin into non-
functional masses in the cell. This disrupts the mitotic spindle, prevents mitosis, and
triggers apoptosis.

FIG. 12.11 Action of the spindle poisons.A. The mitotic spindle is

formed from tubulin dimers. B. The vinca alkaloids prevent tubulin
dimers from assembling into the linear microtubule fibres. C.
Taxanes prevent disassembly of microtubules so that they cannot
shorten to move chromosomes around the cell. Modified from
Stevens CW (2023) Brenner and Stevens’ pharmacology, 6th ed, Fig.
45.5. St. Louis: Elsevier.
The Vinca Alkaloids
Extracts of the periwinkle plant, Catharanthus roseus, had been used in traditional
medicine for centuries for their hypoglycaemic effect, but in the 1950s two Canadian
scientists isolated vinblastine, the first of the spindle poisons to be extracted from this
plant. They prevent the assembly of tubulin proteins into the linear microtubule fibres
(Fig 12.11B). Without an intact spindle, chromosome separation is not possible and cell
division is arrested. The vinca alkaloids are mainly metabolised in the liver and have
variable and potentially very long half-lives: for example, vincristine’s half-life varies
from 19–155 hours. The vinca alkaloids are neurotoxic and should not be given
intrathecally. The main dose-limiting adverse effect of vincristine is dose-dependent
peripheral neurotoxicity, affecting both sensory and motor function, although sensory
manifestations, e.g. paraesthesias, dysaesthesias, and numbness, are more common.
Some studies report up to 100% of patients developing some degree of neurological
dysfunction. It is largely reversible on cessation of treatment, but some patients report
persistent symptoms several years following chemotherapy.

Taxanes
The first taxane, paclitaxel, was derived from fungi living in the bark of the Pacific yew
tree (Taxus brevifolia) and was first tested in cancer in the early 1970s. The newer
taxanes are semi-synthetic taxane derivatives. These drugs prevent tubulin proteins
from dissociating from each other (depolymerisation), which prevents the normal
dynamic shortening and lengthening of spindle fibres essential for pulling chromosomes
around within the cell (Fig. 12.11C). In addition to inhibiting mitosis, taxanes activate
caspases, the enzymes that drive apoptosis, stimulating programmed cell death. The
taxanes are metabolised in the liver. On infusion, they commonly cause mild to severe
hypersensitivity reactions including urticaria, angioedema, and bronchoconstriction,
and an antihistamine or corticosteroid is usually given in advance to reduce the risk or
severity of this.

Drugs that Act on DNA

Drugs that damage DNA, inhibit the enzymes needed for DNA synthesis, replication, or
repair, or mimic the nucleoside (Fig. 11.18) building blocks of DNA are cytotoxic
because they prevent cell division, and the DNA injury they produce may trigger
apoptosis. They are discussed below under their main mechanism of action.
Nucleoside Analogues (False Nucleosides)
Examples of pyrimidine analogues: fluorouracil, azacitidine, decitabine, cytarabine
Examples of purine analogues: mercaptopurine, cladribine, gemcitabine,
nelarabine, tioguanine
These drugs are structurally very similar to true nucleosides and compete with them
during DNA and RNA synthesis, arresting DNA replication in the S phase of the cell
cycle. Some bind to and inhibit one or more of the enzymes of the pathways producing
nucleosides, halting nucleoside synthesis: examples include fluorouracil and
azacitidine. Without a supply of nucleosides, DNA and RNA manufacture is not
possible and the cancer cell cannot divide. Others are used by the polymerase enzymes
building DNA or RNA instead of the true nucleoside, and newly synthesised nucleic acid
contains both true and fake nucleosides. DNA/RNA containing fake nucleosides does
not function normally and DNA cannot be replicated, thus preventing the cancer cell
from dividing again. Examples include gemcitabine and cladribine. Whatever the
mechanism of action of the fake nucleoside, the result is the same: the cancer cells’
capacity to copy its DNA and produce proteins is impaired and the cell does not survive.
Two representative examples are discussed here.

Fluorouracil
Fluorouracil is a pyrimidine analogue which is taken up more extensively in malignant
cells than in healthy cells and binds to and blocks thymidylate synthetase (Fig. 12.12).
Thymidylate synthetase converts 2-deoxyuridylate to 2-deoxythymidylate. This is a key
step in the synthesis of DNA, and FU therefore blocks the cancer cell’s ability to replicate
its DNA and prevents it from dividing. It was first produced in 1957 and is still widely
used today in a range of solid tumours, including some GI and breast cancers, and in
pre-malignant and malignant skin conditions such as actinic keratosis. It has a short
plasma half-life of 10–20 minutes and is metabolised mainly in the liver. Among others,
it causes the standard range of cytotoxic adverse effects (see above) and may cause
cardiotoxicity. Capecitabine and tegafur are pro-drugs which are converted in the
tumour to FU.

Mercaptopurine
Mercaptopurine is used to treat leukaemia and is used for its immunosuppressant action
in some autoimmune disorders including inflammatory bowel disease and severe
psoriasis. It is an adenine analogue, is mistaken for a true adenine nucleoside, and is
incorporated into DNA and RNA in cancer cells. It can cause the standard range of
cytotoxic adverse effects and may cause significant hepatotoxicity: liver function should
be monitored while the drug is being used.

Topoisomerase Inhibitors
Examples of topoisomerase I inhibitors: irinotecan, topotecan
Examples of topoisomerase II inhibitors: etoposide
Topoisomerase I and II are essential enzymes in DNA synthesis and repair. They
cause the general cytotoxic adverse effects described above. Topoisomerase II inhibitors
increase the risk of developing acute myeloid leukaemia later in life.

Topoisomerase I Inhibitors
Topoisomerase I stabilises and repairs DNA during transcription and replication, when
the DNA strands are separated and vulnerable to damage. Irinotecan and topotecan
are derived from camptothecin, which was first isolated from the bark of the Chinese
tree Camptotheca acuminata and has been used in traditional Chinese medicine for
thousands of years. They bind to and block topoisomerase I, causing double-strand
breakages in the DNA molecule which are not repaired and lead to cell death. They are
not absorbed when given orally and so are administered intravenously. Care should be
taken in patients with hepatic or renal impairment. Irinotecan is used in advanced
colorectal cancer and topotecan is used in ovarian, cervical, and small-cell lung cancer.

Topoisomerase II Inhibitors
Topoisomerase II stitches together (ligates) newly synthesised fragments of DNA in
DNA synthesis. Topoisomerase II inhibition causes double-strand breaks in DNA, which
are not repaired and cause cell death. Etoposide is derived from the mandrake root
Podophyllum paltatum. It binds to and inhibits topoisomerase II, preventing DNA
ligation and leaving the cell with non-survivable DNA damage. It is given orally, is partly
metabolised in the liver and partly excreted unchanged, and has a plasma half-life of 4–
11 hours. It is used in testicular cancer, in lymphoma, and in small-cell lung cancer.

Folate Antagonists
Examples: methotrexate, pemetrexed, raltitrexed, fluorouracil
Vitamins are co-factors, essential ‘helper’ substances without which an enzyme cannot
function. Folic acid (vitamin B9) is essential for several key enzymatic steps in the
biochemical pathways that synthesise purine and pyrimidine nucleosides and some key
amino acids, including methionine, serine, glycine, and histidine. Folic acid deficiency
therefore inhibits DNA, RNA, and protein synthesis and so is particularly important in
actively dividing cells. This makes folate metabolism a potential target in cancer therapy
because cancer cells usually divide at a faster rate than normal cells.
Dietary folic acid is converted to dihydrofolate and then to tetrahydrofolate by the
action of the enzyme dihydrofolate reductase (Fig. 12.12; see also Fig. 11.15).
Dihydrofolate reductase is inhibited by methotrexate. Fig. 12.12 shows that
tetrahydrofolate is a co-factor for the enzyme thymidylate synthetase, a key enzyme in
the production of thymine nucleosides for DNA synthesis. This reaction converts
tetrahydrofolate back to dihydrofolate, but dihydrofolate is then recycled back to
tetrahydrofolate by dihydrofolate reductase, keeping tetrahydrofolate availability high.
FU (see above), raltitrexed, and pemetrexed bind to and block thymidylate synthase,
thus blocking the recycling of tetrahydrofolate and blocking DNA, RNA, and protein
production.

Methotrexate
Methotrexate has been used as an anticancer drug since the 1950s and is still widely
used in a range of malignant diseases including some leukaemias, non-Hodgkin’s
lymphoma, and some breast, lung, and ovarian cancers. It is also used as an anti-
inflammatory and immunosuppressant agent in rheumatoid arthritis, inflammatory
bowel disease, and psoriasis. Methotrexate inhibits several enzymes involved in folic
acid metabolism, including dihydrofolate reductase and thymidylate synthase,
preventing the tumour cell from manufacturing DNA, RNA, and key proteins and
leading eventually to apoptosis of the cancer cell (Fig. 12.12). It is given orally or by
injection and causes the standard range of cytotoxic side-effects (see above) and others,
including neurotoxicity, confusion, respiratory problems, and hepatotoxicity. It is poorly
metabolised and is mainly excreted unchanged in the urine, so great care is needed in
people with impaired renal function. It is given once weekly and the half-life is dose-
dependent: it is shorter (3–10 hours) in low-dose treatment, which extends to up to 15
hours in higher-dose treatment and even longer in renal impairment. Clearance varies
significantly between patients.
 FIG. 12.12 The cytotoxic action of fluorouracil and methotrexate.

Folinic acid (also called leucovorin) is used as a rescue medication and is given 24
hours after high-dose methotrexate to help reverse methotrexate-induced
myelosuppression.

DNA Alkylating Agents

Alkylating agents possess one or two active groups (usually two) which damage DNA by
attaching reactive alkyl groups to its guanine and/or adenine bases. Because most of
these agents have two reactive groups, each group can react with a different base which
cross-links the two bases (Fig. 12.13). Alkylated DNA cannot be replicated because the
cross-links prevent the strands from separating, and it is subject to mutations and
breakages, leading to cell death. These agents damage cellular DNA at all stages of the
cell cycle and are among the most toxic of the chemotherapeutic medications. They
cause the general cytotoxic side-effects described above, often with particularly severe
bone marrow toxicity, and increase the risk of leukaemia in later life in a dose-
dependent fashion. Although they are very toxic, they are used in a range of
malignancies. They fall into a few chemically diverse groups.

Nitrogen Mustard Derivatives

Examples: chlorambucil, cyclophosphamide, melphalan, thiotepa
These drugs are derived from or chemically related to nitrogen mustards, which are
related to the sulphur mustards used in World War I as chemical warfare agents and
since banned under the 1925 Geneva Convention. Their chemical structures have been
modified to make them more stable.

FIG. 12.13 Cross-linking of bases in DNA by alkylating

agents. From Ritter JM, Flower RJ, Henderson G, et al. (2020) Rang
 & Dale’s pharmacology, 8th ed, Fig. 56.3. Oxford: Elsevier.

Cyclophosphamide
Cyclophosphamide is used to treat a wide range of cancers in addition to severe
rheumatoid arthritis with systemic complications. Its plasma half-life is between 3 and
12 hours. It is given orally and is a pro-drug activated in the liver and body tissues to the
cytotoxic substances acrolein and phosphoramide. Phosphoramide is thought to be
mainly responsible for alkylation and cross-linking, and acrolein is responsible for most
of cyclophosphamide’s toxicity; it produces large quantities of reactive oxygen species,
which injure cell organelles including the cell membrane, damage DNA, and impair
enzyme function. Acrolein is particularly toxic to the bladder, causing haemorrhagic
cystitis especially at higher doses of cyclophosphamide.

Nitrosoureas
Examples: carmustine, lomustine, streptozocin
Unlike most other alkylating agents, carmustine and lomustine cross the blood–brain
barrier and are used to treat central nervous system tumours. In addition, they are used
in Hodgkin’s lymphoma, and lomustine is used in melanoma and some lung cancers.
They have short plasma half-lives of usually less than 30 minutes, but both are
metabolised in the liver to active metabolites which extend their biological activity.
Intravenous carmustine can cause delayed pulmonary toxicity, which is dose-related
and may be fatal. Streptozocin is not absorbed orally and is given by infusion. It does
not cross the blood–brain barrier; its plasma half-life is usually less than 15 minutes and
it is metabolised mainly in the liver. It has an affinity for pancreatic islet cells and so is
used to treat pancreatic tumours and is particularly renotoxic.

Platinum Compounds (Platins)

Examples: cisplatin, carboplatin, oxaliplatin
The anti-proliferative effects of platinum were discovered by accident in the 1960s
when researchers observed that electrical fields inhibited Escherichia coli division. It
was eventually realised that it was not the electrical field blocking the bacterial cells’
ability to divide, but a platinum compound released from the platinum electrodes used
to generate it. This compound, cisplatin, was trialled in the 1970s in a range of cancers
and platinum compounds have established themselves as important therapies in a range
of cancers, particularly testicular and ovarian cancer. Oxaliplatin is only used in
advanced colorectal cancer.
Cisplatin is particularly renotoxic and a good fluid intake is very important during
courses of therapy. It is also ototoxic, and hearing should be monitored.

Miscellaneous Agents
Examples: busulfan, mitomycin C
Busulfan is rapidly metabolised in the liver and has a plasma half-life of less than 3
hours. It is given orally, is well absorbed, and crosses the blood–brain barrier. In 6–8%
of patients, chronic inflammatory and fibrotic pulmonary changes can occur, often after
the drug has been withdrawn; the risk increases with dose. It is sometimes used in
leukaemia, but its main use is in conditioning treatment before stem cell or bone
marrow transplantations.
Mitomycin C is an old cytotoxic antibiotic derived from Streptomyces caespitosus.
It is mainly metabolised in the liver and can cause chronic lung inflammation and
pulmonary fibrosis.

Other Agents that Directly Damage DNA

These drugs usually have more than one mechanism of action, but the end result is
damaged, broken, or deformed DNA which cannot be translated into mRNA for protein
production or copied for cell division.

Anthracyclines
Examples: daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone
The anthracyclines are intercalating agents which have a range of cytotoxic actions.
They bind (intercalate) between base pairs, distorting the normal shape of the DNA
molecule, preventing DNA replication and the action of RNA transcriptase, the enzyme
which reads the DNA code and produces the mRNA needed for protein synthesis.
Additionally, they produce toxic free radicals when metabolised, which breaks DNA and
damages the cell membrane and cellular proteins. They are used in a range of
haematological malignancies and solid tumours and are given intravenously because
their oral absorption is poor.

Doxorubicin
Doxorubicin is produced by Streptomyces peucetius. Its mechanisms of action include
those described above. Additionally, by inserting itself between the DNA strands, it
prevents topoisomerase II (see above) from stitching together newly synthesised strands
of DNA, and so halts cell division. Its half-life is 20–40 hours and it does not cross the
blood–brain barrier. It should be avoided if possible in those with a current or past
history of heart disease because it is cardiotoxic.

FIG. 12.14 Bleomycin-induced chromosomal damage.A. Healthy

chromosomes isolated from rat cells. B. Fragmentation of
chromosomes induced by bleomycin. From Caporossi D, Ciafrè SA,
Pittaluga M, et al. (2003) Cellular responses to H2O2 and bleomycin-
induced oxidative stress in L6C5 rat myoblasts. Free Radical Biology
and Medicine, 35 (11), pp. 1355-1364.
Cytotoxic Antibiotics
Examples: bleomycin, dactinomycin

Bleomycin
Bleomycin is a mix of antibiotics from Streptomyces verticillus. It binds metal ions into
a complex on the DNA strand, which generates reactive oxygen free radicals and
produces both single- and double-strand breaks. The damage bleomycin inflicts on DNA
is visible under the light microscope as abnormal and fragmented chromosomes (Fig.
12.14). Bleomycin is not given orally because it is not absorbed and is given by injection
or infusion. Its plasma half-life is around 2 hours, and it is metabolised mainly in the
liver. It should be avoided in people with pre-existing lung disease because it is highly
toxic to the lungs, causing potentially fatal pulmonary fibrosis (Fig. 8.2). Incidence of
bleomycin-induced lung toxicity may be as high as 1 in 10 patients. Other adverse effects
include hypersensitivity-type reactions, fever, and skin toxicity including
hyperpigmentation.

Drugs that Inhibit Cyclin-Dependent Kinase

Examples: abemaciclib, palbociclib, ribociclib
CDKs, in conjunction with cyclin proteins, are the enzymes that catalyse the co-
ordinated sequence of events that drives a cell through the cell cycle. CDK activity and
cyclin levels are frequently increased in cancer cells. Inhibiting CDK activity therefore
reduces cancer cell progress through the cell cycle, reducing their proliferation and
increasing apoptosis. There are at least 20 known CDKs, offering multiple potential drug
targets. This is one of the newest areas of drug development and, at the time of writing,
several potentially useful agents including alvocidib and seliciclib were in clinical and
pre-clinical trials.
Abemaciclib was first approved in 2017. It is currently used to treat some advanced
breast cancers but is being trialled in other malignancies. It inhibits CDK4 and CDK6
and prevents cancer cells from progressing from G1 to the S phase of the cell cycle. It is
given orally, and its side-effects include increased risk of clotting, neutropenia, and
anaemia. Palbociclib and ribociclib are similar.

PARP Inhibitors
Examples: niraparib, olaparib, rucaparib
The enzyme poly-ADP ribose polymerase (PARP) binds to and repairs single-strand
breaks in DNA. Inhibition of this enzyme means that strand breaks are not re-joined;
this destabilises the DNA, makes it more susceptible to damage by DNA mutagenic
agents such as radiation, and increases the risk of further damage including double-
strand breaks. This normally triggers apoptosis and cell death. The first PARP inhibitor
to reach the market, olaparib, was approved in 2015, and these drugs are mainly used
in breast and ovarian cancer.
PARP inhibitors have been found to be up to 1000 times more effective in their
anticancer activity in cancers associated with BRCA mutations than those with normal
BRCA function. The BRCA genes are tumour-suppressor genes (see above) that produce
proteins important for DNA repair. When these genes are mutated and non-functional,
the cell is more reliant than normal on DNA repair carried out by PARP. Therefore,
inhibiting PARP in cancer cells without functional BRCA genes means that DNA break
repair either cannot proceed at all or, if a repair is made, it is prone to error. Either way,
the cell experiences genetic instability, predisposing it to further DNA damage and
eventual cell death (Fig. 12.15). PARP inhibitors are therefore used to treat BRCA-
associated tumours not only of the breast and ovary but also, for example, of the
prostate, uterine tube, and peritoneum.

FIG. 12.15 PARP (poly-ADP ribose polymerase) inhibitors are

 particularly effective in cells with mutated, non-functional BRCA
genes.PARP normally repairs single-strand breaks. In cells with
BRCA mutations, the normal repair function of BRCA protein is lost.
In the presence of a PARP inhibitor, DNA damage cannot be
repaired, and the cell undergoes apoptosis. From Sonnenblick A, de
Azambuja E, Azim Jr HA, et al. (2015) An update on PARP inhibitors
—moving to the adjuvant setting. Nature Reviews Clinical Oncology,
12 (1), pp. 27-41.

PARP inhibitors are well absorbed following oral administration and mainly
metabolised in the liver. Their half-lives are variable (olaparib, 6 hours; rucaparib,
26 hours) and they cause general cytotoxic side-effects. They increase the risk of
developing secondary myelodysplastic syndrome and acute myeloid leukaemia, usually
within 8 months to 2.5 years.

Cell Signalling Pathway Inhibitors

Cell signalling is the umbrella term used to mean all the metabolic pathways in the cell
which allows the cell to detect and respond to signals from hormones, growth factors,
neurotransmitters, cytokines, and other chemicals in its environment. Identifying
pathways that are unique to or over-expressed in cancer cells can lead to the design of
specific inhibitors.

Protein Kinase Inhibitors

Examples: gefitinib, imatinib, lapatinib, sorafenib
Protein kinases are a large family of enzymes that activate proteins by adding a
phosphate group to them. They have a wide range of functions in the cell and regulate
the activity of proteins important in cell growth and proliferation and in immune
responses. They have become important targets in cancer because protein kinases are
dysregulated in malignant disease and contribute to the abnormal behaviours and
properties of cancer cells, and a wide range of protein kinase inhibitors is now available,
most for specialist use only in a very limited range of malignancies. Some of these drugs
block more than one protein kinase, and others are much more selective and block very
specific protein kinases in very specific roles. For example, the CDK inhibitors (see
above) specifically target CDKs involved in the cell cycle. Lapatinib blocks protein
kinases associated with HER1, HER2, and EGFRs, and is used in HER2-positive breast
cancers.
Hedgehog Pathway Inhibitors
Examples: glasdegib, vismodegib, taladegib
The charmingly named Hedgehog (Hh) signalling pathway is essential for embryonic
development and cell differentiation. In mature tissues, the Hh pathway is only
selectively activated, e.g. in healing, repair and epithelial regeneration: in most tissues
the pathway is switched off. When an Hh protein binds to its receptor on the cell
surface, it activates a pathway which drives the cell through the cell cycle and promotes
its division. Hh pathway abnormalities are associated with around one-third of all
malignant tumours. With the Hh pathway erroneously activated, cell proliferation and
other characteristics of tumour cell biology such as angiogenesis and increased growth
factor activity are promoted.
The Hh signalling pathway is complex, linking the Hh cell-surface receptors to the
nucleus and to other intracellular structures. There are therefore several potential drug
targets for anti-Hh drugs and currently many potentially useful substances are under
investigation. Glasdegib and vismodegib bind to cell-surface Hh receptors and block
the Hh pathway, suppressing its ability to divide. They are given orally. Vismodegib is
mainly excreted unchanged and is used mainly in advanced basal cell carcinoma;
glasdegib is mainly metabolised in the liver and is used in acute myeloid leukaemia.

Hormone-Responsive Cancers
Cancers developing in sex-hormone-responsive tissues such as breast and prostate may
be hormone-dependent, and so drugs that block the hormone have anti-tumour activity.
Breast cancers that express oestrogen receptors are designated oestrogen (ER)-positive
and those that express progesterone receptors are designated PR-positive. Tumours may
have both (ER/PR-positive), either, or neither (ER/PR-negative). Most breast cancers
are hormone-sensitive, so determining the receptor status of a tumour is an early
standard part of breast cancer management because it dictates treatment decisions.

Antioestrogens
Oestrogen has a range of proliferative actions on breast tissue, and lifetime exposure to
oestrogen is a recognised risk factor for breast cancer. About 75% of breast cancers are
ER-positive, and drugs that block oestrogen receptors are therefore an important
treatment option.

Tamoxifen
Tamoxifen was first developed in the search for oral contraceptives, and although it has
no contraceptive activity in humans, it was trialled in the 1970s as chemotherapeutic
agent in breast cancer. It competes with oestrogen for the ER and blocks its proliferative
effect. It is taken orally, and its plasma half-life is between 5 and 7 days, but it produces
active metabolites with much longer half-lives. It increases the coagulability of the
blood, predisposing to clots, and should not be used in women with a history of
thromboembolism. It can cause endometrial changes including malignant change.
Patients should be advised to report vaginal bleeding or discharge, menstrual
irregularities, or pelvic pain or pressure for prompt investigation. In pre-menopausal
women, it causes menopausal side-effects such as hot flushes.
Tamoxifen may also be used prophylactically in women who have a strong family
history of breast cancer.

Aromatase Inhibitors
Oestrogens are synthesised from testosterone by the action of the enzyme aromatase
(see Fig. 5.14). Aromatase inhibitors therefore block the conversion of testosterone to
oestrogen and reduce oestrogen levels, which inhibits growth of an oestrogen-dependent
tumour. In addition, some breast cancers express elevated aromatase levels and so are
particularly sensitive to the effect of aromatase inhibition.

Anastrozole
Anastrozole is an aromatase inhibitor, and it may be preferred to tamoxifen in ER-
positive breast cancer because it has fewer side-effects. Common side-effects include
osteoporosis, hair loss, vaginal dryness, and hot flushes. Letrozole is a similar agent;
neither should be used in pre-menopausal women.

AntiAndrogens
Examples: abiraterone acetate, darolutamide, flutamide
Eighty to ninety percent of prostate cancers express androgen receptors (ARs) and are
testosterone-dependent in the earlier stages of their development. Androgen-
deprivation treatment using antiandrogens is therefore an important treatment; these
drugs bind to the AR and block testosterone binding, depriving the tumour cell of this
important growth signal. They are given orally.

Glucocorticoids
Glucocorticoids have profound anti-inflammatory and immunosuppressant effects (see
also Ch. 6) and are sometimes used as adjuvant treatment in cancer. Agents such as
prednisolone and dexamethasone are used for their immunosuppressant effect in
lymphomas, myelomas, and some leukaemias: they suppress the proliferation and
activity of the malignant white blood cells and enhance cell death. In many cancers,
however, glucocorticoids are not used as cytotoxic agents, but as supportive drugs to
take the edge off the side-effects of chemotherapy and make the treatments more
tolerable. For example, they may be given to reduce the severity of hypersensitivity
reactions common with agents such as pemetrexed and cisplatin. Their anti-
inflammatory action can help reduce the swelling and inflammation around a tumour,
especially important when an expanding mass is compressing adjacent normal tissues,
i.e. in the confined space of the skull. In this situation, dexamethasone is preferred
because it has no fluid-retaining activity. Glucocorticoids are anti-emetic and stimulate
appetite, so are useful in countering chemotherapy-induced nausea and vomiting and
encouraging food intake. They can have a positive effect on mood and induce feelings of
well-being and contentment, always a beneficial contribution in what is likely to be a
difficult set of life circumstances for anyone dealing with cancer.

Monoclonal Antibody Therapies

Antibodies are defensive proteins specific to a single target and are generated by B-
lymphocytes (B-cells) in response to an immunological challenge, e.g. infection. Because
of their genetic abnormalities, cancer cells express abnormal proteins (antigens) on their
cell membranes, which may offer a good selective target for tumour-specific antibodies
(Fig. 12.16).
Monoclonal antibodies (mAbs) used in cancer treatments are produced in the
laboratory by a population of B-cells all derived from a single B-cell, which are therefore
selective for a single protein. The explosion of knowledge in cancer cell biology in the
last decade has enabled the development of mAbs directed specifically against tumour-
specific proteins, offering an increasingly important contribution to targeted cancer
treatment. The rapidly expanding list of therapeutic mAbs, all with long and complex
names, may seem confusing at first sight, but mAb nomenclature does actually follow a
set of rules; for example, the generic names end in ‘-mab’, indicating that it is a
monoclonal antibody. The one or two letters preceding ‘mab’ indicate the source of the
antibody: for example, ‘zu’ means the source is mainly human but partly from another
source, usually mouse. The one or two letters preceding that indicate the general target:
for example, ‘tu’ means tumour and indicates the mAb is directed against a malignancy
of some sort. Hence, trastuzumab is a monoclonal antibody derived from mainly
human sources which targets cancer cells. mAbs are usually used in combination with
other treatments and are always given by infusion or injection, because they are
degraded by proteolytic enzymes in the GI tract and are poorly absorbed.

FIG. 12.16 The expression of abnormal antigens on tumour-cell

membranes offer selective targets for monoclonal antibody
treatments. Modified from Craft J, Gordon C, Huether S, et al.
(2023) Understanding pathophysiology ANZ, 4th ed, Fig. 37.31.
Sydney: Elsevier Australia.

Adverse Effects
In general, mAbs are less toxic than older chemotherapeutic agents, but they can induce
severe allergic-type reactions, including skin eruptions, hypotension, fever, chills, and
GI upsets. Some can cause target-specific adverse side-effects; for example, drugs which
interfere with VEGF, an agent important in blood-vessel growth and development, can
cause thromboembolism, bleeding, poor wound healing, and hypertension (see also
bevacizumab below).

Mechanisms of Action of mAbs

Monoclonal antibodies have a range of mechanisms of action in cancer treatment. In
each case, the mAb binds to its target protein but there are a variety of effector
mechanisms accounting for their cytotoxic action.
Stimulation of Defensive/Immunological Mechanisms
Direct binding of the mAb to the cancer cell may stimulate a range of defensive and
immunological mechanisms which lead to its destruction. Coating a target cell with
antibodies activates complement, which causes cell lysis and attracts and activates cells
of the immune system, including macrophages and T-cells, which destroy the target cell.
Additionally, antibody binding may trigger apoptosis pathways, leading to cell suicide
(Fig. 12.17).

Rituximab
Rituximab binds to a protein called CD20 which is found on healthy B-cell membranes,
but which is expressed in higher-than-normal quantities by B-cells in chronic
lymphocytic leukaemia and some forms of non-Hodgkin’s lymphoma, making it a
relatively selective target. Binding of the antibody to the B-cell activates complement
and triggers cell lysis, causing a rapid and sustained reduction in B-cell counts. It is also
sometimes used in severe rheumatoid arthritis and other autoimmune disorders in
which B-cells are thought to contribute to the disease pathology. It has a long half-life,
which extends with repeated dosing and can exceed 30 days. Side-effects are numerous
and can be severe. Severe infusion reactions, which can be fatal, have been reported:
widespread cytokine release causes hypotension, cardiac arrhythmias, pulmonary
infiltration, and acute respiratory distress syndrome and shock. Another serious and
potentially fatal reaction is acute renal failure due to the sudden release of B-cell
breakdown products into the bloodstream. Other agents with similar mechanisms of
action to rituximab include ofatumumab and alemtuzumab.

Blocking Cell-Surface Receptors for Growth Factors

Cancer cells are dependent on a range of growth factors to stimulate growth and
survival. Monoclonal antibodies which target the cell’s receptors for these growth factors
block the cell’s ability to respond. Examples include ramucirumab, which targets
VEGF receptors, preventing the tumour from developing its own network of blood
vessels.
 FIG. 12.17 Cytotoxic monoclonal antibodies may trigger cancer cell
death by activating immune or defence mechanisms.Antibody
binding: 1. Activates complement. 2. Attract and activates defence
cells e.g. macrophages. 3. Triggers apoptosis and cell death.

Trastuzumab
Trastuzumab blocks EGFRs on some types of cancer cells and so silences this growth-
stimulating signal. Its mechanism of action is described in more detail above. It is used
mainly in HER2-positive breast cancer but also in other cancers that over-express the
HER2 receptor, including some gastric cancers. Only about 15%–25% of breast cancers
are HER2-positive and therefore respond to trastuzumab, but these tumours tend to be
faster growing and more aggressive than HER2-negative disease, and this drug has
significantly improved prognosis and survival in HER2-positive cases. Its most
significant side-effect is cardiotoxicity, and it can cause arrhythmias, heart failure, and
coronary artery disease, which are usually reversible when treatment stops. The reason
behind this is not completely clear, but it is known that healthy cardiac myocytes
express HER2, and that blocking this receptor may inhibit the myocardial cells’ capacity
to detoxify harmful products of cellular metabolism, including reactive oxygen species,
which then accumulate and damage the cell. Cardiac function should be monitored
during and after treatment. Other HER2 receptor inhibitors include pertuzumab.
Because trastuzumab and pertuzumab block different sites on the HER2 receptor, they
have a synergistic action and can usefully be combined.

Binding to Chemical Factors Essential for Cancer Cell Growth and Survival
Monoclonal antibodies may be targeted against growth factors or other cytokines on
which the cancer cell is dependent. When the mAb binds to the growth factor, it can no
longer bind to its receptor.

Bevacizumab
As a solid tumour expands, it needs its own network of blood vessels to ensure an
adequate supply of oxygen and nutrients, and most tumours produce increased levels of
vascular endothelial growth factor (VEGF) to promote blood vessel growth and survival.
Bevacizumab is a mAb directed against VEGF; it binds to and neutralises the VEGF
molecule, depriving the tumour of this key mediator and inhibiting tumour
angiogenesis. It is used in several cancers including breast, colon, and reproductive tract
tumours and is currently also being trialled in the treatment of severe post–COVID-19
respiratory complications including acute lung injury, in which VEGF seems to
contribute to the disease process. It has an average half-life of 20 days, although this can
be more than doubled in some patients. It is associated with a wide range of side-effects,
including the consequences of blocking VEGF in normal tissues (see above).

Targeted Delivery of Other Cytotoxic Treatments

Monoclonal antibodies can be bound to a cytotoxic drug to form an antibody–drug
conjugate. Because the conjugates bind directly to cancer cells via the mAb component,
the cytotoxic effect of the conjugated drug is increased and its toxicity to healthy tissues
is reduced. Once the mAb binds to its target receptor on the cancer cell, the conjugate is
internalised, and the conjugate is degraded by intracellular enzymes to release the
cytotoxic drug inside the cell (Fig. 12.18). For example, trastuzumab deruxtecan is
a conjugate of trastuzumab and deruxtecan used in advanced HER2-positive breast
cancer. Deruxtecan inhibits topoisomerase and so inhibits the cancer cell’s ability to
repair its DNA during cell division. Trastuzumab emtansine is a conjugate of
trastuzumab with emtansine which is used in advanced breast cancer. Emtansine
interferes with assembly of the microtubule spindle that directs chromosome separation
during mitosis. This arrests the cell cycle, and the tumour cell is killed by apoptosis.
Gemtuzumab ozogamicin is a conjugate of gemtuzumab and ozogamicin.
Gemtuzumab is directed against a cell-surface protein called CD33, which is found in
elevated quantities on the surface of leukaemic myeloblasts in most patients with acute
myeloid leukaemia. CD33 stimulates cell division, so blockade of these receptors inhibits
leukaemic cell proliferation. Once internalised, ozogamicin, which is a cytotoxic
antibiotic, binds to and damages the leukaemic cell’s DNA, activating apoptosis and
inducing cell death.

FIG. 12.18 The action of antibody–drug conjugates.The antibody

gives the conjugate specificity for the target cell. After it binds, the
conjugate is internalised, where the drug is released and exerts its
cytotoxic action. Modified from Senter PD and Sievers EL (2012) The
discovery and development of brentuximab vedotin for use in
 relapsed Hodgkin’s lymphoma and systemic anaplastic large cell
lymphoma. Nature Biotechnology, 30 (7), 631–637.

Immunotherapy
The most familiar role of the immune system is in the prevention and control of
infection, but part of its role is the constant surveillance of tissues to identify and
destroy mutated or abnormal cells. Cancer cells develop ways to conceal and protect
themselves from the unwanted attentions of T-cells and other body defences, including
producing tumour-derived immunosuppressant factors which dampen down normal
immune activity. Immunotherapy is an umbrella term meaning any treatment which in
some way enhances the immune system’s capacity to destroy tumour cells, and these are
among the newest available cancer therapies. The mAbs which coat cancer cells and
stimulate complement (e.g. rituximab, see above) are one example of immunotherapy.
Other examples of immunotherapy include:

Immune Checkpoint Inhibitors

Immune checkpoint proteins are found on the surface of immune cells, and when
activated they inhibit immune responses and promote immune tolerance. In health, this
is an important regulator of immune cell function, putting the brakes on potentially
damaging or inappropriate immune responses. One strategy used by malignant cells to
evade immune killing is to up-regulate the immune checkpoint proteins on T-cells in the
tumour environment. This suppresses T-cell function and reduces their ability to attack
and destroy the cancer cells.
Work on three different immune checkpoint proteins has yielded useful anticancer
drugs in recent years: the PD (programmed cell death)-1 protein, the cytotoxic T-
lymphocyte-associated protein-4 (CTLA-4) and the lymphocyte activation gene-3 (LAG-
3). Monoclonal antibodies that target these checkpoint proteins block them, releasing
the brake on T-cells and increasing their capacity to attack and destroy tumour cells.
Nivolumab and pembrolizumab are examples of PD-1 checkpoint inhibitors and are
used in a range of advanced cancers including metastatic melanoma. Opdualag was
licensed in the US in 2022 for the treatment of advanced malignant melanoma. It is a
combination of two mAbs: nivolumab, which as described above blocks PD-1, and
relatlimab, which blocks LAG-3. Ipilimumab is a CTLA-4 inhibitor licensed in 2011
for the treatment of melanoma.
Immune System Modulators
These drugs enhance the body’s immune response to cancer. Interleukins (ILs) and
interferons are cytokines produced naturally by white blood cells that stimulate
lymphocyte numbers and activity. Used therapeutically, their immunostimulant action
increases immune responses to tumour cells. For example, aldesleukin is synthetic IL-
2 used in some renal cancers. Thalidomide has a dark history because following its
introduction in the 1960s to prevent pregnancy-related sickness, it proved to be a potent
teratogen responsible for tens of thousands of babies born with significant birth defects.
However, along with the related agents pomalidomide and lenalidomide, it is now
used in multiple myeloma. These drugs stimulate the release of pro-inflammatory
cytokines including IL-6 and tumour necrosis factor alpha, promoting inflammatory and
immune function and enhancing malignant cell detection and destruction. There is also
evidence that they inhibit the action of growth factors including VEGF, impairing the
ability of the tumour to develop its own blood supply. This latter action probably
accounts for their teratogenicity.

FIG. 12.19 The mechanism of action of talimogene laherparepvec

(T-VEC).HSV, Herpes simplex virus

Treatment vaccines
Although research in this area is still at a very early stage, it offers the exciting prospect
of personally tailored cancer treatment. Unlike vaccination to prevent infection, cancer
vaccines are not intended as prophylactic therapies. The principle here is that
identification of tumour-specific proteins expressed on the surface of an individual’s
cancer cells can be used to make a vaccine specific to those cancer cells. Administration
of the vaccine to that individual then stimulates an immune response specific to the
cancer cells with resultant destruction of the tumour.
Virus Vaccines
Viruses are intracellular parasites. They enter a cell and hijack the cell’s organelles to
produce new viral proteins and nucleic acids, which are then assembled into new viral
particles (see Fig. 11.17). Depending on the virus, these new viral particles may
accumulate in the host cell until the host cell literally bursts (lysis), releasing the viral
particles into the local vicinity to infect neighbouring cells. One novel approach to
cancer therapy is to use viruses to infect and destroy cancer cells.

Talimogene Laherparepvec
This therapy is a genetically modified preparation of herpes simplex virus type 1. It is
used in malignant melanoma and injected directly into the tumour. The virus is
genetically engineered to selectively enter and replicate within tumour cells, causing the
cell to lyse and release large quantities of melanoma-tumour antigens into the local
environment. This activates defence and immune cells, which multiply and produce a
local and systemic immune response directed against the tumour. The released viral
particles infect neighbouring cancer cells, and the process is repeated (Fig. 12.19). Care
is needed in immunosuppressed patients, for example those on steroid treatment,
because although the pathogenicity of the genetically engineered virus has been
substantially reduced, it may still cause systemic herpes infections in people whose
immune function is impaired.

Miscellaneous Chemotherapy Drugs

Some drugs do not fall tidily into the categories used above.

Proteasome Inhibitors
Examples: bortezomib, carfilzomib, ixazomib
The proteasome is a complex of proteolytic enzymes responsible for destroying
unwanted, abnormal, or misfolded proteins inside the cell. Proteasomes are found in
cells throughout the body, ensure that potentially harmful proteins do not accumulate,
and allow the cell to maintain levels of key regulatory proteins within normal ranges.
Proteasome inhibitors bind to one or more of the enzymatic sites within the proteasome
and block them. This leads to the accumulation of a range of unwanted and abnormal
proteins in the cell, interfering with the cell’s ability to regulate its internal pathways
and triggering apoptosis. These drugs are used in multiple myeloma and can cause a
wide range of side-effects, including cardiovascular events and reactivation of latent
viral infections including herpes zoster and hepatitis B.

Asparaginase
The enzyme asparaginase breaks down the amino acid asparagine. Therapeutically, it is
available in different formulations derived from different sources: for example,
crisantaspase is the asparaginase produced by Erwinia chrysanthemi and there are
formulations prepared from Escherichia coli asparaginase. Pegaspargase is a
PEGylated formulation. Asparagine is needed for DNA and protein synthesis, and
asparagine depletion inhibits the proliferation of tumour cells. Asparaginase is used in
acute lymphoblastic leukaemia.

Retinoic Acid and its Derivatives

Retinoic acid is a metabolite of vitamin A; it enters cells and acts on receptors in the
nucleus to regulate genes that suppress cell proliferation, promote cell differentiation,
and induce apoptosis. Retinoic acid and its derivatives therefore have an anti-tumour
action, although they are highly toxic to healthy cells and in therapeutic use have
significant side-effects including teratogenicity and neuropsychiatric reactions.
Bexarotene is a synthetic retinoid used in T-cell lymphoma, and tretinoin is used in
acute promyelocytic leukaemia. Because of their anti-proliferative activity, tretinoin and
isotretinoin are also used in severe acne.

References
1. Drew Y. The development of PARP inhibitors in ovarian cancer: from bench to
bedside. Br. J. Cancer. 2015;113(Suppl. 1):S3–S9.
2. Pufall M.A. Glucocorticoids and cancer. Adv. Exp. Med. Biol. 2015;872:315–333.
3. Tadesse S, Caldon E.C, Tilley W, et al. Cyclin-dependent kinase 2 inhibitors in
cancer therapy: an update. J. Med. Chem. 2019;62(9):4233–4251.
4. Wang, J., Fang, Y., Fan, R.A., et al., 2021. Proteasome inhibitors and their
pharmacokinetics, pharmacodynamics and metabolism. Int. J. Mol. Sci. 22 (21),
11595

Online resources
Chial H. Proto-oncogenes to oncogenes to cancer. Nat.
Educ. 2008;1(1):33 Available
 at:. https://www.nature.com/scitable/topicpage/proto-oncogenes-to-
oncogenes-to-cancer-
883/#:∼:text=Often%2C%20proto%2Doncogenes%20encode%20proteins,maintena
Emory Winship Cancer Institute, . Cancer biology Available
at:. https://www.cancerquest.org/cancer-biology, 2024.
Sun Y, Liu Y, Ma X, et al. The influence of cell cycle regulation on
chemotherapy. Int. J. Mol. Sci. 2021;22(13):6923 Available
at:. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267727/.
Zahavi D, Weiner L. Monoclonal antibodies in cancer
therapy. Antibodies. 2020;9(3):34 Available
at:. https://www.mdpi.com/2073-4468/9/3/34/htm.
Index

Page numbers followed by “f” indicate figures, “b” indicate boxes, and “t” indicate tables.

abacavir, 4, 219b–220b
abemaciclib, 239
abiraterone acetate, 241
absence seizures, 72

absorption, of drugs, 10–11

acarbose, 92–93
acetaminophen, 5
acetazolamide, 178
acetylcholine (ACh), 46
binding to channel, 34
excitatory and inhibitory receptor response of, 29

in gastric acid secretion, 185

in gastrointestinal tract, 183
removal of, from synapse, 49–50, 50f
acetylcysteine, 157–159
aclidinium, for asthma, 166
acquired immunodeficiency syndrome (AIDS), 219b–220b
action potentials, generation and conduction of, 44
active transport, transfer across cell membranes, 7f, 8
acyclovir, 15b, 218
addiction, opioids and, 106
adenosine, 139
adenosine-receptor antagonists, 152–153, 153f
adenylyl cyclase pathway, G proteins and, 33
ADH, See antidiuretic hormone

adipose tissue, drug distribution in, 11

adjuvant drugs, 145b–146b
administration, of drugs, 21–24
to body cavities, 24
inhalation, 23
intramuscular, 22–23, 22f
intrathecal and epidural administration, 23–24, 23f
intravenous, 22
oral, 22, 22f
subcutaneous/intradermal, 22f, 23
topical, 22
adrenaline, 59, 130–131
absorption of, 24
action of, 28
for asthma, 164
G proteins and, 33
receptor selectivity in, 30–31
adrenergic pharmacology, 47b–48b
adrenergic receptors, 47f–48f, 47b–48b
adrenocorticotrophic hormone, 81

adverse drug reactions (ADR), 37–40

 augmented, 39
biochemically mediated, 38
bizarre, 39
chronic, 39
classification of, 39–40
common, 38–39

cutaneous, 38f, 39
delayed, 40
end-of-dose, 40
hepatic, 38
immunologically mediated, 37–38, 37f–38f
mechanisms of, 37–38
nervous system, 39
pharmacologically mediated, 38
red bone marrow toxicity, 39
renal, 38–39
reproductive function, 39
affinity, 35
afterload, 128, 128f
agomelatine, 59
agonist, 28b
albendazole, 224
alcohol, 90
for asthma, 165–166
causing erectile dysfunction, 179
for cough, 162

insomnia and, 60
 origins of, 1–2
respiratory depression and, 57–58
warfarin and, 150–151
withdrawal, 41
aldesleukin, 243–244
aldosterone, 173

reabsorption and secretion of, 172–173

aliskiren, 145, 145b–146b
allergy
to antibiotics, 204
to histamine, 124
allodynia, 101b
allopurinol, cutaneous adverse drug reactions to, 39
α-adrenergic antagonists (α-blockers), 131, 145b–146b
erectile dysfunction and, 180
α1-blockers, 142
α2 receptors, 47–48, 48f
alprostadil, 180
alteplase, 154
alverine citrate, 190
amantadine, 218
amikacin, 203–204
amiloride, 173, 177–178
aminoglycosides, 206
aminophylline, for asthma, 165
aminosalicylic acid, 214b–215b

amiodarone, 136
 causing delayed reactions, 38
class III agents, 139
renal excretion of, 18–19
warfarin and, 150–151
amitriptyline, 2–3, 56–57, 103, 131
amlodipine, 132, 148

amoxicillin, 208, 209b

for peptic ulcer, 188b–189b
amphotericin, 222
ampicillin, 209b
synergism with, 203–204
anabolic steroids, reproductive function and, 39
anaesthetics
drugs used as adjuncts in, 66, 67t
epidural administration of, 24
general, 66–71
induction and maintenance of, 67
inhalational, 67–69
minimum alveolar concentration of, 67–68, 67b
modified ethers, 68–69
nitrous oxide, 69
pharmacokinetics of, 68, 68f
intrathecal administration of, 24
intravenous, 69–71
etomidate, 69
ketamine, 69–71

pharmacokinetics of, 69
 propofol, 69
thiopental, 69
local, 69b–71b
mechanism of action of, 66–67
stages of, 66–67, 67t
analgesics, 101–125 , 101b

epidural administration of, 24

intrathecal administration of, 24
metabolism of, 17
opioids in, 104–105
anastrozole, 241
androgenic adverse effects, of combined oral contraceptive, 98
angiogenesis, 231
angiotensin II, 140, 140t
angiotensin-converting enzyme (ACE), 141
angiotensin-converting enzyme (ACE) inhibitors, 120, 134b–135b, 143–144,
143f, 145f, 145b–146b, 178
adverse effects of, 144

pharmacokinetics of, 144

renal adverse drug reactions to, 38–39
reproductive function and, 39
angiotensin-receptor antagonists, 144, 145b–146b
anidulafungin, 222
antacids, 120, 186, 186f, 212
antagonist, 28b
anterior pituitary hormones, 81–82

anthracyclines, 238
antiandrogens, 100, 241
anti-arrhythmic drugs, 4, 136–139
class I agents, 138
class II agents, 138
class III agents, 138–139
class IV agents, 139

antibacterial drugs, 200–216

See also antibiotics
combination therapy, 203–204, 204f
antibacterial resistance, 201–203, 202f
mechanisms of, 203
spontaneous mutation in, 200f, 203
transfer of protective genes from one bacterium to another, 201–203, 203f

antibiotics
acting on bacterial cell membrane, 210
acting on bacterial DNA, 210–213, 210b
metronidazole, 211–212
nitrofurantoin, 212
polymyxins, 210
quinolones, 212–213
cutaneous adverse drug reactions to, 39
excretion of, 17
gastrointestinal tract and, 181
general adverse effects of, 204
inhibit protein synthesis, 204–207
aminoglycosides, 206

chloramphenicol, 206
 fusidic acid, 206
macrolides, 206–207
oxazolidinones, 207
tetracyclines, 207
interfere with cell wall integrity, 207–210, 207b
β-lactam antibiotics, 208–210

bacitracin, 210
cell wall structure, 207–208
teicoplanin, 210
vancomycin, 210
interfering with folic acid metabolism, 213–216, 213b
sulphonamides, 213–214
trimethoprim, 214–216
intrathecal administration of, 24
synergism, 203–204
anticancer drugs, 21
See also cytotoxic drugs
anticoagulants, 5, 150–152

adverse reactions of, 39

direct thrombin inhibitors, 152
factor Xa inhibitors, 152
heparin, 151–152, 151f
reproductive function and, 39
vitamin K antagonists, 150–151, 150f
anticonvulsants, 5
for chronic obstructive pulmonary disease, 168–170

cutaneous adverse drug reactions to, 39

 erectile dysfunction and, 179–180
formulations of, 21
half-life of, 19
metabolism of, 17
that block calcium channels, 75
that block sodium channels, 73–74

that enhance gamma-aminobutyric acid, 74

that reduce glutamate activity, 75–76
antidepressants, 4, 51b
absorption of, 24
dependence to, 40
half-life of, 19
mood-regulating drugs and, 56–59
other drugs, 59
that block monoamine re-uptake, 57–58
antidiuretic hormone (ADH), 82, 173
antifungal drugs, 90, 220–223
interfere with cell division, 223
interfere with cell membrane integrity, 222–223
interfere with cell wall integrity, 222
antihelminthic drugs, 224
antihistamines, 51b, 56, 122–124, 196
absorption of, 24
causing delayed reactions, 38
sedating, for cough, 162
antihypertensive drugs, pharmacologically mediated adverse drug reactions to, 38

anti-inflammatory drugs, 101–125

 administration of, 24
for asthma, 166–168
glucocorticoids as, 111–116
administration, routes of, 114–115
adverse effects of, 115–116
drugs, 116, 116f, 117t

mechanism of action of, 112–114, 115f

stress response and, 111–114
in therapeutics, 114–115, 115b
inflammation and, 111–124, 112f–113f, 113t
inhalation of, 23
non-steroidal, 116–122
topical administration of, 22
antimalarial drugs, 223–224
antimicrobial drugs, 197–225
antibacterial drugs, 200–216
antibiotics, See antibiotics
antihelminthic, 224
antiparasitical, 223–224
antiviral, 216–220
resistance, 199
selective toxicity and, 200
topical administration of, 22
warfarin and, 150–151
antimicrobial stewardship, 199–200
antimuscarinic bronchodilators

for asthma, 166

 for chronic obstructive pulmonary disease, 168
antimuscarinic drugs, 55, 190, 196
gastric emptying and, 11
side-effects, 51f, 51b
antioestrogens, 241
antiparasitical drugs, 223–224

for arthropod (insect) infestations, 224

for helminthic infestation, 224, 224f
for protozoal infections, 223–224
antiplatelet drugs, 152–153
antipsychotics, 4, 51b, 64–66
actions of, 64–65
adverse effects of, 65
anti-emetic activity of, 65
blockade of other non-dopamine receptors, 65
endocrine effects of, 64
extrapyramidal adverse effects of, 64, 65f
first-generation, 65
formulations of, 21
second-generation, 65–66
antiretroviral drugs, 219b–220b
antithrombotic drugs, for ischaemic heart disease, 148
anti-tuberculosis drugs, 214f, 214b–215b
antitussives, for cough, 162–163
antiviral drugs, 216–220
nucleic acid synthesis, inhibitors of, 217–218, 217f

foscarnet, 218
 nucleoside analogues, 217–218
protein synthesis, inhibitors of, 218–220, 218f
renal excretion of, 18–19
resistance to, 216–217
uncoating and release, inhibitors of, 218
anxiety disorders, 59–60

apixaban, 150
apomorphine, 54
apoptosis, 229–230, 232f
aprepitant, 183, 195
arachis oil, 191
aripiprazole, 66
aromatase inhibitors, 241
arthropod (insect) infestations, 224
asparaginase, 244
aspirin, 90, 116–117, 119, 121, 152
distribution of, 24
immediate hypersensitivity reactions to, 37
irreversible binding of, 31
metabolism of, 15–16
plasma protein binding and, 14, 14f
transfer across cell membranes, 8
unwanted/dangerous interactions of, 24–25
aspirin-induced bronchoconstriction, 38
asthma, treatment of, 163–168, 164f, 169f, 169b
atazanavir, 219b–220b

atenolol, 131, 148

 adverse effects of, 132
receptor selectivity in, 30–31
atherosclerosis
ischaemic heart disease, 147–148, 147f
risk factors for, 147
atorvastatin, 148

atropine, 185
augmented reactions, of drugs, 39
autonomic nerve supply, 130f
avanafil, for erectile dysfunction, 179
avibactam, 208
axon, 42, 43f
azacitidine, 236
azithromycin, 192, 206–207
azoles, 222–223
adverse effects of, 222–223
erectile dysfunction and, 179–180
pharmacokinetics of, 222–223

β-adrenergic receptor antagonists (β-blockers), 131–132, 145b–146b

adverse effects, 178
adverse reactions of, 39
for anxiety, 59–60
blood glucose control and, 131–132, 131f
bronchoconstriction and, 132

causing erectile dysfunction, 179

 drug treatment, 134b–135b
for ischaemic heart disease, 148
overdose, 85
renin-angiotensin-aldosterone system and, 132
β2-agonists
for asthma, 163–165, 165f

for chronic obstructive pulmonary disease, 168

β-lactam antibiotics, 208–210
immunologically mediated adverse drug reactions to, 37
mechanism of action of, 208f
resistance to, 208–210
bacitracin, 210
bacteria
biology of, 200–204, 201f
cell wall and cell membrane of, 200–201, 202f
DNA and protein synthesis, 201
drug-resistant, prevention of, 203, 204f
metabolism of, 201
protein synthesis, stages of, 205–206, 205f
bactericidal, defined, 200b
bacteriostatic, defined, 200b
barbiturates, 62
basal bolus regimes, 88
beclometasone, for asthma, 166
bedaquiline, 214b–215b
bendrofluazide, 2–3, 134b–135b

reabsorption and secretion of, 172–173

benralizumab, for asthma, 168, 168f
benserazide, 54

benzimidazoles, 224
benzocaine, 69b–71b
benzodiazepines, 46, 74

adverse effects of, 62

adverse reactions of, 40
for anxiety, 59–60
causing erectile dysfunction, 179
dependence to, 40
distribution of, 12
for focal seizures, 72
mechanism of action of, 61f, 61b–62b
pharmacodynamics of, 61, 61b
pharmacokinetics of, 61–62, 62t
pharmacology of, 61b–62b
as premedication, 66
for sleep, 60
topical administration of, 22
toxicity of, 62
withdrawal, 41
benzyl penicillin, 209b
betamethasone, 116, 117t
bevacizumab, 243
bexarotene, 245
binding, defined, 31

biologics, 3–4
bipolar disorder, 62–63
bisacodyl, 191
bismuth, for peptic ulcer, 188b–189b
bisoprolol, 148
bivalirudin, 152

bizarre reactions, of drugs, 39

Black, James, 187
bleomycin, 239, 239f
causing delayed reactions, 38
bleomycin-induced lung damage, histology of, 156, 157f
blood clotting, 119, 119f
blood pressure, increased, combined oral contraceptive and, 97–98
blood vessels
anatomy of, 139–141, 140f
diameter, 139–141, 140f
drugs and, 139–147
vasodilators, 141–143, 141b
blood-brain barrier, 12, 13f
blood-clotting cascade, 149–150
body cavities, drug administration into, 24
body fat
high, drug distribution in, 12–13
low, drug distribution in, 13
partitioning, 12–13
bone health, hormone replacement therapy and, 99b
bortezomib, 244

bosentan, 140, 145–147

 bradykinin, 97–98, 111, 113t
broad-spectrum antibiotics, 201b
bromocriptine, 54
bronchodilators
antimuscarinic

for asthma, 166

for chronic obstructive pulmonary disease, 168
for asthma, 164–166
for chronic obstructive pulmonary disease, 168–170
inhalation of, 23
budesonide, for asthma, 166
bulk-forming laxatives, 191
bumetanide, 175
buprenorphine, 103
buserelin, 82
buspirone, 60
busulfan, 238

cabazitaxel, 235
caffeine
for asthma, 165
insomnia and, 60
calcitonin, 83
calcium (Ca2+), 44
calcium-channel blockers, 128–129, 132–133, 142, 145, 145b–146b

adverse effects of, 133

 erectile dysfunction and, 179–180
induction and inhibition of, 16
pharmacokinetics of, 132–133
canagliflozin, 92
cancer

biology of, 230–234

cells, properties of, 230–232, 232f
genetics of, 232–234
hormone replacement therapy and, 99b
hormone-responsive, 240–241
oldest known case of, 227f
cannabis, 1–2
canrenone, 177–178, 177f
capecitabine, 236
captopril, 143, 145
therapeutic index, 36–37
carbamazepine, 74, 97
for asthma, 165–166
erectile dysfunction and, 179–180
for focal seizures, 72
induction and inhibition of, 16
carbapenems, 208, 210
carbenicillin, 209b
carbidopa, 54
carbimazole, 84–85
carbocisteine, 157–159

carbonic anhydrase, 178, 178f

carbonic anhydrase inhibitor, 178, 178f
cardiac action potential, 135–136
ion movements and, 135–136, 136f
cardiac arrhythmia, 135–139
aetiology of, 136

anti-arrhythmic drugs, 136–139

genesis of, 137f
cardiac conducting system, 128–129
cardiac output, 128, 128f
cardioselective β-blockers, 132
cardiovascular disease, hormone replacement therapy and, 99b
cardiovascular function, 126–154
autonomic control of, 129–130
cardiac arrhythmia, 135–139
drugs and blood vessels, 139–147
haemostasis, 149–154, 149b
ischaemic heart disease, 147–148
myocardium, 127–129
parasympathetic activity and, 130
sympathetic activity and, 130
carfilzomib, 244
carmustine, 238
carvedilol, 131, 148
caspofungin, 222
catechol-O-methyl transferase inhibitors, 55, 55f
cefotaxime, 210

cefuroxime, 210
celecoxib, 122
cell cycle, 228–229, 231f
stages of, 235–240
cell division, 227–230
cell membrane, 6–8, 7f

drug transfer across, 7–10, 7f, 9f

degree of ionisation and, 8
fat solubility and, 7–8
molecular weight and, 7
cell signalling pathway inhibitors, 240
cell-surface receptors, 32–33
central modulation, of pain signals, 102–103
cephalexin, 210
cephalosporins, 208, 210
adverse effects of, 210
for allergy, 204
cytotoxic reactions to, 37–38
pharmacokinetics of, 210
in red bone marrow toxicity, 39
cetirizine, receptor selectivity in, 30
cheese reaction, 59b
chemical name, 5
chemotherapy, See cytotoxic drugs
children, pharmacokinetics in, 25
chlorambucil, for cancer, 237
chloramphenicol, 206

adverse effects of, 206

 pharmacokinetics of, 206
in red bone marrow toxicity, 39
chloride (Cl-), 44
chlormethiazole, 62
chloroquine, 223–224

chlorphenamine, 52, 123, 187

chlorpromazine, 2–3, 65
cytotoxic reactions to, 37–38
hepatic adverse drug reactions to, 38
cholinergic pharmacology, 49b–50b
cholinergic receptors, 49f–50f, 49b
chronic obstructive pulmonary disease, drugs for, 168–170
chronic reactions, of drugs, 39
ciclesonide, for asthma, 166
cilastatin, 210
ciliated epithelium, drugs and, 156–163, 160f
cimetidine, 124, 185, 187
receptor selectivity in, 30
ciprofloxacin, 212
cisplatin, 238, 241
citalopram, 58
cladribine, 236
clarithromycin, 192, 206–207
for peptic ulcer, 188b–189b
clavulanic acid, 208
clomifene, 99, 100f

clomipramine, 57
clonazepam, 61–62, 61b–62b
clonidine, 47–48
clopidogrel, 148–149, 152–153
clotting, 149–150, 149f
clozapine, 65–66

cocaine, 69b–71b
codeine, 106, 107f, 108, 109f, 189
beneficial interactions of, 24
for cough, 162–163
pharmacokinetics of, 108
colistimethate sodium, 210
collecting duct, reabsorption in, 173
combined oral contraceptive (COC), 96–98
adverse effects of, 97–98, 97f
pharmacokinetics of, 97
competitive antagonism, 29t, 31, 31f
constipation, 191
contact inhibition, loss of, 231
contraceptives
formulations of, 21
topical administration of, 22
contrast media, intrathecal administration of, 24
corticosteroids, adverse reactions of, 39–40
corticotropin-releasing hormone (CRH), 79
cortisol
physiological effects of, 112, 114t

secretion, control of, 111, 114f

cough
drugs and, 162–163
suppression, opioids and, 106
COX-1, 117–118, 118f, 119t
COX-2, 117–118, 118f, 119t

coxibs, 122
CRH, See corticotropin-releasing hormone
cromones, for asthma, 166–167
curcumin, 230
Cushing’s syndrome, 115, 116f
cutaneous adverse drug reactions, 38f, 39
cyclic adenosine monophosphate pathway, G proteins and, 33, 34f
cyclin-dependent kinases (CDKs), 229, 239
cyclizine, 52, 105, 124, 196
cyclophosphamide
for cancer, 238
metabolism of, 15, 15b

cystic fibrosis, tailored genetic therapy for, 161f, 161b–162b

cytarabine, 236
cytochrome P450 enzyme family, in drug metabolism, 15, 16f
cytotoxic antibiotics, 239
cytotoxic drugs, 226–245
apoptosis and, 229–230, 232f
approaches and issues in, 234–235
common adverse effects of’, 234–235, 234f

drug resistance, 235

 biochemically mediated adverse drug reactions to, 38
biology of cancer and, 230–234
genetics of cancer, 232–234
properties of cancer cells, 230–232, 232f
cell cycle and, 228–229, 231f
stages of, 235–240

cell signalling pathway inhibitors and, 240

DNA and, 227–230, 227b
agents that directly damage, 238–239
alkylating agents, 237–238, 238f
drugs that act on, 236–239
mRNA and protein synthesis, 228, 230f
replication of, 228, 229f
structure of, 227–228, 228f
hormone-responsive cancers and, 240–241
immunotherapy and, 243–244
intrathecal administration of, 24
intravenous administration of, 22
miscellaneous, 244–245
monoclonal antibody therapies and, 241–243, 241f–243f
in red bone marrow toxicity, 39
reproductive function and, 39

dabigatran, 149–150, 152

dabigatran etexilate, 152

danaparoid, 151–152
dantron, 191
dapagliflozin, 92
darolutamide, 241
darunavir, 218, 219b–220b
daunorubicin, 238
decitabine, 236

deflazacort, 117t
degradative enzymes, 44
delayed reactions, of drugs, 40
dendrites, 43f
deoxyribonucleic acid (DNA), 227–230, 227b
agents that directly damage, 238–239
alkylating agents, 237–238, 238f
drugs that act on, 236–239
mRNA and protein synthesis, 228, 230f
replication of, 228, 229f
structure of, 227–228, 228f
dependence, opioids and, 106
depression
biology of, 56–57, 57t
signs and symptoms of, 56
treatment of, 56, 57f
descending inhibition, 102–103, 103f
desflurane, pharmacological actions of, 67t
desmopressin, 82
desogestrel, 97

dexamethasone, 116, 117t, 196

 for cancer, 241
diabetes mellitus (DM), 85–93
energy metabolism in, 87
insulin for, 88–89
signs and symptoms of, 87–88
type 1, 88

type 2, 88
diamorphine (heroin), 106–108, 108f
for cough, 162–163
diazepam, 61b–62b
excitatory and inhibitory receptor response of, 29
for status epilepticus, 72
diclofenac, 121–122
in red bone marrow toxicity, 39
dicoumarin, 150
digitalis, 2
Digitalis purpurea (foxglove), 2, 2f
digitoxin, 133, 133f
digoxin, 133, 134b–135b, 136
excretion of, 17–19
formulations of, 21
in membrane transport, 35
metabolism of, 14
monitoring of, 21
for peptic ulcer, 188b–189b
reabsorption of, 18

renal adverse drug reactions to, 38–39

 unwanted/dangerous interactions of, 24–25
dihydropyridines, 132
diltiazem, 132, 148
dipeptidyl peptidase inhibitors (gliptins), 91
diphenhydramine, 124
for sleep, 62

diphenoxylate/atropine, 189
dipyridamole, 153
direct thrombin inhibitors, 152
disopyramide, 138
distal convoluted tubule (DCT), reabsorption and secretion in, 172–173, 177f
distribution, of drugs, 11–14
in body fat partitioning, 12–13
plasma protein binding, 13–14, 13f–14f
sanctuary compartments of, 12
in tissues and fluids, 11–12, 11f
volume of, 11–12, 11b, 12f
diuretics, 133, 134b–135b, 144, 173–178, 175f
loop, 175–176, 176f
osmotic, 174–175, 175f
pharmacologically mediated adverse drug reactions to, 38
potassium-sparing, 177–178
proximal convoluted tubule and, 172
thiazide, 176–177, 177f
transfer across cell membranes, 8
DM, See diabetes mellitus

DNA replication, 211–213, 211f

dobutamine, 131
docetaxel, 235
docusate sodium, 191
Domagk, Gerhard, 213
domperidone, 46, 54, 65, 195
dopamine, 40, 46–52, 79, 106, 183

metabolism of, 15–16

Parkinson’s disease and, 53f, 53b–55b
receptor agonists, 54
receptors, 46–51
synthesis and breakdown, 52, 52f
dopamine antagonists, 192, 194–195, 195f
dornase alfa, 159, 160f
dose-response relationships, 36–37, 36f
doxazocin, 131
doxepin, 131
for sleep, 62
doxorubicin, 238
doxycycline, 207
DPP-4 inhibitors, mechanism of action of, 91f
dronedarone, 139
drug(s)
absorption of, 24
administration of, 21–24
to body cavities, 24
inhalation, 23

intramuscular, 22–23, 22f

 intrathecal and epidural administration, 23–24, 23f
intravenous, 22
oral, 22, 22f
subcutaneous/intradermal, 22f, 23
topical, 22
affect cardiac contractility

calcium channel antagonists, 132–133

digoxin, 133
phosphodiesterase inhibitors, 133–135
sympathetic agonists, 130–131, 131f
sympathetic antagonists, 131–132
and blood vessels, 139–147
development process, 4–5, 5f
disposition of, 10–19, 10f
distribution of, 11–14, 24
in body fat partitioning, 12–13
plasma protein binding, 13–14, 13f–14f
sanctuary compartments of, 12
in tissues and fluids, 11–12, 11f
volume of, 11–12, 11b, 12f
endocrine function and, 77–100 , 77b
hypothalamic and pituitary hormones in, 80–82
hypothalamic-pituitary axis, 78
excretion of, 17–19, 24
faecal excretion, 17
renal, 17–19, 18f

formulations of, 21
half-life of, 19–21, 19f
heart and, 130–135, 130b
affect cardiac contractility, 130–135
function, 126–154
interactions of, 24–25
ionisation of, 8–10

for ischaemic heart disease, 148

metabolism of, 14–17, 15b
first-pass, 16–17, 17f
induction and inhibition of, 16, 16f, 16t
phase 1, 15–16, 15f
phase 2, 15f, 16
monitoring of, 21
movement of, in body, 6–10
neurological function and, 42–76
adrenergic pharmacology in, 47b–48b
anaesthetics, 66–71
anticonvulsants, 71–76
antidepressants, 56–63
antimuscarinic side-effects in, 51f, 51b
antipsychotic, 63–66
anxiolytic and sedative, 59–63
cholinergic pharmacology in, 49b–50b
mood stabilisers, 56–63
nerve conduction and synaptic transmission and, 42–44
pancreatic function and, 85–93

diabetes mellitus, 85–93

 glucagon in, 85
insulin in, 85
plasma concentration of, 19f
pulmonary defence mechanisms and, 156–163
renin-angiotensin- aldosterone system and, 143–145
reproductive function and, 93–100

female, 95–99
male, 100
respiratory system and, 155–170 , 157f, 157t
steady state of, 20–21, 20f
therapeutic dose range of, 20–21
thyroid function and, 82–85
hyperthyroidism, 84–85
hypothyroidism, 83–84
drug action
assessment of, 35–37
affinity, efficacy, and potency, 35
dose-response relationships, 36–37, 36f
therapeutic index, 36–37, 36f–37f
levels of, 27–28, 28f, 29t
principal targets of, 28–35, 29f
cell-surface receptors in, 32–33
competitive antagonism in, 29t, 31, 31f
drug receptors in, 28–33, 28f, 28b
enzymes, 35
excitatory and inhibitory receptor responses in, 29–31, 30b

G protein-coupled receptors in, 29t, 32–33, 34f

 ion channels in, 33–35
membrane transport mechanisms, 35
non-mammalian cell targets, 35
nuclear receptors in, 33, 34f
receptor desensitisation and drug tolerance, 35
receptors and their actions in, 32–33, 33f

regulation of receptor number in, 31, 32f

reversible and irreversible drug-receptor binding in, 31
specificity, selectivity, and receptor ‘families’ in, 29t, 30–31, 30f
drug dependence, 40–41, 40f
drug names, 5
drug receptors, 28–33, 28f–29f, 28b
drug tolerance, 35
drug-induced pulmonary toxicity, 156, 157f, 157t
duloxetine
for anxiety, 58
for urinary incontinence, 58

echinocandins, 222
ectopic arrhythmias, 136
efavirenz, 219b–220b
efferent arteriole, 172
efficacy, 35
empagliflozin, 92
enalapril, 15b, 144

endocannabinoids, 196
endocrine control, 77, 77b
endocrine function, drugs and, 77–100 , 77b
hypothalamic and pituitary hormones in, 80–82
hypothalamic-pituitary axis, 78
endocrine system, 77, 78f
end-of-dose reactions, of drugs, 40

endogenous glucocorticoid secretion, suppression of, 116

endogenous opioids, 56
endorphins, 56, 104
excitatory and inhibitory receptor response of, 29
targets of, 28–29
endothelin, 140, 140t
endothelin-receptor antagonists, 145–147
endothelium, biological activity of, 140
endothelium-derived mediators, 140t
enkephalins, 104, 183
excitatory and inhibitory receptor response of, 29
targets of, 28–29
entacapone, 55
enteric nervous system, 183f
enterohepatic recycling, 17, 17f
enzymes, 35
epidural administration, of drugs, 23–24, 23f
epinephrine, for asthma, 164
epirubicin, 238
epithelium, ciliated, drugs and, 156–163, 160f

eplerenone, 177–178
erectile dysfunction, 179–180
eribulin, 235
erythromycin, 192, 206–207
of digitoxin, 133
erectile dysfunction and, 179–180
esketamine, for depression, 59

esomeprazole, 187
ethacrynic acid, 175
ethambutol, 214b–215b
ethanol
dependence to, 40
metabolism of, 15–16
reproductive function and, 39
ether, 66
ethinyloestradiol, 96–97
ethosuximide, 75
for absence seizures, 72
etomidate, 67t, 69
etoposide, 229–230
etoricoxib, 122
etravirine, 219b–220b
excitatory receptor responses, 29–31, 30b
excretion, of drugs
faecal excretion, 17
renal, 17–19, 18f
exenatide, 91

expectorants, 157–162
 ezetimibe, 148

facilitated diffusion, transfer across cell membranes, 7f, 8

factor Xa inhibitors, 152
faecal excretion, of drugs, 17

famciclovir, 217
famotidine, 124, 187
receptor selectivity in, 30
fat solubility, transfer across cell membranes, 7–8
felodipine, 132
felypressin, 82
female reproductive cycle, 95–96, 96f
fenofibrate, 148
fentanyl, 107f, 108–109
pharmacokinetics of, 109
topical administration of, 22
fever, prostaglandins in, 119
fexofenadine, 123–124
fibrinolytic drugs, 153–154, 153f
fibrinolytic system, 153–154
filtration, 172b
first-generation antihistamines, 124, 181
first-order (linear) kinetics, 19–20
flecainide, 138
Fleming, Alexander, 3, 3f

fluconazole, 222
 flucytosine, 223
flumazenil, 62
fluorouracil
for cancer, 236, 237f
transfer across cell membranes, 8
fluoxetine, 58, 153

flupentixol, 65
flutamide, 241
fluticasone, for asthma, 166
focal seizures, 72
folate antagonists, 237
folic acid pathway, 213, 213f
folinic acid, 237
follicle-stimulating hormone, 82, 99
formoterol, for asthma, 164
fosaprepitant, 195
fungi, 220
biology of, 220–222, 220f
infections, pathology of, 220–222
furosemide, 134b–135b, 172, 175
renal adverse drug reactions to, 38–39
renal excretion of, 18–19
unwanted/dangerous interactions of, 24–25
fusidic acid, 206

G protein-coupled receptors in, 29t, 32–33, 34f

G proteins
inhibitory, 33
role of, 34f
stimulatory, 33
GABA, See gamma-aminobutyric acid
gabapentin, 75, 103

for anxiety, 59–60

gamma-aminobutyric acid (GABA), 46, 101–102
binding to channel, 34
excitatory and inhibitory receptor response of, 29
receptors, 46
synthesis and breakdown, 46
ganciclovir, 217
gastric acid secretion, 184–185, 184f
histamine in, 124
stimulants of, 185, 185f
gastric emptying, 11
gastric mucosa, mechanisms protecting, 184–185, 185f
gastric pH, drugs that regulate, 185–189
gastrin, 185
gastrointestinal adverse effects, to antibiotics, 204
gastrointestinal (GI) effects, opioids and, 106
gastrointestinal motility
drugs that increase, 190–193
drugs that reduce, 189–190
gastrointestinal tract, drugs and, 181–196

antiemetics and, 193–196

 gastric function in, 184–189
motility, drugs and disorders of, 189–193
structure and function of, 181–183
main organs of, 181–183, 182f
nervous control of, 182–183, 183f
neurotransmitters in, 183, 183f

gastro-oesophageal reflux disease (GORD), 184

gefitinib, 240
gemcitabine, 236
gemtuzumab ozogamicin, 243
general anaesthetics
for cough, 162
inhalation of, 23
generalised seizures, 72
generic (non-proprietary) name, 5
genetic instability, cancer and, 232
genetics, pharmacokinetics in, 25
genitourinary drugs, 171–180
gentamicin, 133, 206
metabolism of, 14
monitoring of, 21
reabsorption of, 18
gestodene, 97
GHRH, See growth hormone-releasing hormone
ginger, for motion sickness, 56
glasdegib, 240

glibenclamide, 86, 90
glimepiride, 90
glipizide, 90
Gliptins, 86–87, 91
glitazones, 91
glomerular filtration, 171, 173f
glomerular filtration rate, 171, 174f

glucagon, 85
glucocorticoids, 111–116
administration, routes of, 114–115
adverse effects of, 115–116
for asthma, 163–164, 165f, 166
for cancer, 241
for chronic obstructive pulmonary disease, 168
drugs, 116, 116f, 117t
mechanism of action of, 112–114, 115f
stress response and, 111–114
in therapeutics, 114–115, 115b
glutamate, 46, 56
glycerol, 191
glyceryl trinitrate (GTN), 142
metabolism of, 17
pharmacokinetics of, 142
GnRH, See gonadotropin-releasing hormone
gonadotropin-releasing hormone (GnRH), 79, 82, 99
GORD, See gastro-oesophageal reflux disease
goserelin, 82

Gram-negative organisms, 200–201, 202f

Gram-positive organisms, 200–201, 202f
grapefruit juice, erectile dysfunction and, 179–180
griseofulvin, 223
growth hormone, 81
growth hormone-releasing hormone (GHRH), 79
analogues of, 82

gonadorelin, 82
guaifenesin, 157–159
guanylate cyclase-C receptor agonists, 192–193, 193f
H

H2-receptor antagonists, 187

haemostasis, 149–154, 149b
anticoagulants, 150–152

antiplatelet drugs, 152–153

drugs, 154
fibrinolytic drugs, 153–154, 153f
half-life, of drugs, 19–21, 19f
haloperidol, 65
halothane
hepatic adverse drug reactions to, 38
metabolism of, 15
Hashimoto’s disease, 83
heart, conducting system of, 129f
heart failure
cycle of deterioration in, 134f
drug treatment of, 134b–135b
main causes of, 134b
main drug treatment options in, 135f
pathophysiology of, 134b–135b
heart wall, layers of, 127f
hedgehog pathway inhibitors, 240
Helicobacter pylori infection, 185
helminthic infestation, 224, 224f
heparin, 151–152, 151f

adverse effects of, 151

 pharmacokinetics of, 151
in red bone marrow toxicity, 39
subcutaneous/intradermal administration of, 23
unwanted/dangerous interactions of, 24–25
hepatic adverse drug reactions, 38

heroin, 107–108
hirudin, 152
histamine, 46, 52–56, 52t, 77, 113t, 122–124, 123f, 185
in allergy, 124
asthma and, 166–167
gastric acid secretion and, 124
inflammation and, 123–124
motion sickness and, 56
as neurotransmitter, 124
sleep-wake cycle and, 52
synthesis and breakdown, 52b
histamine receptor family, 30
histamine receptors, 52–56, 52t
hormonal contraception, 96–98, 97f
hormone levels
control of, 79–80, 80f
negative feedback and, 78
hormone replacement therapy (HRT), 99b
hormone-responsive cancers, 240–241
5-HT3 antagonists, 195
5-HT3 receptors, 46

hydralazine
 immune-complex mediated reactions to, 38
metabolism of, 16
hydrocortisone, 111, 116, 117t
nuclear receptors in, 33
5-hydroxytryptamine, synthesis and breakdown, 46

hyoscine, 51b, 157, 185

hyoscine butylbromide, 190
hyoscine hydrobromide, 196
hyperalgesia, 101b
hyperglycaemia, 87–88
hypertension, 145b–146b, 146f
hyperthyroidism, 84–85
characteristic signs and symptoms of, 84b
drug treatment in, 84–85
hypnotics, for insomnia, 60–62
hypoglycaemics, cytotoxic reactions to, 37–38
hypothalamic-pituitary axis, 78
control of hormone levels by, 79–80, 80f
hormones of, 79f, 80–82, 81f
hypothalamus-anterior pituitary communication in, 78–80
hypothalamus-posterior pituitary communication in, 79
hypothyroidism, 83–84
characteristic signs and symptoms of, 84b
drug treatment in, 83–84

ibuprofen, 122
 as enzymes, 35
idarubicin, 238
idarucizumab, 152
imatinib, 240
imipenem, 210

immediate hypersensitivity, 37
immune checkpoint inhibitors, 243–244
immune system modulators, 243–244
immunotherapy, 243–244
imunosuppressants
for asthma, 167–168
opioids and, 106
incretin (glucagon-like peptide 1) agonists, 91–92, 91f–92f, 91b
incretins, role of, 87f
indirect negative feedback control, 79–80, 80f
infertility, female, hormonal treatment of, 99
inflammation
histamine and, 123–124
prostaglandins in, 118–119
inflammatory mediators, 111, 113f
inflammatory response, pathophysiology of, 111
inhalation, of drugs, 23
inhaler devices, for respiratory disorders, 158t, 158b–159b, 159f
inhibitory G proteins, 33
inhibitory neurotransmission, 43
inhibitory receptor responses, 29–31, 30b

insecticides, 224
insomnia, 60
insulin, 85, 88–89
action of, 86–88
adverse effects of, 89
adverse reactions of, 39

anabolic effects of, 85f

aspart, 88
degludec, 88
detemir, 88
glargine, 88
inhaled, 89
intermediate, 88
lispro, 88
long-acting, 88
resistance, 88
secretion, control of, 86–87, 86f–87f
short-acting, 88
subcutaneous/intradermal administration of, 23
interferons, for asthma, 165–166
interleukins, 113t
for asthma, 163–164
intramuscular administration, of drugs, 22–23, 22f
intrathecal administration, of drugs, 23–24, 23f
intravenous administration, of drugs, 22
ion channels, 33–35
transfer across cell membranes, 7f, 8

ion movements, cardiac action potential and, 135–136, 136f

 ion trapping, 9–10

ipilimumab, 243
ipratropium, 51b
for asthma, 166
iproniazid, 58

irinotecan, 236
iron salts, transfer across cell membranes, 8
irreversible drug-receptor binding, 31
ischaemic heart disease, 147–148
drugs used to treat, 148
myocardial infarction and, 147–148
isoflurane, pharmacological actions of, 67t
isoniazid, 214b–215b
for asthma, 165–166
metabolism of, 16
isophane insulin, 88
isoprenaline, for asthma, 164

isosorbide dinitrate, 142

isotretinoin, 245
itraconazole, 186, 222
ivacaftor, 161–162
ivermectin, 224
ixazomib, 244

K+-channel openers, 142–143

 ketamine, 59, 69–71
glutamate and, 56
pharmacological actions of, 67t
ketoconazole, 132
erectile dysfunction and, 179–180
hepatic adverse drug reactions to, 38

kidney, structure and function of, 171, 172f

Koch, Robert, 198–199

labetalol, 131–132
lactulose, 191–192
lamivudine, 219b–220b
lamotrigine, 62, 75–76
for focal seizures, 72
lanolin, formulations of, 21
lanreotide, 81–82
lansoprazole, 187
lapatinib, 240
latency, 217
laxatives
bulk-forming, 191
for constipation, 191–192, 191f
osmotic, 191–192
softening, 191
stimulant, 191

Leeuwenhoek, van, 198

lenalidomide, 243–244
leukotriene receptor antagonists, for asthma, 163, 167, 167f
leukotrienes, 113t
levodopa, 54–55, 54f
transfer across cell membranes, 8
levofloxacin, 212

levothyroxine, 83–84
adverse effects of, 84
pharmacokinetics of, 84
lidocaine, 69b–71b, 136, 138
ligand, 28b
lignocaine, as ion channel blocker, 34
linaclotide, 192–193, 193f
linagliptin, 86–87, 91
linear kinetics, 19–20
liothyronine, 84
lipid-modifying drugs, additional, 148
liposomes, 21, 21f
lipoxygenase inhibitors, for asthma, 167
liquid paraffin, 191
liraglutide, 86–87, 91
Lister, Joseph, 198–199
lithium, 62–63
local anaesthetics
absorption of, 24
efficacy, factors affecting, 70–71

blood flow and, 70

 inflamed or infected tissues and, 70–71
neuronal factors and, 71
use-dependence and, 71
mechanism of action of, 69b–71b, 70f
in nerve action potential, 44
pharmacodynamics of, 71, 71t

side-effects of, 71
lomustine, 238
loop diuretics, 175–176, 176f
adverse reactions of, 39
in membrane transport, 35
loop of nephron, reabsorption in, 172
loperamide, 106, 189
loratadine, 124
lorazepam, 61b–62b, 196
losartan, 140, 144
low-dose aspirin, 145b–146b
lung tissue, histology of, 157f
luteinising hormone, 82

macrogols, 191–192
macrolides, 192, 206–207, 214b–215b
adverse effects of, 207
erectile dysfunction and, 179–180
pharmacokinetics of, 207

malaria, 223
malathion, 49–50, 224
male sexual function, 178–180, 178f
mannitol, 159–161
in non-mammalian cell targets, 35
in osmotic diuretics, 174, 175f
MAO inhibitors, 46

marijuana, causing erectile dysfunction, 179

Marshall, Barry J., 188b–189b
mebendazole, 224
mebeverine, 190
medroxyprogesterone acetate, 98
meglitinides, 90
melatonin, for sleep, 62
melphalan, for cancer, 237
membrane transport mechanisms, 35
menopause, hormonal changes at, 98–99
meperidine, 107f, 109
mercaptopurine, 236
metabolism, of drugs, 14–17, 15b
first-pass, 16–17, 17f
induction and inhibition of, 16, 16f, 16t
phase 1, 15–16, 15f
phase 2, 15f, 16
metformin, 89–90
adverse effects of, 90
pharmacokinetics of, 90

renal excretion of, 18–19

methadone, 109
methotrexate, 115, 213
for cancer, 237, 237f
excretion of, 24
monitoring of, 21
reproductive function and, 39

methylene blue, 2–3

methylnaltrexone, 192
methylnaltrexone bromide, 106
methysergide, 46
metoclopramide, 46, 65
for motility, 195
for nausea and vomiting, 183
metoprolol, 148
adverse effects of, 132
metronidazole, 211–212
activation of, 212f
adverse effects of, 212
for peptic ulcer, 188b–189b
pharmacokinetics of, 212
micafungin, 222
microbes, 198b
biology of, 197–200
microbial adaptability, 199–200, 200f
microbiology, history of, 198–200, 198f–199f
midazolam, 61b–62b, 72

binding to channel, 34
 excitatory and inhibitory receptor response of, 29
minocycline, 207
minoxidil, 142–143
miosis, opioids and, 105, 105f
mirtazapine, 59
misoprostol, 120, 184–185, 187–189

mitomycin C, 238
mitoxantrone, 238
moclobemide, 58
modified ethers, 68–69
molecular weight, transfer across cell membranes, 7
mometasone, for asthma, 166
monoamine
adverse effects of, 58–59
breakdown, drugs that block, 58–59, 58f
pharmacokinetics of, 58–59
receptor blockers, 59
monoamine oxidase, 55, 55f
monoclonal antibodies
for cancer, 241–243, 241f
immediate hypersensitivity reactions to, 37
monotherapy, 73
mood-stabilising drugs, 62–63
MOR distribution, 104
MOR signalling, 104, 104f
morphine, 2, 103, 189

beneficial interactions of, 24

 for cough, 162–163
excitatory and inhibitory receptor response of, 29
excretion of, 17
G proteins and, 33
in gastrointestinal tract, 183
immunologically mediated adverse drug reactions to, 37

metabolism of, 17
opioid receptors for, 56
pharmacokinetics of, 107
in receptor desensitisation, 35
targets of, 28–29
motility, cancer and, 231–232
mould, 220b
mucolytics, 157–162
mucus, drugs and, 157–162
muscarinic receptor, subtypes of, 50t
Mycobacteria, 214f, 214b–215b
mycosis, 220b
myelin sheath, 43f
myocardial infarction
combined oral contraceptive and, 98
ischaemic heart disease and, 147–148

myocardium, 127–129
afterload, 128, 128f
blood supply to, 127
cardiac conducting system, 128–129

cardiac output, 128, 128f

 contractility of, 127–128, 127f
key definitions, 128b
preload, 128, 128f
myocyte, 136

nabilone, 196
N-acetylcysteine (NAC), 122
N-acetyl-p-benzoquinone imine (NAPQI), 38
naldemedine, 192
nalidixic acid, 212
naloxegol, 192
naloxone, 24, 103, 110, 110f, 189
naltrexone, 31, 110
naproxen, 122
narrow-spectrum antibiotics, 201b
nateglinide, 90
natural anticoagulants, 150
natural prostaglandins (PGs), 180
nausea
cytotoxic agents and, 234
opioids and, 105
nedocromil sodium, for asthma, 166–167
neomycin, 206
neoplasia, combined oral contraceptive and, 98
neostigmine, 44

nephron, 171
 loop of, reabsorption in, 172
regions of, 171
reabsorption and secretion in the different, 172–173
structure of, 173f
nerve action potential, 44, 44f

nerve conduction, 42–44

nervous system
adverse drug reactions, 39
autonomic, 45–46, 45f
neurotransmitters of, 44–52
parasympathetic, activity, 45–46
peripheral, 44–52
sympathetic, activity, 45–46
netupitant, 195–196
neurokinin-receptor antagonists, 195–196
neurological function, drugs and, 42–76
adrenergic pharmacology in, 47b–48b
anaesthetics, 66–71
anticonvulsants, 71–76
antidepressants, 56–63
antimuscarinic side-effects in, 51f, 51b
antipsychotic, 63–66
anxiolytic and sedative, 59–63
cholinergic pharmacology in, 49b–50b
nerve conduction and synaptic transmission and, 42–44
neurones, 42

neuropathic (neurogenic) pain, 101b

neurotransmitter, histamine as, 124
neurotransmitter action, termination of, 43–44
nicorandil, 143
nicotine, 106
topical administration of, 22

nifedipine, 132, 148

as ion channels blocker, 34
niraparib, 239
nitrate vasodilators, 141–142
nitrates, 142, 148
erectile dysfunction and, 180
nitric oxide (NO), 113t, 140, 140t
erectile dysfunction and, 179
nitrofurantoin, 212
nitrogen mustard derivatives, 237–238
nitrosoureas, 238
nitrous oxide, 69
anaesthesia and, 66
pharmacological actions of, 67t
nivolumab, 243
nociceptive pain, 101b
non-benzodiazepine anxiolytics, 60
non-insulin antidiabetic drugs, 89–93
acarbose as, 92–93
dipeptidyl peptidase inhibitors (gliptins), 91
glitazones as, 91

incretin (glucagon-like peptide 1) agonists, 91–92, 91f, 91b

 mechanisms of action of, 89f
meglitinides as, 90
metformin as, 89–90
sodium/glucose co-transporter inhibitors, 92
sulphonylureas as, 90

non-mammalian cell targets, 35

non-nucleoside HIV reverse-transcriptase inhibitors, 219b–220b
non-rapid-eye movement sleep, 60
non-selective β-blockers, 132
non-selective COX-1 inhibitors, 120–122, 121f
non-selective COX-2 inhibitors, 120–122, 121f
non-steroidal anti-inflammatory drugs (NSAIDs), 90, 116–122
adverse effects of, 120
adverse reactions of, 39
cutaneous adverse drug reactions to, 39
excretion of, 24
formulations of, 21
gastrointestinal tract and, 181
renal adverse drug reactions to, 38–39
topical administration of, 22
noradrenaline, 46, 101–102
action of, 28
G proteins and, 33
in gastrointestinal tract, 183
metabolism of, 15–16
receptor selectivity in, 30–31

removal of, from synapse, 48

 noradrenaline re-uptake inhibitors, 58
norethisterone, 97
norpethidine, 109
nortriptyline, 57
NSAIDs, See non-steroidal anti-inflammatory drugs

nuclear receptors, 33, 34f

nucleoside analogues, 217–218, 236
nucleoside HIV reverse-transcriptase inhibitors, 219b–220b
nystatin, 222
absorption of, 10–11

obstructive airways disease, 163–170, 163f

octreotide, 81–82
oestrogens, 94b–95b, 99
deficiency, signs and symptoms of, 98–99
induction and inhibition of, 16
receptors, 94b–95b
reproductive function and, 39
ofloxacin, 212
olanzapine, 59–60, 62
unwanted/dangerous interactions of, 24–25
olaparib, 239
older adults, pharmacokinetics in, 25
oliceridine, 110, 110f
omalizumab, for asthma, 167–168, 169b

ombitasvir, 218
omeprazole, 184, 186–187
adverse drug reactions to, 37
formulations of, 21
irreversible inhibition of, 31
in membrane transport, 35

ondansetron, 46, 105, 109–110, 183, 195

opdualag, 243
opiates, 103b
opioid(s), 46, 51b, 101–110, 103b, 145
absorption of, 11, 24
actions of, 104–106
for cough, 162–163
gastric emptying and, 11
in gastrointestinal motility, 189–190
immunologically mediated adverse drug reactions to, 37
inhibition, 105f
main, 106–110, 107f
new directions, 110
receptors, 104–106
reversal agents, 110
uses of, 107–110
opioid analgesics
adverse reactions of, 40
dependence to, 40
subcutaneous/intradermal administration of, 23
opioid-induced miosis, 105f

opioid-receptor antagonists, 192

 opium, 103b
origins of, 1–2, 1f–2f
oral administration, of drugs, 22, 22f
organophosphates, 49–50
orphenadrine, 55

oseltamivir, 218
osmotic diuretics, 174–175, 175f
osmotic laxatives, 191–192
oxaliplatin, 238
oxazolidinones, 207
oxprenolol, 132
oxybutynin, 51b
oxytetracycline, 207
oxytocin, 82

pacemakers, secondary, 129

paclitaxel, 228, 235–236
pain
classification of, 101
definition of, 101
inflammatory mediators and, 111, 113f
pathways, 101–103, 102f
physiology of, 101–103
prostaglandins in, 118–119
signalling, 101–103

palbociclib, 239
palonosetron, 195
pancreatic function, drugs and, 85–93
diabetes mellitus, 85–93
glucagon in, 85
insulin in, 85

pancuronium, 66
papaverine, 103
paracetamol, 5, 122, 123f
beneficial interactions of, 24
biochemically mediated adverse drug reactions to, 38
drug action, 27
hepatic adverse drug reactions to, 38
metabolism of, 15

paracrine control, 77
paracrine substances, 77
parasympathetic activity, 130
parathyroid hormone, reabsorption and secretion of, 172–173

Parkinson’s disease
dopamine and, 53f, 53b–55b
drug treatment in, 53–55
signs and symptoms of, 53–55
Pasteur, Louis, 198–199
pegaspargase, 244
pembrolizumab, 243
pemetrexed, 237, 241

penicillamine, cytotoxic reactions to, 37–38

penicillin, 208, 209b
adverse effects of, 209b
advertisement for, 209f
allergy, 39, 204
in babies and children, 25
cytotoxic reactions to, 37–38

half-life of, 19
immediate hypersensitivity reactions to, 37
immunologically mediated adverse drug reactions to, 37
isolation of, 3, 3f
metabolism of, 14
modifications and altered activity of, 209b
pharmacokinetics of, 209b
renal excretion of, 18–19
transfer across cell membranes, 8
Penicillium notatum, 209b
penis, 178–179
peppermint oil, 190
peptic ulcer, treatment of, 188b–189b
permethrin, 224
pertuzumab, 242
pethidine, 109
PGE2, 119
PGI2, 119, 119f
pH, 8–10, 8f–9f
partitioning, 9–10, 10f

pharmacodynamic interactions, 24–25

pharmacodynamics, 27–41
adverse drug reactions, 37–40
augmented, 39
biochemically mediated, 38
bizarre, 39
chronic, 39

classification of, 39–40

common, 38–39
cutaneous, 38f, 39
delayed, 40
end-of-dose, 40
hepatic, 38
immunologically mediated, 37–38, 37f–38f
mechanisms of, 37–38
nervous system, 39
pharmacologically mediated, 38
red bone marrow toxicity, 39
renal, 38–39
reproductive function, 39
drug action in
assessment of, 35–37
levels of, 27–28, 28f, 29t
principal targets of, 28–35, 29f
drug dependence, 40–41, 40f
pharmacogenomics, 3–4, 4f
pharmacokinetics, 6–26

absorption in, 24
 of calcium channel antagonists, 132–133
of digitoxin, 133
distribution in, 24
drug administration in, 21–24
drug disposition in, 10–19, 10f
absorption, 10–11

distribution, 11–14
excretion, 17–19
metabolism, 14–17
drug movement, 6–10
excretion in, 24
interactions of, 24
of loop diuretics, 176
of phosphodiesterase inhibitors, 179–180
of potassium-sparing diuretics, 177–178
special situations of, 25
of sympathetic agonists, 131
of sympathetic antagonists, 132
of thiazide diuretics, 176–177
pharmacology, 1–5
from bench to bedside, 4–5
clinical trials, 5
drug development process, 4–5, 5f
drug names, 5
origins of, 1–4, 1f
biologics, 3–4

pharmacogenomics, 3–4, 4f
 pre-clinical development of, 4
phenelzine, 44, 58
metabolism of, 15–16
phenindione, 150
phenothiazine antipsychotics, 2–3, 195
phenoxymethylpenicillin, 209b

phenytoin, 73–74, 97, 150–151

for absence seizures, 72
adverse reactions of, 39
anticoagulants and, 73
for asthma, 165–166
erectile dysfunction and, 179–180
for focal seizures, 72
monitoring of, 21
for peptic ulcer, 188b–189b
for status epilepticus, 72
for tonic-clonic seizures, 72
zero-order kinetics of, 20
pholcodine, for cough, 162–163
phosphodiesterase enzymes (PDEs), 33
phosphodiesterase inhibitors, 133–135
for chronic obstructive pulmonary disease, 168–170
in erectile dysfunction, 179–180, 179f
pindolol, 132, 148
pioglitazone, 91
piperacillin, 209b

in red bone marrow toxicity, 39

piroxicam, 122
pitolisant, 52
plasma protein binding, 13–14, 13f–14f
platelet activating factor (PAF), 113t
platelets, 149–150
platinum compounds (Platins), 238

poly-ADP ribose polymerase (PARP) inhibitors, 239–240, 240f

polymyxins, 200–201, 210
adverse effects of, 210
pharmacokinetics of, 210
pomalidomide, 243–244
posaconazole, 222–223
posterior pituitary hormones, 82
potassium (K+), 44
potassium-sparing diuretics, 177–178
potency, 35
pramipexole, 54
prasugrel, 153
pravastatin, 148
prazosin, 131
prednisolone, 116, 117t
for cancer, 241
pregabalin, 75
pregnancy, pharmacokinetics in, 25
preload, 128, 128f
primaquine, 223–224

procainamide, metabolism of, 16

procyclidine, 55
progesterone, 93b–95b
progestogen, 93b
progestogen-only preparations, 98
pro-kinetic drugs, 192–193, 192f
prolactin inhibitory factor, 79

promethazine, 2–3, 124

prontosil, 213
propofol, 69
pharmacological actions of, 67t
for status epilepticus, 72
propranolol, 132, 187
adverse effects of, 132
regulation of, 31
proprietary names, 5
propyl gallate, formulations of, 21
propylthiouracil, 84
transfer across cell membranes, 8
prostacyclin, 119–120, 140, 140t
platelets, 149
prostaglandins, 77, 113t, 184–185
biology of, 117–120
biosynthesis of, 117, 118f
in fever, 119
function of, 117–120, 118f
in inflammation, 118–119

in nervous system, 120

 in pain, 118–119
in tumour growth and development, 120
protamine sulphate, 151
protease inhibitors, 219b–220b
proteasome inhibitors, 244–245
protein kinase inhibitors, 240

protein synthesis inhibitors, selective toxicity of, 205b

proton-pump inhibitors, 120, 186–187
adverse effects of, 187
pharmacokinetics of, 187
renal adverse drug reactions to, 38–39
proto-oncogenes, 233, 233f
protozoal infections, 223–224
proximal convoluted tubule (PCT), 171
reabsorption and secretion in, 172
prucalopride, 183, 192
pulmonary toxicity, drug-induced, 156, 157f, 157t
purified factor XIII, 154
pyrazinamide, 214b–215b

quinine, 198
in red bone marrow toxicity, 39
quinolones, 212–213
adverse effects of, 212–213
for peptic ulcer, 188b–189b

pharmacokinetics of, 212

R

racecadotril, 189–190, 190f

radioactive iodine, 84–85
raltitrexed, 237
ramipril, 144

drug action, 27
ranitidine, 187
rapid-eye movement sleep, 60
rational drug design, 4
reabsorption, 172, 172b
receptor desensitisation, 35
receptor ‘families’, 29t, 30–31, 30f

receptor number, regulation of, 31, 32f

receptor proteins, 31
red bone marrow toxicity, 39
re-entrant rhythms, 136
renal adverse drug reactions, 38–39

renal drugs, 171–180

renal excretion, of drugs, 17–19, 18f
renin antagonist, 145
renin-angiotensin-aldosterone system, 141, 141f
renin-angiotensin-aldosterone system, drugs and, 143–145
angiotensin-converting enzyme inhibitors, 143–144, 143f, 145f
angiotensin-receptor antagonists, 144
renin antagonist, 145

repaglinide, 90
reproductive function
of drugs, 39
female, 95–99
hormonal contraception, 96–98
hormonal control of, 95–96
male, 100

pharmacological control of, 93–100

respiratory depression, opioids and, 105
respiratory disorders, inhaler devices for, 158t, 158b–159b, 159f
respiratory passageways, structure of, 155–156
respiratory system, 155–156, 156f
drugs and, 155–170 , 157f, 157t
resting membrane potential, 44
retinoic acid, 245
retinoids, reproductive function and, 39
retroviruses, replication of, 216
re-uptake pumps, 43–44, 43f
reverse transcriptase inhibitors, 219f, 219b–220b
reversible drug-receptor binding, 31
reward pathway, 40f
ribavirin, 217
ribociclib, 239
rifabutin, 214b–215b
rifampicin, 132, 214b–215b
for chronic obstructive pulmonary disease, 168–170
rifamycins, 214b–215b

rilpivirine, 219b–220b
 risperidone, 62, 66
ritonavir, 218, 219b–220b
rituximab, 242
rofecoxib, 122
roflumilast, for chronic obstructive pulmonary disease, 168–170
ropinirole, 54

unwanted/dangerous interactions of, 24–25

rosiglitazone, 91
rotigotine, 54
rucaparib, 239

salbutamol
for asthma, 164
drug action, 27
G proteins and, 33
regulation of, 31
targets of, 28–29
salicin, 116–117
salicylates, zero-order kinetics of, 20
salicylism, 121
salmeterol, for asthma, 164
saquinavir, 219b–220b
saturation kinetics, 19–20, 20f
saxagliptin, 91
schizophrenia, 63–64

clinical features of, 63b

 neurophysiology of, 64, 64f
mesocortical pathway and D1 receptors in, 64
mesolimbic pathway and D2 receptors in, 64
serotonin and glutamate in, 64
scopolamine, 56
secondary pacemakers, 129

second-generation antihistamines, 124

second-line agents, 145b–146b
second-messenger pathways, G proteins and, 29t, 32–33, 34f
secretion, 172b
sedation, opioids and, 105
sedatives, metabolism of, 17
seizure, 71
causes of, 71–72
pharmacological management of, 72–76, 73f
types of, 72
selective-serotonin re-uptake inhibitors, 58
adverse effects of, 58
for anxiety, 59–60
pharmacokinetics of, 58
selective-serotonin re-uptake inhibitors, causing erectile dysfunction, 179
selectivity, of receptors, 29t, 30–31, 30f
selegiline, 44, 55
for Parkinson’s disease, 56
Semmelweiss, Ignaz, 198–199, 198f
senna, 191

sensitisation, in pain pathways, 103

serotonin (5-HT), 46, 58, 101–102, 113t, 183
metabolism of, 15–16
platelets, 149
serotonin receptor agonists, 192
serotonin receptors, 46
sertraline, 58, 153

Sertürner, Friedrich, 3f
sex hormone, 94f, 94b–95b
sildenafil
for erectile dysfunction, 179–180
G proteins and, 33
mechanism of action of, 179f
simvastatin, 148
sinus rhythm, 135
sleep, physiology of, 60
smooth muscle, of respiratory passageways, 155–156
smooth-muscle relaxants, in gastrointestinal motility, 190
sodium (Na+), 44
sodium cromoglicate, for asthma, 166–167
sodium metabisulphite, formulations of, 21
sodium picosulfate, 191
sodium valproate, 62, 75
for absence seizures, 72
hepatic adverse drug reactions to, 38
zero-order kinetics of, 20
sodium/glucose co-transporter inhibitors, 92, 93f

sodium-potassium pump, 44
softening laxatives, 191
soluble insulin, 88
somatostatin, 81–82
analogues, 81–82
somatropin, 81
sorafenib, 240

sotalol, 136, 138–139

specificity, of receptors, 29t, 30–31, 30f
spindle poisons, 235–236, 235f
spironolactone, 134b–135b, 141, 145b–146b, 173, 177, 177f
pharmacokinetics of, 177–178
spontaneous mutation, 203
squill, 157–159
SSRIs, See selective-serotonin re-uptake inhibitors
St. John’s wort, 59, 97, 132
for asthma, 165–166
erectile dysfunction and, 179–180
statins
hepatic adverse drug reactions to, 38
induction and inhibition of, 16
for ischaemic heart disease, 148
status epilepticus, 72
stavudine, 219b–220b
steady state, 20–21, 20f
steroid hormones
actions of, 32

nuclear receptors in, 33

steroid-binding protein, 33
steroids, mechanisms of, 34f
Stevens-Johnson syndrome, 38f
stimulant laxatives, 191
stimulatory G proteins, 33
streptokinase, 153–154

as enzymes, 35
streptomycin, 206
renal adverse drug reactions to, 38–39
streptozocin, 238
stroke, combined oral contraceptive and, 98
subcutaneous/intradermal administration, of drugs, 22f, 23
substance P, 101–102, 113t
intestinal contraction and, 183
sucralfate, for peptic ulcer, 188b–189b
sulfasalazine, 213
sulphamethoxazole, 2–3, 213
sulphonamides, 90, 213–214
adverse effects of, 214
causing delayed reactions, 38
cutaneous adverse drug reactions to, 39
immune-complex mediated reactions to, 38
mechanism of action of, 213f
metabolism of, 16
pharmacokinetics of, 213
in red bone marrow toxicity, 39

synergism with, 203–204

 sulphonylureas, 86, 90
superinfection, 204
suppression, cytotoxic agents and, 234–235
sympathetic activity, 130
sympathetic agonists, 130–131, 131f
sympathetic nervous system, vasodilators and, 142

synapse, 42–44, 43f

synaptic transmission, 42–44
synergism, antibiotics, 203–204
synthetic antidiuretic analogues, 82
synthetic progestogens, 96–97
systemic blood pressure, control of, 141

tadalafil, for erectile dysfunction, 179–180

tailored genetic therapy, for cystic fibrosis, 161f, 161b–162b
taladegib, 240
talimogene laherparepvec, 244, 244f
tamoxifen, 93, 241
tartrazine, formulations of, 21
taxanes, 236
tazobactam, 208
tegafur, 236
tegaserod, 192

teicoplanin, 210
telomerase, 231

temazepam, 61–62
tenecteplase, 154
teratogenicity, cytotoxic agents and, 234
terbinafine, 222
terbutaline, for asthma, 164
terfenadine, 124

terlipressin, 82
testosterone, 94b–95b
tetracaine, 69b–71b
tetracyclines, 207
absorption of, 24
adverse effects of, 207
gastric emptying and, 11
for peptic ulcer, 188b–189b
pharmacokinetics of, 207
thalidomide, 243–244
thebaine, 103
theophylline, 163, 165–166
adverse effects of, 165–166
G proteins and, 33
pharmacokinetics of, 165
therapeutic index, 36–37, 36f–37f
thiamazole, 84
thiazide diuretics, 145b–146b, 176–177, 177f
causing erectile dysfunction, 179
cytotoxic reactions to, 37–38
thiazides, 177, 177f

in membrane transport, 35
thiopental, 69
pharmacological actions of, 67t
for status epilepticus, 72
third-generation antihistamines, 124
thromboembolism, hormone replacement therapy and, 99b

thyroid function, drugs and, 82–85

hyperthyroidism, 84–85
hypothyroidism, 83–84
thyroid gland, 82
thyroid hormones
physiological effects of, 83b
synthesis of, 83f
thyrotropin-releasing hormone (TRH), 79
thyroxine, functions of, 83
tiagabine, 46, 74
ticagrelor, 153
tinea infections, 221f
tinidazole, 211–212
tiotropium, for asthma, 166
tobacco, insomnia and, 60
tobramycin, 206
tolbutamide, 90
tolerance, opioids and, 106
tonic-clonic seizures, 72
topical administration, of drugs, 22
topiramate, 76

topoisomerase I inhibitors, 236–237

topoisomerase II inhibitors, 237
topoisomerase inhibitors, 236–237
topotecan, 236
torasemide, 175
tramadol, 109–110, 109f

tranexamic acid, 154

transpeptidase, 207–208
trastuzumab (Herceptin), 233, 233f, 242
trastuzumab deruxtecan, 243
trastuzumab emtansine, 243
trazodone, 46, 59
tretinoin, 245
TRH, See thyrotropin-releasing hormone
triamcinolone, 116, 117t
triamterene, 177–178
tricyclic antidepressants, 43–44, 57–58, 57f
adverse effects of, 57–58
causing erectile dysfunction, 179
pharmacokinetics of, 57
tri-iodothyronine, functions of, 83
trimethoprim, 214–216
mechanism of action of, 213f
synergism with, 203–204
triple/quadruple therapy, for peptic ulcer, 188f, 188b–189b
tuberculosis, 214b–215b
tumour necrosis factor (TNF), 113t

tumour-suppressor genes, 233–234

 TXA2, 119, 119f

urinary system, 171–178

urine formation, 172b, 172–173, 174f
V

vaccines, cytotoxic drugs and, 244

vancomycin, 210
in red bone marrow toxicity, 39

vasodilators, 134b–135b, 141–143, 141b

for ischaemic heart disease, 148
sympathetic nervous system and, 142
vasopressin, 82
Vaughan Williams classification, of anti-arrhythmic drugs, 137b, 138f, 139
venlafaxine, 58
venous thromboembolism, combined oral contraceptive and, 98
verapamil, 132–133
adverse drug reactions to, 37
erectile dysfunction and, 179–180
as ion channels blocker, 34
renal excretion of, 18–19
vigabatrin, 46, 74, 75f
for absence seizures, 72
for focal seizures, 72
for tonic-clonic seizures, 72
vildagliptin, 86–87
vinca alkaloids, 236
vincristine, 228
vinorelbine, 235
virus

biology of, 216–217

 DNA, replication of, 216, 216f
vismodegib, 240
vitamin B12, transfer across cell membranes, 8
vitamin K (phytomenadione), 150–151
vitamin K antagonists, 150–151, 150f

vomiting, 193
chemosensitive trigger zone and, 193–194
cytotoxic agents and, 234
gastrointestinal tract during, 193, 194f
higher centres and, 193
opioids and, 105
physiology of, 193–196, 194f
vestibular nuclei during, 194
voriconazole, 222

warfarin, 90, 145, 150–151, 212

adverse effects of, 151
distribution of, 24
pharmacokinetics of, 150–151
plasma protein binding and, 14, 14f
reproductive function and, 39
transfer across cell membranes, 8
unwanted/dangerous interactions of, 24–25
Warren, J. Robin, 188b–189b
withdrawal syndromes, 41
X

xenon, 66

yeast, 220b

yohimbine, 47–48

zaleplon, 62
zanamivir, 218
Z-drugs, 62
zero-order (saturation) kinetics, 19–20
zidovudine, 219b–220b
metabolism of, 15b
zileuton, for asthma, 167
zolpidem, 62
zopiclone, 62