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Pharmacology

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ELSEVIER
ALGrawany
Pharmacology
 First and second edition authors:
Magali N F Taylor
Peter J W Reide
James S Dawson

Third edition author:

Gada Yassin

Fourth edition author:

Elisabetta Battista

ALGrawany
 5 th Edition

CRASH COURSE
SERIES EDITORS
Philip Xiu
MA, MB BChir, MRCP
GP Registrar
Yorkshire Deanery
Leeds, UK
Shreelata Datta
MD, MRCOG, LLM, BSc (Hons), MBBS
Honorary Senior Lecturer
Imperial College London
Consultant Obstetrician and Gynaecologist
King’s College Hospital
London, UK

FACULTY ADVISOR
Clive Page
OBE, PhD
Director, Sackler Institute of Pulmonary Pharmacology
Institute of Pharmaceutical Science
King's College London
London, UK

Pharmacology
Catrin Page
BSc, Mb, ChB
Core trainee
St. George’s hospital
London, UK
Senior Content Strategist: Jeremy Bowes
Senior Content Development Specialist: Alex Mortimer
Project Manager: Andrew Riley
Page design: Christian bilbow
Illustration Manager: Karen Giacomucci
Illustrator: MPS North America LLC
Marketing Manager: Deborah Watkins

© 2019 Elsevier Limited. All rights reserved.

The right of Catrin Page to be identified as author of this work has been asserted by her in accordance with the Copyright, Designs
and Patents Act 1988.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including
photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on
how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as
the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted
herein).

Notices
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information,
­methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent
verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier,
authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or
­otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

First edition 1998

Second edition 2002
Third edition 2008
Fourth edition 2013
Updated fourth edition 2015
Fifth edition 2019

ISBN: 978-0-7020-7344-1
eISBN: 978-0-7020-7345-8

Printed in China

ALGrawany
 Series Editors’ foreword

The Crash Course series was conceived by Dr Dan Horton-Szar who as series
editor presided over it for more than 15 years – from publication of the first
edition in 1997, until publication of the fourth edition in 2011. His inspiration,
knowledge and wisdom lives on in the pages of this book. As the new series
editors, we are delighted to be able to continue developing each book for the
twenty-first century undergraduate curriculum.

The flame of medicine never stands still, and keeping this all-new fifth series
relevant for today's students is an ongoing process. Each title within this new
fifth edition has been re-written to integrate basic medical science and clinical
practice, after extensive deliberation and debate. We aim to build on the success
of the previous titles by keeping the series up-to-date with current guidelines for
best practice, and recent developments in medical research and pharmacology.

We always listen to feedback from our readers, through focus groups and
student reviews of the Crash Course titles. For the fifth editions we have
reviewed and re-­written our self-assessment material to reflect today's ‘single-
best answer’ and ‘extended matching question’ formats. The artwork and layout
of the titles has also been largely re-worked and are now in colour, to make it
easier on the eye during long sessions of revision. The new on-line materials
supplement the learning process.

Despite fully revising the books with each edition, we hold fast to the principles
on which we first developed the series. Crash Course will always bring you all
the information you need to revise in compact, manageable volumes that still
maintain the balance between clarity and conciseness, and provide sufficient
depth for those aiming at distinction. The authors are junior doctors who have
recent experience of the exams you are now facing, and the accuracy of the
material is checked by a team of faculty editors from across the UK.

We wish you all the best for your future careers!

Philip Xiu and Shreelata Datta

v
Prefaces

Author
This book has been thoroughly updated to provide an accessible learning and
revision aid for understanding the principles and applications of pharmacology.

The introductory chapter provides a comprehensive overview of the basic

­principles of pharmacology. The remaining chapters highlight the effect of
drugs on ­different o
­ rgan systems and include updates on the most recent
pharmacological advance (e.g. novel anti coagulants and newer targeted
therapies used in oncology). The self-­assessment section has been updated to
reflect the content contained within several ­undergraduate and post-graduate
examinations. The self-­assessment section includes questions focused on clinical
pharmacology and drug –drug interactions and is in a ‘Best of fives’ format.

I hope you find the book informative and enjoyable, and wish you luck in learning
the fascinating and essential subject of pharmacology.

Catrin Page

Faculty Advisor
This volume of Crash Course: Pharmacology has been thoroughly revised
from the previous editions. Even more than ever it provides a comprehensive
and approachable text for medical students and others interested in the study
of pharmacology. As part of the Crash Course series, the overall style is user
friendly, consisting of concise bulleted text with informative illustrations, many
of which are new. The content provides a comprehensive overview of the core
material needed to pass the pharmacology component of the undergraduate
medical curriculum. At the end of the chapter, there is a self-­assessment section
consisting of multiple-choice questions, short-answer questions and extended-
matching questions which test the reader's understanding of the topic.

In line with the new style of curriculum recommended by the General Medical
Council, the pharmacology is organized logically into body systems and the
clinical relevance of the pharmacology is stressed throughout.

I have no doubt that this volume will be a useful study and revision aid for
students. It provides a refreshing means of bringing the medical student up to
speed in pharmacology. I would like to formally acknowledge the hard work
of Catrin Page and the highly professional way she has updated this volume,
significantly improving the value of this book as a revision aid for students.

Clive Page
vi ALGrawany
 Acknowledgements

I would like to thank Professor Clive Page for his advice and encouragement
throughout the process of updating this book. Further thanks to everyone
involved with the book at Elsevier.

I also am grateful for the support given to me by family and for the opportunity
to complete my medical degree and teaching fellow role at the University of
Bristol, which has enabled me to hopefully update this book to be a relevant and
practical source of revision for other students and doctors alike.

Catrin Page

FIGURE ACKNOWLEDGEMENTS
Figures 1.3–1.5, 1.11B, 2.1–2.4, 5.2, 5.4, 5.11, 5.18, 5.19, 6.1–6.5, 6.7, 6.11,
6.17, 7.1–7.5, 8.1, 10.8–10.10 and 10.13 redrawn with kind permission from
Integrated Pharmacology, 3rd edn, edited by Professor C Page, Dr M Curtis,
Professor M Walker and Professor B Hoffman, Mosby, 2006.

KEY TO ICONS

Agonists Closed voltage-gated

ion channel

Antagonist Open voltage-gated

ion channel

Receptor Active state

of pump

Active state Energy-dependent

of an enzyme carrier molecule

Inactive state
of an enzyme

vii
Series Editors’ acknowledgements

We would like to thank the support of our colleagues who have helped in the
preparation of this edition, namely the junior doctor contributors who helped
write the manuscript as well as the faculty editors who check the veracity of the
information.

We are extremely grateful for the support of our publisher, Elsevier, whose
staffs’ insight and persistence has maintained the quality that Dr Horton-Szar
has setout since the first edition. Jeremy Bowes, our commissioning editor, has
been a constant support. Alex Mortimer and Barbara Simmons our development
editors has managed the day-to-day work on this edition with extreme patience
and unflaggable determination to meet the ever looming deadlines, and we are
ever grateful for Kim Benson’s contribution to the online editions and additional
online supplementary materials.

Philip Xiu and Shreelata Datta

viii ALGrawany
 Contents

Series Editors’ foreword . . . . . . . . . . . . . . . . . . . . . . . . v 8 Central nervous system. . . . . . . . . . . . . . . . . . . . . 113

Prefaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi Basic concepts..........................................................113
Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . vii Parkinson disease and parkinsonism........................113
Series Editors’ acknowledgements. . . . . . . . . . . . . . . viii Dementia and Alzheimer disease...............................117
Anxiety and sleep disorders.......................................117
Sleep disorders and hypnotics..................................117
1 Introduction to pharmacology. . . . . . . . . . . . . . . . . . 1
Affective disorders.....................................................121
Molecular basis of pharmacology..................................1
Psychotic disorders...................................................125
Drug–receptor interactions............................................5
Epilepsy......................................................................129
Pharmacokinetics..........................................................8
The eye......................................................................134
Drug interactions and adverse effects.........................15
Drug history and drug development............................16 9 Drug misuse. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .139
2 Peripheral nervous system. . . . . . . . . . . . . . . . . . . .19 Definitions..................................................................139
Basic concepts............................................................19 Drugs of misuse.........................................................139
Nerve conduction.........................................................19 10 Pain and anaesthesia. . . . . . . . . . . . . . . . . . . . . . . 145
Somatic nervous system..............................................20 Basic concepts..........................................................145
Autonomic nervous system.........................................24 Opioid analgesic drugs..............................................147
Nitrergic nervous system.............................................32 Headache and neuralgic pain....................................149
3 Respiratory system. . . . . . . . . . . . . . . . . . . . . . . . . . 33 Local anaesthesia......................................................150
Basic concepts............................................................33 General anaesthesia..................................................151
Obstructive airways diseases......................................33
11 Inflammation, allergic diseases and
Antitussives and mucolytics........................................39
immunosuppression. . . . . . . . . . . . . . . . . . . . . . . . 159
Respiratory stimulants and pulmonary surfactants.....41
Inflammation..............................................................159
4 Cardiovascular system. . . . . . . . . . . . . . . . . . . . . . . 43 Inflammatory diseases...............................................162
The heart......................................................................43 Allergic disorders and drug therapy...........................168
Circulation....................................................................54 Immunosuppressants................................................170
Haemostasis and thrombosis......................................62
Treatment of thrombosis..............................................64 12 Infectious diseases. . . . . . . . . . . . . . . . . . . . . . . . . 173
Blood and fluid replacement........................................67 Antibacterial drugs.....................................................173
Antifungal drugs.........................................................186
5 Kidney and urinary system. . . . . . . . . . . . . . . . . . . . 69
Antiprotozoal drugs....................................................188
Basic concepts............................................................69
Anthelmintic drugs.....................................................192
The kidney....................................................................69
Vaccinations...............................................................194
Diuretics.......................................................................72
The urinary system.......................................................75 13 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
6 Gastrointestinal system . . . . . . . . . . . . . . . . . . . . . . 79 Concepts of cancer chemotherapy...........................195
The stomach................................................................79 Cytotoxic chemotherapy............................................195
Nausea and vomiting...................................................82 Endocrine therapy......................................................201
The intestines...............................................................84 Immunotherapy..........................................................202
The pancreas and gall bladder....................................88 The future and personalized medicine.......................203

7 Endocrine and reproductive systems. . . . . . . . . . . 91

The thyroid gland.........................................................91 Self-Assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
The endocrine pancreas and diabetes Single best answer (SBA) questions . . . . . . . . . . . . . . 207
mellitus......................................................................95 Extended-matching questions (EMQs). . . . . . . . . . . . 219
Adrenal corticosteroids..............................................100 SBA answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
The reproductive system...........................................105 EMQ answers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
Bone and calcium......................................................110 Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

ix
 Introduction to pharmacology
1
have a nonspecific mechanism of action. For this reason,
MOLECULAR BASIS OF these drugs must be given in much higher doses than the
PHARMACOLOGY more specific drugs. Another example would be antacids
used to reduce the effect of excessive acid secretion in the
What is pharmacology? stomach.
Pharmacology is the study of the actions, mechanisms, uses
and adverse effects of drugs. Transport systems
A drug is any natural or synthetic substance that alters
the physiological state of a living organism. Drugs can be Ion channels
divided into two groups. Ion channels are proteins that form pores in the cell mem-
brane and allow selective transfer of ions (charged species)
• Medicinal drugs: substances used for the prevention,
in and out of the cell. Opening or closing of these channels
treatment and diagnosis of disease.
is known as gating; this occurs as a result of the ion channel
• Nonmedicinal (social) drugs: substances used for
undergoing a change in shape. Gating is controlled either by
recreational purposes. These drugs include illegal
a neurotransmitter (receptor operated channels) or by the
substances such as cannabis, heroin and cocaine, as
membrane potential (voltage-operated channels).
well as everyday substances such as caffeine, nicotine
Some drugs modulate ion channel function directly by
and alcohol (see Chapter 9).
blocking the pore (e.g. the blocking action of local anaes-
Although drugs may have a selective action, there is always thetics on sodium channels); others bind to a part of the ion
a risk of adverse effects associated with the use of any drug, channel protein to modify its action (e.g. anxiolytics acting
and the prescriber should assess the balance of desired and on the γ-aminobutyric acid [GABA] channel). Other drugs
adverse effects when deciding which drug to prescribe. interact with ion channels indirectly via a G-protein and
other intermediates.
Drug names and classification
A single drug can have a variety of names and belong to Carrier molecules
many classes. Drugs are classified according to their: Carrier molecules located in the cell membrane facilitate
• pharmacotherapeutic actions the transfer of ions and molecules against their concentra-
• pharmacological actions tion gradients. There are two types of carrier molecule.
• molecular actions 1. Energy-independent carriers: These are transporters
• chemical nature (move one type of ion/molecule in one direction),
When a drug company's patent expires, the marketing of symporters (move two or more ions/molecules) or
the drug is open to other manufacturers. Although the ge- antiporters (exchange one or more ions/molecules for
neric name is retained, the brand names can be changed. one or more other ions/molecules).
2. Energy-dependent carriers: These are termed
pumps (e.g. the Na+/K+ adenosine triphosphatase
How do drugs work? [ATPase] pump).
Most drugs produce their effects by targeting specific cel-
lular macromolecules, often proteins. The majority act as
receptors in cell membranes, but they can also inhibit en-
Enzymes
zymes and transporter molecules. Some drugs directly Enzymes are protein catalysts that increase the rate of spe-
interact with molecular targets found in pathogens. For ex- cific chemical reactions without undergoing any net change
ample, β-lactam antibiotics are bactericidal, acting by inter- themselves during the reaction. All enzymes are potential
fering with bacterial cell wall synthesis. targets for drugs. Drugs either act as a false substrate for the
Certain drugs do not have conventional targets. For enzyme or inhibit the enzyme's activity directly, usually by
example, succimer is a chelating drug that is used to treat binding the catalytic site on the enzyme (Fig. 1.1).
heavy metal poisoning. It binds to metals, rendering them Certain drugs may require enzymatic modification. This
inactive and more readily excretable. Such drugs work by degradation converts a drug from its inactive form (prod-
means of their physicochemical properties and are said to rug) to its active form.

ALGrawany 1
 Introduction to pharmacology

1. Ligand-gated ion 2. G protein-coupled 3. Kinase-linked 4. Nuclear receptors

channels (ionic receptors) receptors (metabotropic) receptors

Ions Ions

R E R/E
R R G G
+ or − + or −

Hyperpolarization Charge Second messengers R

Protein
or inexcitability
phosphorylation Nucleus
depolarization
Gene
transcription
Gene transcription
Ca2+ release Protein Other
phosphorylation
Protein synthesis Protein synthesis

Cellular effects Cellular effects Cellular effects Cellular effects

Time scale
Milliseconds Seconds Hours Hours

Examples
Nicotinic Muscarinic Cytokine receptors Estrogen receptor
ACh receptor ACh receptor

Fig. 1.1 How ion channel enzymes work. ACh, acetylcholine. (From Rang HP, Dale MM, Ritter JM, Moore PK.
Pharmacology. 8th ed. Edinburgh: Churchill Livingstone, 2016.)

Receptors Table 1.1 The four main types of receptor and their uses

Receptors are the means through which endogenous ligands Receptor Time for Receptor Function
produce their effects on cells. A receptor is a specific protein type effect example example
molecule usually located in the cell membrane, although in- Ion Milliseconds Nicotinic Removing
tracellular receptors and intranuclear receptors also exist. channel– acetylcholine hand from
A ligand that binds and activates a receptor is an agonist. linked receptor hot water
However, a ligand that binds to a receptor but does not ac- G-protein– Seconds β-Adrenergic Airway
tivate the receptor and prevents an agonist from doing so is linked receptor smooth
called an antagonist. muscle
relaxation
The following are naturally occurring ligands.
Tyrosine Minutes Insulin Glucose
• Neurotransmitters: Chemicals released from nerve
kinase– receptor uptake into
terminals that diffuse across the synaptic cleft, and bind linked cells
to presynaptic or postsynaptic receptors.
DNA-linked Hours to Steroid Cellular
• Hormones: Chemicals that, after being released locally,
days receptor proliferation
or into the bloodstream from specialized cells, can act
at neighbouring or distant cells.
Each cell expresses only certain receptors, depending on the
function of the cell. Receptor number and responsiveness to
1. Receptors directly linked to ion
external ligands can be modulated. channels
In many cases, there is more than one receptor for each Receptors that are directly linked to ion channels (Fig. 1.2)
messenger so that the messenger often has different phar- are mainly involved in fast synaptic neurotransmission. A
macological specificity and different functions according to classic example of a receptor linked directly to an ion chan-
where it binds (e.g. adrenaline is able to produce different nel is the nicotinic acetylcholine receptor (nicAChR).
effects in different tissues because different adrenergic re- The nicAChRs possess several characteristics:
ceptors are formed of different cell types). • Acetylcholine (ACh) must bind to the N-terminal of
There are four main types of receptor (Table 1.1). both α subunits to activate the receptor.

2
 Molecular basis of pharmacology 1

N N binding domain

Binding domain
C
B

G-protein-
Channel coupling
subunit domain
Channel lining
C
Ions Fig. 1.3 General structure of the subunits of receptors
Fig. 1.2 General structure of the subunits of receptors linked to G-proteins. C, C-terminal; N, N-terminal.
directly linked to ion channels. C, C-terminal; N, N-terminal. (Modified from Page, C., Curtis, M. Walker, M, Hoffman, B.
(Modified from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) Integrated Pharmacology, 3rd edn. Mosby, 2006.)
(eds) Integrated Pharmacology, 3rd edn. Mosby, 2006.)
loop of the receptor is larger than the other loops and inter-
• The receptor shows marked similarities with the two acts with the G-protein.
other receptors for fast transmission, namely the The ligand-binding domain is buried within the mem-
GABAA and glycine receptors. brane on one or more of the α helical segments.
G-proteins
2. G-protein–linked receptors Fig. 1.4 illustrates the mechanism of G-protein–linked
G-protein–linked receptors (Fig. 1.3) are involved in rela- receptors.
tively fast transduction. G-protein–linked receptors are the
predominant receptor type in the body; muscarinic, ACh, • In resting state, the G-protein is unattached to the
adrenergic, dopamine, serotonin and opiate receptors are all receptor and is a trimer consisting of α, β and γ
examples of G-protein–linked receptors. subunits (see Fig. 1.4A).
• The occupation of the receptor by an agonist produces
Molecular structure of the receptor a conformational change, causing its affinity for the
Most of the G-protein–linked receptors consist of a single trimer to increase. Subsequent association of the trimer
polypeptide chain of 400 to 500 residues and have seven with the receptor results in the dissociation of bound
transmembrane-spanning α helices. The third intracellular guanosine diphosphate (GDP) from the α subunit.

Resting state A Receptor Ligand B

occupied

αs αs

β γ β
G GDP γ
p GTP G GDP
p G p
p p
GTP Target protein p
hydrolysed p activated p

D C

αs αs
β β
G GTP γ G GTP γ
p p
p p
p p
ATP cAMP

Fig. 1.4 Mechanism of action of G-protein–linked receptors. α, β, γ, subunits of G-protein; ATP, adenosine triphosphate;
cAMP, cyclic adenosine monophosphate; G, guanosine; GDP, GTP, guanosine di- and triphosphate; p, phosphate.
(Modified from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) Integrated Pharmacology, 3rd edn. Mosby, 2006).

ALGrawany 3
 Introduction to pharmacology

Guanosine triphosphate (GTP) replaces GDP in the ACh receptors (Gi/Go–linked) and β-adrenoreceptors (Gs-
cleft thereby activating the G-protein and causing the α linked) located in the heart produce opposite effects. The
subunit to dissociate from the βγ dimer (see Fig. 1.4B). bacterial toxins cholera and pertussis can be used to deter-
• Alpha-GTP represents the active form of the mine which G-protein is involved in a particular situation.
G-protein (although this is not always the case: in Each has enzymic action on a conjugation reaction with the
the heart, potassium channels are activated by the α subunit, such that:
βγ dimer and recent research has shown that the γ • Cholera affects Gs causing continued activation of
subunit alone may play a role in activation). This adenylyl cyclase. This explains why infection with
component diffuses in the plane of the membrane cholera toxin results in uncontrolled fluid secretion
where it is free to interact with downstream effectors from the gastrointestinal tract.
such as enzymes and ion channels. The βγ dimer • Pertussis affects Gi and Go causing continued inactivation
remains associated with the membrane owing to its of adenylyl cyclase. This explains why infection with
hydrophobicity (see Fig. 1.4C). Bordetella pertussis causes a “whooping” cough,
• The cycle is completed when the α subunit, which has characteristic of this infection, because the airways are
enzymic activity, hydrolyses the bound GTP to GDP. constricted, and the larynx experiences muscular spasms.
The GDP-bound α subunit dissociates from the effector
and recombines with the βγ dimer (see Fig. 1.4D). Targets for G-proteins
This whole process results in an amplification effect because G-proteins interact with either ion channels or secondary
the binding of an agonist to the receptor can cause the ac- messengers. G-proteins may activate ion channels directly,
tivation of numerous G-proteins, which in turn can each, for example, muscarinic receptors in the heart are linked to
via their association with the effector, produce many other potassium channels which open directly on interaction with
molecules intracellularly. the G-protein, causing a slowing down of the heart rate.
Many types of G-protein exist. This is probably attrib- Secondary messengers are a family of mediating chemicals
utable to the variability of the α subunit. Gs and Gi/Go that transduces the receptor activation into a cellular response.
cause stimulation and inhibition, respectively, of the target These mediators can be targeted, and three main secondary
enzyme adenylyl cyclase. This explains why muscarinic messenger systems exist as targets of G-proteins (Fig. 1.5).

G-protein

Target Adenylyl Guanylyl

Phospholipase C
enzymes cyclase cyclase

Second
cAMP cGMP IP3 DAG AA
messengers

+
Ca2 Eicosanoids

Protein Released
kinases PKA PKG PKC as local
hormones

Effectors Enzymes, transport Contractile Ion

proteins, etc. proteins channels

Fig. 1.5 Second-messenger targets of G-proteins and their effects. AA, arachidonic acid; cAMP, cyclic adenosine
monophosphate; cGMP, cyclic guanosine monophosphate; DAG, diacylglycerol; IP3, inositol (1,4,5) triphosphate; PK,
protein kinase.

4
 Drug–receptor interactions 1

Adenylyl cyclase/cyclic adenosine monophosphate is slow (minutes). Examples include the receptors for insulin,
s­ ystem—Adenylyl cyclase catalyses the conversion of ATP platelet-derived growth factor and epidermal growth factor.
to cyclic adenosine monophosphate (cAMP) within cells. Activation of tyrosine kinase receptors results in auto-
The cAMP produced causes activation of certain protein phosphorylation of tyrosine residues leading to the activa-
kinases, enzymes that phosphorylate serine and threonine tion of pathways involving protein kinases. These receptors
amino acid residues in various proteins, thereby producing have become important targets for certain types of antican-
either activation or inactivation of these proteins. An ex- cer drugs (see Chapter 13).
ample of this system can be observed in the activation of
β1-­adrenergic receptors found in cardiac muscle. The acti-
4. Deoxyribonucleic acid–linked receptors
vation of β1-­adrenergic receptors results in the activation of
Deoxyribonucleic acid (DNA)–linked receptors are located
cAMP-­dependent protein kinase A, which phosphorylates
intracellularly and so agonists must pass through the cell
and opens voltage-operated calcium channels. This in-
membrane to reach the receptor. The agonist binds to the
creases calcium levels in the cells and results in an increased
receptor and this receptor–agonist complex is transported
rate and force of contraction. An inhibitory example of this
to the nucleus, aided by chaperone proteins. Once in the
system can be observed in activation of opioid receptors.
nucleus, the complex can bind to specific DNA sequences
The receptor linked to the “Gi” protein inhibits adenylyl cy-
and so alter the expression of specific genes. As a result,
clase and reduces cAMP production.
transcription of this specific gene to messenger ribonu-
Phospholipase C/inositol phosphate system—Activation
cleic acid (mRNA) is increased or decreased and thus the
of M1, M3, 5-hydroxytryptamine (5-HT2), peptide and α1-­
amount of mRNA available, for translation into a protein,
adrenoreceptors, via Gq, cause activation of phospholipase
increases or decreases. The process is much slower than for
C, a membrane-bound enzyme, which increases the rate of
other receptor–ligand interactions, and the effects usually
degradation of phosphatidylinositol (4,5) bisphosphate into
last longer. Examples of molecules with DNA-linked recep-
diacylglycerol (DAG) and inositol (1,4,5) triphosphate (IP3).
tors are corticosteroids, thyroid hormone, retinoic acid and
DAG and IP3 act as second messengers. IP3 binds to the
vitamin D.
membrane of the endoplasmic reticulum, opening calcium
channels and increasing the concentration of calcium within
the cell. Increased calcium levels may result in smooth mus- HINTS AND TIPS
cle contraction, increased secretion from exocrine glands,
increased hormone or transmitter release, or increased force Drugs, like naturally occurring chemical mediators,
and rate of contraction of the heart. DAG, which remains act on receptors located in the cell membrane, in
associated with the membrane owing to its hydrophobic- the cytoplasm of the cell, or in the cell nucleus,
ity, causes protein kinase C to move from the cytosol to the to bring about a cellular, and eventually organ or
membrane where DAG can regulate the activity of the latter.
tissue, response.
There are at least six types of protein kinase C, with over
50 targets which can lead to:
• release of hormones and neurotransmitters
• smooth muscle contraction
• inflammation
• ion transport
DRUG–RECEPTOR INTERACTIONS
• tumour promotion
Most drugs produce their effects by acting on specific pro-
Guanylyl cyclase system—Guanylyl cyclase catalyses
tein molecules called receptors.
the conversion of GTP to cyclic guanosine monophosphate
Receptors respond to endogenous chemicals in the body
(cGMP). This cGMP goes on to cause activation of protein
that are either synaptic transmitter substances (e.g. ACh,
kinase G which in turn phosphorylates contractile proteins
noradrenaline) or hormones (endocrine, e.g. insulin; or lo-
and ion channels. Transmembrane guanylyl cyclase activ-
cal mediators, e.g. histamine). These chemicals or drugs are
ity is exhibited by the atrial natriuretic peptide receptor
classed in two ways.
upon the binding of atrial natriuretic peptide. Cytoplasmic
guanylyl cyclase activity is exhibited when bradykinin acti- • Agonists: Activate receptors and produce a subsequent
vates receptors on the membrane of endothelial cells to gen- response.
erate nitric oxide, which then acts as a second messenger to • Antagonists: Associate with receptors but do not
activate guanylyl cyclase within the cell. cause activation. Antagonists reduce the chance of
transmitters or agonists binding to the receptor and
3. Tyrosine kinase-linked receptors thereby oppose their action by effectively diluting or
Tyrosine kinase-linked receptors are involved in the regula- removing the receptors from the system.
tion of growth and differentiation, and responses to metabolic Electrostatic forces initially attract a drug to a recep-
signals. The response time of enzyme-initiated transduction tor. If the shape of the drug corresponds to that of the

ALGrawany 5
 Introduction to pharmacology

binding site of the receptor, then it will be held there Agonists

temporarily by weak bonds or, in the case of irreversible
antagonists, permanently by stronger covalent bonds. It Agonist (A) binds to the receptor (R) and the chemical en-
is the number of bonds and goodness of fit between drug ergy released on binding induces a conformational change
and receptor that determines the affinity of the drug for that sets off a chain of biochemical events within the cell,
that receptor, such that the greater the number of bonds leading to a response (AR*). The equation for this is:
and the better the goodness of fit, the higher the affinity
A + R (
)
→ AR (
)
1 2
will be. → AR ∗
The affinity is defined by the dissociation constant,
which is given the symbol Kd. The lower the Kd, the higher where: (1) affinity; (2) efficacy.
the affinity. Kd values in the nanomolar range represent Partial agonists cannot bring about the same maximum
drugs (D) with a high affinity for their receptor (R): response as full agonists, even if their affinity for the recep-
tor is the same (Fig. 1.6).
k+1 The ability of agonists, once bound, to activate receptors
D + R  DR is termed efficacy, such that:
k−1 • Full agonists have high efficacy and are able to produce
a maximum response while occupying only a small
The rate at which the forward reaction occurs depends on the percentage of the receptors available.
drug concentration [D] and the receptor concentration [R]: • Partial agonists have low efficacy and are unable to
elicit the maximum response even if they are occupying
Forward rate = K +1 D R  all the available receptors.

The rate at which the backward reaction occurs mainly depends Antagonists
on the interaction between the drug and the receptor [DR]: Antagonists bind to receptors but do not activate them; they
do not induce a conformational change and thus have no
Backward rate = K −1 DR  intrinsic efficacy. However, because antagonists occupy the
K d = K −1 / K +1 receptor, they prevent agonists from binding and therefore
block their action.
Ka is the association constant and is used to quantify affin- Two types of antagonist exist: competitive and non­
ity. It can be defined as the concentration of drug that pro- competitive.
duces 50% of the maximum response at equilibrium, in the
absence of receptor reserve: Competitive antagonists
Competitive antagonists bind to receptors reversibly, and
K a = 1/ K d effectively produce a dilution of the receptors such that:
Drugs with a high affinity stay bound to their receptor for • A parallel shift is produced to the right of the agonist
a relatively long time and are said to have a slow off-rate. dose–response curve (Fig. 1.7).
This means that at any time the probability that any given • The maximum response is not depressed. This reflects
receptor will be occupied by the drug is high. the fact that the antagonist's effect can be overcome
The ability of a drug to combine with one type of re- by increasing the dose of agonist, that is, the block is
ceptor is termed specificity. Although no drug is truly spe- surmountable. Increasing the concentration of agonist
cific, most exhibit relatively selective action on one type of increases the probability of the agonist taking the place
receptor. of an antagonist leaving the receptor.

Full agonist Full agonist

Full agonist (lower affinity)
Tissue response
Tissue response

Partial agonist
Partial agonist

A Agonist concentration B Log agonist concentration

Fig. 1.6 Comparison of a partial agonist and a full agonist showing (A) the dose–response curve and (B) the log dose–
response curve. (From Neal MJ. Medical Pharmacology at a Glance, 6th edition. Wiley-Blackwell, 2009.)

6
 Drug–receptor interactions 1

overcome by the addition of greater doses of agonist. At

low concentrations, however, a parallel shift may occur
Agonist alone without a reduced maximum response. This tells us
Tissue response

Agonist and that not all the receptors need to be occupied to elicit
competitive antagonist
Agonist and irreversible a maximum response because irreversible antagonists
antagonist (low dose) effectively remove receptors, there must be a number of
Agonist and irreversible spare receptors.
antagonist (high dose)

Receptor reserve
Log agonist concentration
Although on a log scale the relation between the concen-
Fig. 1.7 Comparison of the log dose–response curves for tration of agonist and the response produces a symmetric
competitive and noncompetitive (irreversible) antagonists. ­sigmoid curve, rarely does a 50% response correspond to 50%
(From Neal MJ. Medical Pharmacology at a Glance, 6th receptor occupancy. This is because there are spare receptors.
edition. Wiley-Blackwell, 2009.)
This excess of receptors is known as receptor reserve and
• The size of the shift in the agonist dose–response curve serves to sharpen the sensitivity of the cell to small changes in
produced by the antagonist reflects the affinity of the agonist concentration. The low efficacy of partial agonists can
antagonist for the receptor. High-affinity antagonists be overcome in tissues with a large receptor reserve and in
stay bound to the receptor for a relatively long period these circumstances, partial agonists may act as full agonists.
of time allowing the agonist little chance to take the Potency
antagonist's place. Potency relates to the concentration of a drug needed to
This concept can be quantified in terms of the dose ratio elicit a response. The EC50, where EC stands for effective
(known as a Schild plot). The dose ratio is the ratio of the concentration, is a number used to quantify potency. EC50
concentration of agonist producing a given response in the is the concentration of drug required to produce 50% of
presence and absence of a certain concentration of antago- the maximum response. Thus the lower the EC50, the more
nist, for example, a dose ratio of 3 tells us that three times potent the drug. For agonists, potency is related to both af-
as much agonist was required to produce a given response finity and efficacy, but for antagonists, only affinity is con-
in the presence of the antagonist than it did in its absence. sidered because they have no efficacy (Table 1.2).
Other variables can affect the efficacy of a drug beyond
its potency. For example, if a potent drug in vitro is metab-
CLINICAL NOTE olized in the stomach or affected by the pH in the stomach,
less would be available to reach the target site. This means
A 22-year-old man is admitted to hospital with
that, if given as a tablet, it would be less than the in vitro
signs of respiratory depression, drowsiness,
potency predicted.
bradycardia and confusion. His girlfriend tells the • Thus the effectiveness of a drug (Pharmacodynamics:
medical team that he uses heroin and an overdose the biological effect of the drug on the body) is
is therefore suspected. Heroin acts as an agonist, influenced by many factors which are covered by the
activating the opioid receptors. Naloxone is a term pharmacokinetics: the way the body affects the
competitive antagonist at those receptors and so is drug with time, that is, the factors that determine its
administered as treatment. Minutes later the man's absorption, distribution, metabolism and excretion.
condition improves, and his respiratory rate returns
to normal. Careful titration of the naloxone dose
should allow treatment of respiratory depression Table 1.2 Key definitions
without provoking acute withdrawal signs. Definition Explanation
Affinity Number of bonds and goodness of
fit between drug and receptor.
Agonist A ligand that binds and activates a
Noncompetitive antagonists receptor.
Noncompetitive antagonists are also known as irreversible Antagonist A ligand that binds to but does not
antagonists. activate a receptor. Prevents an
agonist from binding.
• Noncompetitive antagonists also produces a parallel
shift to the right of the agonist dose–response curve Efficacy The ability of agonists, once bound,
to activate receptors.
(see Fig. 1.7).
• Their presence depresses the maximum response, Potency Concentration of a drug needed to
reflecting the fact that the antagonist's effect cannot be elicit a response.

ALGrawany 7
 Introduction to pharmacology

gastrointestinal tract, or if the efficacy of absorption

PHARMACOKINETICS from the gastrointestinal tract is uncertain (e.g.
vomiting or diarrhoea).
Pharmacology can be divided into two disciplines. These are:
• In addition, absorption of drugs via the buccal or
Pharmacokinetics and Pharmacodynamics
sublingual route avoids the hepatoportal circulation
and is, therefore valuable when administering drugs
Administration subject to a high degree of first-pass metabolism (which
The drug can be administered by a variety of routes. is unavoidable if taken orally). It is also useful for potent
drugs with a nondisagreeable taste, such as sublingual
Topical nitroglycerin given to relieve acute attacks of angina.
Topical drugs are applied where they are needed, giving them • Also, administration of drugs rectally, such as in the
the advantage that they do not have to cross any barriers or form of suppositories, means that there is less first-pass
membranes. This means a higher concentration of the drug metabolism by the liver because the venous return from
in the target tissue, with less drug being absorbed into the sys- the lower gastrointestinal tract is less than that from
temic circulations and therefore less likelihood of unwanted the upper gastrointestinal tract. It has the disadvantage,
side effects. Examples include skin ointments; ear, nose or eye however, of being inconsistent.
drops; and aerosols inhaled in the treatment of asthma.

Enteral Parenteral
Enteral administration means that the drug reaches its Parenteral administration means that the drug is adminis-
target via the gut. This is the least predictable route of ad- tered in a manner that avoids the gut. The protein drug in-
ministration, owing to potential metabolism by the liver sulin, for example, is destroyed by the acidity of the stomach
following absorption into the hepatoportal circulation (so and the digestive enzymes within the gut and must, there-
called first pass metabolism)(Fig. 1.8), chemical breakdown fore be injected, usually subcutaneously.
and possible binding to food within the gastrointestinal Intravenous injection of drugs is sometimes used and
tract. Drugs must cross several barriers, which may or may has several advantages.
not be a problem according to their physicochemical prop- • It is the most direct route of administration. The drug
erties, such as charge and size. enters the bloodstream directly and thus bypasses
• However, most drugs are administered orally unless absorption barriers.
the drug is unstable, or is rapidly inactivated in the • A drug is distributed in a large volume and acts rapidly.

Heart
Inferior vena Abnormal
cava aorta

Hepatic Proper hepatic

veins artery

Splenic Tributarires from portions

vein of stomach, pancreas, and
portions of large intestine

Hepatic
Liver portal
vein

Superior Tributaries from small

mesenteric intestines and portions
vein of large intestine,
stomach, and pancreas
Fig. 1.8 The hepatoportal circulation and arterial supply and venous drainage of liver.

8
 Pharmacokinetics 1

For drugs that must be given continuously by infusion, or For basic molecules:
for drugs that damage tissues, this is an important method
of administration. BH +  B + H +
Alternative parenteral routes of administration include pK a = pH + log[BH + ]/[B]
subcutaneous, intramuscular, epidural or intrathecal injec-
tions, as well as transdermal patches. Drugs will tend to exist in the ionized form when exposed
Binding the drug to a vehicle or coadministering a va- to an environment with a pH opposite to their own state.
soconstrictor, such as adrenaline, to reduce blood flow to Therefore acids become increasingly ionized with increas-
the site can decrease the rate of drug absorption from the ing pH (i.e. basic).
site of the injection. This approach is commonly used in It is useful to consider three important body compart-
the administration of local anaesthetics and the presence ments to plasma (pH = 7.4), stomach (pH = 2) and urine
of adrenaline in proportions of local anaesthetics has the (pH = 8). Examples include the following.
added benefit of reducing bleeding by reducing blood flow • Aspirin is a weak acid (pKa= 3.5) and its absorption
when used in dental procedures or when carrying out skin will therefore be favoured in the stomach, where it is
biopsies. uncharged, and not in the plasma or the urine, where
it is highly charged; aspirin in high doses may even
Drug absorption damage the stomach.
• Morphine is a weak base (pKa = 8.0) that is highly
Bioavailability takes into account both absorption and charged in the stomach, quite charged in the plasma,
metabolism and describes the proportion of the drug that and half charged in the urine. Morphine can cross
passes into the systemic circulation. This will be 100% after the blood–brain barrier but is poorly and erratically
an intravenous injection, but following oral administration, absorbed from the stomach and intestines, and
it will depend on the physiochemical characterizations of metabolized by the liver; it must, therefore be given by
the drug, the individual and the circumstances under which injection or delayed-release capsules.
the drug is given. • Some drugs, such as quaternary ammonium
Drugs must cross membranes to enter cells or to transfer compounds (e.g. suxamethonium, tubocurarine), are
between body compartments; therefore drug absorption will always charged and must, therefore be injected or
be affected by both physiochemical and physiological factors. inhaled (e.g. tiotropium bromide).

Cell membranes
Cell membranes are composed of lipid bilayers and thus Drug distribution
absorption is usually proportional to the lipid solubility Once drugs have reached the circulation, they are distrib-
of the drug. Unionized molecules (B) are far more solu- uted around the body. Because most drugs have a very small
ble than those that are ionized (BH+) and surrounded by molecular size, they can leave the circulation by capillary
a “shell” of water. filtration to act on the tissues.
The half-life of a drug (t½) is the time taken for the
B + H +  BH +
plasma concentration of that drug to fall to half of its origi-
nal value. Bulk transfer in the blood is very quick.
Size • Drugs exist either dissolved in the blood or bound
Small molecular size is another factor that favours absorp- to plasma proteins such as albumin. Albumin is the
tion. Most drugs are small molecules that are able to diffuse most important circulating protein for binding many
across membranes in their uncharged state. acidic drugs.
pH—Because most drugs are either weak bases, weak • Drugs that are basic tend to be bound to a globulin
acids or amphoteric, the pH of the environment in which fraction that increases with age. A drug that is bound is
they dissolve, as well as the pKa value of the drug, will be confined to the vascular system and is unable to exert
important in determining the fraction in the unionized its actions; this becomes a problem if more than 80% of
form that is in solution and able to diffuse across cell mem- the drug is bound.
branes (see Fig. 1.9). The pKa of a drug is defined as the pH • Drugs can interact, and one drug may displace another.
at which 50% of the molecules in solution are in the ionized For example, aspirin can displace the benzodiazepine
form, and is characterized by the Henderson–Hasselbalch diazepam from albumin.
equation:
For acidic molecules: The apparent volume of distribution (Vd) is the calcu-
lated pharmacokinetic space in which a drug is distributed.
HA  H + + A − dose administered
Vd =
pK a = pH + log [HA]/[A {] initial apparent plasma concentration

ALGrawany 9
 Introduction to pharmacology

Gastric juice Plasma Urine

pH 3 pH 7.4 pH 8

>400

Aspirin
pH
ka line
Weak acid t al
pKa 3.5 st a Anion
re ate A–
ng
is atio
Ion
100
Undissociated
Relative concentration

acid
<0.1 AH

>106

Ion
isat
ion
gre
ate
Pethidine st a
t ac
id p
H
Weak base
pKa 8.6

100 Protonated
base Free
BH+ base B
30

Fig. 1.9 Theoretic partition of a weak acid (aspirin) and a weak base (pethidine) between aqueous compartments (urine,
plasma, and gastric juice) according to the pH difference between them. (From Rang HP, Dale MM, Ritter JM, Moore PK.
Pharmacology. 8th ed. Edinburgh: Churchill Livingstone, 2016.)

• Vd values that amount to less than a certain body

compartment volume indicate that the drug is CLINICAL NOTE
contained within that compartment. For example, Anaesthetists need to consider the weight of
when the volume of distribution is less than 5 L, it is
their patient before administering thiopental
likely that the drug is restricted to the vasculature.
given that it is a highly lipid soluble medication
• Vd values less than 15 L implies that the drug is
restricted to the extracellular fluid. that will accumulate in the fat of obese patients
• Vd values greater than 15 L suggests distribution and thus have a longer half-life than in a thinner
within the total body water. Some drugs (usually patient.
basic) have a volume of distribution that exceeds
body weight, in which case tissue binding is
occurring. These drugs tend to be contained
outside the circulation and may accumulate in
certain tissues. Very lipid-soluble substances,
Drug metabolism
such as thiopental, can build up in fat. Mepacrine, Before being excreted from the body, most drugs are me-
an antimalarial drug, has a concentration in the tabolized. A small number of drugs exist in their fully ion-
liver 200 times that in the plasma because it binds ized form at physiological pH (7.4) and, owing to this highly
to nucleic acids. Some drugs are even actively polar nature, are metabolized to only a minor extent, if at
transported into certain organs, for example, iodine all. The sequential metabolic reactions that occur have been
hormones accumulate in the thyroid. categorized as phases 1 and 2.

10
 Pharmacokinetics 1

Sites of metabolism Phase 1 metabolic reactions

The liver is the major site of drug metabolism although Phase 1 metabolic reactions include oxidation, reduction
most tissues can metabolize specific drugs. Other sites of and hydrolysis. These reactions introduce a functional
metabolism include the kidney, the lung and the gastroin- group, such as OH– or NH2, which increases the polar-
testinal tract. Diseases of these organs may therefore affect a ity of the drug molecule and provides a site for phase 2
drug's pharmacokinetics. reactions.
Orally administered drugs, which are usually absorbed
in the small intestine, reach the liver via the portal circula- Oxidation
tion. At this stage, or within the small intestine, the drugs Oxidations are the most common type of reaction and are
may be extensively metabolized; this is known as the first- catalysed by an enzyme system known as the microsomal
pass metabolism and means that considerably less drug mixed function oxidase system, which is located on the
reaches the systemic circulation than enters the portal vein smooth endoplasmic reticulum. The enzyme system forms
(see Fig. 1.10). This causes problems because it means that small vesicles known as microsomes when the tissue is
higher doses of the drug must be given and, owing to indi- homogenized.
vidual variation in the degree of the first-pass metabolism, • Cytochrome P450 is the most important enzyme, although
the effects of the drug can be unpredictable. Drugs that are other enzymes are involved. This enzyme is a haemoprotein
subject to a high degree of the first-pass metabolism, such that requires the presence of oxygen, reduced nicotinamide
as the local anaesthetic lidocaine, cannot be given orally and adenine dinucleotide phosphate (NADPH) and NADPH
must be administered by some other route. cytochrome P450 reductase to function.

Inferior vena cava

Hepatic
Spleen
Liver
Hepatic portal Short gastric
Left gastric
Cystic
Stomach
Pancreaticoduodenal
Right gastric
Gallbladder
Pancreatic

Duodenum Left gastroepiploic

Pancreas Right gastroepiploic

Superior mesenteric Splenic
Middle colic
Left colic
Transverse colon
Inferior mesenteric
Right colic
Jejunal and ileal
Descending colon
Ascending colon

Ileocolic Sigmoidal

Ileum Sigmoid colon

Cecum Superior rectal
Appendix

Rectum
Drain into superior mesenteric vein
Drain into splenic vein
Drain into inferior mesenteric vein
Fig 1.10 Portal venous system.

ALGrawany 11
 Introduction to pharmacology

• It exists in several hundred isoforms, some of which are • Smokers can show increased metabolism of certain
constitutive, whereas others are synthesized in response drugs because of the induction of cytochrome P448 by a
to specific signals. The substrate specificity of this constituent in tobacco smoke.
enzyme depends on the isoform but tends to be low, • In contrast, some drugs inhibit microsomal enzyme
meaning that a whole variety of drugs can be oxidized. activity and therefore increase their own activity as well
Although oxidative reactions usually result in inactiva- as that of other drugs.
tion of the drug, sometimes a metabolite is produced that is Table 1.3 gives some examples of enzyme-­inducing agents,
pharmacologically active and may have a duration of action and the drugs whose metabolism is affected. Competition
exceeding that of the original drug. In these cases, the drug for a metabolic enzyme may occur between two drugs, in
is known as a prodrug, for example, codeine that is demeth- which case there is a decreased metabolism of one or both
ylated to morphine. drugs. This is known as inhibition.
Enzymes that metabolize drugs are affected by many as-
Reduction pects of diet, such as the ratio of protein to carbohydrate,
Reduction reactions also involve microsomal enzymes but flavonoids contained in vegetables, and polycyclic aromatic
are much less common than oxidation reactions. An exam- hydrocarbons found in barbequed foods.
ple of a drug subject to reduction is prednisone, which is
given as a prodrug and reduced to the active glucocorticoid
Overdose
prednisolone.
Drugs that are taken at 2 to 1000 times their therapeutic
Hydrolysis dose can cause unwanted and toxic effects. Paracetamol can
Hydrolysis is not restricted to the liver and occurs in a va- be lethal at high doses (2–3 times the maximum therapeutic
riety of tissues. Aspirin is spontaneously hydrolysed to sali- dose), owing to the accumulation of its metabolites.
cylic acid in moisture. In phase 2 of the metabolic process, paracetamol is
conjugated with glucuronic acid and sulphate. When high
doses of paracetamol are ingested, these pathways be-
Phase 2 metabolic reactions come saturated and the drug is metabolized by the mixed
Drug molecules possessing a suitable site that was either
present before phase 1 or is the result of a phase 1 reaction,
are susceptible to phase 2 reactions. Phase 2 reactions in- Table 1.3 Examples of drugs that induce or inhibit
drug-metabolizing enzymes
volve conjugation, the attachment of a large chemical group
to a functional group of the drug molecule. Conjugation Drugs modifying enzyme Drugs whose metabolism
results in the drug being more hydrophilic and thus more action is affected
easily excreted from the body. Enzyme induction
• In conjugation it is mainly the liver that is involved, Phenobarbital and other Warfarin
although conjugation can occur in a wide variety of tissues. barbiturates
• Chemical groups involved are endogenous activated Rifampicin Oral contraceptives
moieties such as glucuronic acid, sulphate, methyl,
Phenytoin Corticosteroids
acetyl and glutathione.
• The conjugating enzymes exist in many isoforms and Ethanol Cyclosporine
show relative substrate and metabolite specificity. Carbamazepine
Unlike the products of phase 1 reactions, the conjugate Enzyme inhibition
is almost invariably inactive. An important exception is Allopurinol Azathioprine
morphine, which is converted to morphine 6-glucuronide,
Chloramphenicol Phenytoin
which has an analgesic effect lasting longer than that of its
parent molecule. Corticosteroids Various drugs—TCA,
cyclophosphamide
Cimetidine Many drugs—amiodarone,
Factors affecting metabolism phenytoin, pethidine
Enzyme induction is the increased synthesis or decreased
degradation of enzymes and occurs as a result of the MAO inhibitors Pethidine
­presence of an exogenous substance. Examples include the Erythromycin Cyclosporine
following. Ciprofloxacin Theophylline
• Some drugs can increase the activity of certain MAO, monoamine oxidase; TCA, tricyclic antidepressant.
isoenzyme forms of cytochrome P450 and thus increase Modified from Rang et al. 2012 Pharmacology, 7th edition,
their own metabolism, as well as that of other drugs. Churchill Livingstone.

12
 Pharmacokinetics 1

function oxidases. This results in the formation of the toxic out by the kidneys and, unlike glomerular filtration,
metabolite N-acetyl-p-benzoquinone which is inactivated allows the clearance of drugs bound to plasma proteins.
by glutathione. However, when glutathione is depleted, this Competition between drugs that share the same
toxic metabolite reacts with nucleophilic constituents in the transport mechanism may occur, in which case the
cell leading to necrosis in the liver and kidneys. excretion of these drugs will be reduced.
N-Acetylcysteine or methionine can be administered in • Reabsorption of a drug will depend upon the fraction
cases of paracetamol overdose, because these increase liver glu- of molecules in the ionized state, which is in turn
tathione formation and the conjugation reactions, respectively. dependent on the pH of the urine.
• Renal disease will affect the excretion of certain drugs.
Drug excretion The extent to which excretion is impaired can be
deduced by measuring 24-hour creatinine clearance.
Drugs are excreted from the body in a variety of different
ways. Excretion predominantly occurs via the kidneys into
urine or by the gastrointestinal tract into bile and faeces. Gastrointestinal excretion
Volatile drugs are predominantly exhaled by the lungs into Some drug conjugates are excreted into the bile and subse-
the air. To a lesser extent, drugs may leave the body through quently released into the intestines where they are hydro-
breast milk and sweat. lysed back to the parent compound and reabsorbed. This
The volume of plasma cleared of drug per unit time is “enterohepatic circulation” prolongs the effect of the drug.
known as the clearance.

Renal excretion HINTS AND TIPS

Glomerular filtration, tubular reabsorption (passive and
active), and tubular secretion all determine the extent to The liver is the main site of drug inactivation, and
which a drug will be excreted by the kidneys. the kidneys and gastrointestinal tract the main sites
Glomerular capillaries allow the passage of molecules with for drug excretion. Disease of these organs will
a molecular weight less than 20 000. The glomerular filtrate alter the pharmacokinetics of a drug.
thus contains most of the substances in plasma except proteins.
• In the glomerular capillaries the negative charge of
the corpuscular membrane repels negatively charged
molecules, including plasma proteins. Mathematic aspects of
• In addition, drugs that bind to plasma proteins such as pharmacokinetics
albumin will not be filtered.
Most of the drug in the blood does not pass into the glo- Kinetic order
merular filtrate but passes into the peritubular capillaries of Two types of kinetics, related to the plasma concentra-
the proximal tubule where, depending on its nature, one of tion of a drug, describe the rate at which a drug leaves
two transport mechanisms will transport it into the lumen the body.
of the tubule. One transport mechanism deals with acidic • Zero-order kinetics (Fig. 1.11A) describes a decrease
molecules, the other with basic molecules. in drug levels in the body that is independent of the
• In the peritubular capillaries tubular secretion is plasma concentration, and the rate is held constant by a
responsible for most of the drug excretion carried limiting factor, such as a cofactor of enzyme availability.
Plasma concentration

First order
Plasma concentration

Zero order
of drug
of drug

t1/2 t1/2
time Time
A B
Fig. 1.11 Plasma drug concentration versus time plot. (A) For a drug displaying zero-order kinetics. (B) For a drug
displaying first-order kinetics. t ½, half-life.

ALGrawany 13
 Introduction to pharmacology

When the plasma concentration is plotted against time, If the drug is not administered parenterally, plotting the
the decrease is a straight line. Alcohol is an example of log plasma drug concentration against time will require the
a drug that displays zero-order kinetics. consideration of both absorption and elimination from the
• First-order kinetics (Fig. 1.11B) is displayed by most compartment (Fig. 1.12B).
drugs. It describes a decrease in drug levels in the The one-compartment model is widely used to deter-
body that is dependent on the plasma concentration mine the dose of the drug to be administered. The two-­
because the concentration of the substrate (drug) is the compartment model expands on this model by considering
rate-limiting factor. When the plasma concentration is the body as two compartments to allow some consideration
plotted against time, the decrease is exponential. of drug distribution.

One-compartment model Model-independent approach

The one-compartment model usually gives an adequate For drugs displaying first-order kinetics, the level of the
clinical approximation of drug concentration by consider- drug in the body increases until it is equal to the level ex-
ing the body to be a single compartment. Within this single creted, at which point steady-state is reached (Fig. 1.13),
compartment, a drug is absorbed, immediately distributed, such that:
and subsequently eliminated by metabolism and excretion. • The time to reach steady-state is usually equal to four
If the volume of the compartment is Vd and the dose to five half-lives.
administered D, then the initial drug concentration, Co, • The amount of drug in the body at steady-state will
will be: depend upon the frequency of drug administration:
the greater the frequency, the greater the amount of
C o = D / Vd
drug and the less the variation between peak and
The time taken for the plasma drug concentration to fall trough plasma concentrations. If the frequency of
to half of its original value is the half-life of that drug. The administration is greater than the half-life, then an
decline in concentration may be exponential, but this situ- accumulation of the drug will occur.
ation expresses itself graphically as a straight line when the The loading dose can be calculated according to the de-
log plasma concentration is plotted against the time after sired plasma concentration at steady-state (Css) and the vol-
intravenous dose (Fig. 1.12A). ume of distribution (Vd) of the drug:
Half-life is related to the elimination rate constant (Kel)
by the following equation: Loading dose ( mg / kg ) = Vd ( L / kg ) × C ss ( mg / L )

t1/2 × K el = natural log 2 ( ln 2 )

Adherence
Half-life is related to Vd, but does not determine the ability
of the body to remove the drug from the circulation, be- Lastly, despite not being a pharmacological property, it is im-
cause both Vd and half-life change in the same direction. portant to consider adherence. For some drugs to be effec-
The body's ability to remove a drug from the blood is tive (e.g. antibiotics), they must be taken at regular intervals
termed clearance (Clp) and is constant for individual drugs. and for a certain period of time. Adherence can be an issue
in paediatric and elderly patients. With children, parents
Cl p = Vd × K el must remember to give the medicine and follow ­directions

10.0
10 Co
Co
Log plasma concentration

Log concentration

Slope = Kel Slope = Kel

1 1.0
of drug

t1/2

0.1 0.1
5 10 15 20 25 50 0 5 10 15 20 25
A Time B Time
Fig. 1.12 Log plasma drug concentration versus time plot for a drug compatible with the one-compartment open
pharmacokinetic model for drug disposition. (A) After a parenteral dose, assuming first-order kinetics. (B) After an oral
dose. Co, initial drug concentration; Kel, elimination rate constant. (modified from Page, C., Curtis, M. Walker, M, Hoffman,
B. (eds) Integrated Pharmacology, 3rd edn. Mosby, 2006.)

14
 Drug interactions and adverse effects 1

10 salbutamol, a β2-adrenoceptor agonist given for the

treatment of asthma. The administration of beta-
blockers to asthmatics should therefore be avoided, or
Log concentration

undertaken with caution.

• Administration of monoamine oxidase inhibitors, which
inhibit the metabolism of catecholamines, enhances the
effects of drugs such as ephedrine. This enhancement
causes the release of noradrenaline from stores in the
1 nerve terminal and is known as potentiation.
0 5 10 15 20 25 30 35 40
Time
Fig. 1.13 Log plasma drug concentration versus time plot
Pharmacokinetic interactions
for a drug administered by mouth every 6 hours when its Absorption, distribution, metabolism and excretion all
terminal disposition half-life is 6 hours. affect the pharmacokinetic properties of drugs. Thus any
drug that interferes with these processes will be altering the
a­ ccurately; the child must cooperate and not spit out or spill effect of other drugs.
the medicine. Similarly, elderly patients’ capacity to under- • If administered with diuretics, nonsteroidal
stand and remember to take their medicines must be ascer- antiinflammatory drugs (NSAIDs) will reduce the
tained, as well as their physical ability to carry out the task. antihypertensive action of these drugs. NSAIDs bring
For example, an elderly patient with arthritis may struggle to about this effect by reducing prostaglandin synthesis
administer medicines unaided. Furthermore, adherence is in the kidney, thus impairing renal blood flow and
limited if patients are required to take several medications. consequently decreasing the excretion of waste and
Practical dosage forms are important in achieving ad- sodium. This results in an increased blood volume and
herence. Many tablets are now sugar coated, making them a rise in blood pressure.
easier to take, and a large number of the drugs manufac- • Enzyme induction, which occurs as a result of the
tured for children are in the form of elixirs or suspensions, administration of certain drugs, can affect the metabolism
which may be available in a variety of different flavours, of other drugs served by that enzyme (see Table 1.3).
making their administration less of a problem. In some cases, however, drugs are used together so that
The route of administration of a drug may affect adher- their interaction can bring about the desired effect.
ence. Taking a drug orally, for example, is simpler than in-
jecting it. The wide variety of devices available to deliver • For example, carbidopa is a drug used in conjunction
inhaled drugs are often challenging because this may re- with levodopa (l-dopa) in the treatment of Parkinson
quire good coordination to work properly, something the disease. l-Dopa, which is converted to dopamine in
young, infirm and elderly find difficult. the body, can cross the blood–brain barrier. Carbidopa
The dosing schedule is also an important aspect of ad- prevents the conversion of l-dopa to dopamine;
herence. The easier this is to follow, and the less frequently however, it cannot cross the blood–brain barrier and
a drug needs to be taken or administered, the more likely so acts to reduce the peripheral side effects while still
adherence will be achieved. allowing the desired effects of the drug.

DRUG INTERACTIONS AND CLINICAL NOTE

ADVERSE EFFECTS
Mr Abbas is a 66-year-old man who takes metoprolol,
a β-blocker, for his hypertension. He had a myocardial
Drug interactions
infarction 2 days ago and has now developed
Drugs interact in a number of ways that may produce un- ventricular tachycardia (a type of cardiac arrhythmia).
wanted effects. Two types of interactions exist: pharmaco- He was given amiodarone (a class III antiarrhythmic
dynamic and pharmacokinetic. agent) to slow down his heart rate. Because
amiodarone inhibits the cytochrome P450 enzymes
Pharmacodynamic interactions responsible for breaking down metoprolol, there is
Pharmacodynamic interactions involve a direct conflict a risk that the plasma concentration of metoprolol
between the effects of drugs. This conflict results in the
would be higher than expected. The prescribing
effect of one of the two drugs being enhanced or reduced.
doctor, therefore needs to monitor for an excessive
Examples include the following.
slow beating of the heart and for heart block.
• Propranolol, a β-adrenoceptor antagonist given for
angina and hypertension, will reduce the effect of

ALGrawany 15
 Introduction to pharmacology

Adverse effects DRUG HISTORY AND DRUG

As well as interacting with one another and with their target DEVELOPMENT
tissue, drugs will also interact with other tissues and organs
and alter their function. No drug is without side effects, al- Drug history
though the severity and frequency of these will vary from
drug to drug and from person to person. A patient's drug history is a crucial component of the clerk-
The liver and the kidneys are susceptible to the ad- ing process, because drug effects account for a significant
verse effects of drugs, as these are the sites of drug metab- proportion of hospital admissions, and potential drug inter-
olism and excretion. Some drugs cause hepatotoxicity or actions and adverse events are crucial to foresee.
nephrotoxicity. A complete list of the names and doses of prescribed
Some people are more prone to the adverse effects of drugs taken by the patient (noting the proprietary and
drugs. the generic name, for example, Viagra and sildenafil, re-
spectively) and any other medications or supplements
• Pregnant women must be careful about taking certain
they may have bought themselves over the counter at a
medications that are teratogenic, that is, cause foetal
pharmacy should be documented. Women often forget
malformations (e.g. thalidomide taken in the 1960s for
the contraceptive pill and hormone replacement ther-
morning sickness).
apy and should be sensitively questioned about these.
• Breastfeeding women must also be careful about which
NSAIDs and paracetamol are often taken by patients
drugs they take, because many drugs can be passed on
with arthritis and should be specifically asked about.
in the breast milk to the developing infant.
Make sure to note how often the drugs were taken, and
• Patients with an underlying illness, such as liver
at what times.
or kidney disease. These illnesses will result in
If presented with numerous bottles and packets of tab-
decreased metabolism and excretion of the drug and
lets, ensure they all belong to the patient, and not the part-
will produce the side effects of an increased dose of the
ner of the patient, or to someone else. Always ask the patient
same drug.
if they are taking all their medicines as prescribed.
• Elderly people who tend to take a large number of
Occasionally, it is useful to know what drugs have been
drugs have an increased risk of drug interactions and
taken in the recent and distant past; for example, mono-
the associated side effects. In addition, elderly patients
amine oxidase inhibitors should be stopped at least 3 weeks
have a reduced renal clearance and a nervous system
before starting a different antidepressant therapy.
that is more sensitive to drugs. The dose of drug
Previous adverse reaction to drugs, and to nondrug
initially given is usually 50% of the adult dose, and
products such as latex, is essential to ascertain. Explore what
certain drugs are contraindicated.
happened to the patient, and what was done about it. An
• Children, like the elderly, are at an increased risk of
upset stomach a day after taking penicillin is a common side
toxicity because of immature clearance systems.
effect, and is not grounds for choosing another antibiotics
• Patients with genetic enzyme defects, such as glucose
when treating a penicillin-sensitive infection in the future.
6-phosphate dehydrogenase deficiency. The deficiency
A widespread cutaneous rash and difficulty breathing
will result in haemolysis if an oxidant drug, such as
which required adrenaline and a hospital admission sug-
aspirin, is taken.
gests an allergic drug reaction and therefore this, or any re-
Certain drugs are carcinogenic, that is, induce cancer. lated drug should be clearly avoided in the future. Allergy
Allergic reactions to certain drugs are common, occurring in to drugs should be clearly marked in the patient's notes and
2% to 25% of cases. Most of these are not serious, for exam- drug charts.
ple, skin reactions; however, rarely, reactions such as anaphy- The family history of adverse drug reactions is usually
lactic shock (type 1 hypersensitivity) occur that may be lethal, confined to the anaesthetic history, where the concern is
unless treated with intramuscular adrenaline. The most com- largely in relation to the muscle-relaxing drugs, particularly
mon allergic reaction is to penicillin, which produces an ana- suxamethonium.
phylactic shock in approximately 1 in 50,000 people. A history of recreational or illicit drug use is an import-
ant but sensitive issue to approach. One must use discretion
when questioning the patient. A history of smoking should
HINTS AND TIPS also be established.
Knowledge about any hepatic or renal disease and gen-
Adverse reactions and allergy to a drug are eral health problems is important when it comes to man-
different. Adverse reactions are usually minor agement and prescribing, as are specific considerations,
irritations, whereas an allergic reaction can be life such as not prescribing aspirin in peptic ulcer disease, or
threatening. oestrogen to patients with oestrogen-dependent cancers.
These aspects are usually brought to light in the rest of the
history taking.
16
 Drug history and drug development 1

Table 1.4 The five stages of drug development and

HINTS AND TIPS
monitoring
The salient points of the drug history are: Main aims/means
• current and previous drugs and their doses Phase of investigation Subjects
• adverse drug reactions and allergies Preclinical Pharmacology In vitro
• family history of allergies Toxicology In laboratory
• recreational drug use animals
• existing renal or hepatic and general disease. Phase 1 Clinical Healthy individuals
pharmacology and and/or patients
toxicology
Drug metabolism
Drug development and bioavailability

Hundreds of thousands of substances have been produced Evaluate safety

by the pharmaceutical industry over the past 50 years, al- Phase 2 Initial treatment Small numbers of
though very few ever get past preclinical screening, and studies patients
fewer than 10% of these survive clinical assessment. Evaluate efficacy
There are four stages a potential drug goes through from Phase 3 Large randomized Large numbers of
discovery to being approved (Table 1.4). controlled trials patients
Phase 4 can be regarded as an ongoing phase, where
Comparing new to
drugs are monitored once licensed for general use. By old treatments
this stage, the efficacy and dose–response relationship are
Evaluate safety and
known, although the side-effect profile is often incomplete,
efficacy
and information is gathered on these “adverse reactions”
which are caused by, or likely caused by new drugs. Phase 4 Postmarketing All patients
surveillance prescribed the
In the United Kingdom, this is known as the yellow card
drug
scheme. The British National Formulary (BNF) contains
detachable yellow cards, which medical staff complete, doc- Long-term safety
and rare events
umenting adverse drug reactions in their patients, which
can then be forwarded to the Medicines Control Agency. Yellow card
The Medicines Control Agency collates these data and uses scheme
them for surveillance of common or severe adverse effects.
The data are publicized in future copies of the BNF, or used
in the reassessment of certain drug licences.

Chapter Summary

• Drugs can produce their effects by targeting specific cellular macromolecules, often proteins.
The majority act via receptors in cell membranes but they can also work on transporter
molecules and enzymes.
• Interaction with ligand-gated ion channels (ionic receptors) results in hyperpolarization or
depolarization. Interaction with G protein-coupled receptors (metabotropic) results in
secondary messenger involvement and either calcium release or protein phosphorylation.
Kinase-linked receptor activation results in protein phosphorylation which induces gene
transcription and protein synthesis. Nuclear receptor activation results in gene transcription
and protein synthesis.
• Drugs can be administered topically, enterally, or parenterally. Drug excretion, metabolism and
dosage can be modelled by pharmacokinetics to relate to plasma concentration of a drug.
• Drugs can interact in unwanted ways, involving pharmacokinetics and pharmacodynamics.
Adverse drug effects stem from the drug interacting with tissues and organs to alter their
function. Adverse reactions are usually minor, whereas allergic reactions can be life-threatening.
• Drug development is divided into preclinical and then 4 subsequent phases involving ever larger
trials. Phase 4 is postmarketing surveillance and is always ongoing once the drug is in the market.

ALGrawany 17
This page intentionally left blank
 Peripheral nervous system
2
Extracellular
BASIC CONCEPTS
K+ 3 Na+
4 mmol 145 mmol
The nervous system consists of the peripheral nervous sys-
K+ Na+
tem (PNS), which consists of the nerves and ganglia outside
of the brain and spinal cord (the central nervous system 150 mmol 15 mmol Na+/K+
[CNS]). The PNS connects the CNS to the limbs and organs, K+ Na+ pump
Na+ 2K+
providing a route of transmission between the brain and spi-
nal cord and the rest of the body. The PNS is further divided Intracellular ATP ADP+ Pi
into the somatic nervous system (SNS) and the autonomic
nervous system (ANS). The SNS provides voluntary skele- Fig. 2.1 Intracellular and extracellular sodium and potassium
tal muscle control, whereas the ANS provides involuntary concentrations. The Na+/K+ pump maintains these
control of smooth muscle and glands. Afferent nerves are concentration gradients across the cell membrane. ADP,
Adenosine diphosphate; ATP, adenosine triphosphate.
responsible for relaying sensation from the body to the CNS
and efferent nerves are responsible for sending out com-
mands from the CNS to the body, within the SNS. The hypo-
thalamus regulates the ANS and is responsible for regulating • During a nerve action potential, the rate of sodium
heart rate, respiratory rate, digestion, pupillary response and entry into the nerve axon becomes greater than the
urination as well as the fight-or-flight response. rate of potassium out of the axon, at which point
the membrane becomes depolarised (the loss of an
electrical gradient across the membrane).
• Depolarisation sets off a sodium-positive feedback
NERVE CONDUCTION whereby more voltage-gated sodium channels open and
the membrane becomes more depolarized.
Conduction of impulses through nerves occurs as an all-or- • A threshold, which is usually 15 mV greater than the
none event called the action potential. The action potential resting membrane potential, must be reached if an
is caused by the voltage-dependent opening of sodium and action potential is to be generated.
potassium channels in the cell membrane. • The membrane repolarizes when the sodium channels
All cells maintain a negative internal potential be- become inactivated; a special set of potassium channels
tween −30 mV and −80 mV. This arises because the per- open and potassium leaves the axon.
meability of the plasma membrane is different for sodium • The sodium channels; eventually regain their resting
(Na+) and potassium (K+). The membrane is relatively excitable state and the Na+/K+ ATPase restores the
impermeable to Na+. Na+ is also exchanged for K+ via the membrane potential back to −70 mV.
Na+/K+ pump. The result is that the intracellular K+ con- Fig. 2.3 shows the voltage-operated sodium channels in
centration is higher and the Na+ lower than the respective their inactivated, activated and resting states. Two types of
extracellular concentrations. The sodium equilibrium gate exist within the channel; the m-gates and the h-gates.
potential (Eq Na+) is −60 mV and the potassium equilib- These gates are open or closed according to the state of the
rium potential (Eq K+) is −90 mV. Because a resting nerve channel.
has 50 to 75 more potassium channels open than sodium In the resting sodium channel, the m-gates are held
channels, the resting membrane potential is −70 mV. closed by the strongly negative (−70 mV) electrical gradi-
Fig. 2.1 shows the concentrations of Na+ and K+ inside ent across the membrane. Once an action potential begins
and outside a resting nerve. The Na+/K+ pump (Na+/K+ to propagate, the loss of the membrane potential causes
adenosine triphosphate [ATPase]) is an energy-dependent the m-gates to open, allowing sodium into the cell, further
pump that functions to maintain the concentration gradi- propagating the action potential. After a very short time, a
ent of these two ionic species across the membrane. Three further conformational change causes the h-gates to close,
sodium ions are pumped out of the cell for every two potas- inactivating the sodium channel. The membrane then re-
sium ions pumped in, and thus the excitability of the cell is polarizes, and once at −70 mV, the m-gates again close, and
retained. Fig. 2.2 and Table 2.1 summarize the events that the h-gates open so the sodium channel is back in its rest-
occur during a nerve action potential. ing state.

ALGrawany 19
 Peripheral nervous system

Sodium channel Size of the nerve fibre

The voltage-operated sodium channel is present in all ex- Small nerve fibres are preferentially blocked because of
citable tissues. It is a transmembrane protein made up of their high surface-area to volume ratio. This results in a
four domains, each with six transmembrane regions. It is differential block whereby the small nociceptive (pain) and
sensitive to membrane potential and selectively passes so- autonomic fibres are blocked, but not the larger fibres re-
dium ions. sponsible for the mediation of movement and touch.
Local anaesthetics block the sodium channel (see
Chapter 10), and thus nerve conduction, by binding to the
sixth transmembrane region of the fourth domain.
SOMATIC NERVOUS SYSTEM

4 Neuromuscular junction
The neuromuscular junction is a chemical synapse formed
3 by motor nerve axons and muscle fibres. It is the site where
0 mV
a motor neurone is able to transmit a signal to the muscle
Membrane
5 fibre, resulting in a muscle contraction.
potential
(mV)
Physiology of transduction
2 Skeletal (voluntary) muscle is innervated by motor neurones, the
−55 mV Threshold axons of which can propagate action potentials at high velocities.
6
The area of muscle that lies below the axon terminal is known
1
−70 mV Resting as the motor end plate, and the chemical synapse between the
two is known as the neuromuscular junction (NMJ). The axon
1 2
terminal incorporates membrane-bound vesicles containing the
Time (ms)
­neurotransmitter acetylcholine (ACh). Depolarisation of the pre-
Fig. 2.2 Nerve action potential. For explanation of points 1 synaptic t­erminal of the nerve by an action potential (generated
to 6, see Table 2.1.

Table 2.1 State of sodium and potassium channels and membrane potential at different stages of the neuronal
action potential
Sodium channels Potassium channels Membrane potential
1 Closed resting Closed resting Resting (−70 mV)
2 Open Closed resting Depolarisation (action potential upstroke)
3 More channels open Closed resting More depolarisation
4 Channels close (inactive) Special set of channels start opening Peak of action potential reached
5 All inactivated More channels open Repolarisation
6 Closed resting Channels close Resting membrane potential reestablished

Na+ Na+ Na+

channels channels channels
closed open closed
Outside (inactivated) (activated) (resting)
+ + − − + +
m-gates m-gates
h-gates h-gates
− − + + − −
Inside
Na+

Direction of propagation

Axon

Fig. 2.3 Voltage-operated sodium channels in their inactivated, activated and resting states. The m-gates and h-gates
open or close according to the state of the channel.

20
 Somatic nervous system 2

by sodium influx) causes ­voltage-sensitive calcium channels to (sodium influx), resulting in the opening of
open, allowing calcium ions into the terminal. Normally, the lev- voltage-operated calcium channels, but this time the
els of calcium ions inside the nerves are very low and are much calcium influx mediates contraction.
lower compared with the external concentration. This calcium • ACh is rapidly inactivated by AChE, which hydrolyses
influx results in the release of ACh by exocytosis from vesicles. ACh into the inactive metabolites choline and acetic acid.
ACh diffuses across to the muscle membrane where it binds to • In the synthesis of ACh, the choline generated is taken
the nicotinic acetylcholine receptor (nicAChR) and/or is inac- up by the nerve terminal where another enzyme,
tivated by the enzyme acetylcholinesterase (AChE) (Fig. 2.4). choline acetyl transferase (ChAT), converts it back to
Several events then occur. ACh to be reused.
• During association, ACh binds to the nicAChR, which
is an ion channel that allows cations into the muscle HINTS AND TIPS
(mainly sodium, but also potassium to a lesser extent).
• During the conformational change, the pore of the ion Within the neuromuscular junction, an electrical
channel is open for 1 ms, during which approximately impulse from the motor nerve is converted
20,000 sodium ions enter the cell. The resulting into a chemical signal that results in muscle
depolarisation, called an end-plate potential (EPP), fibre contraction. Several drugs act at the
depolarizes the adjacent muscle fibre. neuromuscular junction.
• If the cellular response is large enough, an action
potential is generated in the rest of the muscle fibre

Motor nerve
_ Non-depolarizing blockers, e.g. tubocurarine
+ Depolarizing blockers, e.g. suxamethonium

Na+

Hemicholinium VOSC
Depolarization
Choline _
Acetyl CoA Ca2+
transporter
+ choline
VOCC _
ChAT
+
ACh Aminoglycosides
+
_ ACh and Mg2
Choline Vesamicol

_
Botulinum toxin
ACh β-Bungarotoxin
ACh

AChE
_
Acetate
Nicotinic acetylcholine receptor

Anticholinesterases
e.g. neostigmine Depolarization
Na+

VOSC

Muscle fibre Contraction

VOCC

Ca2+
Fig. 2.4 Physiology of impulse transduction at the neuromuscular junction (NMJ) showing the site of action of drugs used
in conjunction with the NMJ. ACh, Acetylcholine; AChE, acetylcholinesterase; ChAT, choline acetyltransferase; Vesamicol,
an experimental drug; VOCC, voltage-operated calcium channel; VOSC, voltage-operated sodium channel.

ALGrawany 21
 Peripheral nervous system

Nicotinic acetylcholine receptor Drugs inhibiting acetylcholine release—Calcium en-

The nicAChR is made up of five subunits (two α, one β, try into the nerve terminal is necessary for the release of
two γ) that traverse the membrane and surround a central ACh; thus agents such as aminoglycoside antibiotics (e.g.
pore. The binding site for ACh lies on the α subunits, there- streptomycin) that prevent this step will cause neuromus-
fore ACh must bind to both α subunits to open the channel. cular blockade. Muscle paralysis is occasionally a side effect
Each subunit has four membrane-spanning regions (he- of aminoglycoside antibiotics, but it can be reversed by the
lices), that is, each receptor has a total of 20 regions. One of administration of calcium salts.
the transmembrane helices (M2) from each subunit forms Botulinum toxin is a neurotoxin produced by the anaer-
the lining of the channel pore. obic bacillus Clostridium botulinum. The toxin is very po-
tent, and it is believed to inhibit ACh release by inactivating
Pharmacological targets actin, which is necessary for exocytosis. In botulism, a seri-
There are three major targets within the NMJ for clinically ous type of food poisoning caused by this toxin, patients ex-
useful drugs (Table 2.2). perience progressive parasympathetic and motor paralysis.
β-bungarotoxin contained in snake venom acts in a similar
• Presynaptic release manner to botulinum toxin.
• nicAChR Botulinum toxin type A is sometimes used clinically
• Acetylcholinesterase. in the treatment of excessive muscle contraction disor-
ders (dystonias), spasticity and involuntary movements.
Drugs affecting the neuromuscular Botulinum toxin is also given via a local injection for treat-
junction ment of strabismus, urinary incontinence and hyperhidro-
sis. More often, however, it is used cosmetically to diminish
Presynaptic agents the appearance of wrinkles.
Drugs can block neuromuscular transmission by acting pre-
synaptically to inhibit Ach synthesis or release.
Drugs inhibiting acetylcholine synthesis—The rate-­ CLINICAL NOTE
limiting step in the synthesis of ACh is the uptake of choline
into the nerve terminal. Lambert-Eaton myasthenic syndrome is caused
Hemicholinium is an analogue of choline that compet- by autoantibodies to the presynaptic voltage-
itively blocks the choline transporter and causes a deple- gated calcium channels and is a rare autoimmune
tion of ACh stores. Because of the time taken for the stores disorder associated with small cell lung cancer.
to run down, the onset of this drug is slow. This, and the
frequency-dependent nature of the block (depletion of
­
stores is related to release of ACh), means that it is not useful
clinically. The block is reversed by the addition of choline. Postsynaptic agents
Drugs inhibiting vesicular packaging of acetylcho- Drugs can also block neuromuscular blockade postsynapti-
line—Vesamicol inhibits the active transport of ACh cally and the majority of anaesthetic medications are post-
into storage vesicles and results in neuromuscular block. synaptic agents.
However, this drug is only an experimental tool and is not Nondepolarising blockers—These act as competitive an-
approved for clinical use. tagonists by binding to the nicAChR, but they do not ac-
tivate it. They produce motor paralysis and are often used
as adjuncts to general anaesthesia. Approximately 80% to
Table 2.2 Targets for clinically useful drugs at the 90% of receptors must be blocked to prevent transmission,
neuromuscular junction because the amount of ACh released by nerve terminal
depolarisation usually greatly exceeds what is required to
Site Action Use
generate an action potential in the muscle. The drugs are
nicAChR Block transmission Neuromuscular all quaternary ammonium compounds and therefore do
blockers for not cross the blood-brain barrier or the placenta. They are
surgery poorly absorbed orally and therefore must be administered
AChE Enhance Peripheral via intravenous injection.
transmission neuropathy, e.g. The main side effect is hypotension caused by the block-
myasthenia gravis ing of ganglionic transmission. Bronchospasm may also be
Release Block transmission Spasms, e.g. a problem in certain individuals because of histamine re-
squints, tics, lease from mast cells.
tremors, etc. Some of these drugs cause a “tetanic fade” (nonmain-
AChE, Acetylcholinesterase; nicAChR, nicotinic acetylcholine tained muscle tension during brief nerve stimulation). This
receptor.
is caused by the blocking of presynaptic autoreceptors,

22
 Somatic nervous system 2

Table 2.3 Nondepolarising blockers of postsynaptic receptors at the neuromuscular junction

Side effects
Approximate
Drug duration (mins) Ganglion block Histamine release Other Elimination
Pancuronium 40–60 X Minimal Block of muscarinic Mainly renal
receptors in the
heart → tachycardia
Gallamine 15 X X Block of muscarinic Mainly renal: avoid
receptors in the in patients with
heart → tachycardia renal disease
Alcuronium 20 X X Dose dependency Mainly hepatic
Vecuronium 20–30 X X Mainly hepatic
Atracurium 15–30 X Sometimes Degradation in
plasma at body
pH (Hofmann
elimination)

which usually maintain the release of ACh during repeated • Muscarinic receptor activation resulting in bradycardia.
stimulation. The block can be reversed by anticholinester- Bradycardia can be prevented by the administration of
ases and depolarising drugs. atropine.
The majority of anaesthetic drugs used clinically are • Potassium release from muscle resulting in elevated
nondepolarising blockers. Further details are given in plasma potassium levels. This is usually a problem only
Table 2.3. in the case of trauma.
Depolarising (noncompetitive) blockers—Depolarising
blockers initially activate receptors, causing depolarisation,
but in doing so block further activation. CLINICAL NOTE
Depolarising blockers act on the motor end plate in the Myasthenia gravis is a disorder of neuromuscular
same manner as ACh, that is, they increase the cation per-
transmission resulting from autoantibodies binding
meability of the end plate. However, unlike ACh, which is
to the postsynaptic acetylcholine receptors. This
released in brief spurts and rapidly hydrolysed, depolarising
blockers remain associated with the receptors long enough leads to muscle weakness with easy fatigability.
to cause a sustained depolarization and a resulting loss of In patients with myasthenia gravis, who have
electrical excitability (phase I). fewer niAChRs at the end plate, the blocking
Repeated or continuous administration of depolaris- potency of depolarising blockers is reduced. Thus
ing blockers leads to the block becoming more charac- suxamethonium is likely to have no effect in these
teristic of nondepolarising drugs. This is known as phase patients.
II and is probably caused by receptor desensitisation,
whereby the end plate becomes less sensitive to ACh. The
block starts to show, and it is partly reversed by anticho-
linesterase drugs. Anticholinesterases
Suxamethonium is the only depolarising blocker used Anticholinesterases inhibit AChE and thus increase the
clinically because of its rapid onset time and short duration amount of ACh in the synaptic cleft and enhance choliner-
of action (approximately 4 mins). It must be given by in- gical transmission. Most of the anticholinesterases used are
travenous injection. It is rapidly hydrolysed by plasma cho- quaternary ammonium compounds and, therefore, they do
linesterase, although certain people with a genetic variant not penetrate the blood–brain barrier.
of this enzyme may experience a neuromuscular block that Short-acting anticholinesterases include edrophonium,
may last for hours. Of note, suxamethonium can cause ma- which is selective for the NMJ. Edrophonium’s duration of
lignant hyperthermia (intense muscle spasm and a dramatic action is only 2 to 10 minutes because it binds by electrostatic
rise in body temperature) in some patients with a rare in- forces (no covalent bonds) to the active site of the enzyme.
herited condition affecting calcium channels. Clinically, it is used in the diagnosis of myasthenia gravis.
The side effects of depolarising blockers include the Intermediate-acting anticholinesterases include neostig-
following. mine, pyridostigmine and physostigmine.
• Initial spasms, which occur before paralysis, often Neostigmine is used intravenously to reverse the effects
resulting in postoperative muscle pain. of nondepolarising blockers. Its duration of action is 2 to

ALGrawany 23
 Peripheral nervous system

4 hours, and it is used orally in the treatment of myasthenia preganglionic fibres. These synapse in the appropriate gan-
gravis. Although neostigmine shows some selectivity for the glion, and leave as postganglionic fibres, which reach the
NMJ, atropine is sometimes coadministered to block the effector cells.
muscarinic effects of the drug. The neurotransmitter released by preganglionic fibres at
Pyridostigmine has a duration of action of 3 to 6 hours, autonomic ganglia is ACh. The receptors for ACh are lo-
and it is also used orally in the treatment of myasthenia gra- cated on postganglionic nicotinic fibres.
vis. It has few parasympathetic actions.
Anticholinesterase inhibitors that cross the blood-brain Autonomic ganglia
barrier, such as physostigmine, have marked CNS effects be-
cause of its selectivity for the postganglionic parasympathetic Table 2.4 summarizes the differences between ganglionic
junction. These include bradycardia, hypotension, excessive nicAChR and those found in skeletal muscle at the NMJ.
secretions and bronchoconstriction. A helpful effect is the
reduction of intraocular pressure and therefore physostig- Ganglion-stimulating drugs
mine is used in the form of eye drops to treat glaucoma.
Most of the long-lasting or irreversible anticholinester- Nicotinic agonists
ases are organophosphorus compounds. For example, sarin There are few agonists that act selectively on the nicAChR
and tabun were developed as nerve gases and can cause without affecting muscarinic receptors. Carbachol is the
anticholinesterase poisoning. Parathion was developed as best example of a drug that shows preference for the nic-
an insecticide and these drugs have many adverse effects, otinic receptor, but still its action is not selective. Nicotine
such as bradycardia, hypotension, breathing problems, de- and lobeline both show a preference for ganglionic nicotinic
polarising neuromuscular block, central effects and possible receptors in comparison with the NMJ.
death from peripheral nerve demyelination. These drugs have no clinical use, because their range of
effects is vast, affecting both sympathetic and parasympa-
CLINICAL NOTE thetic transmission.
• Sympathetic effects include tachycardia and
Mrs Thumma, 34 years old, presents with a 3-month vasoconstriction leading to hypertension.
history of early fatigue and muscle weakness. She • Parasympathetic effects include increased
finds it difficult to finish meals, because she gets tired gastrointestinal motility and glandular secretions.
chewing and has now lost 2 kg. She is otherwise a
healthy nonsmoker who rarely drinks alcohol. Her Ganglion-blocking drugs
husband has noticed her voice becoming quieter, Autonomic ganglia can be blocked presynaptically by in-
especially towards the end of the day. hibiting ACh synthesis, vesicular packaging or release, or
postsynaptically by blocking the nicotinic receptors.
On examination, she looks well. Power in all
muscle groups is grossly normal but weakens Nondepolarising ganglion blockers
after repeated testing. Tone, coordination, reflexes A few of these drugs act solely as competitive antagonists,
and sensation are normal. She is referred to a blocking receptors without depolarising the ganglion.
neurologist, who orders more investigations. Serum Most block the ion channel, as well as the associated re-
ceptor, and they produce their action through this former
acetylcholine receptor antibodies test positive. A
mechanism.
computed tomography scan of her thymus reveals
Ganglion-blocking drugs have a wide range of com-
an enlarged thymus gland. plex effects, although the sympathetic and parasympa-
She, therefore has a thymectomy, histopathological thetic systems tend to oppose one another. The effects of
examination of which revealed benign hyperplasia. ­ganglion-blocking drugs include the following.
She is also given the anticholinesterase • Arteriolar vasodilatation leading to a marked reduction
pyridostigmine to treat her myasthenia gravis. in blood pressure (block of sympathetic ganglia).
• Postural and postexercise hypotension (loss of cardiac
reflexes).
• A slight reduction in cardiac output.
AUTONOMIC NERVOUS SYSTEM • Inhibition of gastrointestinal secretions and motility,
leading to constipation, urinary retention, impotence
The autonomic nervous system comprizes the sympathetic and failure of ejaculation.
and parasympathetic systems, which generally have oppo- Despite having a broad pharmacological profile, rocu-
site effects on the body. It innervates all tissues, except skel- ronium and vecuronium are the only widely used drugs
etal muscle (Fig. 2.5). The axons of the autonomic nervous of this class; they are used as muscle relaxants in surgical
system arise from their cell body, located in the CNS, as intubation.

24
 Autonomic nervous system 2

Somatic nervous system

ACh Skeletal
CNS
(nicotinic) muscle

Autonomic nervous system

Parasympathetic
Smooth muscle
ACh
CNS ACh Cardiac muscle
(muscarinic)
(nicotinic) Glands, etc.

Pre Post
ganglionic Ganglion ganglionic
fibre fibre
Sympathetic
Smooth muscle
CNS ACh NA Cardiac muscle
(nicotinic) (adrenoceptor) Glands, etc.

Hormonal
Adrenaline Smooth muscle
CNS ACh NA Cardiac muscle
(+DA, peptides) Glands, etc.
via
bloodstream

Adrenal medulla
Fig. 2.5 Somatic and autonomic nervous systems: organisation and neurotransmitters. ACh, Acetylcholine; CNS, central
nervous system; DA, dopamine; NA, noradrenaline.

These ganglia form a chain along each side of the spinal

Table 2.4 Distinguishing features of the ganglionic
cord, which is known as the sympathetic trunk.
nicotinic acetylcholine receptors and those found in
The major neurotransmitter is noradrenaline.
skeletal muscle at the neuromuscular junction
Skeletal muscle Neurones
HINTS AND TIPS
Structure 2α 2α
1β 3β
Sympathetic transmission is enhanced under
conditions of stress, known as the “fight-or-flight
1γ or ε
response”.
1δ
Specific agonists Suxamethonium DMPP
Specific Gallamine Hexamethonium
antagonists
Adrenal medulla
Some postganglionic neurones in the sympathetic arm do not
Tubocurarine Mecamylamine have axons, but instead they release their transmitters directly
α-Bungarotoxin κ-Bungarotoxin into the bloodstream. These neurones are in the adrenal medulla.
Function End plate region Neuronal On stimulation by preganglionic fibres, the adrenal me-
depolarisation at depolarization in dulla acts as an endocrine gland, releasing its hormones/
NMJ ganglia and CNS transmitters into the systemic circulation and consist of
CNS, Central nervous system; DMPP, dimethylphenylpiperazinium; ~80% adrenaline, ~20% noradrenaline, as well as small
NMJ, neuromuscular junction. amounts of dopamine, neuropeptides and ATP.

Adrenoceptors
The two receptor subtypes are α and β.
Sympathetic nervous system • Potency at α receptors is noradrenaline > adrenaline >
The fibres of the sympathetic nervous system leave the CNS isoprenaline.
from the thoracolumbar regions of the spinal cord (T1–L3). • Potency at β receptors is isoprenaline > adrenaline >
They synapse in ganglia located close to the spinal cord. noradrenaline.

ALGrawany 25
 Peripheral nervous system

Effects mediated by α-adrenoreceptors

Resting plasma catecholamines and urinary
α1 Receptors metanephrines (catecholamine metabolites) are
α1 Receptors are located postsynaptically. Their activation raised, supporting the diagnosis. Imaging reveals a
causes smooth muscle contraction (except for the non- tumour in the adrenal medulla, which is resectable.
sphincter part of the gastrointestinal tract, where activation Intravenous phentolamine is given to safely reduce
causes relaxation), glycogenolysis in the liver, and potassium her blood pressure. Following stabilisation of her
release from the liver and salivary glands. Transduction is
blood pressure, she is put on phenoxybenzamine
via G-proteins and an increase in the intracellular second
to achieve α blockade, with propranolol added later
messengers, inositol (1,4,5) triphosphate (IP3) and diacyl-
glycerol (DAG). to achieve β blockade as well. She is maintained
on this until complete α and β blockade is
α2 Receptors established and plasma volume has reexpanded.
α2 Receptors are located mainly presynaptically, but also Surgery to remove the secreting tumour can then
postsynaptically on liver cells, platelets and the smooth be performed, with an expert anaesthetist and
muscle of blood vessels. The activation of presynaptic α2
surgeon, and readily available nitroprusside.
receptors inhibits noradrenaline release and, therefore pro-
vides a means of end-product negative feedback. Activation
of postsynaptic α2 receptors causes blood vessel constriction
and platelet aggregation. Transduction is via G-proteins and
a decrease in the intracellular second messenger cyclic ade- Effects mediated by β-adrenoceptors
nosine monophosphate (cAMP). β1 Receptors
Some drugs, such as phenoxybenzamine and phen- β1 Receptors are mainly postsynaptic and located in the heart,
tolamine, are nonselective α-adrenoceptor antagonists. platelets and nonsphincter part of the gastrointestinal tract.
Phenoxybenzamine is an irreversible antagonist as it They can, however, be found presynaptically. Activation causes
forms covalent bonds with the receptor, whereas phen- an increase in the rate and force of contraction of the heart,
tolamine binds reversibly and so has a much shorter du- relaxation of the nonsphincter part of the gastrointestinal tract,
ration of action. These drugs cause a fall in arterial blood aggregation of platelets, an increase in the release of noradren-
pressure, caused by the block of α-receptor–mediated aline, lipolysis in fat, and amylase secretion from the salivary
vasoconstriction. glands. Presynaptically, their activation causes an increase in
noradrenaline release. Transduction is via G-proteins and an
increase in the intracellular second messenger cAMP.
β2 Receptors
CLINICAL NOTE β2 Receptors are located postsynaptically. Their activation
causes smooth muscle relaxation, glycogenolysis in the
Mrs Pharasha, a 26-year-old librarian, presents
liver, inhibition of histamine release from mast cells, and
to her doctor with episodes of anxiety, sweating, tremor in skeletal muscle. Transduction is via G-proteins
tremor and palpitations. These attacks had been and an increase in the second messenger cAMP.
increasing in frequency and are now occurring
almost daily. The only change Mrs Pharasha can Drugs acting on the sympathetic system
think of is the increased stress at work, which Fig. 2.6 summarizes the drugs acting on the sympathetic
she now feels she is not handling well. She is a system.
nonsmoker and seldom drinks alcohol. She is on
no medication.
Presynaptic agents
Noradrenaline synthesis—The precursor to noradrena-
On examination, her heart rate is 106 beats per line is l-tyrosine, which is taken up by adrenergic neurones.
minute and her blood pressure is elevated. To treat Drugs decreasing noradrenaline synthesis—The rate-
her hypertension, she is prescribed propranolol, limiting step is the conversion of tyrosine to dihydroxy-
a β-blocker, which causes her blood pressure phenylalanine (dopa), which is catalysed by tyrosine hy-
to increase by 30 mm Hg and her heart rate to droxylase and inhibited by metyrosine. Noradrenaline
reach 145 beats per minute. So, her condition provides a negative feedback upon this step. Carbidopa
worsens markedly. She is rushed to accident inhibits dopa decarboxylase and is used in Parkinson dis-
and emergency where the doctor suspects ease to increase dopamine levels. Because this is not the
rate-limiting step in the synthesis of noradrenaline, drugs
phaeochromocytoma.
that inhibit dopa decarboxylase do not greatly affect
noradrenaline synthesis. Administering α-methyldopa (used

26
 Autonomic nervous system 2

L-Phenylalanine

L-Tyrosine
RLS tyrosine − α-Methyldopa
hydroxylase NA
L-Dopa
Carbidopa
Dopa −
α-Methyldopa
Decarboxylase
Dopamine
Dopamine-β-
Hydroxylase
NA
− Reserpine
Na+

Depolarization Ca2+

NA +

α2
++ Clonidine
− Yohimbine
Cocaine − + −
Imipramine − − Guanethidine, bretylium

Uptake 1 Amphetamines, tyramine, ephedrine

NA

+ β/α agonists
Uptake 2 − β/α antagonists
R
Corticosteroids − G-protein

MAO − Phenelzine
or
COMT − Entacapone 2nd messengers
( IP3 or cAMP)
Metabolites

Response
Fig. 2.6 Drugs affecting adrenergic transmission. cAMP, Cyclic adenosine monophosphate; COMT, catechol-
O-methyltransferase; IP3, inositol triphosphate; MAO, monoamine oxidase; NA, noradrenaline; RLS, rate-limiting step.

in hypertension) results in the formation of a false transmitter, Drugs inhibiting noradrenaline release—These in-
α-methylnoradrenaline, decreasing noradrenaline synthesis. clude guanethidine and bretylium. These are adrenergic
Drugs increasing noradrenaline synthesis—Noradren- neurone-blocking drugs that prevent the exocytosis of
aline is stored in vesicles as a complex with ATP and a pro- noradrenaline from nerve terminals; they are used as hypo-
tein called chromogranin A. tensive drugs. They are taken up by “uptake 1” and concen-
Drugs inhibiting noradrenaline storage—Reserpine is trated in nerve terminals where they have a local anaesthetic
a drug used in the treatment of hypertension and schizo- effect on impulse conduction. The tricyclic antidepressants,
phrenia. It reduces stores of noradrenaline by preventing which inhibit uptake 1, prevent these drugs from exerting
the accumulation of noradrenaline in vesicles. Its action is their effects. Clonidine is an α2-receptor agonist and there-
effectively irreversible because it has a very high affinity for fore inhibits noradrenaline release. It is used as the fourth
the noradrenaline storage site. The displaced noradrenaline line in treatment of hypertension.
is immediately broken down by monoamine oxidase (MAO) Drugs promoting noradrenaline release—These include
and is therefore unable to exert sympathetic effects. amphetamines, tyramine and ephedrine, which are sym-
Drugs inhibiting the breakdown of leaked nor- pathomimetic drugs that act indirectly. They are taken up
adrenaline stores—MAO inhibitors (MAOIs) and by uptake 1 and displace noradrenaline from the vesicles.
­catechol-O-methyltransferase (COMT) inhibitors prevent Because they also inhibit MAO, the displaced noradrenaline
the breakdown of leaked catecholamines so that noradrena- is not broken down and is able to exert sympathetic effects.
line that leaves the vesicles is protected and eventually leaks These drugs act in part through a direct agonist effect on
out from the nerve ending. adrenoceptors. Yohimbine is an α2 receptor antagonist that

27
 Peripheral nervous system

prevents noradrenaline from exerting a negative feedback for inactivation of this neurotransmitter. Uptake 1 has a high
effect on noradrenaline release. affinity for the uptake of noradrenaline (K = 0.3 mmol/L in the
rat), but the maximum rate of uptake is low (Vmax = 1.2 nmol/g
Postsynaptic agents per min in the rat). It has a specificity rank of noradrenaline
Adrenoceptor agonists—These are termed sympathomi- > adrenaline > isoprenaline; it is blocked by cocaine, amphet-
metics. They activate postsynaptic adrenoceptors, eliciting a amines and tricyclic antidepressants (e.g. imipramine), which
response (Table 2.5). therefore potentiate the actions of noradrenaline.
Adrenoceptor antagonists—These are termed sympatho- Uptake 2—Uptake 2 is located outside neurones (e.g. in
lytics. They block postsynaptic adrenoceptors (Table 2.6). smooth muscle, cardiac muscle and endothelium), and it is
the main mechanism for the removal of circulating adrenaline
Inactivation from the bloodstream. It has a low affinity for the uptake of
Uptake 1—Noradrenaline can be taken up into presynap- noradrenaline (K = 250 mmol/L in the rat) but a high maxi-
tic nerve terminals via active transports systems. One of these, mum rate of uptake (Vmax = 100 nmol/g per min in the rat).
termed uptake 1, is located on neuronal terminals and uptake Uptake 2 has a specificity rank of adrenaline > noradrenaline
of noradrenaline into nerve terminals is the main mechanism > isoprenaline, and it is blocked by corticosteroids.

Table 2.5 Adrenoceptor agonists and their clinical uses

Drug Receptor Uses Side effects Pharmacokinetics
Noradrenaline α/β No use clinically Hypertension, tachycardia, Poor oral absorption, metabolized
ventricular arrhythmias by MAO and COMT t½ ~2 min
Adrenaline α/β Anaphylactic shock Hypertension, tachycardia, Poor oral absorption, metabolized
Cardiac resuscitation ventricular arrhythmias by MAO and COMT t½
with local anaesthetics ~2 min given intravenously or
intramuscularly
Oxymetazoline α Nasal decongestant Rebound congestion Given intranasally
Phenylephrine α1 Hypotension Hypertension Metabolized by MAO t½ <1
Nasal decongestant Reflex bradycardia min, given intramuscularly or
intranasally
Clonidine α2 Hypertension Migraine Drowsiness, hypotension Good oral absorption t½ ~12 hours
Isoprenaline β Asthma Arrhythmias, tachycardia Metabolized by COMT, given
Cardiac resuscitation sublingually or as aerosol t½ ~2
hours
Dobutamine β1 Heart failure Tachycardia
Salbutamol β2 Asthma Arrhythmias, tachycardia, Given by aerosol t½ ~4 hours
Premature labour vasodilatation
COMT, Catechol-O-methyltransferase; MAO, monoamine oxidase.

Table 2.6 Adrenoceptor antagonists and their clinical uses

Drug Receptor Uses Side effects Pharmacokinetics
Labetalol α/β Hypertension Postural hypotension Oral absorption t½ ~4 hours
Phentolamine α No clinical use Hypotension Tachycardia Metabolized by the liver, given
Nasal congestion intravenously t½ ~4 hours
Prazosin α1 Hypertension Hypotension Tachycardia Oral absorption, metabolized
Nasal congestion Drowsiness by the liver t½ ~2 hours
Yohimbine α2 No clinical use Hypertension Excitement Oral absorption, metabolized
by the liver t½ ~4 hours
Propranolol β Hypertension Angina Bronchoconstriction Heart Oral absorption, first-pass
Arrhythmias failure metabolism, 90% plasma-
protein bound t½ ~4 hours
Practolol β1 Hypertension Angina Bronchoconstriction Heart Oral absorption t½ ~4 hours
Arrhythmias failure

28
 Autonomic nervous system 2

Note that interaction with other drugs and food is a serious

HINTS AND TIPS issue with MAO inhibitors and includes the “cheese reaction”
in which patients are at risk of severe hypertension follow-
Many of the adrenoceptor agonists and antagonists
ing the ingestion of tyramine-containing foods. When ty-
are not entirely specific for just the α-adrenoceptors
ramine is ingested, it is normally metabolized by MAO and
or β-adrenoceptors, so side effects are common, and little dietary tyramine reaches the systemic circulation. MAO
they should be remembered (see Tables 2.5 and 2.6). inhibition allows tyramine to be absorbed and enhances the
sympathomimetic effect resulting in acute hypertension.
Metabolism of catecholamines by catechol-O-­
Metabolism of catecholamines by the enzyme mono- methyltransferase—COMT is found in all tissues and
amine oxidase—MAO is found on the surface of mitochon- breaks down most catecholamines and the byproducts of
dria, principally within adrenergic nerve terminals but also the actions of MAO. COMT metabolizes catecholamines to
in other cells, such as those of the liver and intestines. MAO give a ­methoxy derivative. Entacapone, a COMT inhibitor,
metabolizes catecholamines into their corresponding alde- is a drug used clinically for parkinsonism.
hydes. It comprizes two major forms: MAOA and MAOB.
Noradrenaline is mainly broken down by MAOA in nerve Parasympathetic nervous system
terminals. Inhibitors of MAO increase the releasable store
of noradrenaline, but they do not greatly potentiate sympa- The fibres of the parasympathetic nervous system leave the
thetic transmission because catecholamines are mainly in- CNS from the sacral region (S3 and S4) of the spinal cord
activated by reuptake. MAOA has a substrate preference for and via cranial nerves III, VII, IX and X. The fibres syn-
5HT (serotonin) and is the main target for antidepressants. apse in ganglia, which, unlike the sympathetic system, are
These include phenelzine and tranylcypromine. MAOB has located within the innervated organs themselves.
a substrate preference for dopamine and is selectively inhib- The major transmitter released by the postganglionic
ited by selegiline used in the treatment of Parkinson disease. fibres at the junction with effector cells is ACh (Fig. 2.7).

Postganglionic
fibre

Na+

Hemicholinium VOSC
Depolarization
Choline _
Acetyl CoA +
transporter Ca2
+ choline
VOCC
ChAT

ACh _
Aminoglycosides
_ ACh _ +
Vesamicol Mg2
Choline
_
_
Botulinum toxin
ACh
ACh
Muscarinic
AChE antagonists
Muscarinic
+
_ agonists
Acetate Muscarinic
_ R
Anticholinesterases,
e.g. neostigmine G-protein

2nd messengers ( IP3 or cAMP)

Response
Fig. 2.7 Drugs acting on the parasympathetic nerve transmission. AChE, Acetylcholinesterase; ChAT, choline acetyl
transferase; VOCC, voltage-operated calcium channel; VOSC, voltage-operated sodium channel.

29
 Peripheral nervous system

Parasympathetic receptors Drugs acting on the parasympathetic

The ACh released by postganglionic nerve fibres acts on system
muscarinic (M) receptors, of which between three and five Fig. 2.7 summarizes the drugs that act on the parasympa-
subtypes exist. thetic system.

Neuroparietal M1 receptors Presynaptic agents

M1 “neuroparietal” receptors are principally found in the For information regarding presynaptic agents, see pp. 34.
CNS, peripheral neurones and gastric parietal cells. Their
Anticholinesterases
effects tend to be excitatory, depolarising membranes
For information regarding anticholinesterases, see p. 31.
through a decrease in potassium conductance. Activation
causes central excitation and gastric acid secretion, whereas Postsynaptic agents
transduction is via G-proteins and an increase in the second Muscarinic-receptor agonists—These are termed para-
messengers IP3 and DAG through stimulation of phospho- sympathomimetic and such drugs activate postsynaptic re-
lipase C. ceptors (Table 2.7).
Muscarinic-receptor antagonists—These are termed para-
Neurocardiac M2 receptors sympatholytic and block postsynaptic receptors (Table 2.8).
M2 “neurocardiac” receptors are found in the heart and Nonselective antagonists can be used as an adjunct to
on peripheral neurones. Their effects are inhibitory, in- anaesthesia to prevent bronchial secretions and vagal slow-
creasing potassium conductance and inhibiting calcium ing of heart rate.
channels. In the heart, their activation causes a decrease Different tissues respond differently to muscarinic antag-
in the rate (via potassium) and force of contraction (via onists (Table 2.9). Salivary, sweat and bronchial glands are
calcium). Transduction is via G-proteins and a decrease the most sensitive and can be blocked by very low doses of
in the second messenger cAMP through inhibition of ad- atropine. In contrast, the parietal cells are the most ­resistant,
enylyl cyclase. and the block of gastric acid secretion requires high doses

Smooth muscle-glandular M3 receptors

M3 “smooth muscle-glandular” receptors are found in Table 2.8 Muscarinic antagonists and their clinical uses
smooth muscle and glands. Their effects tend to be excit- Muscarinic
atory, increasing sodium conductance. Activation causes Drug receptor Specific uses
glandular secretions such as saliva and sweat, and smooth
Atropine Nonselective Reduces GI
muscle contraction. Transduction is via G-proteins and an motility
increase in the second messengers IP3 and DAG. M3 recep- Cardiac arrest
tors are also located on vascular endothelium, activation
Hyoscine Nonselective Motion sickness
of which causes vasodilatation, through the release of an
­endothelium-derived relaxing factor that is now known to Ipratropium Nonselective Bronchodilator
be nitric oxide. Cyclopentolate M4 Dilation of pupil
Tropicamide M4 Dilation of pupil
Eye M4 receptors
Pirenzepine M1 Reduces gastric
M4 “eye” receptors are believed to be exclusive to the eye. acid secretion
Their activation causes constriction of the pupil and accom-
Trihexyphenidyl M1 Parkinson disease
modation for near vision. Transduction is via G-proteins
(benzhexol)
and a decrease in the second messenger cAMP through in-
GI, Gastrointestinal.
hibition of adenylyl cyclase.

Table 2.7 Muscarinic agonists and their clinical uses

Drug Muscarinic receptors Nicotinic receptors Uses
Carbachol ++ + Gut and bladder stimulation
postoperatively
Methacholine +++ +
Bethanechol +++ — Gut and bladder stimulation
postoperatively
Muscarine +++ —
Pilocarpine ++ — To decrease intraocular
pressure in glaucoma

30
 Autonomic nervous system 2

Table 2.9 Summary of the opposing effects of sympathetic and parasympathetic nerve stimulation on body tissues
Target tissue Sympathetic Parasympathetic Overall effect
Nerve terminals α2 Decreased release M2 Decreased release Decreased transmission
Smooth muscle
Blood vessels α½ Contraction M3 Relaxation (via Vasoconstriction
EDRF)
β2 Relaxation Vasodilatation
Bronchi β2 Relaxation M3 Contraction Bronchodilation
α1 Contraction M3 Secretion Bronchoconstriction
Bronchosecretion
GI tract: nonsphincter β/α1 Relaxation M3 Contraction Increased/decreased motility
sphincter secretions and tone GI secretions
Contraction M3 Relaxation
α1 M3 Secretion
Parietal cells M1 Contraction Gastric acid secretion
Pancreas M3 Contraction Increased secretions
Uterus α1 Contraction M3
β2 Relaxation M3
Bladder: detrusor sphincter β2 Relaxation M3 Contraction Micturition
α1 Contraction M3 Relaxation Urine retention
Seminal tract α1 Contraction Ejaculation
β2 Relaxation Ejaculation
Vas deferens α1
Penis: venous sphincter α1 Contraction M3 Vasodilatation Erection
Radial muscle (iris) α1 Contraction M4 Relaxation Pupil relaxation/constriction
β2 Relaxation M4 Contraction
Ciliary muscle M4 Contraction Accommodation
Lacrimal gland Tear secretion
Heart β1 Increased rate and M2 Decreased rate
force and force
Liver α1/β2 Glycogenolysis
Fat β1 Lipolysis
Salivary glands α1/β1 Secretion of thick M3 Abundant secretion
saliva of watery saliva
Platelets α2 Platelet aggregation
Mast cells β2 Inhibition of
histamine release
EDRF, Endothelium-derived relaxing factor; GI, gastrointestinal.

of atropine. Muscarinic receptor antagonists such as glyco- • Paralysis of accommodation: cycloplegia (relaxation of
pyrronium are also used to treat urinary incontinence (see ciliary muscle)
Chapter 10) and motion sickness (hyoscine). • Urinary retention
The side effects of muscarinic antagonists include: • Central excitation: irritability and hyperactivity
• Dry mouth and skin, and increased body temperature • Sedation (hyoscine)
(inhibition of salivary and sweat glands) Certain Muscarinic antagonists can also be administered by
• Blurred vision and pupil no longer responsive to light inhalation (e.g. ipratropium bromide and ­tiotropium bro-
(dilation of the pupil) mide) to treat airways obstruction associated with asthma

31
 Peripheral nervous system

and chronic obstructive pulmonary disease (see Chapter 3) further calcium influx into the cell inhibited by the closure
where the side effects associated with systemically active of calcium channels. The overall effect of a fall in intracellu-
drugs are much reduced. lar calcium is a relaxation of the smooth muscle.
The smooth muscle effects of nitric oxide in the periph-
eral nervous system are now recognized to be important in
the gastrointestinal system, in vascular smooth muscle and
NITRERGIC NERVOUS SYSTEM in sexual arousal in both sexes, particularly in the male.
For example, the therapeutic benefit of nitrovasodilator
Nitric oxide is now well recognized as a neurotransmitter drugs such as nitroglycerin are now recognized as being
and is generated by the action of the enzyme nitric oxide through mimicking the action of nitric oxide in vascular
synthase (NOS) that converts the amino acid, l-arginine smooth muscle to generate the second messenger cGMP.
into nitric oxide. Furthermore, therapeutic manipulation of the nitrergic
Nitric oxide activates the guanylyl cyclase enzyme in- nervous system is confined to the male reproductive sys-
side cells, which is responsible for generating the second tem at present, and the agents currently used in the man-
messenger cyclic guanosine monophosphate (cGMP). In agement of erectile dysfunction (e.g. sildenafil). Such drugs
smooth muscle cells, the synthesis of cGMP in turn acti- inhibit phosphodiesterase 5 (PDE5) which normally breaks
vates a protein kinase, which phosphorylates ion channels down cGMP in cells. Inhibition of PDE5 by sildenafil in-
in the plasma membrane and causes hyperpolarization of creases the intracellular levels of cGMP in the vascular
the smooth muscle cell. Intracellular calcium ions are con- smooth muscle cells of the corpus carvenosum leading to
sequently sequestered into the endoplasmic reticulum, and penile erection.

Chapter Summary

• The peripheral nervous system (PNS) consists of the nerves and ganglia outside of the
brain and spinal cord.
• Conduction of nerve impulses through nerves occurs as an all-or-none event called the
action potential (A). The AP is caused by the voltage-dependent opening of sodium and
potassium channels in the cell membrane.
• Skeletal muscle is innervated by motor neurones via a chemical synapse at
the neuromuscular junction (NMJ). The pre-synaptic axon terminal
incorporates acetylcholine neurotransmitter which is released upon depolarisation. The
ACh then causes a calcium influx at the post-synapse after binding to nicotinic
acetylcholine receptors.
• Drugs can affect the NMJ such as hemicholiunium which depletes ACh stores, and
vesamicol which inhibits the active transport of ACh, botulinum toxin also stops ACh
release by inactivating actin.
• Nondepolarising blockers act as competitive antagonists and need 80-90% blockage of
all receptors to prevent transmission, the vast majority of anaesthetic drugs act in this
way. Depolarising blockers (e.g. suxamethonium) initially activate receptors and then
blocks further activation.
• Anticholinesterases inhibit AChE and this increase the amount of ACh in the synaptic
cleft. Examples include the short-acting edrophonium and intermediate-acting
pyridostigmine.

32
 Respiratory system
3
BASIC CONCEPTS OBSTRUCTIVE AIRWAYS
DISEASES
Respiration is the process of exchange of oxygen and car-
bon dioxide between an organism and its external environ-
ment. This principally involves the lungs, which possess the
Asthma
largest surface area in the body in contact with the external Asthma is a chronic inflammatory disease of the bron-
environment. The respiratory system (Fig. 3.1) has defence chiolar airways. It is characterized by recurrent reversible
mechanisms, which can be divided into physical (such as obstruction to airflow causing airflow limitation, airway
coughing or the mucociliary escalator, to remove foreign hyperresponsiveness and inflammation of the bron-
agents) and immunologic (such as enzymes, pulmonary chi. Asthma may be allergic (extrinsic) or nonallergic
macrophages and lymphoid tissue, to “disarm” foreign (intrinsic).
agents). These defence mechanisms can be launched inap- In asthma, smooth muscle that surrounds the bronchi
propriately or may be insufficient to deal with the triggering is hyperresponsive to stimuli, and underlying inflamma-
agent, and thus disease may occur. tory changes are present in the airways. Asthmatic stimuli

Nasal cavity

Nasopharynx

Epiglottis
Upper
respiratory
tract Larynx

Trachea

Main bronchi
Branch bronchi

Lower Small bronchi

respiratory
Oesophagus
tract
Bronchioles
Distal respiratory tree
(gas-exchange region)

Fig. 3.1 A schematic diagram of the respiratory tract. (From Renshaw, J., Hickin, S., Chapman, R. Crash Course:
Respiratory System, 4th edition. Mosby, London, 2013).

33
 Respiratory system

i­ nclude inhaled allergens (e.g. pollen, animal dander), occu- • Immune reactions (type 1 hypersensitivity) and
pational allergens and drugs or nonspecific stimuli such as release of inflammatory mediators: the cross-linking
cold air, exercise, stress and pollution. of immunoglobulin E (IgE) by allergens causes
The stimuli cause asthmatic changes through several mast cell degranulation, which releases histamine,
complex pathways (Fig. 3.2). The possible mechanisms of eosinophilic and neutrophilic chemotactic factors.
these pathways include the following. The eosinophils, neutrophils and other inflammatory

1 Inhaled allergen Air space

Damaged respiratory
epithelium
Mast cells in
bronchiolar
2 Allergen cross-links IgE
mucosa

−
Ca2+

Mast-cell stabilizers
2 signalling Cromoglycate
( cAMP) ?

3 Mast-cell
activation
and
degranulation
Bronchodilators
• β2-adrenoreceptor agonists
Eosinophil 4 Inflammatory e.g. salbutamol, terbutaline
mediators salmeterol
5 inflammatory • xanthines
cells attracted: e.g. theophylline
Neutrophil • muscarinic antagonists
6 Further release e.g. ipratropium bromide
of mediators by • leukotriene receptor antagonist
inflammatory cells − − − e.g. montelukast

PDE LT-Rc
M3
+
−
β2
¥¥ ¥¥
7 High airway resistance ¥¥ ¥¥ ¥¥ Hyperactive and
¥¥ ¥ ¥¥
due to: • bronchospasm
¥ ¥ hypertrophic
• oedema
• inflammation
¥¥
¥¥¥ smooth muscle

• mucus hypersecretion ¥¥¥ ¥

¥
¥¥¥¥ ¥¥¥¥
¥¥¥
Mucosal Mucus
−
oedema hypersecretion
Glucocorticosteroids
inhaled: beclometasone Bronchiole
oral: prednisolone

Fig. 3.2 Pathogenesis and drug action in asthma. Allergens interact with respiratory mucosa (1) and trigger immunoglobulin
E–mediated mast cell response (2). Activation of mast cells causes them to degranulate (3) and release various proinflammatory
mediators (4) which attract and recruit further inflammatory response cells (5). These cells also secrete mediators, which amplify
the inflammatory response (6). The overall effect is narrowing of small airways (7) by bronchospasm, oedema and increased
secretions. cAMP, Cyclic adenosine monophosphate; LT-Rc, Leukotriene receptor; PDE, phosphodiesterase.

34
 Obstructive airways diseases 3

cells release inflammatory mediators that cause a ­ roteases ­released by neutrophils, thus predisposing to the de-
p
bronchial inflammatory reaction, tissue damage and struction of lung tissue leading to emphysema. Other factors,
an increase in airway hyperresponsiveness. Bronchial such as atmospheric pollution, can also have causal links.
inflammatory mediators include leukotrienes, Patients with COPD experience a cough productive of
prostaglandins, thromboxane, platelet-activating factor sputum, wheeze and breathlessness. Infective exacerbations
and eosinophilic major basic protein. can occur, giving purulent sputum. Current treatment of
• Physiologically, airway smooth muscle tone is COPD is not very satisfactory and is aimed at improving
controlled by the balance between contraction induced the quality of life, minimising progressive lung destruction
by release of acetylcholine (Ach) released from and treating acute exacerbations as they arise.
parasympathetic nerves (carried in the vagus) acting on
muscarinic receptors and relaxation induced by release Management of obstructive airways
of nonadrenergic noncholinergic (NANC) nerves
and circulating noradrenaline. There is also release of
disease
noradrenaline at parasympathetic ganglia to indirectly Antiasthmatic drugs include symptomatic bronchodilators
reduce airway smooth muscle tone. and antiinflammatory agents, which are used for maintenance
• Abnormal calcium flux across cell membranes, increasing treatment. The stepwise management of asthma is summarized
smooth muscle contraction and mast cell degranulation. in Table 3.1; the stage-dependent treatment of COPD is shown
• Leaky tight junctions between bronchial epithelial cells in Fig. 3.3. Most patients with COPD get some symptom relief
allowing allergen access. from bronchodilators and antiinflammatory agents in a fashion
The aforementioned result in symptoms of wheezing, similar to people with asthma, yet the response of their airways
breathlessness and sometimes a cough. In many people, the to these drugs is much less marked, and there are no proven
asthmatic attack consists of two phases: an ­immediate-phase benefits for life expectancy. Long-term oxygen therapy does
response and a late-phase response. prolong survival in patients with COPD; however, this must be
undertaken with care in patients with carbon dioxide retention
because it will reduce their hypoxic drive to breathe.
Immediate-phase response
An immediate-phase response occurs on exposure to the
Bronchodilators
eliciting stimulus. The response consists mainly of bron-
chospasm. Bronchodilators are effective in this early phase. β2-Adrenoceptor agonists
Examples of β2-adrenoceptor agonists include salbutamol
Late-phase response (short acting) and salmeterol (long acting). Salbutamol has
Several hours later, the late-phase response occurs. This a half-life of 4 to 6 hours and salmeterol 12 hours. More
consists of bronchospasm, vasodilatation, oedema and mu- recently indacaterol has been introduced as a once daily-­
cus secretion caused by inflammatory mediators released inhaled drug.
from eosinophils, platelets and other cells, and neuropep- Mechanism of action—Airway smooth muscle does
tides released by axon reflexes. This is associated with an not have a sympathetic nervous supply, but it does contain
influx of inflammatory cells into the airways, particularly β2-adrenoceptors that respond to circulating adrenaline.
eosinophils, which can be inhibited by treatment with glu- The stimulation of β2-adrenoceptors leads to a rise in intra-
cocorticosteroids (see Fig. 3.2). cellular cyclic adenosine monophosphate (cAMP) levels and
subsequent smooth muscle relaxation and bronchodilation.
• β2-Adrenoceptor agonists may also help prevent the
Chronic Obstructive Pulmonary
activation of mast cells, as a minor effect.
Disease • Modern selective β2-adrenoceptor agonists are potent
Chronic Obstructive Pulmonary Disease (COPD) is a bronchodilators and have very few β1-stimulating
chronic and progressive disease with fixed or poorly re- properties at recommended doses (i.e. they do not
versible airflow obstruction. It encompasses several disease affect the heart).
components, namely chronic bronchitis and bronchiolitis, Route of administration—Inhaled.
consisting of inflammation and mucus hypersecretion and Oral administration is reserved for children and people
emphysema, involving the destruction of alveolar walls. unable to use inhalers. In acute bronchoconstriction, salbu-
Long-term smoking is the leading factor in the develop- tamol can be given as a nebulizer and may be given intrave-
ment of COPD. Cigarette smoke activates inflammatory nously if life-threatening.
cells (mainly macrophages and neutrophils), which can Indications—β2-Adrenoceptor agonists are used to relieve
cause connective tissue damage in the lung parenchyma, bronchospasm; as such they are the principle ­bronchodilators
resulting in emphysema and hypersecretion of mucus. used in the management of asthma and COPD. They may be
α1-­Antitrypsin is an endogenous protease inhibitor, used alone but are more commonly used in conjunction with
­deficiency of which can result in decreased inhibition of other drugs, for example, corticosteroids.

35
 Respiratory system

Table 3.1 Management of chronic asthma in adults

Step 1 Inhaled short-acting β2 agonist (SABA)
(Reliever therapy)
Step 2 Inhaled SABA plus low dose inhaled corticosteroid
(Preventer therapy)
Step 3 Add in inhaled long-acting β2 agonist (LABA) to low-dose inhaled corticosteroid (usually
combination inhaler)
Step 4 No response to LABA: stop LABA and consider increased dose of inhaled corticosteroid
If benefit from LABA but control still inadequate: continue LABA and increase inhaled
corticosteroid to moderate dose
If benefit from LABA but control still inadequate: continue LABA and inhaled corticosteroid
and consider trial of other therapy (theophylline or long-acting muscarinic antagonist
Step 5 Consider trials of:
Increasing inhaled corticosteroid to high dose
Addition of fourth drug
Refer to specialist care
Step 6 Use daily steroid tablet in the lowest dose to provide adequate control
Maintain high dose inhaled corticosteroid
Refer to specialist care
Stepping down.
If control is achieved, stepwise reduction in therapy may be possible
Therapy should be started at step 1 and worked upwards until control of symptoms is achieved. Once symptoms have been controlled it
may be possible to step down Adapted from British Thoracic Society Guidance September 2016.
Modified from British Thoracic Society Guidance 2016

Fig. 3.3 Inhaled therapy algorithm. FEV1, Forced expiratory volume during the first second. (From NICE guidance 2010
and updated with GOLD 2016 guidelines. Found in Primary Care Respiratory Society UK https://pcrs-uk.org/sites/pcrs-uk.
org/files/COPDQuickGuide2016Academy.pdf).

36
 Obstructive airways diseases 3

Contraindications—Caution in hyperthyroidism, car- effects, having a narrow therapeutic window. Small increases
diovascular disease, arrhythmias. above the therapeutic dose can be toxic and even fatal.
Adverse effects—Fine tremor, tachycardia, hypokalae-
mia after high doses.
Therapeutic notes—β2-Adrenoceptor agonists treat the DRUG INTERACTION
symptoms of asthma but not the underlying d ­ isease ­process
or inflammation. If a short-acting β2-­adrenoreceptor ag- In poorly controlled asthma, oral theophylline is
onist is used more frequently, it is often an indication of sometimes prescribed. Caution should be taken
poorly controlled asthma or impending acute exacerbation. when prescribing macrolide antibiotics (e.g.
Salmeterol is a long-acting drug that can be administered erythromycin) used in the treatment of respiratory
twice daily. It is not suitable for relief of an acute attack. infections. This is because erythromycin occupies
the enzymes involved in theophylline breakdown,
Anticholinergics (Muscarinic receptor
thus increasing the plasma concentration of
antagonists)
Ipratropium bromide (short acting) and tiotropium theophylline. Small increases above the therapeutic
(long acting) are examples of anticholinergic (antimus- dose of theophylline can be toxic and even fatal.
carinic) drugs.
Mechanism of action—Parasympathetic vagal fibres
provide a bronchoconstrictor tone to the smooth muscle of
the airways. They are activated by reflex on stimulation of Leukotriene receptor antagonists
sensory (irritant) receptors in the airway walls. Montelukast and zafirlukast are examples of leukotriene re-
Muscarinic antagonists act by blocking muscarinic re- ceptor antagonists.
ceptors, especially the M3 subtype, which responds to this Mechanism of action—The leukotriene receptor antago-
parasympathetic bronchoconstrictor tone. nists are believed to act at leukotriene receptors in the bron-
Route of administration—Inhaled. chiolar muscle, antagonising endogenous leukotrienes, thus
Indications—Anticholinergics are used as adjuncts to causing bronchodilation.
β2-adrenoceptor agonists in the treatment of obstructive Leukotrienes are thought to be partly responsible for
airway diseases. airway narrowing which is sometimes observed with the
Contraindications—Glaucoma, prostatic hypertrophy, use of nonsteroidal antiinflammatory drugs (NSAIDs; see
pregnancy. Chapter 10) in people with asthma.
Adverse effects—Dry mouth may occur. Systemic anti- Route of administration—Oral.
cholinergic effects are rare. Indications—Prophylaxis of asthma.
Therapeutic notes—Anticholinergics have a synergistic Contraindications—Elderly, pregnancy, Churg–Strauss
effect when administered with β2-adrenoreceptor agonists syndrome.
in obstructive airway diseases. Adverse effects—Gastrointestinal disturbance, dry
Xanthines mouth, headache.
Theophylline is an example of a xanthine. Therapeutic notes—Leukotriene receptor antagonists
Mechanism of action—The xanthines appear to increase are used for children with asthma and can be prescribed
cAMP levels in the bronchial smooth muscle cells by inhib- for allergic rhinitis. 5-Lipoxygenase inhibitors, for example
iting phosphodiesterase, an enzyme which catalyses the hy- Zileuton, also inhibit the synthesis of leukotrienes and can
drolysis of cAMP to AMP. Increased cAMP relaxes smooth be used in the management of asthma.
muscle, causing bronchodilation.
Route of administration—Oral.
Aminophylline is the intravenous xanthine used in se- DRUG INTERACTION
vere asthma attacks. Nonsteroidal antiinflammatory drugs and
Indications—Xanthines are used in children with
asthma
asthma who are unable to use inhalers and adults with pre-
dominantly nocturnal symptoms. They are administered NSAIDs inhibit cyclooxygenase, and divert
intravenously in status asthmaticus. arachidonic acid breakdown via the lipoxygenase
Contraindications—Cardiac disease, hypertension, he- pathway, liberating leukotrienes among other
patic impairment. mediators. Leukotrienes are thought to cause
Adverse effects—Nausea, vomiting, tremor, insomnia, narrowing of bronchi in some asthmatics. Therefore
tachycardia. caution should be exercised when prescribing
Therapeutic notes—Oral xanthines are formulated as
ibuprofen (and other NSAIDs) in patients with asthma.
sustained-release preparations and are useful in preventing
attacks for up to 12 hours. However, they often cause adverse

37
 Respiratory system

Magnesium sulphate Route of administration—Corticosteroids are usually

Intravenous magnesium sulphate is sometimes given in se- delivered by metered-dose inhaler. Oral and intravenous
vere acute asthma when there has been a limited response administration is reserved for severe chronic asthma and
to inhaled bronchodilator therapy. It is thought to relax status asthmaticus.
smooth muscle and has bronchodilation properties when Indications—Corticosteroids are used in patients with
given intravenously. more than minimal symptoms, often in combination with
β2-agonists or drugs that block allergies (see Table 3.1).
Inhaled corticosteroids are indicated in patients with severe
HINTS AND TIPS COPD who suffer from frequent exacerbations, although there
are growing concerns about an increased risk of pneumonia
In an asthmatic emergency do not forget oxygen
in patients with COPD regularly treated with corticosteroids.
as well as salbutamol, ipratropium bromide and a
Contraindications—Caution in growing children and
glucocorticosteroid. You may also need to consider in those with systemic and local respiratory/ear, nose and
whether an antibiotic is needed to cover an throat (ENT) infections.
infective component of the exacerbation. Adverse effects—Dysphonia, oral thrush and with higher
doses of inhaled corticosteroids, there can be some sys-
temic absorption with the potential for suppression of the
­hypothalamic-pituitary-adrenal axis. If given orally, hyperten-
sion, diabetes and cushingoid effects may occur (Chapter 7).
Prophylactic and antiinflammatory drugs
Therapeutic notes—The initial treatment of severe or
Mast-cell stabilizers refractory asthma and COPD may require oral corticoste-
Sodium cromoglycate and nedocromil sodium are exam- roids. If possible, maintenance should be achieved with in-
ples of mast-cell stabilizers. haled corticosteroids via a metered dose to minimize side
Mechanism of action—The exact modes of action effects. Inhaled corticosteroids are usually effective in 3 to
of mast-cell stabilizers are unclear. These drugs appear 7 days but must be taken regularly. Regular inhaled steroids
to stabilize antigen-sensitized mast cells by reducing improve airway irritability and reduce the number of ex-
calcium influx and subsequent release of inflammatory acerbations. However, acute exacerbations may require oral
mediators. courses of corticosteroids.
Route of administration—Inhaled.
Indications—Mast-cell stabilizers are useful in young
patients (< 20 years old) with marked allergic disease and CLINICAL NOTE
moderate asthma.
Adverse effects—Cough, transient bronchospasm, Mrs Connors is a 62-year-old woman who has
throat irritation. been smoking approximately 15 cigarettes a
Therapeutic notes—Mast-cell stabilizers have a prophy- day for the past 40 years. She presents with
lactic action; they must be taken regularly for several weeks intermittent breathlessness and a 3-month history
before any beneficial effects are noted. These drugs are of a cough, which is productive of sputum.
therefore not of use in acute asthma attacks. A diagnosis of COPD is made based on her
Glucocorticoids history, examination and lung function tests. She is
Antiinflammatory glucocorticoids include beclomethasone commenced on a short-acting β2 agonist (SABA)
dipropionate, fluticasone propionate, fluticasone furoate, to relax the airways and increase the flow of air.
budesonide, mometasone and prednisolone. Over winter, she has several exacerbations and
Mechanism of action—Corticosteroids depress the in- a long-acting β2 agonist (LABA) is added. If her
flammatory response in bronchial mucosa and so diminish forced expiratory volume during the first second
bronchial hyperresponsiveness. The specific effects include (FEV1) falls to < 50%, a combination inhaler
the following. consisting of a LABA and inhaled corticosteroid
• Reduced mucosal oedema and mucus production should be considered. In addition to her inhaled
• Decreased local generation of inflammatory mediators therapy, she should be advised to stop smoking,
(prostaglandins and leukotrienes) and cytokines attend pulmonary rehabilitation and have her
• β2-Adrenoceptor upregulation pneumococcal and annual influenza vaccine. In the
• Long-term reduced T-cell cytokine production,
future, she may require long-term oxygen therapy
and reduced eosinophil and mast-cell infiltration of
at home and short courses of oral steroids for
bronchial mucosa.
exacerbations.
For the intracellular events involved in corticosteroid ac-
tion see Chapter 7.

38
 Antitussives and mucolytics 3

Use of inhalers, nebulizers and oxygen Oxygen

In the treatment of asthma, inhalers and nebulizers are used High-flow oxygen should be given to any patient in respiratory
to deliver drugs directly to the airways. This allows higher distress unless they have COPD and a hypoxic drive. In this sit-
drug concentrations to be achieved locally while minimiz- uation, oxygen can be administered, but at a lower concentra-
ing systemic effects. Whatever device is used, less than 15% tion. In very severe COPD (FEV1 <30% or <50% with chronic
of the dose is deposited on the bronchial mucosa. respiratory failure), long-term oxygen therapy may be required.
Oxygen increases alveolar oxygen tension and decreases
Inhalers the work of breathing necessary to maintain arterial oxygen
There are several types of inhaler: metered dose, breath-­ tension.
activated spray, breath-activated powder. They vary in cost,
delivery efficiency and ease of use.
Phosphodiesterase 4 inhibitors
A number of fixed-dose combination inhalers are now
available for patients with mild to moderate asthma. These Mechanism of action
include fluticasone propionate and salmeterol and the Roflumilast inhibits phosphodiesterase 4 in inflammatory
combination of budesonide and formoterol, which can be cells and, by exhibiting an antiinflammatory effect, im-
administered twice daily. These fixed dose combinations proves lung function and reduces exacerbations of COPD.
increase adherence to taking the medication.
Inhaled long-acting muscarinic receptor antagonists Route of administration
(LAMA), tiotropium bromide that is administered once Oral.
daily by inhalation is commonly used in the treatment of Indications
patients with COPD. However, increasingly LAMAs are Added to existing therapy in severe patients with frequent
administered in fixed-dose combination inhalers with a exacerbations of their COPD in whom long-acting bron-
LABA for “dual bronchodilation”, which appears to provide chodilators have limited control.
improved lung function when compared with the use of a Adjunct to bronchodilators for severe COPD with fre-
single class of bronchodilator (e.g. tiotropium and formo- quent exacerbations
terol) (see Fig. 3.3).
Spacer devices, used in conjunction with inhalers, im- Contraindications
prove drug delivery and are easy to use. Spacers are particu- Severe immunologic disease, heart failure or depression.
larly effective in children and acute attacks. Adverse effects
Nebulizers Narrow therapeutic window and can produce significant gas-
Nebulizers convert a solution of a drug into an aerosol for trointestinal side effects in a proportion of patients. It can also
inhalation. Air or oxygen is driven through a solution of the cause unexplained weight loss when used chronically in some
drug which results in a mist, inhaled via a mask. They are patients as well as insomnia and suicidal ideation.
more efficient than inhalers and are used to deliver higher Therapeutic notes—Phosphodiesterase 4 inhibitor, ro-
doses of a drug. They are useful in the acute hospital treat- flumilast, has been shown to improve lung function and re-
ment of severe asthma. duce the likelihood of exacerbations in COPD. However, it
The long-term use of nebulizers is limited by cost, con- has little impact on quality of life or symptoms.
venience and the danger of patient over reliance.
Biologics/monoclonal antibodies
Novel medications for the treatment of asthma have recently
been developed for use by specialist respiratory physicians.
HINTS AND TIPS Monoclonal antibodies are administered by injection for
patients with severe asthma. They are administered every 2
The choice of medication in chronic asthma may be to 3 weeks because antibodies have a long half-life. An IgE
approached in stages, with the patient starting at the monoclonal antibody, omalizumab, has been shown to re-
appropriate level and moving up or down according duce the need for steroids and need for hospitalisation in se-
to the response to treatment. However, it is essential vere asthmatics. More recently, an interleukin 5 monoclonal
to check inhaler technique and compliance with antibody, mepilumozab, has been introduced for treatment
medication before altering any medication and/or of severe asthma exacerbations by specialists.
dose. Educating patients about avoiding triggers,
using the medications in the correct situation
(e.g. salbutamol as a reliever, inhaled steroid as a ANTITUSSIVES AND MUCOLYTICS
preventer) and being able to identify symptoms is
critical to the management of asthma. Antitussives
Antitussives are drugs that inhibit the cough reflex.

39
 Respiratory system

A cough is usually a valuable protective reflex mecha- Therapeutic notes—A novel drug with “mucolytic”
nism for clearing foreign material and secretions from the properties is dornase alfa, a genetically engineered enzyme
airways. In some conditions, however, such as inflamma- which cleaves extracellular deoxyribonucleic acid, and is
tion or neoplasia, the cough reflex may become inappropri- used in cystic fibrosis, being administered by inhalation.
ately stimulated and, in such cases, antitussive drugs may Mannitol is also a mucolytic, which when administered
be used. by inhalation, improves mucus clearance and has been used
Antitussives either reduce sensory receptor activation as add-on therapy for adults with cystic fibrosis. In the fu-
or work by an ill-defined mechanism, depressing a “cough ture, some patients with cystic fibrosis may be treated with
centre” in the brainstem. cystic fibrosis transmembrane conductance regulator mod-
ulators (e.g. ivacaftor).
Drugs that reduce receptor activation
Menthol vapour and topical local anaesthetics
Allergic rhinitis
Benzocaine is an example of a topical local anaesthetic. Rhinitis means an inflammatory response of the membrane
Mechanism of action—Menthol vapour and topical lo- lining the nose. Allergic rhinitis means that the inflamma-
cal anaesthetics reduce the sensitivity of peripheral sensory tory response is caused by specific allergens causing a type
“cough receptors” in the pharynx and larynx to irritation. 1 hypersensitivity reaction. Based on symptoms, it may be
Route of administration—Topical as a spray, lozenge or further classified as seasonal or perennial (throughout the
vapour. year). The inflammation can cause swelling, blockages to
Indications—Menthol vapour and topical local anaes- airflow and overactivity of the mucous membrane glands,
thetics are used for an unwanted cough. causing excessive mucus production. Allergic rhinitis is
treated with antihistamine drugs (H1 antagonists such as
Drugs that reduce the sensitivity of the cetirizine and loratadine) or local corticosteroid sprays such
as fluticasone propionate. Decongestants such as pseudo-
‘cough centre’ ephedrine can sometimes be helpful by causing vasocon-
Opioids striction of the nasal mucosa.
Opioids (see Chapter 10) reduce the sensitivity of the
cough centre. Examples of these drugs include codeine and Decongestants
pholcodine. Nasal decongestion can occur acutely or be a chronic
Mechanism of action—Although not clearly under- disorder.
stood, opioids seem to work via agonist action on opiate Decongestion relies on administration of agents which
receptors, depressing a cough centre in the brainstem. ultimately have sympathomimetic effects. This results in va-
Route of administration—Oral. soconstriction of the mucosal blood vessels of the nose, and
Indications—Opioids are used for inappropriate a reduction in oedema and secretions.
coughing.
Adverse effects—There are generally few side effects of Ephedrine
opioids at antitussive doses. Unlike pholcodine, codeine can This drug is the most commonly used decongestant.
cause constipation and inhibition of mucociliary clearance. Mechanism of action—Ephedrine's sympathomimetic
activity results in vasoconstriction of nasal blood vessels,
Mucolytics limiting oedema and nasal secretions.
Route of administration—Topical or oral.
N-acetylcysteine, carbocisteine and Indications—Nasal congestion.
mecysteine hydrochloride Contraindications—Caution in children.
Mucolytics are used when excess bronchial secretions need Adverse effects—Local irritation, nausea, headache.
to be cleared. Rebound nasal congestion on withdrawal.
Mechanism of action—Carbocisteine and mecysteine Therapeutic notes—Oral preparations are less effective
hydrochloride reduce the viscosity of bronchial secretions than topical and are contraindicated in diabetes, hyperten-
by cleaving disulphide bonds cross-linking mucus glyco- sion and hyperthyroidism.
protein molecules, loosening sputum and facilitating ex-
pectoration from the bronchial tree.
Route of administration—Oral. Histamine 1 receptor antagonists
Indications—Carbocisteine and mecysteine hydrochlo- There are two types of histamine 1 (H1) receptor antagonists.
ride may be of benefit in some chronic obstructive airways • “Old” sedative types, for example, chlorphenamine and
disease, although there is no evidence supporting their use. promethazine
N-acetylcysteine have successfully been used to reduce ex- • “New” nonsedative types, for example, cetirizine and
acerbations of COPD. loratadine

40
 Respiratory stimulants and pulmonary surfactants 3

They are widely used in the treatment of allergic rhinitis Doxapram

because they antagonize H1 receptors and in the periphery Mechanism of action—Doxapram is used to improve
can inhibit allergic reactions where histamine is the main both rate and depth of breathing. Doxapram is a central
mediator involved (see Chapter 6). stimulant drug that acts on both carotid chemoreceptors
Topical glucocorticosteroids (see Chapter 7) are widely and the respiratory centre in the brainstem to increase
used to treat rhinitis and are commonly administered via respiration.
nasal spray or drops. They help to reduce inflammation and Route of administration—Intravenous.
swelling. Side effects include nasal dryness, irritation and Indications—Acute respiratory failure.
nosebleeds. Adverse effects—Perineal warmth, dizziness, sweating,
increase in blood pressure and heart rate.

RESPIRATORY STIMULANTS AND Pulmonary surfactants

PULMONARY SURFACTANTS Pulmonary surfactants are used in the management of
respiratory distress syndrome, which is most common
Respiratory stimulants amongst premature babies. Pulmonary surfactants act to
decrease the surface tension of the alveoli and allow ventila-
Respiratory stimulants, or analeptic drugs, have a very lim-
tion to occur more easily. They are usually administered via
ited place in the treatment of ventilatory failure in patients
endotracheal tubes directly into the pulmonary tree.
with chronic obstructive airways disease. They have largely
been replaced by the use of ventilatory support. Example
drugs are naloxone, flumazenil and doxapram.

Chapter Summary

• Asthma is characterized by recurrent reversible obstruction and inflammation of the bronchi

• Chronic obstructive pulmonary disease is a chronic and progressive disease with fixed or
poorly reversible airflow obstruction
• Current management of obstructive airways disease requires ß-blockers, anticholinergics,
xanthines and leukotriene receptor antagonists
• Allergic rhinitis is caused by a type 1 hypersensitivity reaction
• Allergic rhinitis is treated with antihistamine, H1 antagonists.

41
This page intentionally left blank
 Cardiovascular system
4
action potential generated by the SAN spreads throughout
THE HEART both atria, reaching the AVN. The AVN delays the action
potential arising from the SAN to encourage the complete
Basic concepts emptying of the atria before the ventricles contract.
The heart is a pump, which together with the vascular sys- The secondary action potential generated by the AVN de-
tem supplies the tissues with blood containing oxygen and scends into the interventricular septum via the bundle of His.
nutrients and removes waste products. The bundle of His splits into left and right branches making
The flow of blood around the body is as follows (Fig. 4.1). contact with the Purkinje fibres, which conduct the impulse
throughout the ventricles, causing them to contract (Fig. 4.2).
• Deoxygenated blood from body tissues reaches the
The orderly pattern of sinus rhythm can be disrupted ei-
right atrium through the systemic veins (the superior
ther by heart disease or by the action of drugs or circulating
and inferior venae cavae).
hormones. Therapeutically, drugs can be used to restore a
• Blood flows into the right ventricle, which then pumps
normal cardiac rhythm where it has become disturbed (e.g.
the deoxygenated blood via the pulmonary artery to
atrial fibrillation [AF] where the heart chambers stop con-
the lungs, where the blood becomes oxygenated before
tracting in a coordinated fashion because the rhythm is re-
reaching the left atrium via the pulmonary vein.
placed by chaotic electrical activity).
• Blood flows from the left atrium into the left ventricle.
From here, it is pumped into the systemic circulation Cardiac action potential
via the aorta, to supply the tissues of the body. The shape of the action potential is characteristic of the lo-
cation of its origin (i.e. whether from nodal tissue, the atria
Cardiac rate and rhythm or the ventricles) (see Fig. 4.2).
The sinoatrial node (SAN) and the atrioventricular node
(AVN) govern the rate and timing of the cardiac action po- Nonnodal cells
tential. The SAN is located in the superior part of the right The resting membrane potential across the ventricular cell
atrium near the entrance of the superior vena cava; the AVN membrane is approximately -85 mV; this is because the
is located at the base of the right atrium. The SAN discharges resting membrane is more permeable to potassium than
at a frequency of 80 impulses per minute; it is the pacemaker to other ions. Four phases occurring at the ventricular cell
for the heart and as such, determines the heart rate. The membrane are (Fig. 4.3).

Superior Aorta Pulmonary

vena cava artery

Pulmonary
veins

Left
atrium

Left ventricle
Right Myocardium
atrium
Endocardium

Inferior
vena cava

Right Pericardium
ventricle
Fig. 4.1 . Blood flow through the heart chambers. (Modified from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds)
Integrated Pharmacology, 3rd edn. Mosby, 2006.)

43
 Cardiovascular system

SA node Bundle of His SA node

AV node

−65 mV
Atria

Atria

−85 mV
Ventricles

Ventricles

Left and right bundle

branches
−85 mV
Right ventricle Left ventricle

Fig. 4.2 . Regional variation in action potential configuration throughout the heart. AV, Atrioventricular; SA, sinoatrial.
(Modified from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) Integrated Pharmacology, 3rd edn. Mosby, 2006.)

• Phase 0 or depolarisation: Occurs when the membrane

potential reaches a critical value of -60 mV. The
upstroke of the action potential is caused by the
Class IV Class III transient opening of voltage-gated sodium channels,
antiarrhythmics antiarrhythmics
allowing sodium ions into the cell. In addition,
potassium conductance falls to very low levels.
+30
1 _ • Phase 1 (partial repolarisation): Occurs as a result of
mV
Ito 2 the inactivation of the sodium current, and a transient
Isi IK outward potassium current.
0 • Phase 2 (plateau phase): The membrane remains
Class lll INa
antiarrhythmics depolarized at a plateau of approximately 0 mV. This is
_
0 3
_ caused by the activation of a voltage-dependent slow
Class la and lb
antiarrhythmics inward calcium current (conducting positive charge
into the cell) and a delayed rectifier potassium current
IKi conducting positive charge out of the cell.
−85 • Phase 3 (repolarisation): Repolarisation is caused by
the inactivation of the calcium current and an increase
0 300 in potassium conductance.
ms
Nodal cells
Fig. 4.3 . Configuration of a typical ventricular action The resting membrane potential of nodal cells is approxi-
potential showing the ionic currents, the phases and where mately -60 mV.
class I, III and IV antiarrhythmic drugs act. 0, 1, 2 and 3,
In nodal cells, there is no fast sodium current. Instead, the
Phases of the action potential; INa, fast inward Na+ current;
Isi, slow inward Ca2+ current; Ito, transient outward K+
action potential is initiated by an inward calcium current, and,
current; IK, delayed rectifier K+ current; IKi, inward rectifier because calcium spikes conduct slowly, there is a delay of approx-
K+ current. (Modified from Page, C., Curtis, M. Walker, imately 0.1 seconds between atrial and ventricular contraction.
M, Hoffman, B. (eds) Integrated Pharmacology, 3rd edn. Nodal cells have a phase known as phase 4 (the pacemaker
Mosby, 2006.) potential). This phase involves a gradual depolarisation that

44
 The heart 4

Table 4.1 Effects of the sympathetic and

Inward curves Outward curves parasympathetic nervous systems on the heart
Sympathetic Parasympathetic
0 IK Heart rate Increased Decreased
mV
Force of Increased Decreased
Class Ia contraction
antiarrhythmics
Isi, If, Ist Automaticity Increased Decreased
_
Class II AV node Facilitated Inhibited
4
antiarrhythmics
conduction
−65
Cardiac efficiency Decreased Increased
Effects mediated Cardiac nerve Vagus nerve
0 100 200
by
ms
Receptors β1-adrenoceptors M2 receptors
Fig. 4.4 . Configuration of a typical sinoatrial node action
activated
potential showing the ionic currents, the phases and
where class Ia and II antiarrhythmic drugs act. 4, Phase of Effects on cAMP Increased Decreased
the action potential; Isi, an inward current carried by Ca2+ and intracellular
ions; If, a ‘funny’ current carried by Na+ and Ca2+ ions; Ist, calcium
the sustained inward Na+ current; IK, the delayed rectifier AV, Atrioventricular; cAMP, cyclic adenosine monophosphate.
current which is an outward K+ current. (Modified from
Page et al. 2006.)
The effects of the sympathetic and parasympathetic ner-
vous systems on the heart are summarized in Table 4.1.
­ ccurs during diastole and is known as the f current (If′ funny).
o
The f current is activated by hyperpolarisation at -45 mV and
consists of sodium and calcium ions entering the cell (Fig. 4.4). Cardiac contractility
Myocardial contraction is the result of calcium entry
through L-type channels, giving rise to an increase in cyto-
CLINICAL NOTE solic calcium in the myocytes (Fig. 4.5).
The calcium is derived from two sources.
When a patient presents with chest pain or
• The sarcoplasmic reticulum within the cell
palpitations (sensation of feeling their heart beat),
• The extracellular medium
check their electrolytes (sodium and potassium),
Extracellular calcium enters the cell, triggering larger amounts
as well as calcium and magnesium levels, because
of calcium to be released from the sarcoplasmic reticulum, a
the patient can be at risk of an arrhythmia if these
process known as calcium-induced–calcium release.
are abnormal. In addition, many medications (e.g. During contraction, the intracellular levels of calcium
digoxin) can affect intracellular potassium levels so increase to levels 10,000 times greater than those at rest.
a thorough drug history must be elicited. Calcium binds to troponin C, thereby modifying the position
of actin and myosin filaments, and allowing the cell to con-
tract. Contraction ceases only once calcium has been removed
from the cytoplasm. This occurs through two mechanisms.
Autonomic control of the heart
Both the parasympathetic and sympathetic nervous systems • Calcium is pumped out of the cell via the electrogenic
influence the heart, although parasympathetic activity pre- Na+/Ca2+ exchanger, which pumps one calcium ion out
dominates. This explains why the heart rate is lower than for every three sodium ions in.
the inherent firing frequency of the SAN. • Calcium is resequestered into sarcoplasmic
The sympathetic nervous system mediates its effects reticulum stores by a Ca2+ adenosine triphosphatase
through the cardiac nerve and activation of β1-adrenoceptors. (ATPase) pump.
These are linked to adenylyl cyclase and their activation causes Cardiac output is the product of heart rate and mean left
increased levels of cyclic adenosine monophosphate (cAMP) ventricular stroke volume (i.e. the volume of blood ejected
and a subsequent increase in intracellular calcium levels. from the ventricle with each heartbeat). Stroke volume is
The parasympathetic nervous system mediates its effects determined by both intrinsic factors (calcium and ATP)
through the vagus nerve and activation of M2 receptors by and extrinsic factors (elasticity and contractility of arteries
acetylcholine (ACh). These are also linked to adenylyl cy- and volume of blood). Drugs that influence these factors are
clase, but their activation causes decreased levels of cAMP essential in the treatment of cardiac dysfunction. Starling’s
and a subsequent decrease in intracellular calcium levels. Law is an important concept to understand—the stroke

45
 Cardiovascular system

Cardiac glycosides

Extracellular space Ca2+ Ca2+ 3Na+

_

ATP ADP ATP ADP ATP ADP

Transverse tubule 3Na+ 2K+

Troponin C
L-type Ca2+ channel
Calcium _
Ca2+ Free cytosolic Ca2+ Myofilaments
channel
blockers
+ Contraction

β1-agonists + AC cAMP
Gs ATP ATP ADP Ca2+ Ca2+
PDE _
β1-antagonists _ β1
5' AMP

Cytosol
Ca2+

Sarcoplasmic reticulum
PDE inhibitors
Cytosol of
myocardial cell

Fig. 4.5 . Effects of drugs on cardiac contractility. AC, Adenylyl cyclase; ADP, adenosine diphosphate; AMP, adenosine
monophosphate; ATP, adenosine triphosphate; β1, β1-adrenoceptor; cAMP, cyclic adenosine monophosphate; Gs,
stimulatory G-protein; PDE, phosphodiesterase.

volume of the heart increases in response to an i­ncrease in excitation–contraction coupling, with progressive systolic
the volume of blood filling the heart (the end- diastolic vol- and diastolic ventricular dysfunction. Some of the causes,
ume). The increased volume of blood stretches the ventricu- symptoms and signs of acute and chronic cardiac failure
lar wall, causing cardiac muscles to contract more forcefully. are given in Table 4.2. The characteristics of left and right
ventricular failure are listed in Table 4.3.
Cardiac dysfunction and treatment The body attempts to compensate for the effects of CCF
by two processes: extrinsic and intrinsic.
Congestive cardiac failure
Congestive cardiac failure (CCF) is the combined fail- Extrinsic cardiac compensation
ure of both the left and right sides of the heart. Around Extrinsic cardiac compensation mechanisms aim to
900,000 people have chronic heart failure in the United maintain cardiac output and blood pressure. The reflex
Kingdom and the incidence is increasing with age. CCF pathway is as follows: hypotension → activation of baro-
occurs when the cardiac output does not meet the needs receptors (receptors responding to changes in pressure) →
of the tissues. This is thought to be caused by defective increased sympathetic activity → increased heart rate and

Table 4.2 Causes and symptoms/signs of acute and chronic cardiac failure
Causes Symptoms/signs
Acute CF Chronic CF Acute CF Chronic CF
Myocardial infarction Systemic hypertension Tachycardia Exertional dyspnoea
Acute valvular lesion Myocardial infarction Hypotension Systemic oedema
Valvular lesions Dyspnoea Cardiomegaly
Cardiomyopathies Pulmonary oedema Fatigue
Systemic oedema Orthopnoea
CF, Chronic cardiac failure.

46
 The heart 4

Positive inotropes and congestive cardiac failure (CCF)

Table 4.3 Characteristics of right and left ventricular
failure
Frank-Starling curve
Right Ventricular Failure Left Ventricular Failure
(Cor pulmonale) (Pink puffers)

Cardiac output (CO)

Normal range
Reduced cardiac output Reduced cardiac output
Positive inotropes
Hypotension Hypotension 4 3
Peripheral oedema Pulmonary congestion
= cough, crackles, wheeze, 1 2 CCF

Forward
failure
tachypnoea
= pulmonary oedema
Backward failure
Raised JVP Fatigue
Hepatomegaly/ Paroxysmal nocturnal Left ventricular end-diastolic pressure
splenomegaly dyspnoea
Left ventricular end-diastolic pressure vs CO
Ascites Orthopnoea Low output symptoms: fatigue (forward failure)
Dyspnoea Congestive symptoms: dyspnoea, oedema (backward failure)
Anorexia and GI Confusion Forward and backward failure
disturbances Normal set point
Weight gain New set point

GI, Gastrointestinal; JVP, jugular venous pressure. Fig. 4.6 . Normal cardiac output is determined by the
pressure in the left ventricle at end-diastole. In congestive
cardiac failure, the set point for cardiac output is reduced
and cardiac output falls (1). Compensatory neurohumoral
­vasoconstriction → increased cardiac contractility and vas-
responses become activated which increase end-diastolic
cular tone → increased arterial pressure. pressure and improve cardiac output; however, this can
However, the greater the resistance (arterial pressure) give rise to backward failure (2). Positive inotropic agents
against which the heart must pump, the greater the re- increase cardiac output (3). The improved cardiac output
duction in both the ejection fraction (the volume of blood reduces the drive for a high end-diastolic pressure, and
ejected by the ventricle relative to its end diastolic volume) decompensation occurs to a new set point (4).
and the perfusion of the tissues.
The reduced perfusion of the kidneys activates the The chemical structure of these drugs consists of three
­renin–angiotensin system (RAS), leading to renin secre- components: a sugar moiety, a steroid and a lactone. The
tion and subsequent elevation of plasma angiotensin II and lactone ring is responsible for cardiotonic activity and the
aldosterone levels (see Fig. 4.8). Angiotensin II causes pe- sugar moiety affects the potency and pharmacokinetic dis-
ripheral vasoconstriction and aldosterone increases sodium tribution of the drug. The steroid nucleus is responsible for
retention, leading to increased water retention, oedema and the positive inotropic effect of these drugs. Positive inotro-
an increased preload. pic actions of cardiac glycosides improve the symptoms of
CCF, but there is no evidence they have a beneficial effect
Intrinsic cardiac compensation
on the long-term prognosis of patients with CCF.
The increased cardiac preload leads to incomplete emptying
Mechanism of action—Cardiac glycosides act by inhibit-
of the ventricles and an increase in end-diastolic pressure.
ing the membrane Na+/K+ ATPase pump (see Fig. 4.5). This
The heart eventually fails, owing to the massive increase in
increases intracellular Na+ concentration, thus reducing the
myocardial energy requirements.
sodium gradient across the membrane and decreasing the
amount of calcium pumped out of the cell by the Na+/Ca2+
Drugs used in heart failure exchanger during diastole. Consequently, the intracellular
Introduction calcium concentration rises, thus increasing the force of car-
The effects of medications are not independent of each diac contraction and maintaining normal blood pressure.
other. A drug affecting the electrical properties of the myo- In addition, cardiac glycosides alter the electrical activity
cardial cell membrane is likely to influence both the cardiac of the heart, both directly and indirectly. At therapeutic doses,
rhythm and myocardial contraction. they indirectly decrease the heart rate, slow atrioventricular
(AV) conductance and shorten the atrial action potential by
Cardiac glycosides stimulating vagal activity. This is useful in AF because when
Digoxin is a commonly used cardiac glycoside. The drugs the ventricular rate is excessively high, the time available for
in this class shift the Frank–Starling ventricular function diastolic filling is inadequate, so slowing the heart rate in-
curve to a more favourable position (Fig. 4.6). creases stroke volume and cardiac efficiency.

47
 Cardiovascular system

At toxic doses, they indirectly increase the sympathetic with cardiac glycosides. There is no evidence that these im-
activity of the heart and cause arrhythmias, including heart prove the mortality rate.
block. The direct effects are mainly caused by loss of in- Mechanism of action—The type 3 PDE isoenzyme is
tracellular potassium and are most pronounced at high found in myocardial and vascular smooth muscle.
doses. The resting membrane potential is reduced, causing PDE is responsible for the degradation of cAMP; thus
enhanced automaticity slowed cardiac conduction, and in- inhibiting this enzyme raises cAMP levels and causes an
creased AVN refractory period. increase in myocardial contractility and vasodilatation
The increased cytosolic calcium concentration may (see Fig. 4.5). Cardiac output is increased, and pulmo-
reach toxic levels thereby saturating the sarcoplasmic re- nary wedge pressure and total peripheral resistance are
ticulum sequestration mechanism and causing oscillations reduced, without much change in heart rate or blood
in calcium owing to calcium-induced calcium release. pressure.
This results in oscillatory after-potentials and subsequent Route of administration—Intravenous.
arrhythmias. Indications—PDE 3 inhibitors are given for severe acute
In addition, cardiac glycosides have a direct effect on heart failure that is resistant to other drugs.
α-adrenoceptors, causing vasoconstriction and a conse- Adverse effects—Nausea and vomiting, arrhythmias,
quent increase in peripheral vascular resistance, which is liver dysfunction, abdominal pain, hypersensitivity.
further enhanced by a centrally mediated increase in sym-
pathetic tone. β-Adrenoceptor and dopamine receptor
Route of administration—Oral. agonists
Indications—To slow the heart rate in AF and treatment Examples of β-adrenoceptor agonists include dobutamine
of heart failure in patients who remain symptomatic despite and dopamine. They are used intravenously in CCF emer-
optimal use of diuretics. gencies (see Fig. 4.5).
Contraindications—Heart block, hypokalaemia (the lack
of competition from potassium potentiates the effects of
cardiac glycosides on the Na+/K+ ATPase pump). HINTS AND TIPS
Adverse effects—Arrhythmias, anorexia, nausea and
vomiting, visual disturbances, abdominal pain and diar- Drugs with proven mortality benefits in
rhoea. cardiac failure should be remembered. They are
Therapeutic notes—The cardiac glycosides have a very β-adrenoceptor antagonists, angiotensin-converting
narrow therapeutic window, and toxicity is therefore rela- enzyme (ACE) inhibitors, nitrates with hydralazine
tively common. Effects of cardiac glycosides are increased and spironolactone.
if plasma potassium decreases, because of reduced compe-
tition at the K+ binding side on the Na+/K+ ATPase. This
is clinically important because many diuretics, which are
often used to treat heart failure, decrease plasma potassium Diuretics
thereby increasing the risk of glycoside-induced dysrhyth- The main diuretic drug classes are:
mias. If this occurs, the drug should be withdrawn and, • thiazides
if necessary, potassium supplements and antiarrhythmic • loop diuretics
drugs administered. For severe intoxication, antibodies spe- • potassium-sparing diuretics
cific to cardiac glycosides are available.
Diuretics inhibit sodium and water retention by the
kidneys, and so reduce oedema because of heart fail-
CLINICAL NOTE ure. Venous pressure and thus cardiac preload are re-
duced, increasing the efficiency of the heart as a pump.
Digoxin is excreted via the kidney; therefore elderly Potassium-sparing diuretics (e.g. spironolactone) ap-
patients and those with overt renal failure require a pears to have a beneficial effect in cardiac failure at doses
reduced dose of digoxin to avoid toxicity. Checking lower than it would be expected to function as a diuretic
the plasma digoxin concentration in the blood is (see Chapter 5)
useful if toxicity is suspected.
Angiotensin-converting-enzyme inhibitors
For details of ACE inhibitors see p. 79.

Nitrates
Phosphodiesterase inhibitors See antianginal drugs (p. 76).
Examples of phosphodiesterase (PDE) 3 inhibitors include
enoximone and milrinone. These have been developed as a Vasodilating drugs
result of the many adverse effects and problems associated Hydralazine is discussed on p. 81.

48
 The heart 4

Arrhythmias result from cellular calcium overload, associated

The most common cause of sudden death in developed with ischaemia, reperfusion and cardiac glycoside
countries is arrhythmia and it usually results from underly- intoxication.
ing cardiovascular pathology such as atherosclerosis.
Myocardial ischaemia is one of the most important Abnormal impulse conduction
causes of arrhythmias and occurs when a coronary artery Heart block—Heart block results from damage to nodal
becomes occluded, thus preventing sufficient blood from tissue, most commonly the AVN (e.g. after a myocardial
reaching the myocardium. Accumulation of endogenous bi- infarction) and can cause ventricular premature beats. AV
ological mediators, including potassium, cAMP, thrombox- block may be first, second or third degree, manifesting itself
ane A2 and free radicals, is believed to initiate arrhythmias. from slowed conduction to complete block of conduction,
Reperfusion after coronary occlusion is necessary for where the atria and ventricles beat independently.
tissue recovery and prevention of myocardial necrosis, but Reentry—Reentry is likely to cause ventricular and
the spontaneous resumption of coronary flow is often itself atrial tachycardia and fibrillation, atrial flutter and Wolff-
a cause of the arrhythmia. Parkinson-White syndrome (a congenital abnormality that
Arrhythmias have been defined according to their ap- results in a supraventricular tachycardia that uses an AV
pearance on the electrocardiogram (ECG) by the Lambeth accessory tract). Reentry is of two types, circus movement
Conventions. These include the following. and reflection.
• Ventricular: premature beats, tachycardia, fibrillation • Circus movement: An impulse reexcites an area of the
and torsades de pointes. myocardium recently excited and after the refractory
• Atrial: premature beats, tachycardia, flutter and period has ended. This usually occurs in a ring of tissue
fibrillation. in which a unidirectional block is present, preventing
anterograde conduction of the impulse, but allowing
The two main mechanisms by which cardiac rhythm retrograde conduction of the same impulse. This results
becomes dysfunctional are abnormal impulse generation in its continuous circulation termed circus movement.
(automatic or triggered) and abnormal impulse conduction. The time taken for the impulse to propagate around
the ring must exceed the refractory period; thus
Abnormal impulse generation administration of drugs that prolong the refractory
Automatic—Automatic abnormal impulse generation is period will interrupt the circuit and terminate reentry.
likely to cause sinus and atrial tachycardia, and ventricular • Reflection: Occurs in nonbranching bundles within
premature beats. It can be enhanced or abnormal. which electrical dissociation has taken place. Owing to
• Enhanced: pathological conditions, such as this electrical dissociation, an impulse can return over
ischaemia, may affect nodal and conducting tissue the same bundle.
so their inherent pacemaker frequency is greater
than that of the SAN (see Fig. 4.2). The automaticity
of the slow pacemakers (AVN, Purkinje fibres, the
CLINICAL NOTE
bundle of His) is enhanced because ischaemia causes
partial depolarisation of tissues (owing to a decrease Mrs Fibbs, presented with palpitations and
in the activity of the electrogenic sodium pump and dyspnoea. She is known to have mitral stenosis.
catecholamine release). This gives rise to an ectopic
On examination, she had an irregularly irregular
focus triggering the development of a premature beat.
pulse, diagnostic of Atrial Fibrillation (AF). This
• Abnormal: A premature beat may also develop in atrial
was confirmed on ECG by absent P waves and
or ventricular tissue, which is not normally automatic.
irregular QRS complexes. Digoxin was given to
Triggered—Forms of triggered abnormal impulse gener-
slow the heart rate. Her management also included
ation are:
anticoagulation, because she is over 65 years
Early after-depolarisations: These are triggered during
repolarisation, that is, phase 2 or 3, of a previously of age and her AF puts her at increased risk of
normal impulse (see Fig. 4.3). There is a decrease in embolic stroke.
the delayed K+ current that results in an abnormally
long action potential. They are therefore more likely
to occur during bradycardia and when taking class III
antiarrhythmic drug treatment. It can cause torsades de Antiarrhythmic drugs
pointes and reperfusion-induced arrhythmias. Antiarrhythmic drugs are classified according to a system
Delayed after-depolarizations (DADs): DADs are triggered devized by Vaughan Williams in 1970 and later modified by
once the action potential has ended, that is, during Harrison. A summary of the effects of the different classes
phase 4, of a previously normal impulse. DADs usually of drug is given in Table 4.4.

49
 Cardiovascular system

Table 4.4 Effects of antiarrhythmic drugs

Myocardial Effective
Class Example contractility AV conduction AP duration refractory period
la Procainamide ↓ ↓ ↑ ↑
lb Lidocaine – – ↓ ↑↑
lc Flecainide ↓↓ ↓↓ – –
II Propranolol ↓↓ –/↓ – –
III Amiodarone – ↑ ↑↑↑ ↑↑↑
IV Verapamil ↓↓↓ ↓↓ ↓↓ –
The number of arrows indicates the degree of the effect caused.
AP, Action potential; AV, atrioventricular.

Class I • Binding to open channels during phase 0, and

All class I drugs block the voltage-dependent sodium chan- dissociating by the next beat, if the rhythm is normal,
nels in a dose-dependent manner. Their action resembles but abolishing premature beats.
that of local anaesthetics (see Chapter 10). • Decreasing action potential duration.
All class I drugs have the following effects. • Increasing the effective refractory period.
• They prolong the effective refractory period (terminateRoute of administration—Lidocaine is administered in-
reentry). travenously, and mexiletine and phenytoin either orally or
• They convert unidirectional block to bidirectional intravenously.
block (prevent reentry). Indications—Ventricular arrhythmias following acute
myocardial infarction. Phenytoin is used in epilepsy (see
Class Ia Chapter 8).
Examples of class Ia drugs include quinidine, procainamide Contraindications—Class Ib drugs should not be given
and disopyramide. to patients with SAN disorders, AV block and porphyria.
Class Ia drugs affect atrial muscle, ventricular muscle, Adverse effects—Hypotension, bradycardia, drowsiness and
the bundle of His, the Purkinje fibres and the AVN. confusion, convulsions and paraesthesia (pins and needles).
Mechanism of action—Class Ia drugs block voltage-­ Lidocaine may cause dizziness and respiratory depres-
dependent sodium channels in their open (activated) or sion; mexiletine may cause nausea and vomiting, constipa-
refractory (inactivated) state (see Figs. 4.3 and 4.4). Their tion, arrhythmias and hepatitis; and phenytoin may cause
effects are to slow phase 0 (increasing the effective refrac- nausea and vomiting and peripheral neuropathy.
tory period) and phase 4 (reducing automaticity) and to
prolong action potential duration. Class Ic
Route of administration—Oral, intravenous. Flecainide is the only drug used from class Ic.
Indications—Ventricular, supraventricular arrhythmias. Mechanism of action—Flecainide blocks sodium chan-
Contraindications—Heart block, sinus node dysfunc- nels in a fashion similar to the class Ia and Ib drugs but
tion, cardiogenic shock, severe uncompensated heart fail- shows no preference for refractory channels. This results
ure. Procainamide should not be given to patients with in a general reduction in the excitability of the myocar-
systemic lupus erythematosus. dium. They markedly inhibit conduction through the His
Adverse effects—Arrhythmias, nausea and vomiting, Purkinje fibres.
hypersensitivity, thrombocytopenia and agranulocytosis. Route of administration—Oral, intravenous.
Procainamide can cause a lupus-like syndrome, and disopy- Indications—Ventricular tachyarrhythmias, tachycardia
ramide causes hypotension. associated with accessory pathways (e.g. Wolff-Parkinson-
Class Ib White syndrome), AF without left ventricular dysfunction.
Examples of class Ib drugs include lidocaine, mexiletine and Contraindications—Structural heart disease, heart fail-
phenytoin. ure, history of myocardial infarction.
Mechanism of action—Class Ib drugs exert their ef- Adverse effects—Dizziness, visual disturbances, arrhythmias.
fects in several ways (see Fig. 4.3). These include the fol-
Class II
lowing.
Examples of class II drugs include propranolol, atenolol and
• Blocking voltage-dependent sodium channels in their metoprolol (see Figs. 4.4 and 4.5).
refractory (inactivated) state, that is, when depolarized, Class II drugs are β-adrenoceptor antagonists (atenolol is
as occurs in ischaemia. β1 selective). Ventricular dysrhythmias following myocardial
50
 The heart 4

infarction are partly the result of increased sympathetic activ- Other antiarrhythmics
ity. β-adrenoceptor antagonists increase the refractory period The cardiac glycosides (e.g. digoxin) and adenosine are
of the AVN and therefore prevent recurrent attacks of supra- agents used in arrhythmias, but which do not fit into the
ventricular tachycardia and AF where there is sympathetic four classes described.
activation. Propranolol has some class I action in addition.
Adenosine
Class III Adenosine is produced endogenously and acts upon many
Examples of class III drugs include amiodarone, drone- tissues, including the lungs, afferent nerves and platelets.
darone, sotalol and ibutilide. Mechanism of action—Adenosine acts at A1 receptors
Mechanism of action—All class III drugs used clinically in cardiac conducting tissue and causes myocyte hyperpo-
are potassium-channel blockers. They prolong cardiac ac- larisation. This acts to slow the rate of the action potential
tion potential duration (increased QT interval on the ECG) rising and brings about delay in conduction.
and prolong the effective refractory period (see Fig. 4.3). Route of administration—Intravenous.
Amiodarone also blocks sodium and calcium chan- Indications—Paroxysmal supraventricular tachycardia.
nels, that is, slows phases 0 and 3, and blocks α and β-­ Aids diagnosis of broad and narrow-complex supraventric-
adrenoceptors. Sotalol is a β-adrenoceptor antagonist with ular tachycardia.
class III activity (it prolongs the cardiac action potential and Contraindications—Second-degree or third-degree heart
QT interval by delaying the slow outward K+ current). block, sick sinus syndrome.
Route of administration—Amiodarone and sotalol are Adverse effects—Transient facial flushing, chest pain,
administered orally or intravenously. dyspnoea, bronchospasm. Side effects are very short lived,
Indications—Class III drugs are given for ventricular and often lasting less than 30 seconds.
supraventricular arrhythmias.
Contraindications—Amiodarone should not be given to Angina pectoris
those with AV block, sinus bradycardia or thyroid dysfunc- Angina is associated with acute myocardial ischaemia and
tion. results from underlying cardiovascular pathology, where
For contraindications regarding sotalol, see under the coronary flow does not meet the metabolic needs of the
β-blockers (p. 76). heart. It results in a radiating chest pain.
Adverse effects—Class III drugs can cause arrhythmias, Stable or classic angina is caused by fixed stenosis of the
especially torsades de pointes. Amiodarone may cause coronary arteries and is brought on by exercise and stress.
thyroid dysfunction, liver damage, pulmonary disorders, Unstable angina (crescendo angina) can occur suddenly at
photosensitivity and neuropathy as well as grey slate disco- rest, and becomes progressively worse, with an increase in
louration of the skin and irreversible corneal deposits. the number and severity of attacks. The following condi-
For adverse effects regarding sotalol see under β-­ tions can all cause unstable angina.
blockers (p. 76).
• Coronary atherosclerosis
Class IV • Coronary artery spasm
Examples of class IV drugs include verapamil and diltiazem • Transient platelet aggregation and coronary
(see Figs. 4.3 and 4.5). thrombosis
Class IV drugs are calcium antagonists that shorten • Endothelial injury causing the accumulation of
phase 2 of the action potential, thus decreasing action po- vasoconstrictor substances
tential duration. They are particularly effective in nodal • Coronary vasoconstriction following adrenergic
cells, where calcium spikes initiate conduction. However, stimulation
verapamil is contraindicated in patients with ventricular Variant angina (Prinzmetal angina) occurs at rest, at the
dysrhythmias and Wolff-Parkinson-White syndrome. same time each day and is usually caused by coronary ar-
Details of the drugs are given in the section on antiangi- tery spasm. It is characterized by an elevated ST segment
nal drugs (p. 76). on the ECG during chest pain and may be accompanied by
ventricular arrhythmias.
DRUG INTERACTION
When prescribing verapamil with digoxin in
HINTS AND TIPS
patients with poorly controlled AF, the dose of
digoxin should be reduced and levels checked. The drugs used in stable angina pectoris are
Verapamil both displaces digoxin from tissue β-adrenoceptor antagonists, nitrates, calcium
binding sites and reduces its renal excretion. There antagonists, antiplatelets and potassium-channel
is a risk of digoxin accumulation and toxicity. activators.

51
 Cardiovascular system

Antianginal drugs β-Adrenoceptor antagonists (β-blockers)

Treatment of angina aims to dilate coronary arteries to al- Examples of β-blockers include propranolol, atenolol, bi-
low maximal myocardial perfusion, decrease the heart rate soprolol and metoprolol.
to minimize oxygen demands of the myocardium, lengthen β-Adrenoceptors are found in many tissues, al-
diastole when cardiac perfusion occurs and to prevent though the β1-adrenoceptor is found predominantly
platelets from aggregating and forming platelet plugs. In in the heart, and the β2-adrenoceptor is found mainly
addition to this, reversible risk factors need to be addressed in the smooth muscle of the vasculature. Some overlap
to limit the progression of the disease. does exist.
Acute attacks of angina are treated with sublingual Different β-blockers have different affinity for the two
nitrates. types of adrenoceptor. Propranolol is nonselective, hav-
In the hospital setting, acute anginal pain is treated with ing equal affinity for both the β1- adrenoceptors and β2-­
an opiate (Chapter 10). adrenoceptors. Atenolol, bisoprolol and metoprolol have a
Stable angina is treated with the following. greater affinity for the β1-adrenoceptor and are therefore
• Long-acting nitrates more “cardiac-specific”. Some β-blockers even appear to
• β-Adrenoceptor antagonists have partial agonistic effects at β-adrenoceptors, as well as
• Calcium antagonists antagonistic effects.
• Antiplatelet agents (e.g. aspirin) Mechanism of action—The aim of using β-adrenoceptor
• Potassium-channel activators antagonists in cardiac disease is to block β-adrenoceptors in
the heart. This has the effect of causing a fall in heart rate
Unstable angina is a medical emergency and requires (slowing of phase 4; see Fig. 4.4), in systolic blood pressure,
hospital admission. Unstable angina is treated with the in cardiac contractile activity and in myocardial oxygen de-
following. mand.
• Antiplatelets: aspirin, clopidogrel and dipyridamole Route of administration—Oral, intravenous.
(adenosine diphosphate [ADP] antagonists) and the Indications—Angina, postmyocardial infarction (reduce
glycoprotein IIb/IIIa inhibitors (p. 89). the risk of death), arrhythmias, hypertension, thyrotoxico-
• Heparin/low-molecular-weight heparin sis, glaucoma and anxiety.
(LMWH) (p. 89). Contraindications—Nonselective β-blockers (e.g. pro-
• Standard antianginal drug regimen pranolol) must not be given to asthmatic patients. At high
doses, β1-adrenoceptor antagonists lose their selectivity and
Organic nitrates should be used with caution in those with asthma. Other
The organic nitrates, glyceryl trinitrate (GTN), isosorbide contraindications for β-blockers include bradycardia, hypo-
mononitrate and isosorbide dinitrate, can relieve angina tension and AV block.
within minutes. Adverse effects—Bronchospasm (therefore are contra-
Mechanism of action—Most nitrates are prodrugs, de- indicated in patients with asthma), fatigue and insomnia,
composing to form nitric oxide (NO), which activates dizziness, cold extremities (β2-adrenoceptor effect), bra-
guanylyl cyclase, thereby increasing the levels of cyclic dycardia, heart block, hypotension and decreased glucose
guanosine monophosphate (cGMP). Protein kinase G is tolerance in diabetic patients.
activated, and contractile proteins are phosphorylated.
Calcium-channel blockers
Dilatation of the systemic veins decreases preload and thus
There are two types of calcium-channel blocker (CCBs).
the oxygen demand of the heart, whereas dilatation of the
coronary arteries increases blood flow and oxygen delivery • Rate-limiting CCBs (verapamil)
to the myocardium. • Dihydropyridine CCBs (short-acting nifedipine or
Route of administration—Sublingual, oral (modified re- long-acting felodipine)
lease), transcutaneous patches. GTN can be given by intra- Mechanism of action—Rate-limiting CCBs block L-type
venous infusion. calcium channels found in the heart and in the vascular
Indications—Organic nitrates are given for the prophy- smooth muscle, thereby reducing calcium entry into cardiac
laxis and treatment of angina, myocardial infarction and in and vascular cells (see Figs. 4.3, 4.5 and Fig. 4.7). This de-
left ventricular failure. crease in intracellular calcium reduces cardiac contractility
Contraindications—Organic nitrates should not be given and causes vasodilatation, which results in several effects:
to patients with hypersensitivity to nitrates, or those with reduced preload caused by the reduced venous pressure; re-
hypotension and hypovolaemia. duced afterload caused by the reduced arteriolar pressure;
Adverse effects—Postural hypotension, tachycardia, increased coronary blood flow; reduced cardiac contractil-
headache, flushing and dizziness. ity and thus reduced myocardial oxygen consumption; and
Therapeutic notes—To avoid nitrate tolerance, a drug- a decreased heart rate. High doses of these drugs affect AVN
free period of approximately 8 hours is needed. conduction.

52
 The heart 4

Extracellular space Ca2+ Ca2+ 3Na+

Nicorandil
+
Minoxidil +
ATP β2
_ ATP ADP ATP ADP ATP ADP
Thiazides? + 3Na+ 2K+ Gs
ATP AC
K+ Calmodulin
Transverse tubule cAMP
Hyperpolarization + +
_ _ _ PKA
Ca2+ MLCK
Ca2+ Free cytosolic calcium
channel
blockers Contraction
+ _
Hydralazine
α1 Antagonists _ PLC IP3 PKG
Gs PI + +
ATP ADP Ca2+ Ca2+ +
_ α1,A2
Angiotensin cGMP + NO
antagonists GC
GTP
+
NO
Cytosol
of smooth muscle cell Ca2+

Sarcoplasmic reticulum Sodium

nitroprusside

Fig. 4.7 . Drugs affecting vascular tone. AC, Adenylyl cyclase; ADP, adenosine diphosphate; α1, α1-adrenoceptor; AMP,
adenosine monophosphate; A2, angiotensin II; ATP, adenosine triphosphate; β2, β2-adrenoceptor; cAMP; cyclic adenosine
monophosphate; cGMP, cyclic guanosine monophosphate; GC, guanylyl cyclase; GS, stimulatory G-protein; IP3, inositol
triphosphate; MLCK, myosin light-chain kinase; NO, nitric oxide; PLC, phospholipase C; PI, phosphatidylinositol; PKA,
protein kinase A; PKG, protein kinase G.

Dihydropyridines block L-type calcium channels in

HINTS AND TIPS
vascular cells. They do not affect cardiac contractility or
AVN conduction, and the beneficial effects are caused by There are three classes of CCBs. Two of them act
increased coronary flow and peripheral vasodilatation. mostly on the heart (verapamil and diltiazem) and
Route of administration—Oral.
the other acts mostly on peripheral vascular tone
Indications—Prophylaxis and treatment of angina and
(nifedipine). Concurrent use of a β-adrenoceptor
hypertension. Dihydropyridines are especially useful in
angina associated with coronary vasospasm (as they dilate antagonist and a nondihydropyridine CCB could
coronary arteries), with the long-acting dihydropyridines result in profound bradycardia.
being particularly useful for hypertension management.
Verapamil and diltiazem are given for supraventricular ar-
rhythmias and nifedipine for Raynaud syndrome (periph-
eral vasoconstriction). Potassium-channel activators
Contraindications—CCBs should not be given to pa- Nicorandil is the only licensed drug in this class.
tients in cardiogenic shock. Mechanism of action—Nicorandil acts to activate the
Dihydropyridines are contraindicated in advanced aortic potassium channels of the vascular smooth muscle. Once
stenosis. Verapamil and diltiazem should not be given to pa- activated, potassium flows out of the cells, causing hyper-
tients with severe heart failure (owing to their negative inotro- polarisation of the cell membrane. The hyperpolarized
pic action), to those taking β-blockers (risk of AV block and membrane inhibits the influx of calcium, and therefore in-
impaired cardiac output), and those with severe bradycardia. hibits contraction; the overall effect is the relaxation of the
Adverse effects—Verapamil and diltiazem may cause hy- smooth muscle and vasodilatation (see Fig. 4.7).
potension, rash, bradycardia, CCF, heart block and consti- Route of administration—Oral.
pation. Indications—Angina prophylaxis.
Dihydropyridines may cause hypotension, rash, tachy- Contraindications—Cardiogenic shock, left ventricular
cardia, peripheral oedema, and flushing and dizziness. failure, hypotension.

53
 Cardiovascular system

Table 4.5 Classes of drugs used to treat angina, cardiac M3-receptor activation
failure and arrhythmias M3-receptor activation causes relaxation of vascular smooth
muscle through the release of endothelium-derived relax-
Angina Heart failure Arrhythmias
ing factor, which is believed to be nitric oxide (NO) (see
Organic nitrates Cardiac Na+-channel Fig. 4.7). Guanylyl cyclase is activated by NO, thus increas-
β1-Adrenoceptor glycosides blockers (class I)
ing the levels of cGMP and activating protein kinase G.
antagonists Phosphodiesterase β1-Adrenoceptor
Ca2+ antagonists inhibitors antagonists (class Protein kinase G inhibits contraction by phosphorylating
Antiplatelets β1-Adrenoceptor II) contractile proteins.
Potassium- agonists K+-channel
channel Diuretics blockers (class III) Renin–angiotensin system
activators ACE inhibitors Ca2+ antagonists
Nitrates (Class IV)
A decrease in plasma volume results in the activation of the
Vasodilating drugs Cardiac RAS (Chapter 5), which is summarized in Fig. 4.8.
glycosides ACE catalyses the production of angiotensin II. The ef-
Adenosine fects of angiotensin II are as follows.
ACE, Angiotensin-converting enzyme. • Potent direct vasoconstriction
• Indirect vasoconstriction by releasing noradrenaline
• Stimulates the secretion of aldosterone

Adverse effects—Headache, cutaneous vasodilatation, ACE also catalyses the inactivation of bradykinin, which
nausea and vomiting. is an endogenous vasodilator.
See Table 4.5 for a summary of the drug classes used in Aldosterone is a steroid that induces the synthesis of so-
cardiac dysfunction. dium channels and Na+/K+ ATPase pumps in the luminal
membrane of the cortical collecting ducts. This results in
Ivabradine and Ranolazine a greater amount of sodium and consequently water being
Ivabradine is used as an antianginal medication in patients reabsorbed, thus increasing the blood volume and pressure.
with normal sinus rhythm. It can also be used in mild to Certain renal diseases and renal artery occlusion will
severe chronic heart failure. Ivabradine slows the heart rate cause activation of the RAS and result in the development
by inhibiting the sinus node current. The heart rate needs of hypertension.
to be monitored to ensure that the patient does not become
bradycardic.
Ranolazine has recently been introduced as an adjunct
Hypertension
to current antianginal medication. It indirectly reduces in- Normal blood pressure is generally regarded as 120/80 mm
tracellular calcium and the force of contraction, without af- Hg (systolic pressure/diastolic pressure). Hypertension is
fecting the heart rate. defined as a diastolic arterial pressure greater than 90 mm
Hg, or a systolic arterial pressure greater than 140 mm Hg.
The condition can be fatal if left untreated because it greatly
increases the risk of thrombosis, stroke and renal failure.
CIRCULATION Three factors determine blood pressure.
• Cardiac output
Control of vascular tone • Peripheral vascular resistance
“Primary” or “essential” hypertension accounts for 90% to
α-Adrenoceptor activation 95% of all cases of hypertension. This has no known cause
α-Adrenoceptor activation (see Fig. 4.7) causes contraction
but is associated with the following.
of vascular smooth muscle through the activation of phos-
pholipase C (PLC). The resulting increased levels of inositol • Age (≥ 40 years)
triphosphate cause the release of calcium from the endo- • Obesity
plasmic reticulum, thus increasing calcium levels. Calcium • Physical inactivity
then binds to calmodulin, thus activating myosin light- • Smoking and alcohol consumption
chain kinase (MLCK) and allowing contraction. • Genetic predisposition
“Secondary hypertension” accounts for the remaining 5% to
β2-Adrenoceptor activation 10% of cases of hypertension. The cause is usually one of
β2-Adrenoceptor activation (see Fig. 4.7) causes relaxation the following.
of vascular smooth muscle through the activation of ad- • Renal disease, which activates the RAS
enylyl cyclase. The resulting increased levels of cAMP • Endocrine disease, for example, phaeochromocytoma,
activate protein kinase A, which phosphorylates and inac- a steroid-secreting tumour of the adrenal cortex or an
tivates MLCK. adrenaline-secreting tumour of the adrenal medulla.

54
 Circulation 4

Table 4.6 Advantages and disadvantages of drugs used in hypertension with respect to associated conditions
ACE inhibitor/angiotensin II Calcium-channel
Diuretics β-Blocker receptor antagonist blockers α-Blocker
Diabetes Carea Carea Yes Yes Yes
Gout No Yes Yes Yes Yes
Dyslipidaemia Careb Careb Yes Yes Yes
Ischaemic heart Yes Yes Yes Yes Yes
disease
Heart failure Yes Carec Yes Cared Yes
Asthma Yes No Yes Yes Yes
e
Peripheral vascular Yes Care Care Yes Yes
disease
Renal artery stenosis Yes Care No Yes Yes
Pregnancy Caution Not in late pregnancy No No Caution
ACE, Angiotensin-converting enzyme.
a
Diuretics may aggravate diabetes; β-blockers worsen glucose intolerance and mask symptoms of hypoglycaemia.
b
Both diuretics and β-blockers disturb the lipid profile.
c
There is some evidence for beneficial effects of some β-blockers when used cautiously in heart failure.
d
Verapamil and diltiazem may exacerbate heart failure, although amlodipine appears to be safe.
e
Patients with peripheral vascular disease may also have renal artery stenosis; therefore ACE inhibitors should be used cautiously.
From Kumar and Clark, Clinical Medicine, 4th edn. WB Saunders 1998.

CLINICAL NOTE
Treatment of hypertension
When prescribing, the choice of drug is usually influenced by
Mr Gill is a 41-year-old African Caribbean, age (over or under 55 years) and ethnicity. People aged under
who presents to his General Practitioner (GP) 55 years are usually commenced on an ACE inhibitor or angio-
with increasing frequency of headaches. He tensin II receptor blockers (ARB). People aged over 55 years or
has noticed recent visual disturbances as well. who are of African or Caribbean origin are started on a CCB
His GP notes he smokes about 15 cigarettes in the first instance (refer to NICE guidance on management
per day and undertakes very little exercise. of hypertension for more detail). Advantages and disadvan-
Urine dipstick was immediately carried out and tages of the different anti hypertensives are shown in Table 4.6.
revealed significant proteinuria. On questioning,
Mr Gill denies any family history of diabetes and Vasodilators
a random blood glucose test gave a score of 4.7, Angiotensin-converting enzyme inhibitors
within the normal range. However, his resting Captopril, enalapril, lisinopril and ramipril are examples of
blood pressure was found to be 210/140 mm ACE inhibitors.
Hg, which is severely elevated and indicative Mechanism of action—ACE inhibitors cause inhibition
of malignant hypertension. Fundoscopy also of ACE with consequent reduced angiotensin II and aldo-
revealed hypertensive changes (silver wiring and sterone levels (see Fig. 4.8), and increased bradykinin levels.
cotton wool spots). He is admitted for immediate This, therefore causes vasodilatation with a consequent re-
duction in peripheral resistance, little change in heart rate
treatment.
and cardiac output and reduced sodium retention.
He was given the long-acting calcium- Route of administration—Oral.
channel blocker, amlodipine. Two days later, Indications—Hypertension, heart failure and renal dys-
bendroflumethiazide (a thiazide diuretic) was also function (especially in diabetic patients to slow progression
added to his management. These two drug classes of diabetic or reduced renal functional nephropathy).
have been shown to be particularly effective in Contraindications—Pregnancy, renovascular disease,
African Caribbeans with hypertension because of aortic stenosis.
their effect on salt sensitivity and volume expansion. Adverse effects—Characteristic cough (caused by increased
He is also advised to stop smoking, eat a healthier bradykinin levels), angioedema, hypotension, dizziness and
salt-restricted diet and do more exercise. headache, diarrhoea, muscle cramps and hyperkalaemia.
Therapeutic notes—First-dose hypotension is relatively
common and should ideally be given just before bed.

55
 Cardiovascular system

Plasma volume

Renal Arterial GFR

sympathetic activity blood pressure Flow to macula densa

NaCl concentration
in macula densa

Juxtaglomerular Lungs
cells

Kidney
ACE
Liver
.
inhibitors

. captopril
enalapril

Renin − Angiotensin-converting enzyme

Angiotensinogen Angiotensin I

Blood vessel Angio-

tensin II

Aldosterone Adrenal
cortex Vasoconstriction
. antagonists
spironolactone
Aldo-
sterone

Stimulates Na+ −
Water
Blood pressure reabsorption by the
reabsorption
cortical collecting ducts
of the kidneys

Fig. 4.8 . Renin–angiotensin system and angiotensin-converting enzyme inhibitors (ACE). GFR, Glomerular filtration rate.

Route of administration—Oral.
DRUG INTERACTION
Indications—Hypertension.
ACE inhibitors + nonsteroidal antiinflammatory Contraindications—Pregnancy, breastfeeding. Caution
drugs (NSAIDs) = hypotension in renal artery stenosis and aortic stenosis.
Adverse effects—Cough (less common than with ACE in-
hibitors), orthostatic hypotension, dizziness, headache and
fatigue, hyperkalaemia and rash.
Angiotensin-II receptor antagonists Calcium antagonists
Losartan and valsartan are examples of angiotensin-II re- Nifedipine has more effect upon vascular tone than diltiazem
ceptor antagonists. or verapamil, which are more cardioselective (see Fig. 4.7).
Mechanism of action—Angiotensin-II receptor antag-
onists cause inhibition at the angiotensin-II receptor (see α1-Adrenoceptor antagonists
Fig. 4.7), resulting in vasodilatation with a consequent re- Prazosin and doxazosin are examples of α1-adrenoceptor
duction in peripheral resistance. antagonists.

56
 Circulation 4

Mechanism of action—α1-Adrenoceptor antagonists Indications—Sodium nitroprusside is given in hyperten-

cause inhibition of α1-adrenoceptor-mediated vasocon- sive crises, and for controlled hypotension in surgery, and
striction, thus reducing peripheral resistance and venous in heart failure.
pressure (see Fig. 4.7). They also lower plasma low-density Contraindications—Sodium nitroprusside should not be
lipoprotein (LDL) cholesterol levels, very-low-density lipo- given to patients with severe hepatic impairment, vitamin
protein (VLDL) levels and triglyceride levels, and increase B12 deficiency or Leber's optic atrophy.
high-density lipoprotein (HDL) cholesterol levels, thus re- Adverse effects—Headache and dizziness, nausea, ab-
ducing the risk of coronary artery disease. dominal pain, palpitations, retrosternal discomfort.
Route of administration—Oral. Therapeutic notes—Sodium nitroprusside is broken
Indications—Hypertension (especially in patients with down in the body to thiocyanate, which has a half-life of
CCF), prostate hyperplasia (reduced bladder and prostate only a few minutes, although prolonged exposure to nitro-
resistance), coronary artery disease. prusside and thiocyanate can result in thiocyanate toxicity
Contraindications—Prazosin should not be given to peo- (weakness, nausea and inhibition of thyroid function).
ple with CCF because of aortic stenosis.
Adverse effects—Postural hypotension, dizziness, head-
ache and fatigue, weakness, palpitations, nausea. HINTS AND TIPS

Hydralazine The more common adverse effects of the

Hydralazine is a second-line or third-line drug for the treat- vasodilating drugs are hypotension and headache,
ment of mild to moderate hypertension. both of which result directly from reducing
Mechanism of action—Hydralazine effects are unclear, peripheral vascular resistance.
although it appears to interfere with the action of inositol
triphosphate in vascular smooth muscle, thereby reducing
peripheral resistance and blood pressure (see Fig. 4.7).
Route of administration—Oral, intravenous. Diuretic drugs
Indications—Moderate to severe hypertension. Also The main diuretics drug classes used in hypertension are:
used in conjunction with β-blockers and thiazides in • thiazides
hypertensive emergencies and in hypertensive pregnant • loop diuretics
women. • potassium-sparing diuretics
Contraindications—Idiopathic systemic lupus erythema-
tosus, severe tachycardia. See Chapter 5 for details of each of these drugs.
Adverse effects—Tachycardia, fluid retention, nausea and Mechanism of action
vomiting, headache. The antihypertensive action of diuretic drugs does not seem
to correlate with their diuretic activity; loop diuretics are
Minoxidil powerful diuretics but only moderate antihypertensives
Owing to its adverse effects, minoxidil is the drug of last whereas thiazides are moderate diuretics but powerful
resort in the long-term treatment of hypertension. antihypertensives.
Mechanism of action—Minoxidil activates vascular It has recently been suggested that the antihyperten-
smooth muscle ATP-sensitive potassium channels, result- sive effects of diuretics (especially the thiazides) are not
ing in hyperpolarisation of the cell membrane and conse- necessarily because of their diuretic effect but rather may
quently reduces calcium entry through L-type channels (see be caused by activation of ATP-regulated potassium chan-
Fig. 4.7). The overall effect is inhibition of smooth muscle nels in resistance arterioles, with a mechanism of action
contraction, and subsequent vasodilatation. similar to that of nicorandil (p. 77) and minoxidil. This
Route of administration—Oral for hypertension; topical causes hyperpolarisation, and thus inhibition of calcium
cream for baldness. entry into vascular smooth muscle cells with consequent
Indications—Severe hypertension, baldness. vasodilatation and reduced peripheral vascular resistance
Contraindications—Phaeochromocytoma, porphyria. (see Fig. 4.7).
Adverse effects—Hirsutism (limits use in women), so-
dium and water retention, tachycardia, cardiotoxicity.
Centrally acting antihypertensive drugs
Sodium nitroprusside Clonidine, methyldopa and moxonidine are examples
Mechanism of action—Sodium nitroprusside is a pro- of centrally acting antihypertensive drugs. These agents
drug that spontaneously decomposes into NO inside are second-line or third-line drugs in the treatment of
smooth muscle cells. NO activates guanylyl cyclase, thus hypertension.
increasing intracellular cGMP levels, and causing vasodi- Mechanism of action—Centrally acting antihyper-
latation (see Fig. 4.7). tensive drugs are α2-adrenoceptor agonists. The activa-
Route of administration—Intravenous. tion of presynaptic α2-adrenoceptors causes inhibition of

57
 Cardiovascular system

­ oradrenaline release and consequent vasodilatation. The

n Vasoconstrictors and the
activation of postsynaptic α2-adrenoceptors causes vaso-
constriction, although presynaptic effects dominate.
management of shock
Centrally acting antihypertensive drugs reduce the ac- Shock
tivity of the vasomotor centre in the brain, causing reduced Shock is a state of circulatory collapse, characterized by an
sympathetic activity and subsequent vasodilatation. They arterial blood pressure unable to maintain adequate tissue
also reduce heart rate and cardiac output. perfusion and oxygen delivery. Shock is a life-threatening
Route of administration—Oral. Clonidine can be given condition.
by intravenous infusion. The body responds inappropriately to shock, releasing
Indications—Hypertensive patients when first-line an- mediators such as histamine, prostaglandins, bradykinin
tihypertensive agents are ineffective or contraindicated. and serotonin, which cause capillary dilatation and in-
Methyldopa is safe for hypertension in pregnancy, asth- creased capillary permeability. This further reduces blood
matic patients and those with heart failure. pressure and cardiac output.
Contraindications—Methyldopa should not be given to Signs of shock include:
people with depression, liver disease or phaeochromocy-
• very low arterial blood pressure
toma.
• a weak, rapid pulse
Adverse effects—Dry mouth, sedation, orthostatic hy-
• cold, pale, sweaty skin
potension, male sexual dysfunction, and galactorrhoea.
• rapid breathing
Methyldopa can cause diffuse parenchymal liver injury, fe-
• dry mouth
ver and, rarely, haemolytic anaemia. Clonidine can cause a
• reduced urine output
withdrawal hypertensive crisis on stopping treatment.
• confusion
Causes of shock include:
Phaeochromocytoma • haemorrhage
Phaeochromocytoma is a rare endocrine tumour, most • burns
commonly of the adrenal gland. These tumours can secrete • dehydration
adrenaline and various intermediates in its biosynthesis. • severe vomiting or diarrhoea
These vasoactive compounds result in the clinical signs and • bacterial septicaemia
symptoms of phaeochromocytomas, which include facial • myocardial infarction
flushing, sweating, breathlessness, anxiety, tachycardia and • pulmonary embolism
paroxysmal hypertension. Types of shock include the following.
Medical management of phaeochromocytoma-induced
• Hypovolemic: caused by a reduction in the circulating
hypertension relies on the powerful α-adrenoceptor antago-
blood volume.
nist, phenoxybenzamine. α-Adrenoceptor blockade reduces
• Cardiogenic: reduced cardiac output caused by “pump
peripheral vascular resistance and lowers blood pressure.
failure”.
The use of β-adrenoceptor antagonists is dangerous be-
• Septic: caused by massive vasodilatation.
cause tumour-secreted sympathomimetics act unopposed
• Anaphylactic: a severe allergic reaction, in which
on α-adrenoceptors, increasing both peripheral vascular
there is a massive generalized release of vasodilating
resistance and blood pressure.
mediators, particularly histamine.
• Spinal: disruption of neuronal control of vascular tone
Phenoxybenzamine and cardiac output.
Mechanism of action—Phenoxybenzamine antagonizes
α-adrenoceptors in the vascular smooth muscles, resulting
in vasodilatation. Management of shock
Route of administration—Oral, intravenous. The medical management of shock ultimately depends
Indications—Hypertensive episodes in phaeochromo­ upon its underlying cause, for example, if a child is shocked
cytoma. because of chronic diarrhoea and vomiting, fluid and elec-
Contraindications—History of cerebrovascular events, trolyte replacement is the most appropriate management. If
postmyocardial infarction. an adult has had significant blood loss, management of their
Adverse effects—Postural hypotension, tachycardia, na- hypovolemic shock may require several blood transfusions.
sal congestion. In addition, in septic shock, urgent antibiotics and fluid re-
Therapeutic notes—Phentolamine is another powerful placement are required.
α-adrenoceptor antagonist which can be used in phaeochro- The following drugs are useful in restoring blood pres-
mocytoma, although it has a much shorter half-life and is com- sure and tissue perfusion, but, on the whole, do not address
monly used before and during surgery to excize the tumour. the underlying cause of the different types of shock.

58
 Circulation 4

Sympathomimetic amines Adverse effects—Tachycardia and hypertension; dopa-

Examples include adrenaline, noradrenaline, phenyleph- mine causes nausea and vomiting and hypotension.
rine and ephedrine. Therapeutic notes—Although low doses of dopamine
Sympathomimetic amines raise blood pressure at the cause vasodilatation, high doses cause vasoconstriction and
expense of vital organs such as the kidneys, and raise pe- may exacerbate heart failure.
ripheral resistance, which is already high in patients with
shock.
Vasopressin and desmopressin
Vasopressin (antidiuretic hormone; ADH), and desmopres-
Mechanism of action—Adrenaline and noradrenaline are
sin are examples of antidiuretic peptides.
agonists at both α- adrenoceptors and β-adrenoceptors, and
Vasopressin is short acting (t½ = 10 minutes) whereas
phenylephrine is an α1-adrenoceptor agonist. Ephedrine is
desmopressin is longer acting (t½ = 75 minutes).
a β-adrenoceptor agonist and causes noradrenaline release.
Mechanism of action—Antidiuretic peptides activate
These drugs work either by activating α-adrenoceptors which
V1 receptors on smooth muscle cells, which stimulate
then activate PLC, causing vasoconstriction and a conse-
PLC, causing contraction. They also activate V2 recep-
quent increase in arterial blood pressure or by activating β-­
tors on the tubular cells of the kidneys, which stimulate
adrenoceptors which then activate adenylyl cyclase, causing an
adenylyl cyclase and thereby increase the permeability of
increased heart rate, increased cardiac contractility and vaso-
these cells to water and reduce sodium and water excre-
dilatation.
tion. Vasopressin has a much greater affinity for V2 recep-
Route of administration—Parenterally, commonly intra-
tors than V1 receptors whereas desmopressin is selective
venously.
for V1 receptors.
Indications—Shock, acute hypotension and reversal
Route of administration—Oral, intravenous, intranasal.
of hypotension caused by spinal or epidural anaesthesia.
Indications—Pituitary diabetes insipidus. The antidi-
Adrenaline is used in cardiac arrest and anaphylaxis.
uretic peptides are no longer used in the management of
Contraindications—Sympathomimetic amines should
shock, although their pharmacology is both academically
not be given during pregnancy or in people who have hy-
interesting and a potential target for future drugs.
pertension.
Contraindications—Vascular disease, chronic nephritis.
Adverse effects—Tachycardia, anxiety, insomnia, ar-
Adverse effects—Fluid retention, nausea, pallor, abdom-
rhythmias, dry mouth, cold extremities.
inal cramps, belching. They may induce anginal attacks
Therapeutic notes—In a cardiac arrest, adrenaline is
(caused by coronary vasoconstriction).
used at a concentration of 1 mg per 10 mL (1:10,000) intra-
venously, whereas, in anaphylaxis, adrenaline is used at a Corticosteroids
concentration of 1 mg per 1 mL (1:1000) intramuscularly. The use of corticosteroids in septic shock remains contro-
versial, although they are also given by intravenous injec-
Dopamine and dobutamine
tion in the treatment of anaphylactic shock as an adjunct to
Mechanism of action—Dopamine is a precursor of
adrenaline (Chapter 7).
noradrenaline. It activates dopamine receptors and α-­
adrenoceptors and β-adrenoceptors. When administered
by intravenous infusion, dopamine acts on the following.
• Dopamine receptors, causing vasodilatation in the
kidneys at low doses.
• α1-Adrenoceptors, causing vasoconstriction in other CLINICAL NOTE
vasculature.
It is possible to distinguish between the types of
• β1-Adrenoceptors, causing positive inotropic and
chronotropic effects. shock clinically.
• Hypovolaemic: low jugular venous pressure
Dobutamine has no effect on dopaminergic receptors but
does activate β1-adrenoceptors. (JVP), cool, clammy peripheries, confusion/
If renal perfusion is not impaired, dobutamine and do- restlessness.
pamine are a more appropriate means of treating shock than • Cardiogenic: raised JVP, cool, clammy
α-adrenoceptor agonists. This form of treatment maintains peripheries, anxiousness/agitation.
renal perfusion and inhibits the activation of the RAS. • Septic: warm, sweaty peripheries, pyrexia,
Route of administration—Intravenous. nausea.
Indications—CCF (emergencies only), cardiogenic • Anaphylactic: warm peripheries, urticaria,
shock, septic shock, hypovolaemic shock, cardiomyopathy, swollen face/mouth.
cardiac surgery. • Spinal: history of trauma or spinal anaesthesia.
Contraindications—Tachyarrhythmias. Dopamine is
contraindicated in people with phaeochromocytoma.

59
 Cardiovascular system

Lipoprotein circulation and 1. Diet-derived lipid breakdown leads to the formation of

atherosclerosis chylomicrons.
Lipoproteins provide a means of transporting lipids (choles- 2. Lipoprotein lipase (LPL), found in the endothelium
terol, triglycerides and phospholipids), which are insoluble of extrahepatic tissues, hydrolyses the triglycerides in
in the blood, around the body. chylomicrons to glycerol and free fatty acids (FFAs),
Four classes of lipoproteins exist. These differ in size, for use by the tissues.
density, constituent lipids and type of surface protein (apo- 3. The liver takes up the chylomicron remnant.
protein). These lipoproteins are as follow. 4. The liver secretes cholesterol and bile acids into the
gut, creating an enterohepatic circulation.
• HDL
• LDL In the endogenous pathway (numbers refer to those in Fig. 4.9):
• VLDL 1. The liver secretes VLDLs, the components of
• Chylomicrons which may be derived either endogenously or
Lipid transport in the blood is via two pathways, exogenous from the diet.
and endogenous, which are summarized in Fig. 4.9. 2. LPL found in the endothelium of extrahepatic tissues,
In the exogenous pathway (numbers refer to those in hydrolyses triglycerides in the VLDLs to glycerol and
Fig. 4.9): FFAs, for use by the tissues, and leaves LDL.

Endogenous pathway Exogenous pathway Food

Bile-acid-
binding gut
Nicotinic acid resins
Liver fat
HMG CoA reductase
inhibitors 4 Bile −
Acetyl CoA acids
Bile acids Enterohepatic −
HMG CoA and cholesterol circulation
_
TAG
cholesterol
Mevalonate
C Orlistat
Fibrates E B48
Cholesterol
3 1
1' Chylomicron
+ TAG > CE
4
_ gemfibrozil ?
4
3

C E B48
E B100
E B100
A
HDL LDL VLDL Chylomycrom Nicotinic acid
TAG > CE 2
CE 4 CE TAG > CE
LCAT Fibrates

4 3 2

Lipoprotein Lipoprotein Endothelium

+ +
lipase lipase

Cholesterol Cholesterol Glycerol Glycerol

free fatty acids free fatty acids

Extrahepatic tissues

Fig. 4.9 . Endogenous and exogenous pathways of lipid transport. CE, Cholesterol ester; HDL, high-density lipoprotein;
HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LCAT, lecithin cholesterol acyltransferase; TAG, triacylglycerol; VLDL,
very-low-density lipoproteins; numbers refer to steps in pathways.

60
 Circulation 4

3. LDL is then taken up by the liver and extrahepatic vary depending upon local policy). Treatment of familial
tissues. hypercholesterolaemia.
4. HDL is secreted by the liver into the plasma, where Contraindications—Pregnancy, breastfeeding, liver dis-
it is modified by lecithin-cholesterol acyltransferase ease.
(LCAT) and uptake of cholesterol from the tissues. Adverse effects—Reversible myositis (rare), constipation
LCAT transfers cholesterol esters to LDLs and VLDLs. or diarrhoea, abdominal pain and flatulence, nausea and
headache, fatigue, insomnia, rash.
Hyperlipidaemias Therapeutics—They are typically prescribed at night to
Hyperlipidaemias are characterized by markedly ele- reduce peak cholesterol synthesis in the early morning.
vated plasma triglycerides, cholesterol and lipoprotein
concentrations.
Cholesterol is deposited in various tissues. DRUG INTERACTION
• Deposition in arterial plaques results in atherosclerosis, Simvastatin + Clarithromycin = myositis
which leads to heart attacks, strokes and peripheral Simvastatin is metabolized by the enzyme CYP3A4
vascular disease.
and concomitant use of medications that inhibit
• Deposition in tendons and skin results in xanthomas.
this enzyme (e.g. the antibiotic clarithromycin) can
Primary lead to myositis.
Primary hyperlipidaemias are genetic, and numerous types
exist.
Secondary
Secondary hyperlipidaemias are the consequences of other Ezetimibe
conditions such as: Cholesterol absorption inhibitor, used as an adjunct to diet
and statins in hypercholesterolaemia.
• diabetes
Mechanism of action—Inhibits absorption of choles-
• liver disease
terol from the duodenum by blocking a transport pro-
• nephrotic syndrome
tein in the brush border of enterocytes, without affecting
• renal failure
the absorption of fat soluble vitamins, triglycerides or
• alcoholism
bile acids.
• hypothyroidism
Route of administration—Oral
• oestrogen administration.
Indications—Hypercholesterolaemia
Treatment (lipid-lowering drugs) Contraindications—Breastfeeding
Changing a patient's diet alone can lower serum choles- Adverse effects—In general, well tolerated. Diarrhoea,
terol and should be the first-line treatment option in mild abdominal pain, headache.
to moderate hyperlipidaemia. The following drug classes,
Fibrates
however, provide pharmacological control of a patient's
Fibrates include bezafibrate, ciprofibrate and gemfibrozil.
cholesterol level, inhibiting its synthesis and its uptake from
Used in the management of mixed dyslipidaemia (raised
the intestine.
serum triglycerides and raised cholesterol).
3-Hydroxy-3-methylglutaryl coenzyme A Mechanism of action—Fibrates work in several ways (see
reductase inhibitors (statins) Fig. 4.9).
Atorvastatin, pravastatin and simvastatin are examples of • Stimulation of lipoprotein lipase, thus reducing the
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) re- triglyceride content of VLDLs and chylomicrons.
ductase inhibitors. These drugs have been shown to reduce • Stimulation of hepatic LDL clearance, by increasing
blood cholesterol by up to 35% in some patients. HMG- hepatic LDL uptake (see Fig. 4.9).
CoA reductase inhibitors can reduce the risk of dying from • Reduction of plasma triglyceride, LDL and VLDL
a coronary event by up to nearly one-half. concentrations.
Mechanism of action—Statins reversibly inhibit the Increase of HDL-cholesterol concentration (except beza-
enzyme HMG-CoA reductase, which catalyses the rate-­ fibrate). Gemfibrozil decreases lipolysis and may decrease
limiting step in the synthesis of cholesterol. The decrease VLDL secretion.
in cholesterol synthesis also increases the number of LDL Route of administration—Oral.
receptors, thus decreasing LDL levels. Indications—Hyperlipidaemia unresponsive to dietary
Route of administration—Oral. control.
Indications—Hyperlipidaemia resistant to dietary con- Contraindications—Gallbladder disease, severe renal
trol, as primary and secondary prevention in patients with or hepatic impairment, hypoalbuminaemia, pregnancy,
serum cholesterol greater than 5.5 mmol/L (this value will breastfeeding.

61
 Cardiovascular system

Adverse effects—Myositis-like syndrome (especially if Ispaghula husk is taken orally, and is presumed to act by
renal function is impaired), gastrointestinal disturbances, binding bile acids, preventing their reabsorption, and is po-
dermatitis, pruritus, rash and urticaria, impotence, head- tentially useful in patients with hypercholesterolaemia but
ache, dizziness, blurred vision. not hypertriglyceridaemia.
Note that a new class of cholesterol-lowering medica-
Nicotinic acid
tions has been developed, two of which are licensed for
The side effects of nicotinic acid limit its use in the treat-
use in the United Kingdom. These are proprotein con-
ment of hyperlipidaemias. Nicotinic acid has been shown to
vertase subtilisin/kexin type 9 (PCSK9) inhibitors (e.g.
reduce the incidence of coronary artery disease.
Evolocumab and Alirocumab). They target the PCSK pro-
Mechanism of action—Nicotinic acid has the following
tein, making it less effective at breaking down LDL recep-
effects (see Fig. 4.9).
tors. The result is more working receptors on the surface of
• It inhibits cholesterol synthesis thereby decreasing liver cells, and more cholesterol can then be removed from
VLDL and thus LDL production. the blood.
• It stimulates lipoprotein lipase thus reducing the
triglyceride content of VLDLs and chylomicrons.
• It increases HDL-cholesterol.
• It increases the levels of tissue plasminogen activator (p. 90)
• It decreases the levels of plasma fibrinogen.
HAEMOSTASIS AND THROMBOSIS
Route of administration—Oral.
Indications—Hyperlipidaemias unresponsive to other
Haemostasis
measures. Haemostasis is the cessation of bleeding from damaged
Contraindications—Pregnancy, breastfeeding. blood vessels. If haemostasis is defective or unable to cope
Adverse effects—Flushing, dizziness, headache, palpita- with blood loss from larger vessels, blood may accumulate in
tions, nausea and vomiting, pruritus. the tissues. This accumulated blood is called a haematoma.
Three stages are involved in haemostasis.
Bile acid binding resins
• Blood vessel constriction
Colestyramine and colestipol have been shown to decrease
• Formation of a platelet plug
the rate of mortality from coronary artery disease.
• Formation of a clot
Mechanism of action—Basic anion exchange resins act
by binding bile acids in the intestine (see Fig. 4.9), thus
preventing their reabsorption and promoting hepatic con- Blood vessel constriction
version of cholesterol into bile acids. This increases he- The first response to a severed blood vessel is the contrac-
patic LDL-receptor activity, thus increasing the breakdown tion of the smooth muscle of the vessel. This is mediated by
of LDL-cholesterol. Plasma LDL-cholesterol is therefore the release of thromboxane A2 and other substances from
lowered. platelets.
Route of administration—Oral. Blood vessel constriction slows the flow of blood through
Indications—When significantly elevated cholesterol is the vessel, thus reducing the pressure, and pushes opposing
caused by a high LDL concentration. surfaces of the vessel together. In very small vessels, this re-
Colestyramine also relieves pruritus associated with par- sults in permanent closure of the vessel, but in most cases,
tial biliary obstruction and primary biliary cirrhosis. blood vessel constriction is insufficient for this to occur.
Contraindications—Complete biliary obstruction.
Adverse effects—Bile acid binding resins are not absorbed
Platelet plug formation
and therefore have very few systemic side effects. Side ef-
Exposure to the collagen underlying the vessel endothe-
fects include nausea and vomiting, constipation, heartburn,
lium, as occurs during vessel injury, allows platelets to
abdominal pain and flatulence and aggravation of hypertri-
adhere to the collagen by binding to von Willebrand fac-
glyceridaemia. They may interfere with the absorption of
tor. This factor, secreted by the platelets and endothelium,
fat-soluble vitamins and certain drugs.
binds to the exposed collagen; platelets then bind to this
Therapeutic notes—To avoid interference with their ab-
complex.
sorption, other drugs should not be taken within 1 hour
The release of adenosine diphosphate (ADP), serotonin,
before or 3 to 4 hours after colestyramine or colestipol ad-
thromboxane A2 and other substances by the platelets
ministration.
causes the platelets to aggregate. Fibrin binds them together.
Other lipid-lowering drugs The synthesis and release of prostacyclin by the intact en-
Fish oils rich in omega-3 marine triglycerides can be useful dothelium inhibits platelet aggregation limiting the extent
in the treatment of severe hypertriglyceridaemia, although of the platelet plug.
may sometimes worsen hypercholesterolaemia. Their role Intact endothelial cells also produce NO, a potent vaso-
in clinical practice remains to be thoroughly ascertained. dilator and inhibitor of platelet aggregation.

62
 Haemostasis and thrombosis 4

Clot formation Plasmin digests fibrin. It is formed from plasminogen

Blood coagulation is the conversion of liquid blood into a through the action of plasminogen activators, the best ex-
solid gel, known as a clot. ample of which is tissue-plasminogen activator (tPA).
• A clot consists of a meshwork of fibrin within which
blood cells are trapped. Thrombosis
• It functions to reinforce the platelet plug. Thrombosis is the pathological formation of a clot known as
Fibrin is formed from its precursor fibrinogen, through a thrombus, which may cause occlusion within blood ves-
the action of an enzyme called thrombin. The formation of sels or the heart, and result in death.
thrombin occurs via two distinct pathways, the intrinsic and • Thrombosis causes arterial occlusion, which may
the extrinsic pathways, which together are known as the co- lead to myocardial infarction, stroke and peripheral
agulation cascade. Both pathways involve the conversion ischaemia; or
of inactive factors into active enzymes, which then go on to • Venous occlusion, which may lead to deep venous
catalyse the conversion of other factors into enzymes (see thrombosis and pulmonary embolism.
Fig. 4.9). The liver is important in coagulation because it is
the site at which many of the clotting factors are produced. It
also produces bile salts necessary for the absorption of vitamin COMMUNICATION
K, which is needed by the liver to produce prothrombin and
clotting factors VII, IX and X. Mr Patel, a 50-year-old male with a body mass
The extrinsic pathway is thus termed because the com- index of 31, presented to A&E with central crushing
ponent needed for its initiation is contained outside the chest pain, shortness of breath and sweating. He
blood. Tissue factor binds factor VII on exposure of blood is a longstanding smoker with a 60-pack a year
to subendothelial cells and converts it to its active form, history and his younger brother recently died
VIIa. This enzyme then catalyses the activation of factors from a stroke associated with significant vascular
X and IX. disease. ECG showed ST segment elevation which,
The intrinsic pathway is thus termed because its compo- combined with the history, is highly suggestive of
nents are contained in the blood. It merges with the extrin- myocardial infarction.
sic pathway at the step before thrombin activation.
The thrombin formed stimulates the activation of fac- He was given oxygen, aspirin (antithrombotic
tors XI, VIII and V, and thus acts as a form of positive agent) to prevent further platelet aggregation,
feedback. morphine for pain relief and the antiischaemic
Listed are three naturally occurring anticoagulants, vasodilating spray (glyceryl trinitrate). To prevent
which limit the extent of clot formation. irreversible ischaemic damage following this
• Tissue factor pathway inhibitor, which binds to the episode of coronary thrombosis, opening the
tissue factor–VIIa complex and inhibits its actions. occluded artery promptly with a combination of
• Protein C, which is activated by thrombin, and ticagrelor (antiplatelet) and fondaparinux (LMWH)
inactivates factors VII and V. is essential to his management. He is then taken
• Antithrombin III, which is activated by heparin, and directly to the cardiac catheter laboratory for
inactivates thrombin and other factors. primary percutaneous intervention. He is later
discharged home with secondary prevention
medications including a ß-adrenoceptor antagonist,
HINTS AND TIPS statin, ACE inhibitor and an antiplatelet agent.
Arterial thrombi form because of endothelial
The liver is important in coagulation because it is
injury, which is, in turn, the result of underlying
the site at which many of the clotting factors are
arterial wall pathology such as atherosclerosis.
produced. It also produces bile salts necessary for
Venous and atrial thrombi tend to form as
the absorption of vitamin K, which is needed by the
a result of blood stasis, allowing the build
liver to produce prothrombin and clotting factors
up of platelets and fibrin. People with
VII, IX and X.
hypercoagulability, caused by a lack of one or
more of the naturally occurring anticoagulants,
are particularly susceptible.
Arterial thrombi consist mainly of platelets, whereas
Fibrinolysis venous thrombi consist mainly of fibrin.
The fibrinolytic or thrombolytic system functions to dis-
solve a clot once repair of the vessel is under way.

63
 Cardiovascular system

TREATMENT OF THROMBOSIS O COO−

Protein CH2 CH2 C Protein CH2 CH
O COO−
Decarboxyprothrombin Prothrombin
Anticoagulants
Vitamin K antagonists CO2
Warfarin and phenindione are vitamin K antagonists.
Mechanism of action—Vitamin K antagonists block the
reduction of vitamin K epoxide, which is necessary for its ac- Vitamin KH2 Vitamin K epoxide
tion as a cofactor in the synthesis of factors II, VII, IX and X
(Figs. 4.10 and 4.11). The onset of action of vitamin K antag-
onists takes several hours, owing to the time needed for the
degradation of factors that have already been carboxylated Warfarin
(t½: VII = 6 hours, IX = 24 hours, X = 40 hours, II = 60 hours). NAD+ NADH
Route of administration—Oral.
Fig. 4.11 . Role of vitamin K in prothrombin formation.
Indications—Prophylaxis and treatment of deep vein
Warfarin inhibits the reduction of vitamin K epoxide. NAD,
thrombosis and pulmonary embolism, the prophylaxis of Nicotinamide adenine dinucleotide.

Intrinsic pathway Extrinsic pathway

Kallikrein XIIa, XIa _
+ vessel damage + vessel damage

Exposed collagen Subendothelial cells

exposed to blood
XII XIIa _
VIIa VII _
+ XI XIa _
_

_ IX IXa IX III, Ca2+, phospholipid

+ VIII VIIIa

IXa + VIIIa + Ca2+ + platelet

phosphotid

_ X Xa X _
Antithrombin III
+ V VA +

Thrombin/antithrombin
_ Prothrombin Thrombin complex
(II) (IIa)

Degradation Fibrinogen (I) Fibrin (Ia)

Fibrin clot
Plasminogen Plasmin
+
Dissolved clot
+ _ Heparin
_ Vitamin K antagonists
+ Fibrinolytic drugs

Fig. 4.10 . Effects of heparin, vitamin K and fibrinolytic drugs on the coagulation cascade. Factor III, factor/tissue
thromboplastin.

64
 Treatment of thrombosis 4

embolisation in AF and rheumatic disease, and in patients Indications—Treatment of deep vein thrombosis and
with prosthetic heart valves. pulmonary embolism; prophylaxis against postoperative
Contraindications—Cerebral thrombosis, peripheral ar- deep vein thrombosis and pulmonary embolism in high-
terial occlusion, peptic ulcers, hypertension, pregnancy. risk patients; myocardial infarction.
Adverse effects—Haemorrhage. Contraindications—Heparin should not be given to pa-
Therapeutic notes—Warfarin can be a therapeutic chal- tients with haemophilia, thrombocytopenia or peptic ulcers.
lenge; under dosing can increase the risk of a thrombus Adverse effects—Haemorrhage (treated by stopping
whereas overdosing can result in haemorrhage. Therefore therapy or administering a heparin antagonist such as pro-
vitamin K antagonists require frequent blood tests to individ- tamine sulphate), skin necrosis, thrombocytopenia, hyper-
ualize the dose and are consequently inconvenient as well as sensitivity reactions, hyperkalaemia.
having a low margin of safety. In addition, many medications Therapeutic regimen—Unfractionated heparin is re-
(and some foods) potentiate or lessen the effect of warfarin. served for patients with renal failure in whom LMWHs are
contraindicated or in emergencies because it has an imme-
diate onset.
DRUG INTERACTION
Patients on warfarin who are concomitantly Hirudins
prescribed an antibiotic (e.g. ciprofloxacin or Mechanism of action—Derived from the medical leech,
metronidazole) are at an increased risk of bleeding. Hirudin or rather its recombinant derivatives, bivalirudin,
This is because the antibiotics inhibit hepatic desirudin and lepirudin, are direct thrombin inhibitors.
drug metabolism and the effects of warfarin are Route of administration—Intravenous.
potentiated. Similarly, patients given NSAIDs Indications—Desirudin is used in patients with type II
(which inhibit platelet function) while on warfarin (immune) heparin-induced thrombocytopenia (HIT) and
are also at risk of bleeding. as prophylaxis of deep vein thrombosis in patients under-
going hip and knee replacement.
Lepirudin is used for thromboembolic disease in pa-
tients with type II (immune) HIT.
Direct Oral Anticoagulants Bivalirudin is used in combination with antiplatelet
Recently emerged, these medications may come to replace drugs in patients undergoing coronary artery surgery.
warfarin. They can be used to prevent venous thromboem- Contraindications—Active bleeding, renal or hepatic im-
bolism following hip or knee replacement. They are licensed pairment.
in patients with AF as prophylaxis against stroke. Adverse effects—Haemorrhage, hypersensitivity reactions.

Dabigatran
Direct thrombin inhibitor, taken orally. Antiplatelet agents
Rivaroxaban and Apixaban Aspirin
Direct inhibitor of factor Xa, taken orally. Aspirin is acetylsalicylic acid, originally derived from the
These drugs require no monitoring. Bleeding is the most willow tree.
common adverse effect. Mechanism of action—Aspirin blocks the synthesis of
thromboxane A2 from arachidonic acid in platelets, by
acetylating and thus inhibiting the enzyme cyclooxygen-
Unfractionated heparin and the ase 1. Thromboxane A2 stimulates PLC, thus increasing
low-molecular-weight heparins calcium levels and causing platelet aggregation. Aspirin
Mechanism of action—Unfractionated heparin activates also blocks the synthesis of prostacyclin from endothe-
antithrombin III, which limits blood clotting by inactivating lial cells, which inhibits platelet aggregation. However,
thrombin and factor Xa. LMWHs (e.g. enoxaparin, daltepa- this effect is short lived because endothelial cells, unlike
rin, fondaparinux) are simply fragments of unfractionated platelets, can synthesize new cyclooxygenase (Fig. 4.12).
heparin, which exhibit very similar activity to heparin, but Route of administration—Oral.
they only increase the action of antithrombin III on factor Indications—Prevention and treatment of myocardial
Xa and not its action on thrombin. LMWH are longer act- infarction and ischaemic stroke. Aspirin is also used as an
ing and used more frequently because their dosing is more analgesic and an antiinflammatory agent (Chapter 11).
predictable and thus requires no monitoring. Contraindications—Children under 12 years of age (risk
Route of administration—LMWHs are given subcutane- of Reye syndrome), during breastfeeding, haemophilia,
ously (once daily). peptic ulcers or known hypersensitivity reactions.
Unfractionated heparin is given 12-hourly by the subcu- Adverse effects—Bronchospasm, gastrointestinal haem-
taneous route or via intravenous infusion. orrhage.

65
 Cardiovascular system

Arachidonic acid Therapeutic notes—Tirofiban and epifibatide (peptide

fragments) act by inhibiting the GPIIb/IIIa receptor. As
peptides, these agents are potentially antigenic, and should
Aspirin − Cyclooxygenase only be used once.

Fibrinolytic agents
PGG2
PGH2
Streptokinase
Mechanism of action
Streptokinase forms a complex with, and activates, plasmin-
ogen into plasmin, a fibrinolytic enzyme.
Thromboxanes Prostaglandins
Route of administration—Intravenous.
e.g. TXA2 e.g. PGI2 (prostacyclin) Indications—Life-threatening venous thrombosis, pul-
platelet endothelial cell monary embolism, arterial thromboembolism and acute
Fig. 4.12 . Inhibition of cyclooxygenase by aspirin, myocardial infarction.
leading to a reduction in the formation of thromboxane Contraindications—Recent haemorrhage, trauma, sur-
and prostacyclin. PG, prostaglandin; PGG2, PGH2, PGI2, gery, bleeding diathesis, aortic dissection, coma, history of
prostacyclin; TXA2, thromboxane A2. cerebrovascular disease.
Adverse effects—Nausea and vomiting, bleeding.
Dipyridamole Therapeutic regimen—Streptokinase is often used in
Mechanism of action—Dipyridamole causes inhibition conjunction with antiplatelet and anticoagulant drugs. The
of the phosphodiesterase enzyme that hydrolyses cAMP. clinical preference is to use fibrinolytics with a faster onset of
Increased cAMP levels result in decreased calcium levels action, such as tissue plasminogen activators. Furthermore,
and inhibition of platelet aggregation. streptokinase is derived from haemolytic streptococci and
Route of administration—Oral. is thus antigenic. Repeated administration of streptokinase
Indications—Prophylaxis of stroke in patients with tran- could result in an anaphylaxis-like reaction. If repeated fi-
sient ischaemic attacks (especially if given with aspirin). brinolytic therapy is needed, the nonantigenic tissue-type
Adverse effects—Hypotension, nausea, diarrhoea, headache. plasminogen activators should be used.

Adenosine diphosphate inhibitors Tissue-type plasminogen activators

These include clopidogrel, prasugrel and ticagrelor. Alteplase and reteplase are examples of tPAs.
Mechanism of action—Ticlopidine, clopidogrel and pras- Mechanism of action—tPAs are tissue-type plasminogen
ugrel inhibit ADP-induced platelet aggregation by irrevers- activators.
ible inhibition of P2Y receptors. Ticagrelor is a reversible Route of administration—Intravenous.
noncompetitive inhibitor of P2Y receptors. Indications—Life-threatening pulmonary embolism,
Route of administration—Oral. acute thrombotic stroke within 4 hours in selected patients
Indications—Secondary prevention of cardiovascular and thrombosed shunts.
and cerebrovascular events. Contraindications—As for streptokinase.
Adverse effects—Haemorrhage, abdominal discomfort, Adverse effects—Nausea and vomiting, bleeding.
nausea and vomiting.
Therapeutic notes—If a patient is truly allergic to aspirin,
clopidogrel can be used in its place. CLINICAL NOTE
Glycoprotein llb/llla inhibitors Although the administration of a fibrinolytic drug
Abciximab is the main drug currently in this class. could improve the life expectancy of someone
Mechanism of action—Abciximab is an antibody frag- suffering from an acute thrombotic stroke, it could
ment directed towards the glycoprotein IIb/IIIa (GPIIb/
also have disastrous effects. There are stringent
IIIa) receptor of platelets. Binding and inactivation of the
criteria for administering or not administering
GPIIb/IIIa receptor prevents platelet aggregation.
Route of administration—Intravenous. fibrinolytic drugs. You should learn these.
Indications—Prevention of ischaemic cardiac compli-
cations in patients undergoing percutaneous coronary
­intervention; short-term prevention of myocardial infarc-
tion in patients with unstable angina.
Bleeding disorders
Contraindications—Active bleeding. Hereditary bleeding disorders are rare. Haemophilia is a ge-
Adverse effects—Haemorrhage, nausea, vomiting, hypo- netic disorder in which excessive bleeding occurs, owing to
tension. the absence of factor VIII (haemophilia A) or IX (haemo-

66
 Blood and fluid replacement 4

philia B). Abnormal bruising and mucosal bleeding charac- Tranexamic acid
terize Von Willebrand disease. Mechanism of action—Tranexamic acid is antifibrino-
Acquired bleeding disorders may be caused by liver dis- lytic, inhibiting plasminogen activation and therefore pre-
ease, vitamin K deficiency or anticoagulant drugs. Caution venting fibrinolysis.
should be taken when using the aforementioned drugs in Route of administration—Oral, intravenous.
patients with thromboembolic disease. Indications—Tranexamic acid agents are used in the
management of haemorrhage (e.g. gastrointestinal bleed or
Treatment of bleeding disorders trauma). It can also be used in patients at risk of haemorrhage
(e.g. haemophilia, menorrhagia and dental extraction).
Vitamin K (phytomenadione) Contraindications—Thromboembolic disease.
Mechanism of action—Vitamin K is needed for the post- Adverse effects—Nausea and vomiting, diarrhoea.
transcriptional γ-carboxylation of glutamic acid residues of Thromboembolic events are rare.
prothrombin (factor II) and clotting factors VII, IX and X
by the liver (see Fig. 4.11). Vitamin K is also necessary for Aprotinin
normal calcification of bone. Mechanism of action—Aprotinin inhibits the proteolytic
Route of administration—Oral, intramuscular, intravenous. enzymes plasmin and kallikrein, thus inhibiting fibrinolysis.
Indications—Vitamin K is used as an antidote to the effects Route of administration—Intravenous.
of vitamin K antagonists, and in patients with biliary obstruc- Indications—Aprotinin is used when there is a risk of blood
tion or liver disease, where vitamin K deficiency may be a prob- loss after open-heart surgery and in hyperplasminaemia.
lem. It is also used after prolonged treatment with antibiotics Adverse effects—Allergy, localized thrombophlebitis.
that inhibit the formation of vitamin K by intestinal bacteria Etamsylate
and prophylaxis against haemorrhagic disease of the newborn. Mechanism of action—Etamsylate corrects abnormal
Adverse effects—Haemolytic anaemia and hyperbiliru- platelet adhesion.
binaemia in the newborn. Route of administration—Oral, intravenous.
Protamine Indications—Etamsylate is used to reduce capillary bleed-
Mechanism of action—Protamine is a strongly basic pro- ing and periventricular haemorrhage in premature infants.
tein, which forms an inactive complex with heparin, and as Contraindications—Porphyria.
such is used in patients in whom heparin treatment has re- Adverse effects—Nausea, headache, rashes.
sulted in haemorrhage. High doses of protamine appear to
have anticoagulant effects through an unknown mechanism.
Route of administration—Intravenous. BLOOD AND FLUID
Indications—Haemorrhage secondary to heparinisation. REPLACEMENT
Adverse effects—Nausea, vomiting, flushing, hypoten-
sion.
Anaemia
Clotting factors
Anaemia is a common problem worldwide. In the young,
Deficiencies of clotting factors can be replaced by the ad-
it is commonly caused by nutritional deficiencies (vitamin
ministration of fresh plasma. Factors VIII and IX are avail-
B12, folate and iron), in fertile women menstrual loss ac-
able as freeze-dried concentrates.
counts for most cases, and in the elderly, malignancy and
Mechanism of action—All clotting factors are necessary
renal failure are the more common causes.
for normal blood coagulation.
Route of administration—Intravenous.
Iron
Indications—Haemophilia; an antidote to the effects of
Ferrous sulphate, ferrous fumarate and ferrous gluconate
oral anticoagulants.
are the commoner iron salt preparations.
Adverse effects—Allergic reactions, including fevers and
Mechanism of action—Dietary supplementation of iron
chills.
increases serum iron and stored iron in the liver and bone.
Desmopressin Adequate iron is necessary for normal erythropoiesis, as
Desmopressin is a synthetic analogue of vasopressin. well as for numerous iron-containing proteins.
Mechanism of action—Desmopressin causes the release Route of administration—Oral, or intravenous as
of factor VIII. It is also used in diabetes insipidus because it ­second-line therapy.
has antidiuretic effects. Indications—Iron-deficiency anaemia.
Route of administration—Parenteral. Contraindications—Caution in pregnancy.
Indications—Desmopressin is given for mild factor VIII Adverse effects—Gastrointestinal irritation, nausea, epi-
deficiency and in the treatment of diabetes insipidus. gastric pain, altered bowel habits.
Adverse effects—Fluid retention, hyponatraemia, and Therapeutic notes—Iron overdose or chronic iron over-
headache, nausea and vomiting. load can be harmful, and either acquired or inherited in the

67
 Cardiovascular system

form of haemochromatosis. The iron-chelating agent des- Route of administration—Parenteral.

ferrioxamine can be given parenterally, which allows iron to Indications—Anaemia of chronic renal failure, anaemia
be excreted in the urine. following cancer chemotherapy, before autologous blood
donation.
Vitamin B12 Contraindications—Uncontrolled hypertension.
Hydroxocobalamin and cyanocobalamin are vitamin B12 Adverse effects—Dose-dependent increase in blood pres-
drug preparations. sure and platelet count, influenza-like symptoms.
Mechanism of action—Vitamin B12 is required for deoxyri- Therapeutic notes—Erythropoietin often features in the
bonucleic acid (DNA) synthesis and effective erythropoiesis. news, as an increased haemoglobin concentration most
Route of administration—Intramuscular, oral. probably improves an athlete's performance, making this
Indications—Pernicious anaemia, other macrocytic drug a potential drug of ‘ “misuse” in sport.
megaloblastic anaemias. Prophylactically after surgical re-
moval of the stomach (site of intrinsic factor) or terminal
ileum (site of vitamin B12 absorption).
Myeloproliferative disorders
Contraindications—None. The pharmacological management of the myeloproliferative
Adverse effects—Itching, fever, chills, flushing, nausea. disorders is outside the scope of this text, although it relies
Therapeutic notes—Initial treatment requires regular on cytotoxic drugs. Information on these agents should be
weekly injections, but once serum vitamin B12 is normal- learnt from a haematology or general medical textbook.
ized, injections should be given at 3-monthly intervals.
Folate Fluid replacement
Folic acid in the form folate is administered.
Mechanism of action—Folate is required for DNA syn- Fluid replacement should ideally be achieved orally, al-
thesis and effective erythropoiesis. though this is often not practical. Intravenous administra-
Route of administration—Oral. tion of fluids is commonplace in the hospital.
Indications—Macrocytic megaloblastic anaemia, pre- • Intravenous fluids are given for many reasons. In
vention of neural tube defects in pregnancy. Patients taking septicaemia, they are used to raise blood pressure and
methotrexate (folate antagonist). tissue perfusion; in those who are unable to eat or drink
Contraindications and adverse effects—None. (e.g. unconscious or presurgery) they are used to replace
Therapeutic notes—Since the introduction of folate acid water and electrolytes not being taken orally or that are
supplements for pregnant women, the rate of neural tube lost in urine and via insensible routes. In trauma, they
defects in newborn babies has fallen markedly. can help increase the blood pressure and buy time before
Erythropoietin replacing blood loss with blood products.
Epoetin is a recombinant erythropoietin. Erythropoietin is • There are many types of intravenous fluid. The more
synthesized in the kidney in response to a fall in the oxygen common fluids given intravenously are blood and
tension of the blood passing through it. the crystalloids (sodium chloride and dextrose).
Mechanism of action—Erythropoietin acts upon the Supplements can be added to intravenous fluids.
bone marrow to stimulate stem cells to divide, to produce • The art of fluid replacement and fluid management is best
cells of the red cell lineage. learnt from an anaesthetics or general medical textbook.

Chapter Summary

• The heart is a pump which supplies the tissues with oxygen and nutrients via blood and
removes waste.
• In heart failure, cardiac glycosides such as digoxin are used to shift the Frank-Starling
ventricular function to a more favourable position. Diuretics are used to inhibit water and
sodium retention.
• Anti-arrhythmic drugs can be classified as Class Ia, Ib, Ic, II, III, IV under the Vaugh-
Williams classification.
• In hypertension ACE inhibitors, AIIR antagonists, calcium antagonists and diuretics can
be used amongst others.
• Treatment of hyperlipidaemias can be with statins, ezetimibe, fibrates, nicotinic acids and
bile acid binding resins.
• Treatment of bleeding disorders can be with vitamin K, protamine, tranexamic acid,
aprotinin, etamsylate and replacement of clotting factors.

68
 Kidney and urinary system
5
BASIC CONCEPTS The nephron
Each kidney is made up of approximately one million func-
Despite making up only 1% of the total body weight, the tional units, known as nephrons (Fig. 5.1). Each nephron
kidneys receive approximately 25% of the cardiac out- consists of a renal corpuscle, which comprizes a glomeru-
put reflecting their importance to the maintenance of lus and a Bowman's capsule; and a tubule, which comprizes
homeostasis. a proximal tubule, loop of Henle, distal convoluted tubule
The volume of plasma filtered by the kidneys is termed and collecting duct system.
the glomerular filtration rate (GFR) and is equal to approx-
imately 180 L per day for a person weighing 70 kg. This
means that the entire plasma volume is filtered about 60
Blood supply
Blood reaches each kidney via the renal artery, which di-
times a day. The kidneys have a large functional reserve and
vides into numerous branches before forming the afferent
the loss of one kidney normally produces no ill-effects. The
arterioles. These afferent arterioles enter the glomerular
kidneys have several complex functions (see later), whereas
capillaries (the glomeruli) and leave as the efferent arteri-
the ureters function mainly as conduits for the transport of
oles. Leaving most nephrons is the efferent arteriole, which
urine from the kidney to the bladder, where urine is stored.
immediately branches into a set of capillaries known as the
The bladder functions primarily as a storage sac, and urine
peritubular capillaries.
leaves the bladder through the urethra. In women, this is a
These branch extensively and form a network of capil-
short tube that opens just in front of the vagina. In men, the
laries surrounding the tubules in the cortex into which re-
tube is longer, passing through the prostate and the penis.
absorption from the tubule occurs, and from which various
substances are secreted into the tubule.

THE KIDNEY Glomerular filtration

During glomerular filtration, the fluid fraction of blood
in the glomerulus is forced through the capillary endo-
Functions of the kidney thelium, a basement membrane, and the epithelium of the
The kidney has several functions. These include the Bowman's capsule, to enter a fluid-filled space known as the
following. Bowman's space. Approximately 20% of the plasma entering
the glomerulus is filtered. The filtered fluid is known as the
• Regulation of body water content
glomerular filtrate and consists of protein-free plasma.
• Regulation of body mineral content and composition
• Regulation of body pH
• Excretion of metabolic waste products, for example, Tubular function
urea, uric acid and creatinine The tubules are involved in reabsorption and secretion.
• Excretion of xenobiotics, for example, drugs Important components of plasma tend to be reabsorbed
• Secretion of renin, erythropoietin and more or less completely, for example, sodium and glucose
1,25-dihydroxyvitamin D3 are 99% to 100% reabsorbed. Waste products are only par-
• Gluconeogenesis tially reabsorbed, for example, approximately 45% of urea
is reabsorbed.
The tubules secrete hydrogen and potassium ions, as
CLINICAL NOTE well as organic species such as creatinine, and certain drugs
such as penicillin.
The kidneys are the main organ by which drugs
and their metabolites are eliminated from the body. Sodium and water reabsorption
When prescribing drugs in patients with impaired Approximately 99% of filtered water and sodium is reab-
kidney function (e.g. the elderly) the dose must be sorbed, but none is secreted. The Na+/K+-adenosine tri-
adapted. phosphatase (ATPase) pump sits within the basolateral
membrane of tubular cells which pumps sodium out of the
cell and into the interstitium.

69
 Kidney and urinary system

Loop of Henle
The loop of Henle consists of a descending limb, a thin
Bowman s capsule Distal
tubule ascending limb and a thick ascending limb. Some 25% of
Bowman s space filtered sodium is reabsorbed in the thick ascending limb
Afferent (see Fig. 5.3), but this portion of the tubule is impermeable
arteriole Proximal to water. The increase in the solute load (sodium) in the
Efferent tubule interstitium between the ascending loop and the collecting
arteriole tubules sets up an osmotic gradient which subsequently
Cortical
Glomerulus permits water reabsorption from the collecting tubules; the
collecting
duct countercurrent multiplier system.
Cortex
Juxtaglomerular apparatus
Medulla Where the afferent and efferent arterioles enter the glomer-
ulus, a group of specialized cells, the macula densa, are situ-
ated in the juxtaglomerular apparatus.
Thick ascending
loop of Henle These cells secrete renin, which is a fundamental part of
Medullary the renin–angiotensin system. The renin–angiotensin sys-
collecting tem is involved directly in vascular tone and in the release
duct of aldosterone (Chapter 4).

CLINICAL NOTE

Renal prostaglandins are vasodilators and

are synthesized in response to ischaemia,
Loop of Henle
angiotensin II and antidiuretic hormone (ADH).
When vasoconstrictors are released, local
Fig. 5.1 Structure of the juxtaglomerular nephron. (Modified
release of renal prostaglandins (e.g. prostacyclin)
from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) compensate and preserve renal blood flow by their
Integrated Pharmacology, 3rd edn. Mosby, 2006.) vasodilator action. Nonsteroidal antiinflammatory
drugs (NSAIDs) inhibit prostaglandin production
by inhibiting cyclooxygenase. In normal renal
This forms a concentration gradient of sodium; high function, they have no effect. However, in patients
concentrations within the filtrate of the tubule lumen, and in which renal blood flow is dependent on
a low concentration of sodium within the cytoplasm of the
vasodilator prostaglandins (e.g. heart failure or
tubular cells. This gradient forms the basis of most reab-
liver cirrhosis), NSAIDs can precipitate acute renal
sorption and secretion processes that subsequently occur.
Sodium reabsorption from the lumen varies according to failure. In addition, NSAIDs exacerbate salt and
the section of the tubule (see Figs. 5.2–5.5). water retention in patients with heart failure by
Water is reabsorbed by passive diffusion, following impairment of prostaglandin-mediated vasodilation.
the movement of sodium ions, and through specific wa-
ter channels (aquaporins) in the collecting tubules, which
greatly increases the reabsorption of water. Distal convoluted tubule and collecting tubule
Proximal tubule The distal tubule is continuous with the collecting duct.
The Bowman's capsule extends into the proximal tubule, The collecting duct is the site at which the tubules of many
which is made up of an initial convoluted section and nephrons merge before draining into the renal pelvis. The
a straight section. The proximal tubule is permeable to renal pelvis is continuous with the ureter.
water and ions and is the site into which many drugs are The late distal tubule and collecting duct contain two cell
secreted. Approximately two-thirds of the filtrate vol- types (see Fig. 5.5).
ume is reabsorbed back into the blood in the proximal • Principal cells, which incorporate sodium and
tubule. potassium channels.
Sodium movement into the cell is coupled with that of • Intercalated cells, which incorporate H+-ATPases that
glucose and amino acids, whereas chloride movement is by secrete hydrogen ions.
passive diffusion (see Fig. 5.2). Reabsorption of bicarbonate Sodium movement into the principal cells exceeds potas-
also takes place in the proximal tubule. sium movement out of the cells so that a negative potential

70
 The kidney 5

Lumen

Interstitium/
blood
Na+
glucose
amino acids
ATP

2K+
Cl−
ADP 3Na+

Na+

HCO3− + H+
Amiloride −
methazolamide c.a. H+ HCO3−

HCO3−
H2CO3

H2CO3
H2O + CO2
c.a. − Amiloride
methazolamide
H2O + CO2

Fig. 5.2 The proximal tubule is one of the sites of bicarbonate (HCO3-) reabsorption. Carbonic acid (H2CO3) is formed in the
cytoplasm from the action of carbonic anhydrase (c.a.) on carbon dioxide (CO2) and water. H2CO3 immediately dissociates
into HCO3-, which moves down its concentration gradient across the basolateral membrane, and H+, which is secreted into
the lumen in exchange for Na+. In the lumen, H+ combines with filtered HCO3- to form H2CO3 and subsequently CO2 and
water, which are able to diffuse back into the cell. ADP, Adenosine diphosphate; ATP, adenosine triphosphate. (Modified
from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) Integrated Pharmacology, 3rd edn. Mosby, 2006.)

difference is established. Sodium is transported across the Atrial natriuretic peptide, derived from the atria of the
basolateral membrane by Na+/K+ -ATPase, and potassium heart in response to fluid overload, is believed to act on the
is moved into the cell before being forced out by the nega- distal nephron causing a water and solute diuresis.
tive potential.
This part of the tubule is the major site for potassium
secretion. CLINICAL NOTE
The late distal tubule and collecting duct also contain
ADH’s release from the posterior pituitary gland
mineralocorticoid receptors. When aldosterone binds to
these, it produces an increase in the synthesis of Na+ and K+ results in the increased expression of aquaporin
channels, Na+/K+ -ATPase, and ATP, so that Na+ reabsorp- causing an increase in the passive reabsorption
tion is increased, and K+ and H+ secretion are also increased. of water. Consequently, the urine excreted is
The collecting tubule is also the site for water reabsorp- concentrated. Note that lithium (used in the
tion via aquaporin channels. Fine-tuning of the amount of treatment of certain psychiatric conditions
water to be reabsorbed is controlled by the hypothalamus, [Chapter 8]) can inhibit the action of ADH. Defective
which governs how much antidiuretic hormone (ADH or ADH secretion results in diabetes insipidus, an
vasopressin) is released from the pituitary gland. The re- uncommon condition in which patients secrete
lease of ADH results in more aquaporins being inserted into large volumes of dilute urine.
the luminal membrane, increasing the amount of water that
is reabsorbed (Chapter 4).

71
 Kidney and urinary system

lumen lumen

loop
diuretics interstitium/
thiazide
blood
diuretics
interstitium/
blood

1 Na+
Na+ ATP
K+
2Cl− K+
Na+ ATP
2Cl− 2K+
Cl− Na+
Cl− 2K+
ADP 1
3Na+
2 ADP
K+ 3Na+

K+
K+

K+
Cl−
K+ K+
Cl− Cl−
Ca2+
Cl−
Ca2+
2 3Na+
+
Ca2+

Na+ 3
Mg2+ −
Ca2+

Na+
Mg2+
Ca2+ 3

Fig. 5.3 Transport mechanism in the thick ascending Fig. 5.4 Transport mechanisms in the early distal tubule.
loop of Henle. Loop diuretics block the Na+/K+/2Cl– Thiazide diuretics increase the excretion of Na+ and Cl– by
cotransporter (1) thereby increasing the excretion of Na+ inhibiting the Na+/Cl– cotransporter (1). The reabsorption
and Cl–. These drugs also decrease the potential difference of Ca2+ (2) is increased by these drugs by a mechanism
across the tubule cell, which arises from the recycling of K+ that may involve stimulation of Na+/Ca2+ countertransport
(2), and this leads to increased excretion of Ca2+ and Mg2+ (3) caused by an increase in the concentration gradient for
by inhibiting paracellular diffusion (3). ADP, Adenosine Na+ across the basolateral membrane. ADP, Adenosine
diphosphate; ATP, adenosine triphosphate. (Modified from diphosphate; ATP, adenosine triphosphate. (Modified from
Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) Integrated Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) Integrated
Pharmacology, 3rd edn. Mosby, 2006.) Pharmacology, 3rd edn. Mosby, 2006.)

DIURETICS into the capillaries. The most common causes for sys-
temic oedema are as follows.
Diuretics work by altering kidney function and are crucial
in the management of cardiovascular disease (Chapter 4) • Congestive cardiac failure
and renal disease. Diuretics work on the kidneys to increase • Hypoalbuminaemia (including liver failure and
urine volume by reducing salt and water reabsorption from nephrotic syndrome)
the tubules. They are prescribed for the treatment of oe- Loss of fluid from the intravascular space into the inter-
dema, where there is an increase in interstitial fluid volume stitial compartment results in an apparent hypovolaemic
leading to tissue swelling. state. Poor perfusion of the kidneys activates the renin–­
Oedema occurs when the rate of fluid formation ex- angiotensin system, which causes sodium and water reten-
ceeds that of fluid reabsorption from the interstitial fluid tion. This exacerbates the problem of oedema.

72
 Diuretics 5

lumen interstitium/ Types of diuretics

blood
Loop diuretics
Furosemide and bumetanide are examples of loop diuretics.
Loop diuretics cause the excretion of 15% to 25% of fil-
Cl−
tered sodium as opposed to the normal 1% or less. This can
Cl−
result in a profound diuresis.
2
Site of action—Loop diuretics act at the thick ascending
+ segment of the loop of Henle.
Principal cell Mechanism of action—Loop diuretics inhibit the Na+/
K+/2Cl– cotransporter in the luminal membrane (see
K+ Fig. 5.3). This increases the amount of sodium reaching the
K+ collecting duct and thereby increases K+ and H+ secretion.
Amiloride
Calcium and magnesium reabsorption is also inhibited, ow-
triamterene 1 ATP ing to the decrease in potential difference across the cell nor-
2K+ mally generated from the recycling of potassium (Fig 5.6).
3Na+
2 Loop diuretics additionally have a venodilator action,
Na+ ADP
which often brings about the relief of clinical symptoms be-
MR Aldosterone fore the onset of diuresis.
1 Route of administration—Oral, intravenous or intramuscu-
Spironolactone lar. The intravenous route is used in patients with acute pulmo-
nary oedema because the therapeutic effect is much quicker
Nucleus (about 30 minutes compared with 4–6 hours for an oral dose).
AIP
mRNA Indications—Used predominantly in the treatment of
ATP salt and water overload associated with acute pulmonary
3
oedema, chronic heart failure (CHF), liver ascites and ne-
Mitochondrion
2
phrotic syndrome. It can also be used in the treatment of
+ hypertension complicated by impaired renal function.
Contraindications—Loop diuretics should not be given
to those with severe renal impairment. They should be
given with caution to patients receiving:
• Cardiac glycosides because the hypokalaemia caused
by loop diuretics potentiates the action of cardiac
Intercalated cell
ATP
glycosides and consequently increases the risk of
H+
cardiac glycoside-induced arrhythmias (Chapter 4).
HCO3− • Aminoglycoside antibiotics (e.g. gentamicin) because
H+ ATPase ADP H2CO3 these interact with loop diuretics and increase the risk
of ototoxicity and potential hearing loss that can occur
CO2 + H2O with this class of antibiotic.
Adverse effects—Hypokalaemia, hyponatraemia, hypo-
Fig. 5.5 Transport mechanisms in the late distal tubule and
collecting duct. Amiloride and triamterene block the luminal Na+ tension and hypovolaemia. Metabolic alkalosis may occur
channels, which reduces the lumen-negative potential difference because of increased hydrogen secretion and thus excretion.
across the principal cell and decreases the driving force for Hypocalcaemia and hypomagnesaemia are also possible.
K+ secretion from the principal cell and H+ secretion from the Hyperuricaemia can precipitate acute gout.
intercalated cell. The net effect is increased Na+ excretion
and decreased K+ and H+ excretion. Aldosterone binds to a
HINTS AND TIPS
cytoplasmic mineralocorticoid receptor (MR) stimulating the
production of aldosterone-induced proteins (AIP), which (1)
Several different sodium channels exist in the renal
activate and increase the synthesis of Na+ and K+ channels;
(2) increase the synthesis of Na+/K+ ATPase, and (3) increase tubule, which is why the various diuretic drugs act
mitochondrial production of adenosine triphosphate (ATP). at different sites along its course; they have different
The effect of aldosterone is to decrease Na+ excretion and molecular actions and different side effects. Most
increase K+ and H+ excretion in urine, whereas spironolactone, diuretic drugs block sodium reabsorption from the
an aldosterone antagonist, has the opposite effects. ADP,
renal tubule, which leads to a high solute load in the
Adenosine diphosphate; mRNA, messenger ribonucleic acid.
(Modified from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) tubule resulting in an osmotic diuresis.
Integrated Pharmacology, 3rd edn. Mosby, 2006.)

73
 Kidney and urinary system

Na+ 145, 100% Na+ 30, 10% Na+ 13%

Cl- 115, 100% Cl- 30, 10% Cl- 3%

H+
1
DT Na+ Cl-
Na+
3

TAL
Thiazides
Interstitia PCT
CT
K+
Osmotic diuretics
modify filtrate Na+
Amiloride
content 2
2Cl- – Cl-
–
Na+ 145, 100% Na+
Cl- 115, 100% Interstitia
Loop 4
diuretics
Aldosterone
Interstitia –

Spironolactone

Na+ 0.1-2%
Cl- 0.1-2%

Fig. 5.6 Schematic showing the absorption of sodium and chloride in the nephron and the main sites of action of drugs.
(From Ritter, J.M., Flower, R.J., Henderson, G, Rang, H.P. Rang and Dale’s Pharmacology. 8th edition, 2015, p. 358, Fig. 29.4.)

Thiazide and related diuretics cardiac glycosides, or to those with diabetes mellitus (thia-
Bendroflumethiazide, chlortalidone, metolazone and in- zides may cause hyperglycaemia).
dapamide are examples of thiazide or related diuretics. Adverse effects—Better tolerated than loop diuretics but
Thiazides produce a moderately potent diuresis, causing still increase urinary frequency. Hypokalaemia, hyperuri-
the excretion of 5% to 10% of filtered sodium. Although less caemia, hyponatraemia, hypermagnesaemia, hypercalcae-
potent than loop diuretics when prescribed alone, coadmin- mia and metabolic alkalosis.
istration results in a synergistic effect and increased potency.
Site of action—Thiazide diuretics act on the early distal CLINICAL NOTE
tubule.
Mechanism of action—Thiazide diuretics inhibit the Mrs Hurst, 77 years old, has developed increasing
Na+/Cl– cotransporter in the luminal membrane (see dyspnoea and fatigue associated with ankle
Fig. 5.4). Similar to loop diuretics, they increase the secre- swelling preventing her from wearing her normal
tion of K+ and H+ into the collecting ducts, but, in contrast, shoes. She has a medical history of angina,
they decrease Ca2+ excretion by a mechanism possibly in- takes aspirin regularly and glyceryl trinitrate when
volving the stimulation of a Na+/Ca2+ exchange across the
required. Following electrocardiogram (ECG)
basolateral membrane; this is caused by reduced tubular cell
and B-type natriuretic peptide testing, she was
sodium concentration (see Fig. 5.6).
Route of administration—Oral, having a peak effect at 4 diagnosed as having heart failure.
to 6 hours. Her symptoms, being caused by pulmonary and
Indications—Third-line treatment for hypertension, thia- peripheral oedema, were treated with the loop
zides have been shown to reduce the risk of heart attack and diuretic furosemide with the aim of decreasing her
strokes in patients with hypertension. Mild heart failure (loop di- fluid overload. Enalapril (an angiotensin-converting
uretics preferred). Occasionally used for prophylaxis of calcium- enzyme [ACE] inhibitor) and carvedilol (a β-blocker)
containing renal stones. May be preferred in elderly patients were started concurrently because they have been
with osteoporosis because thiazides reduce calcium excretion. shown to improve symptoms and decrease mortality.
Contraindications—Hypokalaemia, hyponatraemia, hy-
percalcaemia. Caution when prescribing to patients taking

74
 The urinary system 5

Potassium-sparing diuretics Passive water reabsorption is reduced by the presence of this

Spironolactone, amiloride and triamterene are all potassium- nonreabsorbable solute within the tubule lumen. The net ef-
sparing diuretics. fect is increased water loss, with a relatively smaller loss of
Potassium-sparing diuretics produce mild diuresis and sodium.
cause the excretion of 2% to 3% of filtered sodium. Route of administration—Mannitol is administered
Site of action—Potassium-sparing diuretics work at the intravenously.
late distal tubule and collecting duct (see Fig. 5.5). Indications—Osmotic diuretics are used mainly for
Mechanism of action—There are two classes of potassium- raised intracranial, and rarely, raised intraocular pressure
sparing diuretics. (glaucoma).
• Sodium-channel blockers: For example, amiloride and Contraindications—Congestive cardiac failure and pul-
triamterene. These drugs block sodium reabsorption monary oedema.
by the principal cells, thus reducing the potential Adverse effects—Chills and fever.
difference across the cell and reducing K+ secretion. Therapeutic notes—Osmotic diuretics are seldom used
Secretion of H+ from the intercalated cells is also in heart failure, as an expansion of blood volume can be
decreased. greater than the degree of diuresis produced.
• Aldosterone antagonists: For example, spironolactone,
eplerenone. These drugs are a competitive antagonist
at aldosterone receptors, and thus reduce Na+
reabsorption and therefore K+ and H+ secretion. The THE URINARY SYSTEM
degree of diuresis depends on aldosterone levels (see
Fig. 5.6). Urinary retention
Route of administration—Oral. Acute urinary retention is treated with urethral catheter-
Indications—These diuretics prolong survival in patients isation. Chronic urinary retention is usually painless, and
with heart failure (in conjunction with a loop or thiazide management depends upon the underlying cause. In men,
diuretic). They also prevent hypokalaemia, maintaining the most common cause for chronic urinary retention is be-
normal serum potassium levels when coadministered with nign prostatic hyperplasia (BPH). Surgery is the definitive
other diuretics. treatment, although many patients can be treated medically.
Aldosterone antagonists are used in the treatment of hy- Three classes of drugs can be used to treat bladder outflow
peraldosteronism, which can be primary (Conn syndrome) obstruction secondary to BPH as follows.
or secondary (as a result of CHF, liver disease or nephrotic
syndrome). • α-Blockers
Contraindications—Potassium-sparing diuretics inter- • Parasympathomimetics
act with ACE inhibitors, increasing the risk of hyperka- • Antiandrogens.
laemia. They should not be given to patients with renal
failure. α-Blockers
Adverse effects—Gastrointestinal disturbances, hyperka- Doxazosin and prazosin are examples of α-blockers and act
laemia and hyponatraemia. Aldosterone antagonists have by relaxing the smooth muscle at the urethra opening of the
a wide range of adverse effects, including gynaecomastia, bladder, increasing the flow of urine. Because α-­blockers
menstrual disorders and male sexual dysfunction because are also used as vasodilators in cardiovascular disease
of their action on aldosterone and androgen receptors in (Chapter 4), postural hypotension can be a side effect, al-
other organs. though are otherwise well tolerated.
Therapeutic notes—Low-dose spironolactone has bene-
ficial effects in CHF. Several preparations exist which com- Parasympathomimetics
bine a potassium-sparing diuretic with either a thiazide or Parasympathomimetics, such as bethanechol, act by in-
a loop diuretic, for example, co-amilofruse, which contains creasing detrusor muscle contraction. Their effect is most
amiloride and furosemide marked when there is bladder outlet obstruction, and they
have no role in the relief of acute urinary retention. Side
effects include sweating, bradycardia and intestinal colic.
Osmotic diuretics They are now used infrequently, being superseded by
Mannitol is an osmotic diuretic. catheterisation.
Site of action—Osmotic diuretics exert their effects in tu- Antiandrogens—Finasteride is a specific inhibitor of
bular segments that are water permeable; proximal tubule, the enzyme 5α-reductase, which converts testosterone to
descending loop of Henle, and the collecting ducts (see the more potent androgen dihydrotestosterone. This inhi-
Fig. 5.6). bition leads to a reduction in prostate size, and improve-
Mechanism of action—Osmotic diuretics are freely filtered ment of urinary flow. The antiandrogens are described in
at the glomerulus, but only partially, if at all, r­eabsorbed. Chapter 7.

75
 Kidney and urinary system

Desmopressin
CLINICAL NOTE
Desmopressin is an analogue of ADH, given by mouth or
Mr Raheem, 80 years old, presents with increasing by nasal spray. It can be used in the treatment of nocturnal
nocturia, urgency and reduced urinary flow enuresis in children or in adults with troublesome nocturia
(see Chapter 4).
for the past 2 years. Urinalysis was negative.
Renal function and ultrasound were normal. His
urine flow rate showed moderate impairment. Mirabegron
This selective β-agonist has recently been licensed for the
Digital rectal examination revealed a smooth,
treatment of overactive bladder.
enlarged prostate, suggestive of BPH. Prostate
serum antigen was within the normal range.
His symptoms were managed medically with
Erectile dysfunction
Tamsulosin, an α-adrenergic blocker. However, in Erectile dysfunction (impotence) is a common problem
the future, he may require a transurethral resection worldwide and has numerous causes, including side effects
of the prostate. arising from several prescribed medications (e.g. antipsy-
chotics, antihypertensives and antidepressants).
The penis is innervated by autonomic (involuntary) and
somatic (voluntary) nerves. Parasympathetic innervation
Urinary incontinence brings about erection, and sympathetic innervation is re-
sponsible for ejaculation. Nonadrenergic, noncholinergic
Urinary incontinence is the involuntary leakage of urine. neurotransmission (NANC) (nitrergic) also appears to pro-
There are three main types of urinary incontinence. mote erection.
• True incontinence (fistulous track) Nitric oxide is the neurotransmitter released by NANC
• Stress incontinence (incompetent sphincter) nerves innervating the corpus carvenosum and is believed
• Urge incontinence (detrusor instability) to be the principal mediator of inducing and sustaining an
Urge incontinence is the only type that is practically amena- erection. Nitric oxide activates the guanylyl cyclase enzyme,
ble to pharmacological intervention, mostly with musca- which subsequently generates cyclic guanosine monophos-
rinic receptor antagonists. phate (cGMP) in the vascular smooth muscle cells of the
corpus carvenosum. The synthesis of cGMP, in turn, acti-
vates a protein kinase, which phosphorylates ion channels
Muscarinic receptor antagonists in the plasma membrane, and causes hyperpolarisation of
Oxybutynin is the most widely used muscarinic recep- the smooth muscle cell. Intracellular calcium ions are con-
tor antagonist for the treatment of urge incontinence, al- sequently sequestered into the endoplasmic reticulum, and
though newer muscarinic receptor antagonists are in use further calcium influx into the cell inhibited by the closure
(e.g. solifenacin, tolterodine). of calcium channels. The overall effect of the fall in intra-
Mechanism of action—Oxybutynin relaxes the detrusor cellular calcium is a relaxation of the smooth muscle and
muscle of the bladder. increased blood flow to the penis.
Route of administration—Oral, transdermal (patches). Although nitric oxide has a very short half-life and is
Indications—Urinary frequency, urgency, urge molecularly unstable, cGMP is broken down by a specific
incontinence. group of enzymes, the phosphodiesterases, which subse-
Contraindications—Intestinal obstruction, significant quently results in the penis returning to its flaccid state.
bladder outflow obstruction, glaucoma. Inhibition of phosphodiesterase 5 found in the penis is the
Adverse effects—Dry mouth, constipation, blurred vi- target of one class of drugs used in the treatment of erectile
sion, urinary retention, nausea and vomiting. dysfunction.
Therapeutic notes—The main side effects are typically
caused by these drugs blocking muscarinic receptors else-
where in the parasympathetic nervous system, and are
Phosphodiesterase inhibitors
Sildenafil is a selective inhibitor of phosphodiesterase
commonly dose related.
type 5.
Mechanism of action—Inhibition of phosphodiesterase-
Duloxetine mediated degradation of cGMP. This enhances the
Duloxetine is a serotonin/noradrenaline reuptake inhibitor ­vasodilator effects of nitrous oxide because of higher
(see Chapter 8) that can be used as second-line treatment intracellular levels of cGMP. Thus there is the continual
for stress incontinence, in patients who do not want, or who relaxation of penile smooth muscle and maintenance of
are unsuitable for surgery. an erection.

76
 The urinary system 5

Route of administration—Oral. Prostaglandin E1

Indications—Erectile dysfunction. There are strict Alprostadil is a synthetic prostaglandin E1 analogue.
guidelines in the United Kingdom as to which groups of Mechanism of action—It has a similar effect on penile
patients can be prescribed sildenafil on the National Health smooth muscle as nitric oxide.
Service. These include patients with erectile dysfunction Route of administration—Direct injection into the cor-
resulting from diabetes, multiple sclerosis, Parkinson dis- pus cavernosum of the penis or applied into the urethra.
ease, poliomyelitis, prostate cancer, severe pelvic injury, Indications—Erectile dysfunction.
single-gene neurological disease, spina bifida or spinal Contraindications—Predisposition to prolonged erec-
cord injury. tion, urethral stricture and use of other agents for erectile
Contraindications—Concurrent treatment with nitrates. dysfunction.
Conditions in which vasodilation or sexual activity are Adverse effects—Penile pain, priapism.
inadvisable.
Adverse effects—Many of the unwanted effects are caused
by vasodilation in other vascular areas. These include hypo-
tension, flushing and headache. In addition, dyspepsia and HINTS AND TIPS
visual disturbances.
Therapeutic notes—Nonspecific inhibition of phospho- Phosphodiesterase enzymes degrade the cyclic
diesterase type 6 in the retina is responsible for occasional nucleotides cyclic adenosine monophosphate
colour disturbances in some patient's vision. An erection (cAMP) and cGMP. Inhibitors of the
will not occur unless there is sexual stimulation and a nor- phosphodiesterases, such as sildenafil, and the
mal sexual drive. less specific xanthines such as theophylline, result
Papaverine is a nonselective phosphodiesterase inhibi- in accumulation of these mediators, which brings
tor, which is injected directly into the corpus cavernosum about the physiological effects of these drugs.
and causes vasodilation and thus an erection. However,
most men do not like these injections.

Chapter Summary

• The kidneys function to regulate water, mineral content, body pH and excretion of metabolic
waste products. As well as manufacturing vitamin D3.
• The kidney nephron consist of the proximal tubule, loop of Henle, juxtaglomerular
apparatus, distal convoluted tubule and the collecting tubule.
• Drugs such as diuretics, loop diuretics and thiazides work on altering kidney function to
increase excretion of salts.
• Urinary incontinence can be managed by muscarinic receptor antagonists like
oxybutynin or mirabegron.
• Erectile dysfunction can be managed by phosphodiesterase inhibitors, and direct injection
of prsotaglandin E1.

77
This page intentionally left blank
 Gastrointestinal system
6
The ­secretion of HCl is controlled by the activation of three
THE STOMACH main receptors on the basolateral membrane of the parietal
cell. These include the following.
Basic concepts • Gastrin receptors, which respond to gastrin secreted by
The stomach stores food but also helps mechanically and the G cells of the stomach antrum.
chemically (through hydrochloric acid [HCL] and digestive • Histamine (H2) receptors, which respond to histamine
enzymes) to break it down. Peptic ulceration and gastro-­ secreted from the enterochromaffin-like paracrine cells
oesophageal reflux disease (GORD) are two of the common that are adjacent to the parietal cell.
problems that can occur in the stomach. • Muscarinic (M1, M3) receptors on the parietal cell,
which respond to acetylcholine (ACh) released from
Peptic ulceration neurones innervating parietal cells.
Although the parietal cells possess muscarinic and gas-
The gastric epithelium secretes several substances: HCl trin receptors, both ACh and gastrin mainly exert their
(from parietal cells), digestive enzymes (from peptic cells) acid secretory effect indirectly, by stimulating nearby
and mucus (from mucus-secreting cells). The acid and en- enterochromaffin-like cells to release histamine. Histamine
zymes convert food into a thick semi-liquid paste called then acts locally on the parietal cells where activation of the
chyme. The production of acid also kills harmful pathogens. H2 receptor results in the stimulation of adenylyl cyclase
The mucus protects the stomach from its own corrosive and the subsequent secretion of acid. Excessive production
secretions. of gastrin from a rare tumour, a gastrinoma, can result in
Peptic ulceration results from a breach in the mucosa excess acid production, and in peptic ulceration, a condi-
lining the alimentary tract. Unprotected mucosa rapidly tion known as Zollinger–Ellison syndrome.
undergoes autodigestion leading to a range of damage; in-
flammation or gastritis, necrosis, haemorrhage, and even
perforation as the erosion deepens. CLINICAL NOTE
Gastric and duodenal ulcers differ in their location,
­epidemiology, incidence and aetiology but present with Mr. Springfields is a 56-year-old city worker, who
similar symptoms, and treatment is based on similar princi- presents to A&E with epigastric pain. Normally
ples. Peptic ulcer disease is chronic, recurrent and common, this pain is relieved with eating or antacids, but
affecting at least 10% of the population in developed coun- today he vomited dark-coloured blood and had
tries. Helicobacter pylori plays a role in the pathogenesis of a an episode of malaena. He has been taking
significant proportion of peptic ulcer disease. ibuprofen for back pain over the past 2 months.
He is pale and tachycardic, with a blood pressure
Protective factors of 110/65 mm Hg. He is stabilized with oxygen
The mucosal defences against acid/enzyme attack consist of and 1 unit of blood. Upper gastrointestinal flexible
the following. endoscopy reveals a shallow ulcer overlying a
• The mucous barrier (approximately 500 mm thick), blood clot. A biopsy is taken to test for H. pylori
a mucous matrix into which bicarbonate ions are and returns positive. His ibuprofen is discontinued,
secreted, producing a buffering gradient. and he is prescribed H. pylori eradication therapy
• The surface epithelium and prostaglandins E2 and I2, (a proton-pump inhibitor and antibiotics) consisting
synthesized by the gastric mucosa, are thought to
of omeprazole, amoxicillin and metronidazole.
exert a cytoprotective action by increasing mucosal
blood flow.

Acid secretion Gastrooesophageal reflux

The regulation of acid secretion by parietal cells is espe-
cially important in peptic ulceration and constitutes a ma- Stomach contents are normally prevented from reentering
jor target for drug action (Fig. 6.1). Acid is secreted from the oesophagus by the lower oesophageal sphincter (LOS).
gastric parietal cells by a unique proton pump that catal- Loss of tone of the LOS or a rise in intraabdominal pressure
yses the exchange of intracellular H+ for extracellular K+. are the most common causes of GORD, of which heartburn

79
 Gastrointestinal system

Vagus

Histamine (H2)
antagonists
. cimetidine G ACh

. ranitidine M
+ +

Histamine
−

Enterochromaffin-
ACh PGE2 H G like cell
M1 H2
Adenylyl Mucus cell
− cyclase +

Ca2+ Ca2+

cAMP ATP
Protein kinases

K+ K+ Cl−
Parietal
cell

Mucus

Stomach lumen −
H+

R− + H+
neutralization
Proton pump RH
inhibitors
. omeprazole
. lansoprazole
Antacids
. Al (OH)
. Mg (OH) 3

. Na HCO 3
2

Fig. 6.1 Acid secretion from parietal cells is reduced by muscarinic antagonists, histamine (H2) antagonists and the
proton-pump inhibitors. Gastrin (G) and acetylcholine (ACh) stimulate the parietal cell directly to increase acid secretion
and also stimulate enterochromaffin-like cells to secrete histamine, which then acts on the H2 receptors of the parietal
cell. Antacids raise the luminal pH by neutralising hydrogen ions. Mucosal strengtheners adhere to and protect ulcer
craters and may kill Helicobacter pylori. ATP, Adenosine triphosphate; cAMP, cyclic adenosine monophosphate; PGE2,
prostaglandin E2. (Modified from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) Integrated Pharmacology, 3rd edn.
Mosby, 2006,)

is the major symptom. Conservative treatment options

include raising the head of the patient's bed, avoiding ex- Prevention and treatment
cessive alcohol consumption, losing weight and smoking
cessation. Patients should avoid medications, which affect
of acid-related disease
oesophageal motility (e.g. nitrates or tricyclic antidepres- Drugs that are effective in the treatment of peptic ulcers
sants) or damage the mucosa (e.g. nonsteroidal antiinflam- either reduce/neutralize gastric acid secretion or increase
matory drugs [NSAIDs] or alendronic acid). The drugs mucosal resistance to acid-pepsin attack. Peptic ulcers can
used in the management of GORD are the same as for other be treated quite easily but the eradication of H. pylori is key
acid-related disorders (Fig. 6.2). to prevent recurrence.

80
 The stomach 6

Symptoms
Mechanism of action—H2-receptor antagonists com-
e.g. heart burn, excess petitively block the action of histamine on parietal cells
salivation, acid reflux (see Fig. 6.1) that inhibits gastric acid secretion.
Route of administration—Oral. Some H2-receptor antag-
onists can be given intravenously.
Indications—H2-receptor antagonists are used in the
Lifestyle changes treatment of peptic ulcer disease and GORD.
e.g. smoking cessation,
Contraindications—H2-receptor antagonists may mask
weight loss, minimal
alcohol intake symptoms of gastric cancer. Before prescribing, gastric
malignancy should be excluded if any “alarm features” are
No/minimal response present.
Adverse effects—Dizziness, fatigue, gynaecomastia, rash.
Add in Therapeutic notes—H2-receptor antagonists do not reduce
proton pump acid production to the same extent as PPIs but do relieve the
inhibitors
pain of ulcer and promote healing. The drugs are adminis-
tered at night when acid buffering by food is at its lowest.
No/minimal response
The usual regimen is twice daily for 4 to 8 weeks. Cimetidine
inhibits the P450 enzyme system, reducing the metabolism
Add in
H2-receptor
of drugs such as warfarin, phenytoin, theophylline and
antagonists 3,4-Methylenedioxymethamphetamine (MDMA)(“ecstasy”),
potentiating their pharmacological effect and thus should be
No/minimal response used with caution in patients taking these medications.
Mucosal strengtheners
Long-term PPI or
anti-reflux
Misoprostol—Mechanism of action
surgery Misoprostol is a synthetic analogue of prostaglandin
E. It imitates the action of endogenous prostaglandins
Fig. 6.2 Treatment of gastrooesophageal reflux disease: a (PGE2 and PGI2) in maintaining the integrity of the gas-
stepwise approach. (Modified from Colledge, N.R., Walker, B., troduodenal mucosal barrier and promotes healing (see
Ralston, S.H. Davidson's Principles and Practice of Medicine,
Fig. 6.1).
23rd edition, Churchill Livingstone, Edinburgh, 1999.)
Route of administration—Oral.
Indications—Ulcer healing and ulcer prophylaxis with
Reduction of acid secretion
NSAID use.
Proton pump inhibitors Contraindications—Misoprostol should not be given to
Omeprazole, lansoprazole and pantoprazole are examples people with hypotension, or to women who are pregnant
of proton-pump inhibitors (PPIs). (causes termination) or breastfeeding.
Mechanism of action—PPIs cause irreversible inhibition Adverse effects—Diarrhoea, abdominal pain, sponta-
of H+/K+ -ATPase that is responsible for H+ secretion from neous abortion in pregnancy.
parietal cells (see Fig. 6.1). They are inactive prodrugs and Therapeutic notes—Misoprostol is most effective at
are converted at acidic pH to sulphonamide, which com- correcting the deficit caused by NSAIDs that inhibit
­
bines covalently and thus irreversibly with -SH groups on cyclooxygenase-1 and reduce prostaglandin synthesis
­
H+/K+ adenosine triphosphatase (ATPase). This inhibition (Chapter 11). Misoprostol can prevent NSAID-associated
is highly specific and localized. ulcers, and therefore is particularly useful in patients who
Route of administration—Oral. Some PPIs can be given are reliant on NSAIDs.
intravenously.
Indications—Short-term treatment of peptic ulcers,
Chelates
Bismuth chelate and sucralfate appear to help protect the
eradication of H. pylori, severe GORD, confirmed oesopha-
gastric mucosa by several means, including inhibiting the
gitis, Zollinger–Ellison syndrome.
action of pepsin, promoting synthesis of protective pros-
Contraindications—No important contraindications are
taglandins and stimulating the secretion of bicarbonate.
reported.
Chelates are sometimes used in combination regimes
Adverse effects—Gastrointestinal upset, nausea, head-
to treat H. pylori. They are administered orally and are
aches. There might be a risk of gastric atrophy with long-
generally well tolerated. However, they can cause black-
term treatment. Can also cause hyponatraemia.
ening of the tongue and faeces. Note that sucralfate can
Histamine H2-receptor antagonists reduce the absorption of a number of other drugs, in-
Examples of H2-receptor antagonists include cimetidine cluding theophylline, tetracycline antibiotics, digoxin and
and ranitidine. amitriptyline.

81
 Gastrointestinal system

Antacids
Examples of antacids include aluminium hydroxide and HINTS AND TIPS
magnesium carbonate. Peptic ulcer disease is very common and
Mechanism of action—Antacids consist of alkaline alu-
potentially life-threatening. Always check
minium (Al3+) and magnesium (Mg2+) salts that are used to
with patients if they have an ulcer or ulcer-
raise the luminal pH of the stomach. They neutralize acid
and, as a result, may reduce the damaging effects of pepsin, like symptoms before prescribing NSAIDs or
which is pH dependent (see Fig. 6.1). In addition, Al3+ and corticosteroids.
Mg2+ salts bind and inactivate pepsin.
Route of administration—Oral.
Indications—Symptomatic relief of ulcers, nonulcer dys-
pepsia and GORD. Terlipressin
Contraindications—Aluminium hydroxide and mag- Terlipressin is a vasoactive drug that is used in the emer-
nesium hydroxide should not be given to people with gency treatment of oesophageal varices in patients with
hypophosphataemia. raised portal hypertension associated most commonly with
Adverse effects—Constipation (aluminium salts), diar- liver cirrhosis. It causes vasoconstriction of dilated splanch-
rhoea (magnesium salts). nic blood vessels thus reducing blood flow and arresting the
Therapeutic notes—Antacids are the simplest way to catastrophic variceal haemorrhage.
treat symptoms of excessive gastric acid secretion and can
provide symptomatic relief from ulceration. Although fre-
quent high dosing can promote ulcer healing, this is rarely
practical.
NAUSEA AND VOMITING
Alginates Basic concepts
Alginate-containing antacids are administered orally and
form an impenetrable raft, which floats on the surface of The most common causes of nausea and vomiting are shown
the gastric contents. This layer prevents gastric acid from in Fig. 6.3. Many drugs, notably chemotherapy, opioids and
refluxing into the oesophagus and is, therefore, most useful general anaesthesia, cause nausea and vomiting. The act of
in GORD. This class of drug is very well tolerated but does vomiting is coordinated in the vomiting centre within the
not have any effect on acid secretion, or on preventing or brainstem. This centre receives neuronal input from several
healing of peptic ulcers. sources, although fibres from the chemoreceptor trigger zone
(CTZ) of the fourth ventricle appear fundamental in bringing
about emesis (vomiting). The CTZ lies outside the blood–brain
Helicobacter pylori eradication
barrier and is sensitive to many stimuli, such as certain drugs,
regimens and endogenous and potentially exogenous chemical media-
H. pylori plays a significant role in the pathogenesis of tors. The CTZ contains numerous dopamine receptors, which
peptic ulcer disease. It does not cause ulcers in everyone partially explains why antiparkinsonian drugs (dopaminergic
it infects (50%–80% of the population) but, of those who drugs) (Chapter 8) often induce nausea and vomiting, whereas
develop ulcers, 90% can be found to have an H. pylori in- some antidopaminergic drugs are used as antiemetics.
fection in their antrum. It is routine practice to test for
H. pylori, using a carbon-13 urea breath test or a stool
­antigen test because the eradication of this infection can Emetic drugs
promote rapid and long-term healing of the ulcer. It is advantageous, occasionally, to induce emesis to empty
Treatment of peptic ulcer disease should include eradi- the stomach of an ingested toxic substance. Ipecacuanha is
cation of H. pylori. The rate of recurrence of duodenal ul- given as a liquid and causes gastric irritation resulting in
cer after healing can be as high as 80% within 1 year when emesis. There is no evidence to support its use, however,
H. pylori eradication is not part of the treatment, but less and gastric lavage is the preferred method.
than 5% when H. pylori is eradicated.
The ideal treatment for H. pylori eradication is not yet
clear. These are the current regimens under evaluation.
Antiemetic drugs
• The “classic” triple therapy: 1 or 2 weeks' treatment The main neurotransmitters (i.e. serotonin [5-HT], hista-
with omeprazole, metronidazole and amoxicillin or mine and dopamine) involved in the mechanism of vomit-
clarithromycin. This eliminates H. pylori in 90% of ing are target sites for many antiemetic medications.
patients but adverse effects, compliance and resistance
can be problematic. H1-receptor antagonists
• Quadruple therapy: Omeprazole, two antibiotics and Cyclizine, cinnarizine and promethazine are H1-receptor
bismuth chelate. antagonist antiemetics.

82
 Nausea and vomiting 6

Sensory input (pain, smell, sight) Higher cortical Memory, fear, anticipation
centers

Histamine antagonists
Muscarinic antagonists Benzodiazepines
Dopamine antagonists
Cannabinoids

Chemoreceptor
Chemotherapy
trigger zone Vomiting center
Anaesthetics
(area prostrema (medulla)
Opioids
4th ventricle)

Vomiting
reflex

Labyrinths Surgery

5HT3
antagonists
Sphincter
modulators

Chemotherapy Stomach Neuronal pathways

Surgery Small intestine
Radiotherapy Factors which can cause
nausea and vomiting

Gastroprokinetic Sites of action of drugs

agents

Fig. 6.3 Common causes of nausea and vomiting.

Mechanism of action—These H1-receptor antagonists Contraindications—May exacerbate existing parkinso-

have little effect on nausea and vomiting induced by sub- nian symptoms.
stances acting directly upon the CTZ, although appear ef- Adverse effects—Sedation, postural hypotension, in-
fective antiemetics in the treatment of motion sickness and creased prolactin levels, extrapyramidal effects.
vestibulocochlear disease.
Route of administration—Cyclizine: oral, intramuscular, Dopamine antagonists
intravenous. Cinnarizine: oral. Domperidone and metoclopramide are examples of the an-
Indications—Motion sickness, vestibular disorders, vertigo. tiemetic dopamine antagonists.
Cyclizine is commonly used for morning sickness in Mechanism of action—Domperidone and metoclopra-
pregnancy. mide antagonize dopamine receptors and act on the CTZ.
Adverse effects—Drowsiness, dry mouth, blurred vision. They also act peripherally on the gastrointestinal tract, in-
Therapeutic notes—Older H1-receptor antagonists that creasing the motility of the oesophagus, stomach and intes-
can cross the blood–brain barrier also have significant an- tine. They are not only antiemetic but also promote gastric
timuscarinic activity and should be used with caution in emptying and small intestine peristalsis.
prostatic hypertrophy, urinary retention and glaucoma. Metoclopramide also acts as a dopamine receptor
antagonist elsewhere in the central nervous system, pro-
Phenothiazines ducing a number of unwanted side effects including dis-
Prochlorperazine and chlorpromazine are the most widely orders of movement, particularly in children and young
used antiemetic drug in this class, although the pheno- adults.
thiazines are also used for their antipsychotic properties Route of administration—Metoclopramide: oral, intra-
(Chapter 8). muscular, intravenous. Domperidone: oral, rectal.
Mechanism of action—Numerous effects. Antagonize Indications—Nausea and vomiting, functional
dopamine, H1 and muscarinic receptors. dyspepsia/GORD.
Route of administration—Oral, rectal, intramuscular. Haloperidol and levomepromazine also act as D2
Indications—Nausea and vomiting, vertigo, psychosis antagonists in the CTZ and can be used for acute
­
(Chapter 8). ­chemotherapy-induced emesis.

83
 Gastrointestinal system

Contraindications—Metoclopramide is not routinely Together, these autonomic ganglionated plexi control the
given to patients under the age of 20 years because there is functioning of the gastrointestinal tract through complex
an increased risk of extrapyramidal side effects in the young. local reflex connections between sensory neurones, smooth
Adverse effects—Metoclopramide can cause oculogyric muscle, mucosa and blood vessels.
crises (involuntary upward eye movement) and spasmodic Extrinsic parasympathetic fibres from the vagus are
torticollis (involuntary twisting of the neck). It also stim- excitatory and extrinsic sympathetic fibres are inhib-
ulates prolactin causing galactorrhoea and disorders of itory. The enteric autonomic nervous system is a major
menstruation. target for the pharmacological therapy of gastrointestinal
Domperidone can cause hyperprolactinaemia and ex- disorders.
trapyramidal side effects, but to a lesser degree because it
penetrates the blood-brain barrier much less easily than Hormonal control
metoclopramide. The activity of the gastrointestinal tract is influenced both
by endocrine (e.g. gastrin) and paracrine (e.g. histamine,
Serotonin-receptor antagonists secretin, cholecystokinin, vasoactive intestinal peptide)
Ondansetron is an example of 5-HT3 receptor antagonist. secretions.
Mechanism of action—Antagonism of 5-HT3 receptors
in the CTZ believed to be responsible for the antiemetic ef- Drugs that affect intestinal motility
fects of this class of drugs. Four classes of drug are used clinically for their effects on
Route of administration—Oral, rectal, intramuscular, gastrointestinal motility (Fig. 6.4).
intravenous. • Motility stimulants
Indications—Nausea and vomiting, especially postop- • Antispasmodics
eratively and when associated with the administration of • Laxatives (purgatives)
cytotoxic drugs. • Antidiarrhoeals.
Adverse effects—Constipation, headache.
Motility stimulants
Other antiemetics Agents that increase the motility of the gastrointestinal
The synthetic cannabinoid nabilone has antiemetic proper- tract without a laxative effect are used for motility disorders
ties where there is direct stimulation of the CTZ. Hyoscine is such as GORD and gastric stasis (slow stomach emptying).
a muscarinic-receptor antagonist, and like the H1-receptor Domperidone and metoclopramide in addition to their an-
antagonists is most effective in the treatment of motion tiemetic effects, both act to increase gastric and intestinal
sickness. Betahistine dihydrochloride is used in Ménière motility, although their mechanism of action for the latter
disease, although its prime effects are assumed to be on the remains unclear.
vestibulocochlear nerve. High dose glucocorticoids (par-
ticularly dexamethasone; see Chapter 7) can also control Antispasmodics
emesis, especially when induced by cytotoxic drugs. The smooth muscle relaxant properties of antispasmodic
drugs may be useful as adjunctive treatment for nonul-
cer dyspepsia, irritable bowel syndrome and diverticular
disease.
THE INTESTINES There are two classes of antispasmodic drug.
• Muscarinic receptor antagonists (antimuscarinics)
Basic concepts • Drugs acting directly on smooth muscle
Muscarinic receptor antagonists—Examples include
Intestinal motility ­atropine, propantheline and dicyclomine.
Normal motility, or peristalsis, of the intestinal tract, acts
Mechanism of action—Muscarinic receptor antagonists
to mix bowel contents thoroughly and to propel them in a
act by inhibiting parasympathetic activity causing relax-
caudal direction. Regulation of normal intestinal motility is
ation of the gastrointestinal smooth muscle.
under neuronal and hormonal control.
Route of administration—Oral.
Indications—Nonulcer dyspepsia, irritable bowel syn-
Neuronal control drome, diverticular disease.
Two principal intramural plexuses form the enteric nervous Contraindications—Muscarinic receptor antagonists
system. tend to relax the lower oesophageal sphincter and should
• The myenteric plexus (Auerbach's plexus), which is be avoided in GORD. Other contraindications include
located between the outer longitudinal and middle ­angle-closure glaucoma, myasthenia gravis, paralytic ileus
circular muscle layers. and prostatic enlargement.
• The submucous plexus (Meissner's plexus), which is on Adverse effects—Anticholinergic effects; dry mouth,
the luminal side of the circular muscle layer. blurred vision, dry skin, tachycardia, urinary retention.

84
 The intestines 6

Antidiarrhoeal treatments
Motility stimulants
Rehydration therapy e.g. metoclopramide
domperidone
Antimicrobial agents
H2O ?
− + salts
Opiate-like antidiarrhoeal
drugs, Bacteria ACh
e.g. loperamide,
morphine, codeine −
ACh +
Stretch receptors
Bulk +
Stool modifiers, adsorbants
e.g. kaolin, chalk +
+
Mucosa
Submucosa etc
Circular muscle
Longitudinal muscle
H2O H2O
Submucous plexus
Myenteric plexus

Laxatives
ACh +
Bulk laxatives,
− e.g. bran, methylcellulose

Osmotic laxatives,
Antispasmodics H2O
e.g. lactulose, MgSO4, MgOH
sodium acid phosphate
Antimuscarinics, −
e.g. atropine Stimulant laxatives,
propantheline, dicyclomine e.g. senna, danthron,
bisacodyl
Acting directly
on smooth muscle, Faecal softeners,
e.g. mebeverine, e.g. liquid paraffin, docusate
alverine, peppermint oil sodium

Fig. 6.4 Intestinal motility: control and site of drug action. ACh, Acetylcholine; MgOH, magnesium hydroxide; MgSO4,
magnesium sulphate.

Drugs acting directly on smooth muscle—Mechanism Laxatives

of action Laxatives are drugs used to hasten transit time in the gut
Mebeverine, alverine and peppermint oil are believed to be and encourage defecation. Laxatives are used to relieve con-
direct relaxants of smooth muscle. stipation (an infrequent or difficult passage of stool) and to
Route of administration—Oral. clear the bowel before medical and surgical procedures.
Indications—Irritable bowel syndrome and diverticular It should be remembered that individuals’ bowel habits
disease. vary considerably. The frequency and volume of the stool
Contraindications—Paralytic ileus. are best regulated by diet, but drugs may be necessary. The
Adverse effects—Nausea, headache, heartburn are occa- passage of food through the intestine can be hastened by:
sional problems. • bulk-forming laxatives
• osmotic laxatives
• stimulant laxatives
HINTS AND TIPS • faecal softeners.

Diarrhoea can be life threatening, especially in Bulk-forming laxatives

children. Management in most cases relies on Bran, methylcellulose, sterculia and ispaghula husk are ex-
fluid replacement with oral rehydration therapy, amples of bulk-forming laxatives.
before treating the underlying cause. Exclude other Mechanism of action—Bulk-forming laxatives increase
the volume of the nonabsorbable solid residue in the gut,
causes before treating with an antidiarrhoeal.
distending the colon and stimulating peristaltic activity.
Route of administration—Oral.

85
 Gastrointestinal system

Indications—Constipation, particularly when small hard Route of administration—Oral. docusate sodium can be
stools are present. administered rectally.
Contraindications—Dysphagia, intestinal obstruction, Indications—Constipation, faecal impaction, haemor-
colonic atony, faecal impaction. rhoids, anal fissures.
Adverse effects—Flatulence, abdominal distension and Contraindications—Should not be given to children
gastrointestinal obstruction. younger than 3 years.
Therapeutic notes—Adequate fluid intake should be Adverse effects—The prolonged use of liquid paraffin
encouraged, and clinical effects may take several days to may impair the absorption of fat-soluble vitamins A and D
develop. and cause “paraffinomas”. However, it is now seldom used
clinically.
Osmotic laxatives Therapeutic notes—Prolonged use of faecal softeners is
Examples of osmotic laxatives include lactulose, macrogols not recommended.
and saline purgatives. In pregnancy, if dietary and lifestyle changes fail to con-
Mechanism of action—Osmotic laxatives are poorly ab- trol constipation, a bulk-forming laxative (ispaghula husk)
sorbed compounds that increase the water content of the should be tried first. An osmotic laxative (lactulose) or stim-
bowel by osmosis. Lactulose is a semisynthetic disaccha- ulant laxative (senna) may also be suitable. In children who
ride that is not absorbed from the gastrointestinal tract. are constipated, osmotic laxatives are first line. Lactulose is
Similarly, magnesium and sodium salts are poorly absorbed often used to soften stools and macrogols is used to clear
and are osmotically active. By producing an osmotic load, faecal impaction.
these agents trap increased volumes of fluid in the lumen
of the bowel, accelerating the transfer of the gut contents Antidiarrhoeal drugs
through the small intestine. Diarrhoea is the passage of frequent, liquid stools. There
Route of administration—Oral. is an increase in the motility of the gastrointestinal tract,
Indications—Constipation, hepatic encephalopathy. accompanied by an increased secretion, coupled with a de-
Contraindications—Intestinal obstruction. creased absorption of fluid, leading to electrolyte and water
Adverse effects—Flatulence, cramps, abdominal discom- loss. Causes of diarrhoea include infections, toxins, certain
fort, electrolyte disturbance. drugs, chronic disease and anxiety.
There are four approaches to the treatment of severe
Stimulant laxatives
acute diarrhoea.
Senna, danthron, Bisacodyl and sodium picosulphate are
examples of stimulant laxatives. • Maintenance of fluid and electrolyte balance through
Mechanism of action—Stimulant laxatives increase oral rehydration therapy (ORT)
gastrointestinal peristalsis and water and electrolyte se- • Use of appropriate antimicrobial drugs
cretion by the mucosa, possibly by stimulating enteric • Use of opiate-like antimotility drugs
nerves. • Use of stool modifiers/adsorbents.
Route of administration—Oral. Maintenance of fluid and electrolyte balance
Bisacodyl is often given by suppository. It stimulates the
through oral rehydration therapy
rectal mucosa inducing defecation in 15 to 30 mins.
Oral rehydration therapy (ORT) should be the first priority
Indications—Constipation and bowel evacuation before
in the treatment of acute diarrhoea of all causes and can be
medical/surgical procedures.
life saving.
Contraindications—Intestinal obstruction.
ORT solutions are isotonic or slightly hypotonic; they
Adverse effects—In the short term, side effects of stim-
vary in their composition, but a standard formula would
ulant laxatives include intestinal cramp. Prolonged use can
contain sodium chloride (NaCl), potassium chloride (KCl),
lead to damage to the nerve plexuses resulting in the deteri-
sodium citrate and glucose in appropriate concentrations.
oration of intestinal function and atonic colon. Danthron is
Intravenous rehydration therapy is needed if dehydration
potentially carcinogenic, hence its limited use.
is severe. In the ileum, there is cotransport of Na and glucose
Therapeutic notes—Stimulant laxatives should be given
across the epithelial cell. The presence of glucose (in ORT)
for short periods only, and danthron is indicated for use
therefore enhances Na absorption and thus water uptake.
only in the terminally ill.

Faecal softeners Use of antimicrobial drugs

Liquid paraffin and docusate sodium are examples of faecal Antibiotic treatment of diarrhoea is useful only when
softeners. a bacterial pathogen has been identified or is highly sus-
Mechanism of action—Faecal softeners promote defaeca- pected. Acute infectious diarrhoea is usually self-limiting.
tion by softening (e.g. docusate sodium) and/or lubricating Antibiotic therapy itself carries certain risks.
(e.g. liquid paraffin) faeces to aid their passage through the • Spreading antibiotic resistance among
gastrointestinal tract. enteropathogenic bacteria.

86
 The intestines 6

• Destroying normal commensal gut flora, allowing Inflammatory bowel disease

overgrowth of the bacterium Clostridium difficile,
which can result in pseudomembranous colitis, a The main two inflammatory bowel diseases are Crohn
potentially fatal condition. disease and ulcerative colitis. Crohn disease can affect the
entire gut and inflammation occurs throughout the full
Antibiotic treatment is indicated in the following.
thickness of the bowel wall, whereas ulcerative colitis affects
• Severe cholera or Salmonella typhimurium infection: only the large bowel and inflammation is limited to bowel
tetracycline mucosa. These autoimmune conditions cause relapsing and
• Shigella species infections: ampicillin remitting symptoms.
• Campylobacter jejuni: erythromycin or ciprofloxacin Treatment of these conditions is not only pharmacologi-
Antibiotics are discussed in detail in Chapter 12. cal but also depends on psychological support, correction of
nutritional deficiencies and often surgical resection.
Use of opiate-like antimotility drugs Drug treatment is aimed at controlling inflammation
Examples of opiate-like antimotility drugs include lopera- and bringing about remission, and the mainstay of drug
mide and codeine. treatment for these diseases are:
Mechanism of action—Opiate-like antimotility drugs act
on μ-opiate receptors in the myenteric plexus, which in- • glucocorticoids
creases the tone and rhythmic contraction of the intestine • aminosalicylates
but lessens the propulsive activity. Loperamide and codeine • immunosuppressants and cytotoxics
also have an antisecretory action. • biologics
Route of administration—Oral.
Indications—Opiate-like antimotility drugs diminish Glucocorticoids
propulsive activity of the intestine and thus have a consti- Examples of glucocorticoids include prednisolone,
pating effect. They have a limited role to fluid and electro- budesonide and hydrocortisone.
lyte replacement in acute diarrhoea. They are also used as Mechanism of action—Glucocorticoids have an antiin-
adjunctive therapy in some chronic diarrhoeal conditions. flammatory effect (Chapter 7).
Contraindications—Opiate-like antimotility drugs Route of administration—In localized disease, gluco-
should not be given to people with diarrhoeal conditions corticoids may be administered rectally as enemas, sup-
such as acute ulcerative colitis or antibiotic-associated coli- positories or foams. In extensive or severe disease, oral or
tis. They are not recommended for children. intravenous therapy may be required.
Adverse effects—Nausea, vomiting, abdominal cramps, Indications—Glucocorticoids are given for acute relapses
constipation, drowsiness. of inflammatory bowel disease.
Therapeutic notes—Loperamide is the most appropriate Contraindications—Bowel obstruction or perforation, or
opioid for local effects on the gut and is commonly used in treatment for prolonged periods.
those with travellers’ diarrhoea (often caused by Escherichia
coli). It has a relatively selective action on the gastrointesti-
nal tract, reducing the frequency of abdominal cramps, de- CLINICAL NOTE
creasing the passage of faeces and shortening the duration
of the illness. An 18-year-old girl presents to her General
Practitioner (GP) with a 6-week history of bloody
Use of stool modifiers/adsorbents
diarrhoea associated with lower abdominal cramps
Examples of stool modifiers/adsorbents include kaolin,
chalk, charcoal and methylcellulose. and some weight loss. On direct questioning,
Mechanism of action—It has been suggested that stool she reports pain in her knees and that her older
modifiers/adsorbents act by absorbing toxins or by coating brother has Crohn disease. She smokes 5
and protecting the intestinal mucosa, although there is no cigarettes a day but only drinks alcohol socially.
evidence to support this. On examination, she is pale and has a tender
Route of administration—Oral. abdomen. She has several investigations including
Indications—There is little evidence to recommend ad- blood tests, stool culture and microscopy and
sorbents at all. faecal calprotectin. An endoscopy confirms Crohn
Contraindications—Adsorbents are not recommended disease. A gastroenterologist starts her on oral
for acute diarrhoea.
prednisolone to induce remission. Unfortunately,
Adverse effects—Stool modifiers/adsorbents may reduce
she has two more inflammatory exacerbations and
the absorption of other drugs.
Therapeutic notes—Adsorbents are popular “remedies” so azathioprine is added in. She is also advised to
for the treatment of diarrhoea, although there is little evi- stop smoking.
dence of their benefits.

87
 Gastrointestinal system

Adverse effects—Cushingoid side effects may occur with Obesity

long-term glucocorticoid use (Chapter 7).
Therapeutic notes—Budesonide is locally acting and Obesity is becoming increasingly common in the West and
poorly absorbed, so has fewer systemic side effects. is associated with many diseases such as cardiovascular dis-
Glucocorticosteroids are useful for acute attacks of in- ease, diabetes mellitus, gallstones and osteoarthritis.
flammatory bowel disease. They are also used for inducing Dietary restriction and an exercise programme should
remission in relapses of ulcerative colitis. be explored before surgical or pharmacological interven-
tion. The most widely used antiobesity drugs act directly
upon the gastrointestinal tract. There are also centrally act-
Aminosalicylates ing appetite suppressants.
Sulfasalazine, mesalazine and olsalazine are examples of
aminosalicylates. Drugs acting on the gastrointestinal tract
Mechanism of action—Sulfasalazine is broken down in Orlistat and methylcellulose are examples of such antiobe-
the gut to the active component 5-aminosalicylate (5-ASA) sity drugs.
and sulfapyridine, which transports the drug to the co- Mechanism of action—Orlistat is a pancreatic lipase in-
lon. Mesalazine is 5-ASA and olsalazine is two molecules hibitor and reduces the breakdown and subsequent absorp-
of 5-ASA. The mechanism of action of the active molecule tion of fat from the gut. Methylcellulose is believed to act as
5-ASA is unknown, although is postulated to act by scav- a bulk-forming agent and reduces food intake by promoting
enging free radicals or interfering with cytokine networks. early satiety (fullness).
Route of administration—Oral, rectal. Route of administration—Oral.
Indications—Maintenance and long-term therapy of in- Adverse effects—Orlistat often results in oily, fre-
flammatory bowel conditions. quent stools, flatulence, abdominal and rectal pain.
Mesalazine is now the treatment of choice for induction Methylcellulose may produce flatulence and abdominal
and maintenance of remission of mild to moderate ulcer- distension.
ative colitis and has been shown to reduce the risk of col-
orectal cancer in these patients. Other antiobesity drugs
Contraindications—Aminosalicylates should not be The centrally acting appetite suppressant sibutramine is
given to people with salicylate hypersensitivity and renal licensed for adjunctive management of obesity but for no
impairment. more than 1 year's usage; weight loss may return after ces-
Adverse effects—Sulfapyridine is responsible for much sation. Numerous other drugs are being evaluated for their
of this drug’s side effects. Nausea, vomiting, headache antiobesity properties, including the endogenous mam-
and rashes. Blood disorders and oligospermia have been malian peptide leptin, which appears to induce satiety and
reported. counteract the properties of another transmitter, neuropep-
tide Y, which is believed to promote feeding.
Immunosuppressants and
cytotoxics Anal disorders
In severe inflammatory bowel disease, immunosuppressant Haemorrhoids, anal fissures and pruritus are commonly
medications such as methotrexate (Chapters 11 and 13), encountered problems. Bland ointments are the best treat-
azathioprine (Chapter 11), mercaptopurine and cyclospo- ment option, with careful attention to cleanliness. When
rine are used as adjuncts to the aforementioned therapies. necessary, topical preparations containing a local anaes-
Azathioprine interferes with purine synthesis and depresses thetic (Chapter 10) or corticosteroid (Chapter 7) may pro-
antibody-mediated immune reactions. Cyclosporine can vide symptomatic relief. Perianal thrush can be treated with
be used in severe refractory colitis and reduces the risk of nystatin (Chapter 12). Haemorrhoids can be treated by in-
surgery, although it carries a 3% mortality risk given its jection with a sclerosant, commonly oily phenol.
toxicity.

Biologics: Monoclonal antibodies

THE PANCREAS AND GALL
Infliximab and adalimumab block the action of the cytokine BLADDER
tumour necrosis factor alpha (TNF-α), which mediates in-
flammation in Crohn and ulcerative colitis. It is used in the
treatment of severe disease or when conventional therapy Pancreatic supplements
cannot be used. Pancreatic exocrine secretions contain important enzymes that
break down proteins (trypsin, chymotrypsin), starch (amylase)
and fats (lipase). These are essential for efficient digestion.

88
 The pancreas and gall bladder 6

Pancreatin is an extract of pancreas containing protease, common and can result in blockage of the draining duct,
lipase and amylase, that is given by mouth to compensate with subsequent infection and inflammation (cholecysti-
for reduced or absent exocrine secretions in cystic fibrosis, tis). Surgical removal of the gall bladder (cholecystectomy)
and following pancreatectomy, total gastrectomy or chronic has largely replaced the use of drugs in the management
pancreatitis. Pancreatin is inactivated by gastric acid and so of symptomatic gallstones, although this is suitable for pa-
precautions must be taken to optimize delivery of the pan- tients not treatable by other means.
creatin to the duodenum. The dissolution of small cholesterol stones is carried out
Pancreatin preparations are best taken with food. by prolonged oral administration of the bile acid ursode-
Histamine H2 antagonists (e.g. cimetidine) may be taken oxycholic acid.
an hour before ingestion of the pancreatin to reduce gastric
acid secretion, although acid-resistant (enterically coated)
formulations are now available. Ursodeoxycholic acid
The bile salt ursodeoxycholic acid is administered orally
and handled by the body in the same fashion as endogenous
HINTS AND TIPS bile salt. It works by decreasing secretion of cholesterol into
the bile, and decreasing cholesterol absorption from the
Even though pancreatin contains peptides, which
intestine.
would normally be degraded in the stomach, these The net effect is a reduced cholesterol concentration in
tablets are coated in an acid-resistant layer, and the bile and a tendency for the dissolution of existing stones.
the enzymes and proenzymes within them have It is therefore most commonly used for the dissolution of
endogenous resistance to both acid and proteases gallstones but can also be used to slow the progression of
and become active in the small intestine. primary biliary cirrhosis.
The main side effect of ursodeoxycholic acid is diarrhoea.

Cholestyramine
Gall bladder This orally administered anion-exchange resin binds bile
Bile is secreted by the liver and is stored in the gall bladder. acids in the gut and prevents their reabsorption and entero-
Bile contains cholesterol, phospholipids and bile salts. Bile hepatic recirculation. It is used in the treatment of pruritus
salts are important for keeping cholesterol in solution. The associated with partial biliary obstruction and primary bili-
formation of “stones” in the bile (cholelithiasis) is relatively ary cirrhosis, and in hypercholesterolaemia.

Chapter Summary

• Peptic ulcer disease (PUD) is commonly caused by H. pylori. Eradication involves a

proton-pump inhibitor (PPI) and antibiotics
• PPIs cause irreversible inhibition of H+/K+-ATPase: used in the treatment of peptic
ulcer disease and reflux disease
• H2-receptor antagonists inhibit gastric acid secretion: used in treatment of PUD and
reflux disease
• H1-receptor antagonists are used in managing motion sickness, 5-HT3 antagonists are
useful postoperatively
• Misoprostol is a prostaglandin E analogue used as ulcer prophylaxis with NSAID use
• Glucocorticosteroids and aminosalicylates are the main drugs used in managing
inflammatory bowel disease
• Orlistat is a pancreatic lipase inhibitor used in the management of obesity

89
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 Endocrine and reproductive
systems 7
THE THYROID GLAND TRH

Basic concepts Feedback

inhibition
Production of thyroid hormones
The thyroid gland synthesizes and secretes three hormones:
triiodothyronine (T3), thyroxine (T4) and calcitonin. The
effects of the thyroid hormones are summarized in Box 7.1. TSH
The follicular cells of the thyroid gland synthesize and gly-
cosylate thyroglobulin before secreting it. The iodination of
Thyroid
thyroglobulin is catalysed by thyroid peroxidase and pro-
duces T4 and T3. The iodine required for the synthesis of
T3 and T4 comes mainly from the diet in the form of iodide.
Through the action of a thyrotrophin-dependent pump, io-
T3+T4
dide is concentrated in the follicular cells, where it is con- Peripheral
tissue
verted into iodine by thyroid peroxidase. T4

Control of thyroid hormone secretion

The hypothalamus contains thyroid-hormone receptors
that are able to detect and respond to decreased levels of
T3 and T4 by causing the release of thyrotropin-releasing
hormone (TRH). TRH reaches the anterior pituitary via the Deiodination T3
Circulation
portal circulation and stimulates TRH receptors on thyro- (heart/
trophic cells, which in turn secrete thyroid-stimulating hor- blood
Target tissue vessels)
mone (TSH).
TSH reaches the thyroid gland through the systemic Fig. 7.1 Hypothalamic–pituitary–thyroid axis: control of
circulation where it stimulates thyroid hormone secretion thyroid hormone synthesis. T3, Triiodothyronine;
T4, thyroxine; TSH, thyroid-stimulating hormone;
(Fig. 7.1). Both T3 and T4 bind to proteins in the plasma
TRH, thyrotropin-releasing hormone. (Modified from Page,
(mostly thyroxine-binding globulin), and less than 1% of
C., Curtis, M. Walker, M, Hoffman, B. (eds) Integrated
Pharmacology, 3rd edn. Mosby, 2006.)

BOX 7.1 PHYSIOLOGICAL EFFECTS OF

THYROID HORMONES
total thyroid hormones are free. It is the free thyroid hor-
• Foetal development (physical and cognitive) mones, which exert the physiological effects. T3 is about five
• Metabolic rate times more biologically active than T4, and T4 is converted
• Body temperature to T3 in some peripheral tissues.
T3 and T4 both exert negative feedback on the hypothal-
• Cardiac rate and contractility
amus and pituitary.
• Peripheral vasodilatation
• Red cell mass and circulatory volume
• Respiratory drive
• Peripheral nerves (reflexes) HINTS AND TIPS
• Hepatic metabolic enzymes
• Bone turnover Most modern laboratory thyroid function tests
• Skin and soft tissue effects measure just TSH, although levels of free and total
T3 and T4 can be measured, as well as thyroxine-
Modified from Page et al. 2006. binding globulin.

91
 Endocrine and reproductive systems

Thyroid dysfunction Adverse effects—Arrhythmias, tachycardia, anginal

pain, cramps, headache, restlessness, sweating, weight
Hypothyroidism loss.
Hypothyroidism, thyroid insufficiency, is relatively com- Therapeutic regimen—The starting dose of levothyrox-
mon in adults and associated with tiredness and lethargy, ine sodium should be no greater than 100 μg daily (reduce
weight gain, intolerance to cold, dry skin, bradycardia and in the elderly or those with cardiovascular disease) and in-
mental impairment. Children with hypothyroidism mani- crease by 25 to 50 μg every 4 weeks until a dose of 100 to
fest delayed bone growth, whereas a deficiency in utero also 200 μg is reached.
results in mental retardation.
Hashimoto thyroiditis is an autoimmune disease result- Liothyronine sodium (L-triiodothyronine
ing in fibrosis of the thyroid gland. It is the most common sodium)
cause of hypothyroidism and, similar to most autoimmune Because liothyronine is bound only slightly by thyroid bind-
diseases is more prevalent in women. Myxoedema is also ing globulin, it has a more rapid onset of effect and a shorter
immunological in origin and represents the most severe duration of action than levothyroxine.
form of hypothyroidism, sometimes causing coma. Mechanism of action—Liothyronine is rapidly metabo-
Thyroid-hormone resistance and reduced TSH secretion lized in vivo to T3. It has a half-life of 2 to 5 days and a peak
will also produce the symptoms of hypothyroidism. onset of 1 to 2 days.
The causes of hypothyroidism are summarized in Route of administration—Oral, intravenous.
Table 7.1. Indications—Liothyronine is given for severe hypothy-
roidism where a rapid effect is needed.
Contraindications—Liothyronine should not be given to
Management of hypothyroidism people with cardiovascular disorders.
The only effective treatment for hypothyroidism, unless
Adverse effects—Arrhythmias, tachycardia, anginal
it is caused by iodine deficiency (which is treated with io-
pain, cramps, headache, restlessness, sweating, weight
dide), is to administer the thyroid hormones themselves as
loss.
replacement therapy.
Therapeutic regimen—The dosage of liothyronine so-
Levothyroxine dium should be gradually increased as with levothyroxine
Thyroxine is given as levothyroxine sodium for maintenance sodium (20 μg liothyronine sodium is equivalent to 100
therapy. It has a half-life of 6 days and a peak onset of 9 days. μg levothyroxine sodium). Intravenous liothyronine is the
Mechanism of action—Levothyroxine is converted to T3 drug of choice in the emergency treatment of myxoedema
in vivo to replace endogenous hormone. (hypothyroid) coma.
Route of administration—Oral.
Indications—Hypothyroidism. Hyperthyroidism
Contraindications—Levothyroxine should not be given Hyperthyroidism, thyroid excess, results either from
to people with thyrotoxicosis and should be used with cau- the overproduction of endogenous hormone or expo-
tion in those who have cardiovascular disease. sure to excess exogenous hormone. Symptoms include
increased basal metabolic rate (BMR) with consequent
weight loss, increased appetite, increased body tempera-
Table 7.1 Causes of hypothyroidism ture, and sweating, as well as nervousness, tremor and
Primary Chronic lymphocytic thyroiditis tachycardia.
(Hashimoto disease) Graves disease (diffuse toxic goitre) is the most com-
Subacute thyroiditis mon cause of hyperthyroidism. It is an autoimmune
Painless thyroiditis (postpartum disease caused by the activation of TSH receptors by au-
thyroiditis) toantibodies. This results in an enlargement of the gland
Radioactive iodine ingestion and therefore excess hormone production. Patients with
Postthyroidectomy Graves disease may develop classical ophthalmic changes
Iodine deficiency or excess (e.g. exophthalmos).
Inborn errors of thyroid hormone Toxic nodular goitre is the second most common cause
synthesis of hyperthyroidism. It is caused by either a single adenoma
Secondary Pituitary disease (hyperfunctioning adenoma) or multiple adenomas (multi-
nodular goitre).
Target tissues Thyroid hormone resistance
The causes of hyperthyroidism are summarized in
Modified from Page et al. 2006.)
Box 7.2.

92
 The thyroid gland 7

In the body, carbimazole is rapidly converted to active

CLINICAL NOTE compound thiamazole.
Mrs Akasuki, 41 years old, presents to her General
Mechanism of action—The thioureylenes cause inhibi-
tion of thyroid peroxidase with a consequent reduction in
Practitioner (GP) with tremor and weight loss of
thyroid hormone synthesis and storage (Fig. 7.2). The ef-
6.5 kg (1 stone) over 4 weeks, despite increased
fects of PTU may take several weeks to manifest because the
appetite. She admits to feeling hot and sweaty both body has stores of T3 and T4. PTU also inhibits the periph-
day and night, which has affected her sleep. On eral deiodination of T4 to T3.
examination, a diffuse goitre is seen. Her pulse is Route of administration—Oral.
rapid and she has noticeable exophthalmos. Indications—Thioureylenes are used for the treatment
A pregnancy test is negative. A blood sample is of hyperthyroidism. Patients sensitive to carbimazole are
taken and reveals an elevated serum T3 and T4 given PTU.
with suppressed TSH levels. Mrs Akasuki is Contraindications—Thioureylenes should not be given
diagnosed as having hyperthyroidism. She is given to people with a large goitre. PTU should be given at a re-
propranolol for her symptoms and is started on
duced dose in patients with renal impairment.
Adverse effects—Nausea and headache; allergic reactions,
carbimazole to suppress her thyroid. She is advised
including rashes; hypothyroidism and, rarely, hepatotoxic-
to report symptoms of a sore throat and has a blood
ity and alopaecia. The most dangerous unwanted effects are
test to ensure that she has not become neutropenic, neutropenia and agranulocytosis secondary to bone mar-
a possible dangerous side effect of carbimazole row suppression. This is relatively rare and is reversible on
treatment. If her exophthalmos required further cessation of treatment.
treatment, glucocorticosteroids are sometimes used. Therapeutic regimen—Carbimazole is given at 20 to 60
mg daily until the patient is euthyroid (4–11 weeks later),
then the dose is progressively reduced to a maintenance
level of 5 to 15 mg daily. Treatment is usually given for
18 months. PTU is given at 300 to 600 mg daily until the
BOX 7.2 CAUSES OF HYPERTHYROIDISM patient is euthyroid, then the dose is progressively reduced
to a maintenance level of 50 to 150 mg daily.
• Excess exogenous thyroid hormone
• Diffuse toxic goitre (Graves disease) Anion inhibitors
• Hyperfunctioning adenoma (toxic nodule) Iodine, iodide and potassium perchlorate are examples of
• Toxic multinodular goitre anion inhibitors.
• Painless thyroiditis Potassium perchlorate inhibits the uptake of iodine by
the thyroid (see Fig. 7.2) but is no longer used owing to the
• Subacute thyroiditis
risk of aplastic anaemia.
• Thyroid-stimulating hormone (TSH)-secreting
Iodide is the most rapidly acting treatment against thy-
adenoma rotoxicosis and is given in thyrotoxic crisis (thyroid storm).
• Human chorionic gonadotropin (hCG)-secreting Iodide is also used for the preparation of hyperthyroid pa-
tumours tients for surgical resection of the gland.
Mechanism of action—Iodine and iodide cause inhibi-
(Modified from Page et al. 2006.)
tion of conversion of T4 to T3 and inhibit hormone secre-
tion. They also reduce the size and vascularity of the gland,
which is evident after 10 to 14 days of treatment.
Route of administration—Oral.
Management of hyperthyroidism Indications—Preoperative hyrotoxicosis and thyroid
Hyperthyroidism is most commonly treated with drugs. cancer.
Surgery is used only when there are mechanical problems Contraindications—Iodine and iodide should not be
resulting from compression of the trachea by the thyroid. given to pregnant and breastfeeding women because they
cause a goitre in infants.
Thioureylenes Adverse effects—Iodine and iodide can cause hypersen-
The thioureylenes are the first-line drugs for the treatment sitivity reactions including rashes, headache, lacrimation,
of hyperthyroidism. Carbimazole, thiamazole, and prop- conjunctivitis, laryngitis and bronchitis. With long-term
ylthiouracil (PTU) are examples of thioureylenes. treatment, depression, insomnia and impotence can occur.

93
 Endocrine and reproductive systems

Lumen T4 T3
MIT DIT
Storage as colloid
Thyroglobulin in thyroid follicles

Thyroid Endocytosis
epithelial cell Thyroid
peroxidase

− MIT DIT

Thionamides: Thyroglobulin Lysosome

thiamazole
carbimazole
PTU
Thyroglobulin
− synthesis Phagolysosome

Thyroid
peroxidase Proteolysis of
thyroglobulin

MIT

Iodide
−
DIT T4 T3
Anion inhibitors:
potassium perchlorate + − Plasma

Iodide
TSH Iodide

Fig. 7.2 Synthesis of thyroid hormones and the site of action of some antithyroid drugs. DIT, Diiodotyrosine; MIT,
monoiodotyrosine; PTU, propylthiouracil; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone. (Modified
from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) Integrated Pharmacology, 3rd edn. Mosby, 2006.)

Therapeutic regimen—Iodine and iodide are given Radioiodine

10 to 14 days before partial thyroidectomy, with either The use of radioactive iodine to treat hyperthyroidism is not
­carbimazole or PTU. They should not be given long-term classically considered pharmacology, although it is used in
because iodine becomes less effective. the management of thyroid disorders. The uptake of ­iodine
isotopes is also used diagnostically as a test of thyroid func-
β-Adrenoceptor antagonists tion. Radioiodine emits radiation that is absorbed by the
Propranolol and atenolol are examples of β-adrenoceptor
thyroid tissue enabling it to exert a powerful cytotoxic action
antagonists. They are used to attenuate the symptoms of in-
on the thyroid follicles resulting in significant tissue destruc-
creased thyroid hormone levels, and the effect of increased
tion. Hypothyroidism will eventually occur with radioiodine
numbers of adrenoceptors caused by thyroid hormone.
but is easily managed with hormone replacement therapy.
They are useful for decreasing the symptoms and signs as-
sociated with hyperthyroidism.
Mechanism of action—β-Adrenoceptor antagonists re- HINTS AND TIPS
duce tachycardia, the basal metabolic rate, nervousness and
tremor. Amiodarone is rich in iodine and can cause either
Route of administration—Oral. hyperthyroidism or hypothyroidism. Thyroid
Indications—Thyrotoxic crisis; preoperatively for thy- function tests should be checked before prescribing
roid surgery. amiodarone and every 6 months during treatment.
Contraindications—β-Adrenoceptor antagonists should Amiodarone should be withdrawn if thyrotoxicosis
not be given to people with asthma.
or hypothyroidism are refractory to treatment.
Adverse effects—The side effects of β-adrenoceptor an-
tagonists are given in Chapter 4.

94
 The endocrine pancreas and diabetes mellitus 7

In response to high blood glucose levels (as occurs after

THE ENDOCRINE PANCREAS AND a meal), as well as to glucosamine, amino acids, fatty acids,
DIABETES MELLITUS ketone bodies and sulphonylureas, the β-cells of the endo-
crine pancreas secrete insulin along with a C-peptide.
Control of plasma glucose Insulin release is mediated by adenosine triphosphate (ATP)-
dependent potassium channels located in the membrane of the
Blood glucose levels are maintained at a concentration of
β-cells. These close in response to elevated cytoplasmic ATP
about 5 mmol/L, and usually, do not exceed 8 mmol/L. A
and decreased cytoplasmic adenosine diphosphate (ADP) lev-
plasma glucose concentration of 2.2 mmol/L or less may re-
els, resulting in depolarisation of the membrane. This triggers
sult in hypoglycaemic coma and death caused by a lack of
calcium entry into the cell through voltage-dependent calcium
energy reaching the brain. A plasma glucose concentration
channels, and subsequent insulin release (Fig. 7.3).
of more than 10 mmol/L exceeds the renal threshold for glu-
Insulin release is inhibited by low blood glucose levels,
cose and means that glucose will be present in the urine.
growth hormone, glucagon, cortisol and sympathetic ner-
Osmotic diuresis then occurs.
vous system activation.
The islets of Langerhans, located in the pancreas, con-
The effects of insulin are summarized in Table 7.2.
tain glucose receptors and secrete the hormones glucagon
and insulin. These hormones are short-term regulators of
plasma glucose levels with opposite effects. In addition, CLINICAL NOTE
their release can be influenced by gastrointestinal hormones
and autonomic nerves. Mrs. Rait, a 52-year-old female, presents to her GP
Glucose receptors are also found in the ventromedial with polyuria, polydipsia and frequent infections
nucleus and lateral areas of the hypothalamus. These are over the past month. She is a current smoker and
able to regulate appetite and feeding, and also indirectly has high blood pressure. She has a family history
stimulate the release of a variety of hormones, including of stroke. She is found to have glucose in her urine
adrenaline, growth hormone and cortisol, all of which affect and her random venous glucose is 12 mmol/L. Her
glucose metabolism. haemoglobin A1c (HbA1c) is 7%. Her renal function
The hormones involved in blood glucose regulation tar- is normal, and she is commenced on metformin
get the liver, skeletal muscle and adipose tissue. to control her glucose levels. She is advised to
stop smoking, exercise more and to cut out sugary
Insulin and carbohydrate high foods. She is also started
Insulin is a 51–amino acid peptide made up of an α-chain on ramipril for her blood pressure. Her HbA1c is
and a β-chain linked by disulphide bonds. It has a half-life checked in 3 months and a short-acting sulfonylurea
of 3 to 5 minutes and is metabolized to a large extent by the may be added if her blood sugars are still high.
liver (40%–50%), but also by the kidneys and muscles.

Glucose
Sulphonylureas:
Glucose • tolbutamide
• chlorpropamide
− − . glibenclamide
ATP

+ K+

Ca2+ ATP-dependent
Depolarization K+ channel

......
Voltage-dependent
Ca2+ channel Insulin-
containing
vesicle
Insulin
+
β-cell

.......
Insulin

Receptors

Response
Fig. 7.3 Mechanism of insulin secretion from pancreatic β-cells. ATP, Adenosine triphosphate.

95
 Endocrine and reproductive systems

Table 7.2 Metabolic effects of insulin on fuel metabolic acidosis. Body fluids become hypertonic, result-
homeostasis ing in cellular dehydration, and patients are at risk of a hy-
perosmolar coma.
Carbohydrates Increase glucose transport
Patients diagnosed with type 1 diabetes typically present
Increase glycogen synthesis
Increase glycolysis
at a young age and are not normally obese. There is often a
Inhibit gluconeogenesis genetic predisposition.
Fats Increase lipoprotein lipase activity
Increase fat storage in adipocytes Type 2 diabetes
Inhibit lipolysis (hormone-sensitive In type 2 diabetes, patients have peripheral insulin resis-
lipase) tance and impaired insulin secretion. On average, 50% of
Increase hepatic lipoprotein synthesis the β-cells remain active. Patients with type 2 diabetes are
Inhibit fatty acid oxidation often obese and physically inactive, presenting in adult life.
Proteins Increase protein synthesis The incidence rising progressively with age as β-cell func-
Increase amino acid transport tion declines. Ketosis is less of a feature in type 2 diabe-
Modified from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) tes because ketone production is suppressed by the small
Integrated Pharmacology, 3rd edn. Mosby, 2006. amounts of insulin produced by the pancreas. A hyperos-
molar hyperglycaemic state is the type 2 diabetes equivalent
to ketoacidosis and occurs when patients with type 2 diabe-
tes have a concomitant illness leading to reduce fluid intake.
Diabetes mellitus It is characterized by hyperglycaemia, hyperosmolarity and
Diabetes mellitus is characterized by an inability to regulate dehydration without significant ketoacidosis. It has a high
plasma glucose within the normal range. There is an abso- mortality rate, but if diagnosed early, responds rapidly to
lute or relative insulin deficiency leading to hyperglycae- fluids and insulin.
mia, glycosuria (glucose in the urine), polyuria (production
of large volumes of dilute urine) associated with cellular Secondary diabetes mellitus
potassium depletion and polydipsia (intense thirst), in ad- Not to be confused with type 2 diabetes, secondary diabetes
dition to weight loss. mellitus accounts for less than 2% of all new cases of diabetes
There are two main types of diabetes mellitus. and is most commonly caused by pancreatic disease (pancre-
• Type 1 diabetes (absolute insulin deficiency) atitis, carcinoma, cystic fibrosis), endocrine disease (Cushing
• Type 2 diabetes (insulin resistance) syndrome, acromegaly) or is drug-induced (following treat-
ment with thiazide diuretics or corticosteroid therapy).
In addition, pregnant women who have never had diabe-
tes before, but who have high blood glucose levels during
pregnancy are said to have gestational diabetes, affecting 4% Management of diabetes mellitus
of pregnancies. There is also maturity-onset diabetes of the Insulin
young and diabetes caused by pancreatic disease or it can be The aim of exogenous insulin preparations is to mimic basal
medication-induced. levels of endogenous insulin and meal-induced increases in
Patients with type 1 or type 2 diabetes have an increased insulin. Insulin is essential for the treatment of type 1 diabe-
risk of cardiovascular and cerebrovascular events, periph- tes and often used in patients with type 2 diabetes alongside
eral and autonomic neuropathy, nephropathy, and retinop- other oral antidiabetic medications.
athy in the long term. Nowadays the most-used insulin preparation is the hu-
man (recombinant) insulin (however, insulin preparations
Type 1 diabetes of bovine origin are also available). Insulin is available as
In type 1 diabetes, pancreatic β-cells are destroyed by an short-acting, intermediate-acting, and long-acting prepara-
autoimmune T-cell attack. This leads to a complete inabil- tions (Table 7.3).
ity to secrete insulin. In addition to polyuria, polydipsia Short-acting insulins are soluble. These preparations
and weight loss, insulin deficiency causes muscle wast- most resemble endogenous insulin and can be given in-
ing through increased breakdown and reduced synthesis travenously in the hospital. The rapid-acting insulins,
of proteins. In the absence of insulin, there is accelerated aspart and lispro, have a faster onset and shorter dura-
breakdown of fat to acetyl-CoA, which is converted to ac- tion of action than the traditional short-acting insulin.
etoacetate and β-hydroxybutyrate (which causes acidosis) Intermediate-acting and long-acting insulins are not as
and acetone (a ketone) resulting in patients with type 1 soluble as the short-acting preparations. Their solubility
diabetes being at risk of the diabetic ketoacidosis, an acute is decreased by precipitating the insulin with zinc or pro-
emergency. Some untreated patients have a plasma glucose tamine (a basic protein), which prolongs their release into
concentration of up to 100 mmol/L and the production the blood stream following subcutaneous injection of a
of ketone bodies from fatty acids leads to ketonuria and depot preparation.

96
 The endocrine pancreas and diabetes mellitus 7

Table 7.3 Insulin preparations Therapeutic regimen—Different regimens are used ac-
cording to the patient's needs and age.
Insulin Peak activity Duration
preparation Action (hours) (hours) • Short-acting insulin (e.g. lispro) three times daily
(before breakfast, lunch and dinner) and intermediate-
Rapid-acting Very rapid 0–2 3–4
acting insulin (e.g. isophane insulin) at bedtime.
insulin
• Short-acting insulin and intermediate-acting insulin
Short-acting Rapid 1–3 3–7 mixture twice daily before meals.
insulin
• Short-acting insulin and intermediate-acting insulin
Isophane Intermediate 2–12 12–22 mixture before breakfast, short-acting insulin before
insulin dinner, and intermediate-acting insulin before bedtime.
Insulin zinc Prolonged 4–24 24–28 • Short-acting insulin and intermediate-acting insulin
suspension mixture before breakfast are adequate for some Type 2
diabetes patients needing insulin.
• Improved glucose control can be achieved with
Mechanism of action—Insulin preparations mimic en-
multiple daily injections of rapid-acting insulin
dogenous insulin.
analogues given with meals, and a basal insulin
Route of administration—Insulin must always be given
analogue (e.g. glargine) injected once daily.
parenterally (intravenously, intramuscularly or subcuta-
neously), because it is a peptide and thus metabolized in Therapeutic notes—Preparations are now available which
the gastrointestinal tract. Short-acting insulin is given in- contain mixtures of short-acting, intermediate-acting and
travenously in emergencies, but the administration of the long-acting insulins, allowing patients to inject themselves
insulin preparations in maintenance treatment is usually only once each time they require insulin.
subcutaneous.
Oral hypoglycaemics
Indications—Type 1 diabetes
Oral hypoglycaemics act to lower plasma glucose. The bigu-
• Type 2 diabetes. In the long-term about one-third anides and the sulphonylureas are the main oral hypogly-
of patients ultimately benefit from insulin. Patients caemics, but newer drugs are also now available and widely
usually require insulin if maximal therapy, with a prescribed as summarized in Table 7.4.
combination of oral antidiabetic medications, is not Biguanides—Metformin is the only biguanide used
sufficiently controlling blood sugar levels. clinically
• Gestational diabetes, if glucose is not controlled by diet Mechanism of action—Metformin increases the periph-
alone. eral utilisation of glucose, by increasing uptake, and decreas-
• Emergency treatment of hyperkalaemia (given with ing gluconeogenesis. It decreases hepatic glucose production
glucose to lower extracellular K+ via redistribution in by inhibiting the mitochondrial respiratory chain complex.
cells). Metformin also reduces carbohydrate absorption from the
Adverse effects—Local reactions, and in overdose, hypo- intestine and increases fatty acid oxidation. To work, met-
glycaemia. Rarely, there may be immune resistance. Rebound formin requires the presence of endogenous insulin; thus
hyperglycaemia can follow insulin-induced hypoglycaemia, patients must have some functioning β-cells.
because of the release of counter-regulatory hormones. Route of administration—Oral.

Table 7.4 Summary of commonly prescribed antidiabetic medications

Family of drug GLP-1 agonist Biguanide Sulfonylurea Thiazolidinediones DPP-4 inhibitors
Example Exenatide Metformin Glibenclamide Pioglitazone Sitagliptin
Administration Subcutaneous Oral Oral Oral Oral
injection
Mechanism of Increase glucose Stimulate insulin Increase insulin Stimulate
action uptake Reduced secretion and sensitivity insulin secretion
gluconeogenesis reduce plasma Potentiate
glucose endogenous
incretins
Effect on weight Weight loss Weight loss Weight gain Weight gain Weight neutral
Important adverse Lactic acidosis Hypoglycaemia Risk of oedema, Pancreatitis
effects fractures and bladder
cancer
GLP-1 Glucagon-like peptide-1, DPP-4, dipeptidylpeptidase-4.

97
 Endocrine and reproductive systems

Indications—Type 2 diabetes, where dieting has proved α-Glucosidase inhibitors—Acarbose is the only avail-
ineffective and is used off-licence in the treatment of gesta- able drug in this class.
tional diabetes. Mechanism of action—Acarbose inhibits intestinal α-­
Metformin is associated with improved outcome in pa- glucosidases, and delays the absorption of starch and su-
tients with diabetes and compensated heart failure. crose, reducing postprandial increases in blood glucose.
Management of polycystic ovary syndrome, associated Route of administration—Oral.
with insulin resistance. Indications—Diabetes mellitus inadequately con-
Contraindications—Metformin should not be given to trolled by diet alone or in combination with other oral
patients with severe hepatic or renal impairment (owing to hypoglycaemics.
the risk of lactic acidosis), or those in shock. Contraindications—Pregnancy, breastfeeding, bowel disease.
Adverse effects—Dose-related gastrointestinal distur- Adverse effects—Flatulence, diarrhoea.
bances (anorexia, nausea, vomiting, diarrhoea), lactic aci- Therapeutic notes—Similar to metformin, acarbose is
dosis and decreased vitamin B12 absorption. particularly useful in the obese diabetic patient.
Therapeutic notes—metformin is given in divided doses Thiazolidinediones—Rosiglitazone and pioglitazone
up to a max dose of 2g. It can be used alone or in combina- belong to the thiazolidinediones. Pioglitazone is the only
tion with other antidiabetic medications. Metformin should drug that remains in clinical use.
be taken with or after food. Metformin causes anorexia and Mechanism of action—These agents bind to a receptor
encourages weight loss; therefore, it is a good option in pa- found mainly on adipose tissue (as well as in muscle and
tients who are overweight with type 2 diabetes. the liver) and increase lipogenesis and uptake of fatty acids
Sulphonylureas—Gliclazide, tolbutamide, chlorpropa- and glucose. They are believed to reduce peripheral insulin
mide and glibenclamide are examples of sulphonylureas. resistance, leading to a reduction in plasma glucose because
Mechanism of action—Sulphonylureas block ATP- they act to enhance the effectiveness of endogenous insulin.
dependent potassium channels in the membrane of the Although pioglitazone takes 2 to 3 months to have maximum
pancreatic β-cells, causing depolarisation, calcium influx effect, it can reduce the need for exogenous insulin by 30%.
and insulin release. The overall effect of sulphonylureas is to Route of administration—Oral.
stimulate insulin secretion and thus reduce plasma glucose. Indications—Type 2 diabetes inadequately controlled by
Route of administration—Oral. diet alone or in combination with either a sulphonylurea or
Indications—Sulphonylureas are used in patients with type metformin.
2 diabetes mellitus, in patients with residual β-cell activity. Contraindications—Hepatic impairment, history of
Contraindications—Breastfeeding or pregnant women, heart failure, pregnancy and breastfeeding.
or people with ketoacidosis. Long-acting sulphonylureas Adverse effects—Gastrointestinal disturbance, weight
(chlorpropamide, glibenclamide) should be avoided in el- gain and fluid retention. Potentially liver failure. Increased
derly people and in those with renal and hepatic insuffi- risk of fractures, cardiovascular disease and bladder cancer
ciency because these drugs can induce hypoglycaemia. with long-term use.
Adverse effects—Hypoglycaemia, which can be severe Therapeutic notes—Before prescribing pioglitazone, a
and prolonged. Weight gain; sensitivity reactions, including physician experienced in treating type 2 diabetes should
rashes; gastrointestinal disturbances; headache; flushing af- check liver function tests.
ter alcohol, and although rare, bone marrow toxicity can be Gliptins—Sitagliptin, vildagliptin, saxagliptin
severe. and ­ linagliptin are drugs that competitively inhibit
Therapeutic regimen—Tolbutamide is given at 500 mg, ­dipeptidylpeptidase-4 (DPP-4).
2 or 3 times daily and lasts for 6 hours; chlorpropamide is Mechanism of action—Lower blood glucose by potenti-
given at 100 to 250 mg daily and lasts for 12 hours; gliben- ating endogenous incretins glucagon-like-peptide-1 recep-
clamide is given at 2.5 to 15 mg daily and lasts for 12 hours. tor agonist (GLP-1) and glucose depedent insulinotropic
peptide (GIP) which stimulate insulin secretion.
Route of Administration—Oral.
Indications—Type 2 diabetes.
DRUG INTERACTIONS
Contraindications—Ketoacidosis, acute pancreatitis.
Nonsteroidal antiinflammatory drugs (NSAIDs), Adverse effects—Usually well tolerated but can cause gas-
trimethoprim and alcohol can produce severe trointestinal upset and worsening of heart failure. Risk of
hypoglycaemia when coprescribed with a pancreatitis. Weight neutral.
GLP-1 agonist—Exenatide and liraglutide are GLP-1
sulfonylurea. High doses of thiazide diuretics
agonists.
and glucocorticosteroids decrease the action of
Mechanism of action—Lower blood glucose by increas-
sulfonylureas. Therefore blood sugar levels should
ing insulin secretion, suppressing glucagon secretion and
be monitored carefully in these instances. slowing gastric emptying.
Route of administration—Subcutaneous injection.

98
 The endocrine pancreas and diabetes mellitus 7

Indication—Obese patients with type 2 diabetes who insulin to enter cells. As soon as insulin is administered, how-
have unsuccessfully reduced their blood glucose despite ever, potassium follows glucose into cells, and hypokalaemia
dual therapy. becomes the danger. Consequently, it is important to monitor
Contraindication—Ketoacidosis, severe gastrointestinal plasma K+ when treating patients in a hyperosmolar hyper-
disease. glycaemic state and replace it accordingly.
Adverse effects—Gastrointestinal disturbances, pancreatitis. Diabetic patients are also at risk of metabolic acidosis
Therapeutic notes—GLP-1 agonists cause modest weight caused by excessive ketone production.
loss. They are administered twice daily before meals. A
modified release version can be given as a once-weekly
injection and is used in combination with metformin and CLINICAL NOTE
sulfonylurea in poorly controlled obese patients with type
2 diabetes. A 19-year-old, with type 1 diabetes, presents to
Sodium glucose cotransporter 2 inhibitors—Dapagli- A&E feeling generally unwell with vomiting. He
flozin and canagliflozin are examples of a sodium glucose has recently started his second year of university
cotransporter (SGLT2) 2 inhibitor. and has been erratic with taking his insulin. On
Mechanism of action—These drugs inhibit the SGLT examination, he looks dehydrated and his breath
thus allowing increased amounts of glucose to be excreted smells sweet. His blood glucose is 20 mmol/L
by the kidney as glucose reabsorption is inhibited.
and he has blood ketones of 3.2 mmol/L in
Route of administration—Oral.
his urine. A venous blood gas gives a pH of
Indication—Used as dual therapy, with metformin, in adults
with type 2 diabetes who cannot tolerate sulphonylureas. 7.25, indicating acidosis. He is diagnosed with
Contraindications—Ketoacidosis, breastfeeding and diabetic ketoacidosis and given multiple bags
pregnancy, severe renal impairment. of intravenous fluid with sodium chloride 0.9%.
Adverse effects—Hypoglycaemia, urinary tract infec- In addition, he is given intravenous insulin and
tions, thrush, polyuria and hypotension. his glucose levels are monitored carefully. His
Therapeutic note—Before prescribing a SGLT2 inhibitor, potassium levels are also checked and once
renal function must be checked and should be monitored they fall into the normal range, the potassium is
annually. replaced with the fluid. Once he can eat and drink
and he is no longer acidotic, he is seen by the
Diet and fluid replacement diabetic specialist nurse who educates him on the
importance of taking his insulin appropriately, and
Dietary control
he is discharged home on his normal insulin.
Dietary control is important for both type 1 and type 2
diabetes.
The diet should aim to derive its energy from the follow-
ing constituents, in the following amounts.
Hypoglycaemia
• 50% carbohydrate (slowly absorbed forms)
• 35% fat Hypoglycaemia is relatively common in patients with diabe-
• 15% protein. tes who take insulin, and sulphonylureas.
The symptoms of hypoglycaemia are driven by the sym-
This regimen aims to reduce total fat intake, increase pro-
pathetic nervous system and include sweating, tremor, anx-
tein intake, and increase the intake of high fibre foods,
iety and altered consciousness.
which slow the rate of absorption from the gut.
The history may reveal the patient has not eaten as sched-
Simple sugars, as found in sweet drinks and cakes,
uled, exercised or taken too much insulin. Check that the co-
should be avoided. Meals should be small and regular, thus
prescription of a new drug has not precipitated hypoglycaemia.
avoiding large swings in blood glucose levels.
Management depends on the consciousness of the pa-
Rehydration therapy tient. If the patient is alert, glucose can be given orally as
Patients commonly present acutely with very high blood a syrup, or as simple sugar. If consciousness is altered, oral
glucose levels and require significant fluid replacement be- administration of glucose is dangerous, and there is a risk
cause their fluid deficit can be as high as 7 to 8 L given the of the patient aspirating. In this situation, glucose should
diuretic effect of hyperglycaemia. Rehydration therapy is be administered intravenously, or glucagon can be given by
essential to regain fluid and electrolyte balance and takes intramuscular or intravenous injection.
precedence over the administration of insulin.
Hyperkalaemia is a common and serious consequence Glucose (dextrose monohydrate)
of a lack of insulin associated with patients presenting with Glucose is administered parenterally as dextrose
acutely high glucose levels. This is because potassium requires mono­hydrate.

99
 Endocrine and reproductive systems

Mechanism of action—Dextrose mimics endogenous Glucocorticoids

glucose and is used by cells. The release of cortisol is controlled by negative feedback
Route of administration—Intravenous. to the hypothalamic–pituitary–adrenal axis (see Fig. 7.4).
Indications—Hypoglycaemia, or as part of rehydration There is a diurnal pattern of activity with an early morning
therapy. peak in cortisol release.
Contraindications—Hyperglycaemia. A variety of sensorineural inputs regulate the release of
Adverse effects—Venous irritation, thrombophlebitis. corticotrophin-releasing factor (CRF) in the hypothalamus;
Hypokalaemia may occur. examples include physiological and psychological “stress”,
Therapeutic notes—Glucose is also available in numer- injury and infection. CRF, a 41-amino-acid p ­ olypeptide,
ous oral preparations, although the patient must be alert reaches the anterior pituitary in the hypothalamo-­
and conscious before these are administered because aspi- hypophysial portal system where it stimulates the release of
ration can occur. adrenocorticotrophic hormone (ACTH). ACTH is formed
from a larger molecule, proopiomelanocortin, and is re-
Glucagon leased into the circulation where it stimulates the synthesis
Glucagon is a polypeptide hormone, normally secreted by and release of cortisol from the adrenal cortex.
the pancreatic α-cells. Natural and artificial glucocorticoids circulating in the
Mechanism of action—Glucagon acts on the liver to con- blood exert a negative feedback effect on the production of
vert glycogen to glucose and to synthesize glucose from both CRF and ACTH.
noncarbohydrate precursors (gluconeogenesis). The overall
effect is to raise plasma glucose levels. Mineralocorticoids
Route of administration—Parenteral. Aldosterone release is also partially controlled by ACTH,
Indications—Insulin-induced hypoglycaemia. but other factors, especially the renin–angiotensin system
Contraindications—Phaeochromocytoma. (RAS), and plasma potassium levels, are more important
Adverse effects—Nausea, vomiting, diarrhoea, hypo­ (see Chapter 5).
kalaemia.
Therapeutic notes—Unlike intravenous glucose, glu-
cagon can be administered easily by nonmedical per- Mechanism of action of
sonnel and can be carried by the patient as a prefilled corticosteroids
syringe pen.
Endogenous and synthetic corticosteroids act in a similar
way. The hormone or drug circulates to peripheral tissues
where it enters cells (steroids are lipid soluble) and binds to
cytosolic corticosteroid receptors. After hormone binding,
ADRENAL CORTICOSTEROIDS
these receptors are translocated to the nucleus where they
interact with deoxyribonucleic acid and lead to the tran-
Basic concepts scription of corticosteroid-responsive genes (CRG).
The adrenal cortex secretes several steroid hormones The products of these CRGs have diverse effects on the
into the bloodstream. These are categorized by their ac- target tissues (Table 7.5). The actions of corticosteroids are
tions into two main classes: mineralocorticoids and divided into effects on inorganic metabolism (mineralocor-
glucocorticoids. ticoid effects) and effects on organic metabolism (glucocor-
Aldosterone is the main mineralocorticoid and is syn- ticoid effects).
thesized in the zona glomerulosa. It affects water and elec-
trolyte balance and possesses salt-retaining activity. Therapeutic use of corticosteroids
Hydrocortisone (cortisol) and cortisone are the main
glucocorticoids and are synthesized in the zona fasciculata Corticosteroids have wide-ranging and powerful effects on
and zona reticularis. These affect carbohydrate, fat and pro- human physiology. There are two main areas where these
tein metabolism, and suppress inflammatory and immune properties are taken advantage of in the therapeutic use of
responses. Cortisol and cortisone also possess some miner- corticosteroids: physiological replacement therapy of cor-
alocorticoid activity. ticosteroid deficiency, and antiinflammatory therapy and
Small quantities of some sex steroids, mainly androgens, immunosuppression (Chapters 11 and 13).
are also produced by the adrenal cortex.
Exogenous corticosteroids
Both naturally occurring, and a number of synthetic corti-
Synthesis and release costeroids are available for clinical use. These vary in their
Adrenal corticosteroids are not preformed but are synthe- potency, half-life and the balance between glucocorticoid
sized when required from cholesterol (Fig. 7.4). versus mineralocorticoid activity (Table 7.6).

100
 Adrenal corticosteroids 7

Stress:
• physical
• emotional
• chemical (hypoglycaemia)
• others

Hypothalamus
− −

Artificial CRF −
negative
feedback Long + Short
pathway negative negative
leading to feedback feedback
adrenal loop loop
suppression
−

Anterior pituitary

ACTH

. Renin−angiotensin
Medulla
+ . system
Hyperkalaemia

Cortex
Exogenous Exogenous
glucocorticoids Adrenal gland mineralocorticoids
e.g. prednisolone e.g. fludrocortisone

Glucocorticoids Mineralocorticoids

+ + + +

Peripheral actions Peripheral action

• metabolic • renal
• anti-inflammatory e.g. Na+ and H2O
• immunosuppressive retention

Fig. 7.4 Hypothalamic–pituitary–adrenal axis: control of adrenal corticosteroid synthesis and secretion. ACTH,
Adrenocorticotrophic hormone; CRF, corticotrophin-releasing factor.

Mechanism of action—Exogenous corticosteroids imi- Because all the actions of natural corticosteroids are re-
tate endogenous corticosteroids. quired, a glucocorticoid with mineralocorticoid activity
Indications—The therapeutic use of corticosteroids (cortisol) or separate glucocorticoid and mineralocorticoid
falls into the two main categories of physiological re- are given.
placement therapy, and antiinflammatory therapy and The antiinflammatory and immunosuppressive effects
immunosuppression. of glucocorticoids are used to treat a wide variety of con-
Corticosteroid replacement therapy is necessary when en- ditions (Table 7.7). In these cases, synthetic glucocorticoids
dogenous hormones are deficient, as happens in the following. with little mineralocorticoid activity are used (Chapter 11).
• Primary adrenocortic destruction (Addison disease) Contraindications—Exogenous corticosteroids should
• Secondary adrenocortic failure caused by deficient not be given to people with systemic infection unless spe-
ACTH from the pituitary or postadrenalectomy cific antimicrobial therapy is being given.
• Suppression of the hypothalamic–pituitary–adrenal Route of administration—Replacement therapy is given
axis caused by prolonged glucocorticoid therapy. orally twice a day at physiological doses to try to mimic as

101
 Endocrine and reproductive systems

Table 7.5 Major effects of corticosteroids

Glucocorticoids
Immunological • Decreased production of T and B lymphocytes and macrophages, involution of lymphoid tissue
• Decreased function of T and B lymphocytes, and reduced responsiveness to cytokines
• Inhibition of complement system
Antiinflammatory • Profound generalized inhibitory effects on inflammatory response
• Reduced production of acute inflammatory mediators, especially the eicosanoids (prostaglandins,
leukotrienes, etc.), owing to production of lipocortin, an enzyme that inhibits phospholipase A2,
thus blocking the formation of arachidonic acid and its metabolites (see Chapter 11)
• Reduced numbers and activity of circulating immunocompetent cells, neutrophils, and
macrophages
• Decreased activity of macrophages and fibroblasts involved in the chronic stages of inflammation,
leading to decreased inflammation and decreased healing
Carbohydrate • Increased gluconeogenesis, decreased cellular uptake and use of glucose, increased storage of
metabolism glycogen in the liver (hyperglycaemic actions)
Fat metabolism • Redistribution of lipid from steroid-sensitive stores (limbs) to steroid-resistant stores (face, neck,
trunk)
Protein metabolism • Increased catabolism, decreased anabolism, leading to protein degradation
Cardiovascular • Increased sensitivity of vascular system to catecholamines, reduced capillary permeability leading
to raised blood pressure
Central nervous • High levels can cause mood changes (euphoria/depression) or psychotic states, perhaps caused
system by electrolyte changes
Anterior • Negative feedback effect of CRF and ACTH with the result that endogenous secretion of
hypothalamus and glucocorticoids is reduced, and may remain so after prolonged glucocorticoid therapy (‘adrenal
pituitary suppression’)
Mineralocorticoids
Kidney • Increased permeability of the apical membrane of cells in the distal renal tubule to sodium
• Stimulation of the Na+/K+ ATPase pump leading to reabsorption of Na+ and loss of K+ in the urine
• Water is passively reabsorbed owing to sodium retention; thus extracellular fluid and blood
volume are increased (raising blood pressure)
ACTH, Adrenocorticotrophic hormone; ATPase, adenosine triphosphatase; CRF, corticotrophin-releasing factor.

Table 7.6 Examples of therapeutically used liver high concentrations to the target site while minimising
corticosteroids
systemic absorption and adverse effects (see Table 7.7).
Glucocorticoids Mineralocorticoids At high doses, even topically administered glucocorti-
‘Natural coids can achieve systemic penetration.
hormones’ Synthetic Synthetic Adverse effects—Overdosage or prolonged use of corti-
Hydrocortisone Prednisolone Fludrocortisone
costeroids may exaggerate some of their normal physiologi-
(cortisol) Betamethasone Deoxycortone cal actions, leading to mineralocorticoid and glucocorticoid
Dexamethasone side effects. Many of these effects are similar to those seen in
Beclomethasone Cushing syndrome, a condition caused by excess secretion
Triamcinolone of endogenous corticosteroids (Fig. 7.5).
The metabolic side effects of glucocorticoids include the
following.
closely as possible the level and rhythm of natural cortico- • Central obesity and a “moon” face, as fat is
steroid secretion. redistributed
When used to suppress inflammatory and immune re- • Hyperglycaemia, which may lead to clinical diabetes
sponses, corticosteroids may be given orally or intravenously, mellitus, caused by disturbed carbohydrate metabolism
but, depending on the condition, the topical administration • Osteoporosis, caused by catabolism of protein matrix
of glucocorticoids is preferred, if feasible, because it can de- in bone

102
 Adrenal corticosteroids 7

Table 7.7 Examples of conditions in which corticosteroids are used for their antiinflammatory and
immunosuppressive effects
Systemic uses Topical uses
Acute inflammatory conditions, e.g. anaphylaxis, status asthmaticus, Asthma Aerosol
fibrosing alveolitis, angioneurotic oedema
Chronic inflammatory conditions, e.g. rheumatoid arthritis, inflammatory Allergic rhinitis Nasal spray
bowel disease, systemic lupus erythematosus, glomerulonephritis
Neoplastic disease myelomas, lymphomas, lymphatic leukaemias Eczema Ointment or cream
Miscellaneous organ transplantation Inflammatory bowel Foam enema
disease

Euphoria:
(though sometimes depression or psychotic symptoms and emotional lability)

(Benign intracranial
hypertension)
(Cataracts)

Moon face, with red

Buffalo-hump (plethoric) cheeks

Thin arms and legs:

muscle wasting

Increased
abdominal fat
(Avascular necrosis
of femoral head)
(Hypertension)

Thinning of skin
easy bruising,
poor wound
Osteoporosis
healing

Also: Tendency to
negative nitrogen hyperglycaemia
balance (anti-insulin effect)
increased appetite
increased susceptibility
to infection
obesity
Fig. 7.5 Effects of prolonged corticosteroid use; the Cushingoid appearance.

• Loss of skin structure, with purple striae, and easy Corticosteroid therapy suppresses endogenous secre-
bruising, caused by altered protein metabolism tion of adrenal hormones via negative feedback on the
• Muscle weakness and wasting, caused by protein ­hypothalamic–pituitary–adrenal axis.
catabolism Adrenal atrophy can persist for years after withdrawal
• Suppression of growth in children from prolonged corticosteroid therapy. Replacement

103
 Endocrine and reproductive systems

c­ orticosteroid therapy is needed to compensate for the Prednisolone:

lack of sufficient adrenocortic response in times of stress • Prednisolone is predominantly glucocorticoid in
(e.g. illness, surgery). Steroid therapy must be withdrawn activity.
slowly after long-term treatment because sudden with- • It is the oral drug most widely used in allergic and
drawal can lead to an acute adrenal insufficiency crisis. inflammatory diseases.
With glucocorticoid therapy, the modification of inflam- Deflazacort
matory and immune reactions leads to an increased suscep- • Dfelazacort is derived from prednisolone, with high
tibility to infections. This can progress unnoticed because glucocorticoid activity.
of the suppression of normal indicators of infection, such • It is administered orally, and indicated for the
as inflammation. Increased susceptibility occurs to usually treatment of inflammatory and allergic disorders.
pathogenic and opportunistic bacterial, viral and fungal or- Betamethasone and dexamethasone
ganisms. Reactivation of latent infections (e.g. tuberculosis, • Betamethasone and dexamethasone have very
herpes viruses) can occur. high glucocorticoid activity with insignificant
The effects are most serious when corticosteroids are mineralocorticoid activity.
being used systemically, although topical use can exac- • They are very potent drugs used orally and by injection
erbate superficial skin infections, and inhaled cortico- to suppress inflammatory and allergic disorders, and
steroids can encourage oropharyngeal thrush and so on. to reduce cerebral oedema; they do not possess salt-
Inhaled corticosteroids have also been recently associ- retaining or water-retaining actions.
ated with an increased risk of pneumonia, particularly Beclometasone
in elderly patients with chronic obstructive pulmonary • Beclometasone is the dipropionate ester of
disease. betamethasone.
The other effects of glucocorticoids include mood • It is a very potent drug with no mineralocorticoid
changes (euphoria and, rarely, psychosis), peptic ulceration activity that is useful topically because it is poorly
caused by inhibition of gastrointestinal prostaglandin syn- absorbed through membranes and skin.
thesis, and eye problems such as cataracts and exacerbation • It is used topically to treat asthma and allergic rhinitis,
of glaucoma. and as a cream and ointment in eczema to provide high
Fluid retention, hypokalaemia and hypertension can all local antiinflammatory effects with minimal systemic
be side effects of any corticosteroids that possess significant penetration.
mineralocorticoid activity. Triamcinolone
• Triamcinolone is a moderately potent drug which can
be used in severe asthma.
• It can also be administered by intraarticular injection
HINTS AND TIPS for the treatment of rheumatoid arthritis.

Corticosteroids cause several side effects, Mineralocorticoids

which are important to remember. These include Fludrocortisone
• Fludrocortisone has such high mineralocorticoid
hypertension, sodium and water retention,
activity that glucocorticoid activity is insignificant.
diabetes, osteoporosis, proximal myopathy and
• It is administered orally, in combination with a
Cushing syndrome. In addition, they can cause glucocorticoid, in replacement therapy.
skin thinning, bruising, mood disturbances and an
increased risk of infections.
CLINICAL NOTE

A patient presents with a gradual history of

muscle weakness, weight loss and low mood.
Therapeutic notes on specific steroid On examination, he appears slightly tanned
agents and his blood pressure is low, with a significant
postural drop. He also has a low blood sugar. His
Glucocorticoids
Hydrocortisone (cortisol) bloods show a low Na and a high K level, and
• Hydrocortisone is administered orally for adrenal a low morning cortisol, with a raised ACTH. He
replacement therapy and possesses mineralocorticoid is diagnosed with primary adrenal insufficiency
activity. (Addison disease). He is prescribed hydrocortisone
• It is administered intravenously in status asthmaticus and fludrocortisone, and he is seen in endocrine
and anaphylactic shock. follow-up regularly.
• It is applied topically for eczema, inflammatory bowel
conditions and so on.
104
 The reproductive system 7

Management of Cushing syndrome Hypothalamus

Cushing syndrome is caused by prolonged exposure to ele- Neuronal
vated levels of either endogenous or exogenous glucocorti- systems
costeroids. Patients present with symptoms as described in GnRH
Fig. 7.5. Patients with Cushing syndrome as a consequence
of treatment with exogenous glucocorticosteroids, must be
managed by stopping the drugs slowly. Patients with excess
endogenous glucocorticosteroids secondary to a pituitary Anterior
pituitary
adenoma require definitive management with surgical re-
moval of their tumour.
Medical therapy includes metyrapone (a competitive in- Oestradiol LH
progesterone
hibitor of 11B hydroxylation) and ketoconazole (inhibits 17
(inhibin) FSH
α-hydroxylase), which lower cortisol by directly inhibiting
enzymes involved in the synthesis and secretion of cortisol
in the adrenal gland.
Ovary
Other medications used in the treatment
of endocrine-related conditions
Somatostatin analogues
Physiologically, somatostatin is a hormone that acts on the Autocrine and
hypothalamus to inhibit the release of growth hormone paracrine factors
and in the pancreas to inhibit the release of glucagon and
insulin. Fig. 7.6 Hypothalamic-pituitary-ovarian axis. FSH, Follicle-
stimulating hormone; GnRH, gonadotrophin-releasing
Octreotide is a long-acting analogue of somatostatin
hormone; LH, luteinizing hormone.
and is used clinically to treat acromegaly (oversecretion of
growth hormone causing headaches, visual field defects,
turn, these act upon the ovaries to stimulate the release of
enlarged hands, feet and tongue associated with cardiac
oestradiol, progesterone and other ovarian hormones.
features). Side effects of octreotide include gastrointestinal
The ovarian hormones are able to exert a negative feed-
disturbances, gallstones and hyperglycaemia.
back on the hypothalamus and/or the pituitary. Some of
Dopamine receptor agonists these are selective in their inhibition; for example, inhibin
Bromocriptine and cabergoline are examples of dopa- selectively inhibits FSH release from the pituitary, activin
mine receptor agonists used clinically in the treatment selectively stimulates FSH release from the pituitary, and
of ­
prolactin-secreting tumours of the pituitary gland. gonadotrophin-surge-attenuating factor selectively inhibits
Unwanted side effects include dizziness, constipation and LH secretion from the pituitary.
postural hypotension.
Menstrual cycle
The menstrual cycle is divided into a follicular phase (days
1–14) and a luteal phase (days 14–28). The cycle proceeds as
THE REPRODUCTIVE SYSTEM follows (numbers refer to Fig. 7.7).
1. Day 1 is the first day of menstruation, which involves
Hormonal control of the the shedding of the uterine endometrium. Plasma
reproductive system oestrogen levels are low and thus little negative
feedback occurs. As a result, the secretion of LH and
Physiology of the female reproductive FSH begins to increase.
tract 2. Between 10 and 25 preantral follicles start to enlarge
The female gonads, or ovaries, are responsible for oogen- and secrete oestrogen.
esis and the secretion of the steroid sex hormones, namely 3. FSH stimulates the granulosa cells to secrete
oestrogens (mainly oestradiol) and progesterone. The pro- oestrogen, the levels of which rise.
duction of the female sex hormones is controlled by the 4. About 1 week into the cycle, one of the follicles
­hypothalamic–pituitary–ovarian axis (Fig. 7.6). becomes dominant, and the others undergo atresia.
Gonadotrophin-releasing hormone (GnRH) is secreted The dominant follicle secretes increasingly larger
by the hypothalamus and stimulates the pulsatile secretion amounts of oestrogen.
of the gonadotrophins, follicle-stimulating hormone (FSH) 5. Plasma oestrogen levels rise significantly as a result of
and luteinising hormone (LH) by the anterior pituitary. In increased sensitivity of the granulosa cells to FSH.

105
 Endocrine and reproductive systems

Ovarian
phase Follicular Luteal HINTS AND TIPS
Ovulation Many female patients forget to mention the oral
8
50 contraceptive pill when they list their medications, so
Plasma gonadotrophins

ensure to ask specifically because numerous important

(arbitrary units)

40

30 drug interactions may need to be considered.

20 LH
10 FSH
6
1 13 16
0 Physiology of the male reproductive tract
The male gonads, or testes, are responsible for spermato-
genesis and the secretion of the steroid sex hormone tes-
7
15 tosterone. Spermatogenesis takes place in the lumen of the
(arbitrary units)
Plasma steroids

12
10 5
seminiferous tubules of the testis. The production of the
9 male sex hormones is controlled by the hypothalamic–­
5 Oestrogen 15
3
Progesterone
pituitary axis (Fig. 7.8).
0 The Sertoli cells are connected to one another by tight
junctions and extend from the basement membrane of the
10 11
seminiferous tubules into the lumen. Under the influence
14
Ovarian 4 of FSH, these synthesize testosterone receptors and inhibin.
2
follicle The Leydig cells are found in the connective tissue be-
tween the tubules. Under the influence of LH, these synthe-
Day 1 5 10 15 20 25 28
size testosterone. Testosterone acts locally to increase sperm
Fig. 7.7 The menstrual cycle. FSH, Follicle-stimulating production, and also peripherally on the testosterone-­
hormone; LH, luteinizing hormone.
sensitive tissues of the body.

6. Elevated oestrogen levels provide negative feedback,

Hypothalamus
and FSH secretion decreases. GnRH
−
7. Plasma oestrogen levels are now so high (> 200
pg/mL) that they exert a positive feedback on + −
gonadotrophin secretion. This occurs for about
−
2 days, during which FSH stimulates the appearance
of LH receptors on the granulosa cells. −
FSH Pituitary LH
8. An LH surge occurs. This results in a decrease in
oestrogen secretion, an increase in progesterone Inhibin +
secretion by the granulosa cells, and the resumption + Testosterone
of meiosis in the egg.
Sperm cell
9. Oestrogen levels decline after ovulation.
10. The first meiotic division is completed.
11. On day 14, ovulation, the release of the ovum,
occurs. This is approximately 18 hours after the LH Sperm
surge. Leydig cell
12. The granulosa cells are transformed into the Testis
corpus luteum, which secretes both oestrogen and
progesterone in large quantities.
13. There is a rise in the levels of oestrogen and
progesterone. As a result, FSH and LH secretion are Tubule
suppressed, and their levels fall.
14. If fertilisation does not take place, the corpus luteum Sertoli cell
degenerates after about 10 days. Fig. 7.8 Hormonal control of Sertoli, Leydig and sperm
15. Oestrogen and progesterone levels fall; menstruation cell function. FSH, Follicle-stimulating hormone; GnRH,
is imminent. gonadotrophin-releasing hormone; LH, luteinizing hormone.
16. FSH and LH secretion increase once more, and the (Modified from Page, C., Curtis, M. Walker, M, Hoffman, B.
28-day cycle begins again. (eds) Integrated Pharmacology, 3rd edn. Mosby, 2006.)

106
 The reproductive system 7

Testosterone and inhibin are able to exert negative feed- same time each day, with a 7-day break to induce a with-
back control over the anterior pituitary, the former decreas- drawal bleed. If the delay in taking the pill is greater than 12
ing LH secretion and the latter decreasing FSH secretion. In hours, the contraceptive effect may be lost.
addition, testosterone and inhibin act on the hypothalamus
to decrease GnRH secretion. Progesterone-only pill (mini pill)
The mini-pill consists of low-dose progestogen; ovulation
still takes place and menstruation is normal.
Drugs that affect the reproductive Mechanism of action—The mini-pill causes thickening
system of cervical mucus preventing sperm penetration. It also
causes suppression of gonadotrophin secretion, and occa-
Oral contraceptives sionally ovulation, but the latter effect does not occur in the
majority of women.
Combined oral contraceptive pill
Route of administration—Oral.
The combined oral contraceptive pill (COCP) contains
Indications—Contraception (but less effective than the
both an oestrogen (usually ethinylestradiol, 20–50 μg) and
COCP). It is more suitable for heavy smokers and patients
a progestogen (an analogue of progesterone).
with hypertension or heart disease, diabetes mellitus and
COCPs provide a highly effective form of contraception.
migraine, or in those who have other contraindications for
Their efficacy is reduced by some broad-spectrum antibiot-
oestrogen therapy.
ics, which reduce enterohepatic recirculation of oestrogen
Contraindications—Pregnancy, arterial disease, liver dis-
by killing gut flora.
ease, breast or genital tract carcinoma.
Mechanism of action—The levels of steroids mimic the
Adverse effects—Menstrual irregularities, nausea, vomit-
luteal phase of the menstrual cycle, and suppress, via neg-
ing and headache, weight gain, breast tenderness.
ative feedback effects, the secretion of gonadotrophins.
Therapeutic regimen—The mini-pill is taken as one tab-
Oestrogen inhibits secretion of FSH via negative feedback on
let daily, at the same time, starting on day 1 of the menstrual
the anterior pituitary and thus suppresses the development
cycle and then continuously. If the delay in taking the pill is
of the ovarian follicle. Progestogen inhibits secretion of LH
greater than 3 hours, the contraceptive effect may be lost.
and therefore prevents ovulation. As a result, follicular selec-
tion and maturation, the oestrogen surge, the LH surge, and
thus ovulation, do not take place. In addition, the cervical
CLINICAL NOTE
mucus prevents the passage of sperm. Both progestogen and
oestrogen reduce the ability of an egg implanting. Mrs Hayat, 29 years old, recently had a pulmonary
Route of administration—Oral. embolism on return from her holiday to Egypt. A
Indications—Contraception and menstrual symptoms.
few weeks later, she goes to her GP to enquire
Contraindications—Pregnancy, breastfeeding, or those with
about oral contraception. Because she has
a history of heart disease or hypertension, hyperlipidaemia or
any prothrombotic coagulation abnormality, diabetes mellitus, a predisposition to venous thrombosis, the
migraine, breast or genital tract carcinoma or liver disease. GP advises her to take oral progestogen-only
Adverse effects—Nausea, vomiting and headache, weight contraceptives, rather than a COCP.
gain, breast tenderness, impaired liver function, impaired
glucose tolerance in diabetic women, “spotting” (slight
bleeding at the start of the menstrual cycle), thromboembo-
lism and hypertension, a slightly increased risk of cervical
cancer, and a possibly increased risk of breast cancer. Other contraceptive regimens
Therapeutic regimen—COCPs are taken for 21 days Depot-progesterone
(starting on the first day of the menstrual cycle) at about the Examples of depot-progesterone drugs include medroxy-
progesterone acetate and the etonogestrel-releasing im-
DRUG INTERACTION plant. These provide long-term contraception.
Mechanism of action—Depot-progesterone causes thick-
COCP or progesterone-only pill + drugs ening of cervical mucus. It also causes suppression of go-
that induce hepatic enzyme activity (e.g. nadotrophin secretion, and occasionally ovulation, but the
carbamazepine, phenytoin, rifampicin) = reduced latter effect does not occur in the majority of women.
efficacy. Route of administration—Medroxyprogesterone acetate
Both contraceptives are metabolized by hepatic is administered intramuscularly. The etonogestrel-releasing
cytochrome P450 enzymes, which are induced by implant system relies on a hormone rod placed subdermally.
lots of other coprescribed medications.
Indications—Contraception.
Contraindications—Pregnancy arterial disease, liver dis-
ease, osteoporosis, breast or genital tract carcinoma.

107
 Endocrine and reproductive systems

Adverse effects—Menstrual irregularities, nausea, vomit- Contraindications—Pregnancy, oestrogen-dependent

ing and headache, weight gain, breast tenderness. cancer, active or previous thromboembolic disease.
Therapeutic notes—Medroxyprogesterone acetate pro- Adverse effects—Increased risk of endometrial cancer
vides protection for about 12 weeks. The etonogestrel-­ and possibly an increased risk of breast cancer after many
implant system provides protection for 3 years. years of treatment.
Therapeutic regimen—Oestrogen agonists are given for
Emergency contraception several years, starting in the perimenopausal period.
The “morning-after” pill, levonorgestrel, provides a form of
emergency contraception. Oestrogen antagonists
Mechanism of action—High doses of a progestogen alone Examples of oestrogen antagonists include tamoxifen, clo-
or a progestogen with an oestrogen prevent implantation of mifene and toremifene.
the fertilized egg. Contractions of the uterine smooth mus- Mechanism of action—Tamoxifen has an antioestrogenic
cle are induced, and these accelerate the movement of the effect on breast and uterine tissue.
fertilized egg into the unprepared uterine endometrium. Clomifene inhibits the negative feedback effects on the
Route of administration—Oral. hypothalamus and anterior pituitary. This stimulates and
Indications—The morning-after pill is used for emer- enlarges the ovaries, increasing oestrogen secretion and in-
gency contraception after unprotected intercourse. ducing ovulation.
Contraindications—Preparations containing oestrogens Route of administration—Tamoxifen is administered
should not be used in patients who have contraindications orally or by intravenous or subcutaneous injection, whereas
to oestrogens (see earlier). clomifene is administered orally.
Adverse effects—Nausea, vomiting and headache, dizzi- Indications—Tamoxifen is prescribed to reduce the risk
ness, menstrual irregularities. of breast cancer in postmenopausal women with osteoporo-
Therapeutic regimen—The morning-after pill regimen sis or high risk, as well as to treat breast cancer.
depends upon the type of pill being taken but commonly Clomiphene is used in the treatment of infertility.
consists of one or two tablets within 72 hours of intercourse Contraindications—Hepatic disease, ovarian cysts, endo-
and one or two tablets 12 hours later. metrial carcinoma.
Insertion of an intrauterine device is more effective Adverse effects—Multiple pregnancies and hot flushes.
than hormonal methods and works up to 5 days after Withdrawal causes visual disturbances and ovarian
intercourse. hyperstimulation.

Oestrogens and antioestrogens Progestogens and antiprogestogens

Oestrogen agonists Progestogen agonists
The adverse symptoms of the menopause can be attributed Examples of progestogen agonists include progesterone,
to decreased levels of oestrogen that occur as the ovaries medroxyprogesterone, dydrogesterone, hydroxyprogester-
begin to fail. Evidence suggests that oestrogen given in low one and norethisterone.
doses to menopausal women will reduce postmenopausal Mechanism of action—Progestogen agonists mimic en-
osteoporosis, vaginal atrophy and the incidence of stroke dogenous progesterone.
and myocardial infarction. Route of administration—Oral, or by transdermal
A progestogen is coadministered with oestrogen to in- patches, gels or subcutaneous implants.
hibit oestrogen-stimulated endometrial growth and thus Indications—Progestogen agonists are given for premen-
reduce the risk of uterine cancer and fibroids. strual symptoms, severe dysmenorrhoea, menorrhagia, en-
Examples of oestrogen agonists include oestradiol and dometriosis, contraception and as part of HRT.
oestriol. Contraindications—Pregnancy or to those with ar-
Mechanism of action—Oestrogen agonists mimic pre- terial disease, liver disease or breast or genital tract
menopausal endogenous oestrogen levels. carcinoma.
Route of administration—Oral, or by transdermal Adverse effects—Menstrual irregularities, nausea, vomit-
patches, gels or subcutaneous implants. ing and headache, weight gain, breast tenderness.
Indications—Oestrogen agonists are used alone for hor-
mone replacement therapy (HRT) in menopausal women Progestogen antagonists
who have undergone a hysterectomy. However, because oes- Mifepristone is an example of a progestogen antagonist.
trogen causes an overgrowth of cells in the uterus, it must be Mechanism of action—Progestogen antagonists bind to
given in conjunction with progestogen (causes endometrial progesterone receptors but exert no effect. They sensitize
shedding) in females with a uterus to reduce the risk of en- the uterus to prostaglandins and can, therefore be used in
dometrial cancer developing. combination with prostaglandins in the termination of early
Also used as replacement therapy in patients with pri- pregnancy.
mary or secondary ovarian failure. Route of administration—Oral.

108
 The reproductive system 7

Indications—Progestogen antagonists are used in the ter-

mination of pregnancy. HINTS AND TIPS
Contraindications—Progestogen antagonists should not Similar to breast cancer in women, prostate
be given to pregnant women (64 days gestation or more), to
cancer in men is most often hormone dependent.
women with adrenal failure or haemorrhagic disorders, or
Exogenous androgens can promote, and
to those on anticoagulant or long-term corticosteroid treat-
ment, or to smokers aged 35 years and over. antiandrogens can suppress, tumour growth.
Adverse effects—Vaginal bleeding, faintness, nausea and
vomiting.

Androgens and antiandrogens Anabolic steroids

Nandrolone and stanozolol are examples of anabolic steroids.
Androgen agonists Mechanism of action—Anabolic steroids are androgenic;
Testosterone and mesterolone are examples of androgen stimulate protein synthesis.
agonists. Route of administration—Nandrolone is administered by
Mechanism of action—Androgen agonists mimic endog- deep intramuscular injection and stanozolol orally.
enous androgens. Indications—Anabolic steroids can be used in the man-
Route of administration—Oral, intramuscularly or by agement of aplastic anaemias.
implant or cutaneous patch. Anabolic steroids, although banned, are frequently used
Indications—Androgen agonists are given as by athletes to increase skeletal muscle bulk.
­androgen-replacement therapy in castrated men, for pitu- Contraindications—Hepatic impairment, men with
itary or testicular disease causing hypogonadism, and for prostate or breast cancer, pregnant women.
breast cancer. Adverse effects—Acne, sodium retention causing oe-
Contraindications—Androgen agonists should not dema, virilisation in women, amenorrhoea, inhibition of
be given to men with breast or prostate cancer, to people spermatogenesis, liver tumours.
with hypercalcaemia, or to women who are pregnant or
breastfeeding. Gonadotropin-releasing hormone
Adverse effects—Sodium retention causing oedema, hy- agonists and antagonists
percalcaemia, suppression of spermatogenesis, virilism in
women and premature closure of epiphyses in prepubertal Agonists
boys. The incidence of prostate abnormalities and prostate Goserelin, leuprolide and buserelin are examples of GnRH
cancer is also increased. agonists.
Mechanism of action—GnRH agonists are given inter-
Androgen antagonists mittently and mimic endogenous GnRH. Continuous use
Cyproterone is an androgen antagonist that is a progester- desensitizes the GnRH receptors that gonadotrophs act on
one derivative. Both oestrogens and progestogens have an- and inhibits gonadotrophin synthesis.
tiandrogenic properties. Route of administration—Buserelin is administered in-
Mechanism of action—Androgen antagonists are partial tranasally, whereas goserelin and leuprolide are adminis-
agonists at androgen receptors and act on the hypothalamus tered by subcutaneous injection.
to reduce the synthesis of gonadotrophins. They inhibit Indications—GnRH agonists are used for ovulation in-
spermatogenesis, causing reversible infertility, but are not duction in those with GnRH deficiency, endometriosis, pre-
contraceptives. cocious puberty, and sex-hormone-dependent cancers and
Route of administration—Oral. prostate cancer.
Indications—Androgen antagonists are used in the treat- Adverse effects—Menopause-like symptoms, including
ment of prostate cancer, acne, female hirsutism, and preco- hot flushes, palpitations, and decreased libido because of
cious puberty. In addition, used for male hypersexuality and hypooestrogenism, and breakthrough bleeding.
sexual deviation.
Contraindications—Androgen antagonists should not be Antagonists
given to people with hepatic disease or severe diabetes, or to Danazol and gestrinone are examples of GnRH antagonists.
those aged 18 years and under because their bones are not Mechanism of action—GnRH antagonists inhibit the re-
fully matured. lease of GnRH and the gonadotrophins. They bind to the
Adverse effects—Fatigue and lethargy, and hepatotoxicity. sex steroid receptors, displaying androgenic, antioestro-
Therapeutic notes—Finasteride is technically an antian- genic, and antiprogestogenic effects.
drogen, although it inhibits the enzyme 5α-reductase which Route of administration—Oral.
metabolizes testosterone to the more potent androgen dihy- Indications—GnRH antagonists are given for endome-
drotestosterone. Finasteride is indicated in benign prostatic triosis, menstrual disorders, including menorrhagia, cystic
hyperplasia and is administered orally. breast disease, gynaecomastia.

109
 Endocrine and reproductive systems

Contraindications—Pregnancy, hepatic, renal or cardiac Serum calcium is ultimately controlled by the peptide,
impairment, vascular disease. parathyroid hormone (PTH), derived from the parathy-
Adverse effects—Nausea and vomiting, weight gain, an- roid glands. PTH maintains serum calcium by acting on
drogenic effects such as acne and hirsutism. the kidney to reabsorb calcium from the tubular filtrate,
Therapeutic notes—Cetrorelix and ganirelix are lutein- and to stimulate the activation of vitamin D. PTH also acts
izing hormone-releasing hormone antagonists, inhibiting directly on bone, mobilising calcium. Activated vitamin
the release of the gonadotrophins. They are administered D (1,25-dihydroxycholecalciferol) promotes absorption of
parenterally and are used for infertility in specialist centres. calcium from the gut. PTH is secreted in response to low
serum calcium.
Oxytocic drugs Calcitonin, from the thyroid gland, inhibits calcium mo-
The oxytocic drugs, oxytocin, ergometrine, prostaglandins bilisation from bone and decreases reabsorption from the
E and F (e.g. gemeprost [PGE1 analogue], dinoprostone renal tubules.
[PGE2] and carboprost [15-methyl PGF2a]) all cause uterine
contractions. Disorders of bone and calcium
Oxytocin is a posterior pituitary hormone that acts on Osteoporosis is an overall loss of bone mass, and commonly
uterine muscle to induce powerful contractions. It does this occurs in women after the menopause, when oestrogens
directly and also indirectly by stimulating the muscle to fall, and bone mobilisation slowly increases. Other causes
synthesize prostaglandins. of osteoporosis include thyrotoxicosis, and excessive gluco-
In addition, prostaglandins ripen and soften the cervix, corticoids (exogenous or endogenous).
further aiding the expulsion of uterine contents. Osteodystrophy occurs in renal failure and is driven by
Mechanism of action—Oxytocin acts on oxytocin recep- secondary hyperparathyroidism. Rickets (vitamin D defi-
tors. The mechanism for ergometrine is not well understood ciency) is now rare in the West, although the adult variant,
but may be via partial agonist action at α-adrenoceptors or osteomalacia, is not uncommon. Hypercalcaemia is a medi-
5-hydroxytryptamine receptors. The prostaglandins act at cal emergency and is most often caused by malignancy.
prostaglandin receptors.
Route of administration—Gemeprost and dinoprostone HINTS AND TIPS
are administered by vaginal pessary; dinoprostone can also
be administered extraamniotically; oxytocin is administered Rehydration therapy is as important in
by slow intravenous infusion, and oxytocin and ergometrine hypercalcaemia as it is in ketoacidosis
together are injected intramuscularly. Prostaglandins can be (hyperglycaemia) because the fluid will be lost in
administered by intravenous infusion. the urine as a result of osmotic diuresis.
Indications—Prostaglandins are used to induce abortion.
Oxytocin and dinoprostone are used for the induction of
labour whereas oxytocin, ergometrine and carboprost (in
those unresponsive to oxytocin and ergometrine) are used
for the management of the third-stage of labour and preven- Drugs used in bone and calcium
tion and treatment of postpartum haemorrhage. disorders
Contraindications—Oxytocic drugs should not be given
to women with vascular diseases; ergometrine should not Bisphosphonates
be used to induce labour. Alendronate, disodium etidronate, pamidronate and zole-
Adverse effects—Nausea and vomiting, vaginal bleeding, dronate are examples of bisphosphonates.
uterine pain. Oxytocin can cause hypotension and tachycardia. Mechanism of action—Bisphosphonates inhibit and po-
tentially destroy osteoclasts, which are responsible for mo-
bilising calcium from bone.
Route of administration—Oral, parenteral.
BONE AND CALCIUM Indications—Prevention of postmenopausal osteopo-
rosis and corticosteroid-induced osteoporosis, and for the
Bone and calcium physiology management of hypercalcaemia of malignancy.
Alendronate and risedronate for prophylaxis and treat-
Bone is a tissue comprized mainly of calcium, phosphates ment of osteoporosis.
and a protein meshwork, in addition to the components of Pamidronate via intravenous infusion to treat hypercal-
the bone marrow. caemia of malignancy or Paget disease
Bone functions to provide support and enables us to Zoledronate via intravenous infusion to treat Paget dis-
carry out various physiological processes such as respiration ease, selected cases of osteoporosis (often the second line)
and movement. Bone is also an active tissue and crucial in once a year.
the homeostasis of calcium and phosphate. Contraindications—Renal impairment, hypocalcaemia.

110
 Bone and calcium 7

Adverse effects—Nausea, oesophagitis (with oral prepa-

rations), hypocalcaemia. Atypical femoral fractures can CLINICAL NOTE
develop if taking long-term bisphosphonate treatment. Mrs Price, 73 years old, weighing 44 kg, presents
Zoledronate can rarely cause jaw osteonecrosis; dental
with a painful, swollen and “dinner fork-like”
checks are required pretreatment.
deformity of her wrist. Radiography shows she has
Therapeutic note—Bisphosphonates given orally must be
taken on an empty stomach with plenty of water in a sitting fractured both radial and ulnar styloid processes
or standing position at least 30 minutes before breakfast (Colles fracture). The doctor was concerned that
because food impairs absorption and bisphosphonates can she had poor bone density and sent her for a
cause oesophagitis, strictures and gastric erosions. DEXA (dual energy X-ray absorptiometry) scan.
The scan indicated Mrs Price had developed early
Calcium salts osteoporosis. Her bones are manually aligned and
Calcium gluconate, calcium lactate and calcium carbonate put in a cast to be reviewed in 6 weeks. She is put
are calcium salts. on alendronate, a bisphosphonate, to increase
Mechanism of action—Calcium supplementation re- her bone density and thus help prevent further
places calcium deficiencies. fractures. Also, she is prescribed calcium and
Route of administration—Oral, intravenous. vitamin D supplements.
Indications—Hypocalcaemia, calcium deficiency, os-
teoporosis. Calcium gluconate is given intravenously as
emergency treatment of hyperkalaemia to stabilize cardiac
function. Calcium carbonate is used in the management of
hyperphosphataemia (binds phosphate in the gut).
Contraindications—Hypercalcaemia. Selective oestrogen-receptor
Adverse effects—Mild gastrointestinal disturbance, bra-
modulator
dycardia, arrhythmias.
The drug is called raloxifene.
Therapeutic notes—If calcium is given parenterally, se-
Mechanism of action—Raloxifene has both oestrogen an-
rum calcium should be repeatedly monitored.
tagonistic (uterine endometrium and breast tissue) and ag-
Vitamin D onistic properties (bone and lipid metabolism). Raloxifene
Vitamin D can be administered in its inactive form as ergo- stimulates osteoblasts and inhibits osteoclasts.
calciferol, or in its active form as calcitriol. Route of administration—Oral.
Mechanism of action—Vitamin D acts on the gut to ab- Indications—Treatment and prevention of postmeno-
sorb calcium from the diet. pausal osteoporosis (third line).
Route of administration—Oral, parenteral. Contraindications—History of venous thromboembo-
Indications—Vitamin D deficiency, hypocalcaemia sec- lism, undiagnosed uterine bleeding, hepatic or severe renal
ondary to hypoparathyroidism, renal failure and postmeno- impairment, pregnancy, breastfeeding.
pausal osteoporosis. Adverse effects—Venous thromboembolism, thrombo-
Contraindications—Hypercalcaemia. phlebitis, hot flushes, leg cramps, peripheral oedema, flu-
Adverse effects—Symptoms of overdosage include anorexia, like symptoms.
lassitude, nausea and vomiting, weight loss, hypercalcaemia. Therapeutic notes—It may reduce the incidence of
Therapeutic notes—Serum calcium should be monitored ­oestrogen-receptor positive breast cancer and cardiovascu-
closely once vitamin D therapy has started, and if symptoms lar events, but there is no clear evidence of this.
of hypercalcaemia appear.
Denosumab
Calcitonin Mechanism of action—Denosumab is a recombinant hu-
Mechanism of action—Calcitonin binds specific recep- man monoclonal antibody that inhibits receptor activator
tors on osteoclasts inhibiting their mobilisation of bone and of nuclear factor kappa B ligand (RANKL), the primary
acts on the kidney to limit calcium reabsorption from the signal for bone resorption.
proximal tubules. Route of administration—Subcutaneous injection every
Route of administration—Subcutaneous or intramuscular. 6 months (or monthly for bone metastases)
Indications—Hypercalcaemia, Paget disease of bone, Indications—Second-line treatment of osteoporosis in
bone pain in neoplastic disease. postmenopausal women at risk of fracture.
Contraindications—Caution if history of allergy, or renal Men with prostate cancer at increased risk of osteoporo-
impairment. sis because of hormone ablation.
Adverse effects—Nausea, vomiting, flushing, diarrhoea, Prevent fractures and reduce pain in patients with bone
tingling of hands. metastases from solid tumours.

111
 Endocrine and reproductive systems

Contraindications—Hypocalcaemia, pregnancy. Other drugs

Adverse effects—Altered bowel habit, hypocalcaemia, re- Teriparatide is a recombinant parathyroid hormone. When
current infections, atypical femoral fractures. given in small doses, teriparatide stimulates osteoblast
Therapeutic notes—Dental work needs to be undertaken activity and enhances bone formation. Prescribed subcu-
before treatment to reduce the risk of osteonecrosis of the jaw. taneously by specialists to treat patients with severe osteo-
porosis. Well tolerated but can cause nausea, headache and
Vitamin D preparations arthralgias.
Ergocalciferol and alfacalcidol are examples of vitamin D Strontium ranelate inhibits bone resorption and
preparations used in the treatment of vitamin D deficien- stimulates bone formation, through inhibition of osteo-
cies, renal osteodystrophy and hypoparathyroidism. They are clasts. Treatment of severe osteoporosis by specialists
given orally, and the main adverse effect is hypercalcaemia. only.

Chapter Summary

• Iodide is given in thyrotoxic crises because it rapidly inhibits thyroid hormone secretion
and the conversion of T4 to T3
• β-adrenoceptor antagonists are useful for reducing somatic symptoms associated with
hyperthyroidism
• Thyroid function tests should be checked before amiodarone is prescribed and every
6 months thereafter.
• Patients with type 1 diabetes require insulin subcutaneously, whereas patients with type
2 diabetes can take oral medication
• The COCP is contraindicated in patients with migraine, diabetes or previous
thromboembolism
• The progesterone-only pill is less effective but can be given to patients who smoke or
have heart disease
• Bisphosphonates are commonly used in the treatment of osteoporosis

112
 Central nervous system
8
to those of idiopathic Parkinson disease. Drugs that
BASIC CONCEPTS block dopamine receptors can also induce parkinsonism.
Neuroleptic drugs (p. 126) used in the treatment of schizo-
The central nervous system (CNS) consists of the brain
phrenia can produce parkinsonian symptoms as an adverse
and the spinal cord, which are continuous with one
effect. Rare causes of parkinsonism are cerebral ischaemia
­another. The brain is composed of the cerebrum (which
(progressive atherosclerosis or stroke), viral encephalitis or
consists of the frontal, temporal, parietal and occipital
other pathological damage.
lobes), the diencephalon (which includes the thalamus
and hypothalamus), the brainstem (which consists of the
midbrain, pons and medulla oblongata) and the cerebel-
HINTS AND TIPS
lum. The brain functions to interpret sensory information
obtained about the internal and external environments RATS! Symptoms of parkinsonism include rigidity,
and send messages to effector organs in response to a situ- akinesia, tremor and shuffling gait.
ation. Different parts of the brain are associated with spe-
cific functions (Fig. 8.1).

Pathogenesis
PARKINSON DISEASE AND
Postmortem analysis of the brains of patients with Parkinson
PARKINSONISM showed a substantially reduced concentration of dopamine
(less than 10% of normal) in the basal ganglia. The basal
Parkinsonism is characterized by a resting tremor, slow ini-
ganglia exert an extrapyramidal neural influence that nor-
tiation of movements (bradykinesia), and muscle rigidity. A
mally maintains smooth voluntary movement.
patient with parkinsonism will present with characteristic
The main pathology in Parkinson disease is a progressive
signs including the following.
degeneration of the dopaminergic neurones of the substan-
• A shuffling gait tia nigra, which project via the nigrostriatal pathway to the
• A blank “mask-like” facial expression corpus striatum (Fig. 8.2). The inhibitory dopaminergic ac-
• Speech impairment tivity of the nigrostriatal pathway is, therefore considerably
• An inability to perform skilled tasks reduced (by 20%–40%) in people with Parkinson disease.
Parkinsonism is most commonly caused by Parkinson The reduction in the inhibitory dopaminergic activity of
disease, although other causes exist. the nigrostriatal pathway results in unopposed cholinergic
Parkinson disease is a progressive neurological disorder neurone hyperactivity from the corpus striatum, which con-
of the basal ganglia that occurs most commonly in elderly tributes to the pathological features of parkinsonism. Frank
people. symptoms of parkinsonism appear only when more than 80%
of the dopaminergic neurones of the substantia nigra have
degenerated. However, peripheral symptoms such as consti-
Aetiology
pation often appear much earlier than movement disorders.
The cause of Parkinson disease is unknown in most cases Untreated Parkinson eventually results in dementia and
(idiopathic), although both endogenous and environmen- death.
tal neurotoxins are known to be responsible for causing
parkinsonism.
Treatment of Parkinsonism
Parkinson disease is progressive, with continued loss of
dopaminergic neurones in the substantia nigra correlating The treatment of parkinsonism is based on correcting the
with worsening of clinical symptoms. The possibility of a imbalance between the dopaminergic and cholinergic sys-
neurotoxic cause has been strengthened by the finding that tems at the basal ganglia (Fig. 8.3). Two major groups of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a drugs are used: drugs that increase dopaminergic activ-
chemical contaminant of heroin, causes irreversible dam- ity between the substantia nigra and the corpus striatum,
age to the nigrostriatal dopaminergic pathway. Thus this and anticholinergic drugs that inhibit striatal cholinergic
damage can lead to the development of symptoms ­similar activity.

113
 Central nervous system

Parietal lobe
• somatic sensation
• body orientation
Frontal lobe
• reasoning Occipital lobe
• planning • vision
• memory
• motor function
• social Wernicke’s area
inhibition
• speech
expression Cerebellum
• coordination of
Broca’s area muscle movements

Temporal lobe Pons

• hearing
• comprehension,
Medulla oblongata
naming
• respiratory and cardiac centres
• verbal
• cough, swallow and vomit centres
memory

Spinal cord
• transmits sensory information
to brain
• transmits commands to
effector organs
Fig. 8.1 Parts of the brain and their known functions.

Corpus striatum Thalamus Motor cortex ceptors (see Fig. 8.3). Dopamine itself is not used, owing to
GABA its inability to cross the blood–brain barrier.
?
Route of administration—L-dopa is administered orally.
ACh
It reaches peak plasma concentrations after 1 to 2 hours, but
only 1% reaches the brain, owing to peripheral metabolism.
Degenerates Indications—L-dopa is used in the treatment of parkin-
in Parkinson's DA sonism (excluding drug-induced extrapyramidal symp-
Impulse travels
disease GABA
via the spinal cord toms) and is often used first line for symptom control.
to muscles Contraindications—Closed-angle glaucoma.
Adverse effects—The extensive peripheral metabolism of
l-dopa means that large doses have to be given to produce
therapeutic effects in the brain. Large doses are more likely
to produce adverse effects including the following.
Substantia nigra
Fig. 8.2 Basal ganglia systems involved in Parkinson
• Nausea and vomiting
disease. ACh, Acetylcholine; DA, dopamine; GABA, • Psychiatric side effects (schizophrenia-like symptoms)
γ-aminobutyric acid. (Modified from Page, C., Curtis, M. • Cardiovascular effects (hypotension)
Walker, M, Hoffman, B. (eds) Integrated Pharmacology, 3rd • Dyskinesias
edn. Mosby, 2006.) Nausea and vomiting are caused by stimulation of dopa-
mine receptors in the chemoreceptor trigger zone in the
Drugs that increase dopaminergic area postrema, which lies outside the blood–brain barrier.
activity Psychiatric side effects are common limiting factors in
l-dopa treatment; these include vivid dreams, confusion
Dopamine precursors and psychotic symptoms more commonly seen in patients
An example of a dopamine precursor is levodopa (l-dopa). with schizophrenia. These effects are probably a result of
Mechanism of action—l-dopa is the immediate precur- increased dopaminergic activity in the mesolimbic area of
sor of dopamine and is able to penetrate the blood–brain the brain, possibly similar to that found pathologically in
barrier to replenish the dopamine content of the corpus schizophrenia (dopaminergic overactivity is implicated in
striatum. l-dopa is decarboxylated to dopamine in the schizophrenia; see p. 125).
brain by dopa decarboxylase, and it has beneficial effects Hypotension is common but usually asymptomatic.
produced through the actions of dopamine acting on D2 re- Cardiac arrhythmias are caused by increased catecholamine

114
 Parkinson disease and parkinsonism 8

Blood–brain barrier MAOB inhibitor

Dopamine precursor
• L-dopa • selegiline
• rasagiline
Dopa
Peripheral dopa COMT inhibitors
decarboxylase – decarboxylase inhibitors • entacapone
• carbidopa • tolcapone
• benserazide
Metabolites
L-dopa
DA Dopa
Peripheral dopamine –
receptor antagonist decarboxylase
COMT Releases dopamine
• domperidone – • amantadine
DA
MAOB

– DA +

DA
Peripheral D2 DA
receptors Reuptake Dopamine agonists
+ • bromocriptine
• ropinirole
• cabergoline
• pramipexole
• lisuride
ACh • apomorphine
ACh D2 receptor
ACh
ACh
Muscarinic
receptors
ACh
Anticholinergic drugs –
• muscarinic antagonists
e.g. benzatropine Excitation Inhibition
orphenadrine

Fig. 8.3 Drugs used to treat parkinsonism and their site of action. ACh, Acetylcholine; COMT, catechol-O-methyl
transferase DA, dopamine; l-dopa, levodopa; MAOB, monoamine oxidase B.

stimulation following the excessive peripheral metabolism block the stimulation of dopamine receptors in the
of l-dopa to noradrenaline. periphery.
Dyskinesias can often develop following treatment • Selegiline and entacapone, monoamine oxidase
with L-dopa and tend to involve the face and limbs. They (MAOB) and catechol-O-methyltransferase (COMT)
usually reflect overtreatment and respond to simple dose inhibitors, respectively, which inhibit dopamine
reduction. metabolism in the CNS.
Three strategies have been developed to optimize l- Therapeutic notes—Initially, treatment with l-dopa
dopa treatment, to maximize the central effects of l-dopa is effective in 80% of patients with possible restoration of
within the brain and minimize its unwanted peripheral near-normal motor function. Although l-dopa restores
effects. These strategies involve coadministration of the dopamine levels in the short term, it has no effect on the
following. underlying degenerative disease process.
• Carbidopa (given with l-dopa as co-careldopa) or As progressive neuronal degeneration continues, the
benserazide (given with l-dopa as co-beneldopa), capacity of the corpus striatum to convert l-dopa to dopa-
inhibitors of dopa decarboxylase in the periphery mine diminishes. This affects the majority of patients within
that cannot penetrate the blood–brain barrier. Hence, 5 years and manifests itself as “end of dose deterioration” (a
extracerebral conversion of l-dopa to dopamine is shortening of the duration of each dose of l-dopa), and the
inhibited. “on-off effect” (rapid fluctuations in clinical state, varying
• Domperidone, a dopamine antagonist, that does not from increased mobility and a general improvement to in-
penetrate the blood–brain barrier and can, therefore creased rigidity and hypokinesia). The latter effect occurs

115
 Central nervous system

suddenly and for short periods (from a few minutes to a ­ otentiated, thus allowing the dose to be reduced by up to
p
few hours), tending to worsen with the length of treatment. one-third. There is also evidence to suggest that selegiline
may slow the progression of the underlying neuronal de-
Dopamine agonists
generation in Parkinson disease.
Examples of dopamine agonists include bromocriptine,
Route of administration—Oral.
ropinirole, cabergoline, pergolide, pramipexole, lisuride
Indications—MAOB inhibitors can be used on their own
and apomorphine.
in mild cases of parkinsonism or in conjunction with l-
Mechanism of action—Bromocriptine, ropinirole, caber-
dopa to reduce ‘end-of-dose’ deterioration in severe parkin-
goline (longer acting), pergolide, pramipexole, lisuride and
sonism. Early treatment with selegiline can delay the need
apomorphine are dopamine agonists selective for the D2 re-
for levodopa therapy.
ceptor (see Fig. 8.3). Apomorphine also has agonist action at
Adverse effects—The adverse effects of MAOB inhibitors
D1 receptors. Pramipexole has a high affinity for D3 receptors.
are caused by potentiation of l-dopa. Common adverse ef-
Route of administration—Usually given orally but apo-
fects include a dry mouth, blurred vision and hypertension
morphine is given via the subcutaneous route.
(see section under antidepressants).
Indications—Dopamine agonists are used in combination
with l-dopa in an attempt to reduce the late adverse effects
of l-dopa therapy (end of dose deterioration and on-off ef- HINTS AND TIPS
fect) or when l-dopa alone does not adequately control the
Note that with the possible exception of
symptoms.
Dopamine agonists are sometimes used in the manage- selegiline, none of the drugs used in the treatment
ment of prolactinomas or acromegaly. of Parkinson disease affects the inevitable
Adverse effects—The adverse effects of dopamine ago- progressive degeneration of nigrostriatal
nists are similar to those of l-dopa (i.e. nausea, postural hy- dopaminergic neurones. The disease process is
potension, psychiatric symptoms), but they tend to be more unaffected, just compensated for by drug therapy.
common and more severe. Apomorphine produces pro-
found nausea and vomiting. Ergot-derived dopamine ag-
onists (bromocriptine, cabergoline, lisuride and pergolide)
can cause fibrosis. Dopamine agonists have also been Catechol-O-methyltransferase inhibitors
linked to the development of compulsive or disinhibited Entacapone and tolcapone are examples of COMT inhibitors.
behaviours (e.g. pathological gambling or hypersexuality). Mechanism of action—Dopamine can also be metabo-
Therapeutic notes—Currently, bromocriptine is the most lized by a second pathway, in addition to that of MAOB. The
used of the dopamine agonists in the treatment of Parkinson enzyme COMT can metabolize dopamine to inactive meth-
disease, mainly in the treatment of younger patients with ylated metabolites. COMT inhibitors reversibly inhibit the
this condition. Patients and their families should be made peripheral breakdown of levodopa by the COMT enzyme.
aware of the potential disinhibited behaviours associated Route of administration—Oral.
with dopamine agonists. Indications—As an adjunct to l-dopa preparations when
end-of-dose is problematic.
Drugs stimulating release of dopamine Contraindications—Phaeochromocytoma.
Amantadine is an example of a drug that stimulates the re- Adverse effects—Nausea, vomiting, abdominal pain and
lease of dopamine (see Fig. 8.3). diarrhoea.
Mechanism of action—Facilitation of neuronal dopa- Therapeutic notes—Because of hepatotoxicity, tolcapone
mine release and inhibition of its reuptake into nerves. should only be prescribed under specialist supervision.
Amantadine has muscarinic receptor antagonist actions.
Route of administration—Oral. Drugs that inhibit striatal cholinergic
Indications—Amantadine has a synergistic effect when
used in conjunction with l-dopa therapy in Parkinson disease. activity
Adverse effects—Anorexia, nausea, hallucinations. Anticholinergic agents/Muscarinic receptor
Therapeutic notes—Amantadine has modest antiparkin- antagonists
sonian effects, but it is only of short-term benefit because Benzatropine, procyclidine and orphenadrine are examples
most of its effectiveness is lost within 6 months of initiating of anticholinergic (muscarinic receptor antagonist) agents
treatment. used in the treatment of Parkinson disease.
Monoamine oxidase inhibitors Mechanism of action—Benzatropine, procyclidine and
Selegiline is an example of a MAOB inhibitor. orphenadrine are muscarinic receptor antagonists that act
Mechanism of action—Selegiline selectively inhibits the at the muscarinic receptors mediating striatal cholinergic
MAOB enzyme in the brain that is normally responsible excitation (see Fig. 8.3). Their major action in the treatment
for the metabolism of dopamine (see Fig. 8.3). By reduc- of Parkinson disease is to reduce the excessive striatal cho-
ing the metabolism of dopamine, the actions of l-dopa are linergic activity that characterizes the disease.

116
 Sleep disorders and hypnotics 8

Route of administration—Oral. Cholinesterase inhibitors

Adverse effects—Typical peripheral anticholinergic effects,
such as a dry mouth and blurred vision, are less common. More Donepezil, galantamine and rivastigmine are cholinesterase
often, patients experience a variety of CNS adverse effects, rang- inhibitors, licensed for use for the treatment of dementia.
ing from mild memory loss to acute confusional states. Mechanism of action—The cholinesterase inhibitors
Therapeutic notes—Termination of anticholinergic treat- prevent the breakdown of acetylcholine (ACh) within the
ment should be gradual because parkinsonism can worsen synaptic cleft, and they enhance endogenous cholinergic
when these drugs are withdrawn. Anticholinergic drugs activity within the CNS and peripheral tissues.
are most effective in controlling tremor rather than other Route of administration—Oral.
symptoms of Parkinson disease. Indications—Mild to moderate dementia in Alzheimer
disease.
Contraindications—Pregnancy, breastfeeding, hepatic
Nonmedical options and renal impairment.
Surgical treatment can be used for severe on-off fluctuations
Adverse effects—Nausea, vomiting, diarrhoea, anorexia
and drug failure. In addition, deep brain simulation has
and agitation.
been used to reverse rigidity and tremor. Transplantation
and gene therapy are potential future options.
N-Methyl-D-aspartate antagonists
CLINICAL NOTE
Memantine is a N-Methyl-D-aspartate (NMDA) antagonist
Mrs Jones, a 62-year-old barrister, presents to her Mechanism of action—Thought to work by selectively
inhibiting excessive and pathological activation of NMDA
General Practitioner (GP) complaining of shaking
receptor.
arms, the right arm more prominently so than the
Route of administration—Oral.
left. She reports that her handwriting is becoming
Indication—Second-line option for patients with moder-
too small to read. She is referred to a neurologist, ate Alzheimer disease or treatment of severe disease.
who observes her face to be expressionless, a Contraindication—History of convulsions.
resting tremor and increased muscle tone. Her Adverse effects—Headache, dizziness, constipation and
power, reflexes, coordination and sensation are drowsiness.
found to be normal. Examination of her gait shows
she is slow getting started and has difficulty
stopping and starting. A diagnosis of Parkinson
disease is made, and the implications discussed
ANXIETY AND SLEEP DISORDERS
with Mrs Jones. Given that her symptoms are
interfering with her daily life, she is commenced Anxiety and anxiolytics
on treatment. She is given co-beneldopa and this Anxiety is a state characterized by psychological symp-
helps to control her symptoms. toms such as a diffuse, unpleasant and vague feeling of ap-
prehension, often accompanied by physical symptoms of
autonomic arousal such as palpitations, light-headedness,
perspiration, “butterflies” and, in some people, restlessness.
Although occasional anxiety is perfectly normal, it is
DEMENTIA AND ALZHEIMER a common and disabling symptom in a variety of mental
illnesses including phobias, panic disorders and obsessive-
DISEASE compulsive disorders. Drugs used to treat such anxiety dis-
orders are called anxiolytics.
Alzheimer disease is a specific process that results in dementia
and is unrelated to the dementias associated with stroke, brain
trauma or alcohol. Its prevalence increases markedly with age.
Alzheimer disease is progressive, and it is associated SLEEP DISORDERS AND
with atrophy of the brain substance, loss of neuronal tissue HYPNOTICS
and deposition of amyloid plaques. The clinical features
include deterioration in cognitive function, disorientation Insomnia is a common and nonspecific disorder that may
and generalized confusion. be reported by 40% to 50% of people at any given time.
Loss of neurones in the forebrain is most marked and a Causes of insomnia include medical illness, alcohol or
relative selective loss of cholinergic neurones most likely ac- drugs, periodic limb movement disorder, sleep apnoea and
counts for the features of this dementia. An obvious therapeu- psychiatric illness. Without an obvious underlying cause, it
tic approach is, therefore restoration of cholinergic function. is known as primary or psychophysiological.

117
 Central nervous system

Hypnotics are drugs used to treat psychophysiological GABA released from nerve terminals binds to postsyn-
(primary) insomnia. The distinction between the treatment aptic GABAA receptors, the activation of which increases
of anxiety and that of sleep disorders is not clear cut, partic- the Cl– conductance of the neurone. Occupation of the ben-
ularly if anxiety is the main impediment to sleep. zodiazepine sites by benzodiazepine receptor agonists en-
hances the actions of GABA on the Cl– conductance of the
γ-Aminobutyric acid receptor neuronal membrane. The barbiturates similarly enhance
the action of GABA, but by occupying a distinct modula-
The γ-aminobutyric acid (GABA) receptors of the GABAA tory site (Fig. 8.4).
type are involved in the actions of some classes of hypnotic/
anxiolytic drugs.
• The benzodiazepines
Anxiolytic and hypnotic drugs
• Newer nonbenzodiazepine hypnotics, e.g. zopiclone The pharmacotherapy of anxiety and sleep disorders
• The now obsolete barbiturates involves several different classes of drug, as shown in
The GABAA receptor belongs to the superfamily of Table 8.1, and nonpharmacological management relying on
ligand-gated ion channels. It consists of several subunits (α, cognitive and behaviour psychotherapy.
β, γ and δ), which form the GABA/Cl– channel complex, as
well as containing benzodiazepine and barbiturate modu- Benzodiazepines
latory receptor sites. The GABA binding site appears to be Benzodiazepines are drugs with anxiolytic, hypnotic, mus-
located on the α and β subunits whereas the benzodiazepine cle relaxation and anticonvulsant actions that are used in
modulatory site is distinct and located on the γ subunit. the treatment of both anxiety states and insomnia.

GABA-ergic Resting GABA GABA

nerve terminal state release release
and
presence of
BDZ

Synaptic
cleft

GABA BDZ
receptor site

Postsynaptic
membrane

Cl− conductance low Cl− conductance moderate Cl− conductance high because of
BDZ potentiation of GABA binding
Postsynaptic membrane Moderate hyperpolarization
at resting potential postsynaptic membrane Postsynaptic membrane
hyperpolarized and refractory to
excitatory depolarization
GABA BDZ Cl−

Fig. 8.4 Diagrammatic representation of the GABAA receptor and how its activity is enhanced by benzodiazepines and
similarly by barbiturates. BDZ, Benzodiazepine; Cl–, chloride ion; GABA, γ-aminobutyric acid. (Modified from Page, C.,
Curtis, M. Walker, M, Hoffman, B. (eds) Integrated Pharmacology, 3rd edn. Mosby, 2006.)

118
 Sleep disorders and hypnotics 8

Table 8.1 Drugs used to treat anxiety and sleep disorders

Anxiolytics Hypnotics
Benzodiazepines (act on GABAA receptors) e.g. Benzodiazepines (act on GABAA receptors) e.g. triazolam,
diazepam, lorazepam temazepam, lormetazepam, nitrazepam
Acting on serotonergic receptors (act on 5-HT1A or 5-HT3 Nonbenzodiazepine hypnotics (act on GABAA receptors)
receptors) e.g. buspirone e.g. zopiclone, zolpidem and zaleplon
Other drugs e.g. propranolol antidepressants Other drugs e.g. chloral hydrate clomethiazole barbiturates
(obsolete) sedative antidepressants sedative antihistamines
5-HT, 5-Hydroxytryptamine; GABA, γ-aminobutyric acid.

Benzodiazepines are marketed as either hypnotics or Table 8.2 Approximate elimination half-lives of the
anxiolytics. It is mainly the duration of action that deter- benzodiazepines and their common uses
mines the choice of drug (see later).
Approximate Commonly
Mechanism of action—Benzodiazepines potentiate the Benzodiazepine half-life (hours) used as
action of GABA, the primary inhibitory neurotransmitter
in the CNS. They do this by binding to a site on GABAA Midazolam 2–4 Anaesthesia
Sedative
receptors, increasing their affinity for GABA. This results
in an increased opening frequency of these ligand-gated Temazepam 8–12 Sleeping pill
Cl– channels, thus potentiating the effect of GABA release Anxiolytic
in terms of inhibitory effects on the postsynaptic cell (see Lormetazepam 10 Sleeping pill
Fig. 8.4). Anxiolytic
Indications—Benzodiazepines are used clinically in the Lorazepam 12 Sleeping pill
short-term relief of severe anxiety and severe insomnia, Anticonvulsant
preoperative sedation (e.g. midazolam), status epilepti- Nitrazepam 24 Anxiolytic
cus (e.g. lorazepam) and acute alcohol withdrawal (e.g.
Diazepam 32 Anticonvulsant
chlordiazepoxide). Sedative
Route of administration—Oral is the usual route.
Intravenous, intramuscular and rectal preparations are also
available. temazepam) are metabolized to inactive compounds, and
Contraindications—Benzodiazepines should not be these are used mainly as sleeping pills because of the rela-
given to people with lung disease, and they have additive tive lack of “hangover” effects in the morning. Some long-
or synergistic effects with other central depressants such as acting agents (e.g. diazepam) are converted to long-lasting
alcohol, barbiturates and H1-receptor antagonists. active metabolites with a half-life longer than the adminis-
Adverse effects—Benzodiazepines have several adverse tered parent drug. With others (e.g. nitrazepam), it is the
effects. parent drug itself that is metabolized slowly. Such drugs
• Drowsiness, ataxia and reduced psychomotor are more suitable for an anxiolytic effect maintained all
performance are common; therefore care is necessary day long, or when early morning waking is the problem.
when driving or operating machinery. Benzodiazepines, in general, are used for acute anxiety, par-
• Dependence becomes apparent after 4 to 6 weeks ticularly for patients with panic disorders. Diazepam and
and is both physical and psychological. The lorazepam are often used in the acute treatment of status
withdrawal syndrome (in 30% of patients) comprizes epilepticus.
rebound anxiety and insomnia, tremulousness and
twitching.
Although in overdose, benzodiazepines alone are rela- CLINICAL NOTE
tively safe when compared with other sedatives, such as
barbiturates. If benzodiazepines are taken in combination Patients with insomnia should be advised about
with alcohol, the CNS-depressant effects are potentiated, sleep hygiene (e.g. limiting caffeine intake, avoid
and fatal respiratory depression can result. Treatment of a napping during the day, regular exercise). In
­benzodiazepine-only overdose is a benzodiazepine antago- addition to medical therapy, patients should be
nist such as flumazenil. referred to psychological services for cognitive
Therapeutic notes—Benzodiazepines are active orally, behavioural therapy.
and they differ mainly with respect to their duration of ac-
tion (Table 8.2). Short-acting agents (e.g. lorazepam and

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 Central nervous system

Nonbenzodiazepine hypnotics Route of administration—Oral.

Zopiclone, zolpidem and zaleplon are the newer-generation Indications—Beta-blockers are indicated in patients
hypnotics that have a short duration of action with little or with predominantly somatic symptoms; this, in turn, may
no hangover effect. Although these drugs are not benzodiaz- prevent the onset of worry and fear. Patients with predom-
epines, they act in a comparable manner to benzodiazepines inantly psychological symptoms may obtain no benefit.
on the GABAA receptor, although not at exactly the same sites. Beta-blockers can be useful in patients with social phobias
They are an effective short-term treatment for insomnia. and to reduce performance anxiety in musicians, for whom
fine motor control may be critical.
Anxiolytic drugs acting at serotonergic Contraindications—Beta-blockers should not be used in
people with asthma.
receptors Adverse effects—Beta-blockers can cause brady-
The serotonergic theory of anxiety suggests that serotoner- cardia, heart failure, bronchospasm and peripheral
gic transmission is involved in anxiety because, in general, vasoconstriction.
stimulation of this system causes anxiety whereas a reduc-
tion in serotonergic neuronal activity reduces anxiety.
The serotonergic theory prompted the development of
HINTS AND TIPS
anxiolytic drugs that act to moderate serotonergic neuro-
transmission while not causing sedation and incoordination. An understanding of the GABAA/Cl– channel
Serotonergic agonists complex is central to the mechanism of action of
Buspirone is a serotonergic (5-HT1A) agonist. several classes of hypnotic/anxiolytic drugs. You
Mechanism of action—In the raphe nucleus, the den- should be aware of what these are.
drites of serotonergic neurones possess inhibitory pre-
synaptic autoreceptors of the 5-HT1A subtype that, when
stimulated, decrease the firing of 5-HT neurones. This class
of anxiolytic agents called the azapirones are thought to Miscellaneous agents
reduce 5-HT transmission by acting as partial agonists at A number of miscellaneous hypnotic agents have been
these 5-HT1A receptors. Buspirone is an example. used historically and are still prescribed under certain
Route of administration—Oral. circumstances.
Indications—Buspirone is indicated for the short-term Chloral hydrate—Chloral hydrate is metabolized to tri-
relief of generalized anxiety disorder. It is less effective in chloroethanol, which is an effective hypnotic. It is cheap but
the management of severe anxiety states or panic attacks. causes gastric irritation and there is no convincing evidence
Contraindications—5-HT1A agonists should not be used that it has any advantage over the newer benzodiazepines.
in people with epilepsy. Chloral hydrate and its derivatives were previously pop-
Adverse effects—The adverse effects of 5-HT1A ago- ular hypnotics for children. Current thinking does not jus-
nists include nervousness, dizziness, headache and light tify the use of hypnotics in children, and these drugs now
headedness. have very limited uses.
In contrast to benzodiazepines, buspirone does not Clomethiazole (chlormethiazole)—Clomethiazole has
cause significant sedation or cognitive impairment, and it been used in the treatment of insomnia in elderly people
carries only a minimal risk of dependence and withdrawal. because it does not cause the hangover effect. Similarly, it
It does not potentiate the effects of alcohol. was used in the management of acute alcohol withdrawal,
Therapeutic notes—The anxiolytic effect of buspirone but this has been replaced by the benzodiazepine, chlor-
gradually evolves over 1 to 3 weeks. Buspirone does not act diazepoxide. In essence, this drug has been superseded and
in the same way as benzodiazepines; when switching, grad- is very rarely prescribed.
ually reduce the benzodiazepine. Antidepressants—If the underlying cause of insomnia
Beta-adrenoceptor blockers is associated with depression, or particularly in depressed
Beta-adrenoceptor blockers or beta-blockers, for exam- patients exhibiting anxiety and agitation, then tricyclic
ple, propranolol, can be very effective in alleviating the antidepressants (TCAs) with sedative actions (p. 122), for
somatic manifestations of anxiety caused by marked sym- example, amitriptyline, may be useful, because they act as
pathetic arousal, such as palpitations, tremor, sweating and hypnotics when given at bedtime. Alternatively, selective
diarrhoea. serotonin reuptake inhibitors (SSRIs; p. 122) may correct
Mechanism of action—Beta-blockers act as antagonists at the mood disorder and lessen the symptoms of anxiety or
beta-adrenoceptors so that excessive catecholamine release insomnia.
does not produce the sympathetic responses of tachycardia, Sedative H1-receptor antagonists (antihista-
sweating, and so on. Beta-blockers are also used in the treat- mines)—The older H1-receptor antagonists, for example,
ment of cardiovascular disease (see Chapter 4). diphenhydramine and promethazine, also have ­muscarinic

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 Affective disorders 8

receptor antagonist actions and cross the blood–brain mood in depressed patients, for example, TCAs and
barrier, commonly causing drowsiness and psychomotor MAO inhibitors.
impairment. • The concentration of monoamines and their
Proprietary brands of diphenhydramine are available metabolites is reduced in the cerebrospinal fluid (CSF)
over the counter to relieve temporary sleep disturbances of depressed patients.
because these drugs are relatively safe. However, prometha- • In some postmortem studies, the most consistent
zine has a long half-life and may result in a hangover effect. finding is an elevation in cortical 5-HT2 binding.
Melatonin—Melatonin is an agonist at melatonin (MT1) However, the monoamine theory cannot explain why:
receptors. Prolonged-release melatonin improves sleep on-
• A number of compounds that increase the
set and quality in patients aged over 55 years with persistent
functional availability of monoamines, for example,
insomnia. It is also used in children with autism who have
amphetamines, cocaine and l-dopa, have no effect on
insomnia.
the mood of depressed patients.
• Some older, atypical antidepressants, for example,
CLINICAL NOTE iprindole, worked without manipulating
monoaminergic systems.
Elderly people are at significant risk of falls and • There is a “therapeutic delay” of 2 weeks between the
confusion as a result of taking hypnotics. They full neurochemical effects of antidepressants and the
should, therefore be prescribed very cautiously in start of their therapeutic effect.
this population. All patients prescribed hypnotics It is unlikely, therefore, that monoamine mechanisms alone
should be advised about the risks of driving (e.g. are responsible for the symptoms of depression. Other
impaired judgement). systems that may be involved in depression include the
following.
• The GABA system
• The neuropeptide systems, particularly vasopressin and
the endogenous opiates
• Secondary-messenger systems also appear to have a
AFFECTIVE DISORDERS crucial role in some treatments.
Affective disorders involve a disturbance of mood (cogni-
tive/emotional symptoms) associated with changes in be- Unipolar affective disorders
haviour, energy, appetite and sleep (biological symptoms). A common unipolar affective disorder is depression, which
Affective disorders can be thought of as pathological ex- is characterized by low mood, malaise, despair, guilt, apathy,
tremes of the normal continuum of human moods, from indecisiveness, low energy and fatigue, changes in sleeping
extreme excitement and elation (mania) to severe depres- pattern, loss of appetite and suicidal thoughts. Attempts
sive states. have been made to classify types of depression as either “re-
There are two types of affective disorder: unipolar affec- active” or “endogenous” in origin.
tive disorders and bipolar affective disorders. Reactive depression is where there is a clear psy-
chological cause, for example, bereavement. It involves
Monoamine theory of depression less-severe symptoms and less likelihood of biological
disturbance. It affects 3% to 10% of the population, with
The aetiology of major depressive disorders is not clear. the incidence increasing with age, and it is more common
Genetic, environmental and neurochemical influences have in females.
all been examined as possible aetiological factors. Endogenous depression is where there is no clear cause
The most widely accepted neurochemical explanation and more severe symptoms, for example, suicidal thoughts,
of endogenous depression involves the monoamines (nor- and a greater likelihood of biological disturbance, for ex-
adrenaline; serotonin [5-HT]; dopamine). The original ample, insomnia, anorexia. Some 5% of the population ex-
hypothesis of depression, “the monoamine theory”, stated periences an episode of depression, and severe depression
that depression resulted from a functional deficit of these requiring treatment affects 1 in 4 women and 1 in 10 men.
transmitter amines, whereas conversely mania was caused However, antidepressants are not recommended for mild
by an excess. depression and are generally prescribed only for moderate
The monoamine theory explains why: to severe depression.
• Drugs that deplete monoamines are depressant, for The distinction between reactive and endogenous de-
example, reserpine and methyldopa. pression is of importance because there is some evidence
• A wide range of drugs that increase the functional that depressions with endogenous features tend to respond
availability of monoamine neurotransmitters improve better to drug therapy.

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 Central nervous system

Treatment of unipolar depressive • Histamine-blocking effects leading to sedation

• Weight gain
disorders
TCAs are relatively dangerous in overdose. Patients present
The major classes of drug that are used to treat depres- with confusion, mania, and potentially fatal arrhythmias
sion, and their mechanisms of action, are summarized in caused by the cardiotoxic nature of the drug.
Table 8.3. Therapeutic notes—No individual TCA has superior an-
tidepressant activity, and the choice of drug is usually de-
Tricyclic antidepressants and related termined by the most acceptable or desired side effects. For
drugs example, drugs with sedative actions, such as amitriptyline
Examples of TCAs and related drugs include amitriptyline, or trimipramine, are the TCAs of choice for patients in agi-
imipramine, dosulepin (dothiepin) and lofepramine. tated or anxious states. The most recent TCA, lofepramine,
Mechanism of action—TCAs act by blocking 5-HT and causes fewer antimuscarinic side effects and is less danger-
noradrenaline uptake into the presynaptic terminal from the ous if taken in overdose.
synaptic cleft (Fig. 8.5). They also have a certain affinity for Therapeutic effects take 2 to 3 weeks to develop. TCA-
H1 and muscarinic receptors, and for α1- and α2-receptors. related antidepressants should be withdrawn slowly.
Contraindications—TCAs and related drugs should not Note that amitriptyline is sometimes used in lower doses
be used in the following situations. for the treatment of neuropathic pain.
• Recent myocardial infarction or arrhythmias
(especially heart block) because TCAs increase the risk
Selective serotonin reuptake inhibitors
SSRIs are the most recently introduced class of antide-
of conduction abnormalities.
pressant agent. Fluoxetine (Prozac) is an SSRI. Other ex-
• Manic phase
amples include citalopram, fluvoxamine, paroxetine and
• Severe liver disease
sertraline.
• Epilepsy, where TCAs lower the seizure threshold
Mechanism of action—SSRIs act with a high specificity
• Patients taking other anticholinergic drugs, alcohol
for potent inhibition of serotonin reuptake into nerve ter-
and adrenaline alongside TCAs potentiate the effects of
minals from the synaptic cleft, while having only minimal
these.
effects on noradrenaline uptake (see Fig. 8.5). They block
Lidocaine is contraindicated in combination with TCAs, serotonin transporters, which belong to a class of Na+/
owing to a potentially fatal drug interaction. Cl–-coupled transporters.
Adverse effects—Although TCAs are an effective therapy Contraindications—SSRIs should not be used with MAO
for depression, their adverse effects can reduce patient com- inhibitors because the combination can cause a potentially
pliance and acceptability. Side effects include the following. fatal serotonergic syndrome of hyperthermia and cardio-
• Muscarinic blocking effects such as a dry mouth, vascular collapse.
blurred vision, constipation Adverse effects—The side-effect profile of SSRIs is much
• α-Adrenergic blocking effects causing postural better than that of TCAs and MAO inhibitors because there
hypotension are no amine interactions, anticholinergic actions, adren-
• Noradrenaline uptake block in the heart, increasing the ergic blockade or toxic effects in overdose. Adverse effects,
risk of arrhythmias however, caused by their effect on serotonergic nerves

Table 8.3 Major classes of antidepressant drugs and their mechanisms of action
Class of antidepressant drug Examples Mode of action
Tricyclic antidepressants (TCAs) Amitriptyline imipramine lofepramine Nonspecific blockers of monoamine
uptake
Selective serotonin reuptake inhibitors Fluoxetine paroxetine sertraline Selective blockers of 5-HT reuptake
(SSRIs)
Serotonin-noradrenaline reuptake Venlafaxine Selective blockers of 5-HT and
inhibitors (SNRIs) noradrenaline uptake
Monoamine oxidase inhibitors Phenelzine Noncompetitive, nonselective
(MAOIs) Tranylcypromine irreversible blockers of MAOA and
MAOB
Reversible inhibitors of MAOA (RIMAs) Moclobemide Reversibly inhibit MAOA selectively
Atypical Reboxetine mirtazapine Act by various mechanisms that are
poorly understood
5-HT, 5-Hydroxytryptamine; MAO, monoamine oxidase.

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 Affective disorders 8

Metabolites Monoaminergic nerve terminal

i.e. either noradrenergic or
Monoamine oxidase inhibitors
serotinergic nerve, not both
e.g. • phenelzine Degradation
• tranylcypromine
−
Monoamine
reversible inhibitors of MAOA
MAO synthesis
e.g. • moclobemide
(i.e. 5-HT or NA)

5-HT
NA
Selective serotonin reuptake 5-HT
inhibitors NA
e.g. • fluoxetine
• paroxetine 5-HT
• sertraline
− feedback
NA inhibition
− of release

5-HT reuptake Release

NA
NA reuptake
Tricyclic antidepressants
e.g. • amitriptyline NA
• imipramine 5-HT
− NA
Serotonin−noradrenaline Synaptic cleft
reuptake inhibitors
5-HT 5-HT NA
e.g. • venlafaxine

5-HT receptor
NA receptor
Postsynaptic cell

Fig. 8.5 Site of action of the major classes of drug used to treat unipolar depression. 5-HT, 5-Hydroxytryptamine
(serotonin); MAO, monoamine oxidase; NA, noradrenaline.

throughout the body, include nausea, diarrhoea, insomnia, Adverse effects—The adverse effects of SNRIs are similar
anxiety and agitation. Sexual dysfunction is sometimes a to those of SSRIs, but they occur with lower frequency.
problem. Therapeutic notes—The pharmacological effects of ven-
Therapeutic notes—SSRIs have a similar efficacy to that lafaxine are similar to those of the TCAs, but adverse effects
of TCAs. It is their clinical advantages and lack of side ef- are reduced because it has little affinity for cholinergic and
fects that have led to their popularity. SSRIs are now the histaminergic receptors or α-adrenoceptors.
most widely prescribed antidepressants because they are
first-line treatment for depression.
CLINICAL NOTE
Serotonin-noradrenaline reuptake
inhibitors Mild depression can be managed with cognitive
Venlafaxine is the most commonly used serotonin- behavioural therapies (CBT). However effective
noradrenaline reuptake inhibitor (SNRI)-type anti­ management of moderate to severe depression
depressant. often requires CBT and a combination of
Mechanism of action—SNRIs cause potentiation of neu- antidepressants. In severe, life-threatening cases,
rotransmitter activity in the CNS, by blocking the norepi- electroconvulsive therapy may be used to gain fast
nephrine and serotonin reuptake transporter (see Fig. 8.5). and short-term improvement of severe symptoms
Contraindications—The drug interactions of SNRIs are when other treatment options have failed.
much like those of SSRIs; however, extra care must be taken
with hypertensive patients as venlafaxine raises blood pressure.

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 Central nervous system

Monoamine oxidase inhibitors Neither reboxetine nor mirtazapine are currently first-line
Examples of irreversible MAO inhibitors include phenelzine, drugs for the treatment of depression. Tryptophan requires spe-
tranylcypromine and isocarboxazid, and an example of a re- cialist supervision because of the stated adverse effect.
versible inhibitor of MAOA (RIMAs) is moclobemide.
Mechanism of action—MAO inhibitors block the action
of MAOA and MAOB, which are neuronal enzymes that me-
Bipolar affective disorder
tabolize the monoamines (noradrenaline, 5-HT and dopa- Bipolar affective disorder presents with mood and be-
mine) (see Fig. 8.5). MAO has two main isoforms, MAOA haviour oscillating between depression and mania, and it is,
and MAOB. Inhibition of the MAOA form correlates best previously known as manic-depressive disorder.
with antidepressant activity. Both nonselective irreversible Bipolar affective disorder develops earlier in life than
blockers of MAOA and MAOB, and drugs that reversibly in- unipolar depressive disorders, and it tends to be inherited.
hibit MAOA are available. It affects 2% of the population, and it can have associated
Adverse effects—Dietary interactions may occur, such elements of psychotic phenomena.
as the “cheese reaction”. MAO in the gut wall and liver nor-
mally breaks down ingested tyramine. When the enzyme is
inhibited, tyramine reaches the circulation, and this causes
Treatment of bipolar affective
the release of noradrenaline from sympathetic nerve ter- disorders
minals; this can lead to a severe and potentially fatal rise in Bipolar affective disorder is treated with a combination
blood pressure. Patients on MAO inhibitors must, therefore of mood stabilizers and antidepressants, and sometimes
avoid foods rich in tyramine, which include cheese, game antipsychotics. Mood stabilizers include lithium and
and alcoholic drinks. Preparations containing sympathomi- carbamazepine.
metic amines (e.g. cough mixtures and nasal decongestants)
should also be avoided. MAO inhibitors are not specific, and
they reduce the metabolism of barbiturates, opioids and al-
Lithium
Lithium is administered as lithium carbonate, and it is the
cohol. Side effects include CNS stimulation causing excite-
most widely used mood stabilizer, with antimanic and anti-
ment and tremor, sympathetic blockade causing postural
depressant activity.
hypotension, and muscarinic blockade causing a dry mouth
Mechanism of action—The mechanism of action of
and blurred vision. Phenelzine can be hepatotoxic.
lithium is unclear, but it probably involves modulation of
Therapeutic notes—Response to treatment may be de-
secondary-messenger pathways of cyclic adenosine mono-
layed for 3 weeks or more. Patients with depression or pho-
phosphate and inositol triphosphate. It is known that lith-
bias with atypical, hypochondriac or hysterical features are
ium inhibits the pathway for recapturing inositol for the
said to respond best to MAO inhibitors. MAO inhibitors
resynthesis of polyphosphoinositides. It may exert its effect
are largely reserved for depression refractory to other an-
by reducing the concentrations of lipids important in signal
tidepressants because of the dietary and drug interactions
transduction in neurones in the brain.
outlined earlier.
Indications—Lithium salts are mainly used in the pro-
Atypical antidepressants phylaxis and treatment of bipolar affective disorder (usually
Examples of atypical antidepressants include reboxetine, second line), but also in the prophylaxis and treatment of
mirtazapine and tryptophan. acute mania, and in the prophylaxis of resistant recurrent
Mechanism of action—Reboxetine is a selective inhibi- depression.
tor of noradrenaline reuptake, increasing the concentration Contraindications—Some drugs may interact causing
of this neurotransmitter in the synaptic cleft. Mirtazapine a rise in plasma lithium concentration and so should be
has α2-adrenoceptor-blocking activity, which, by acting on avoided. Such drugs include antipsychotics, nonsteroidal
inhibitory α2-autoreceptors on central noradrenergic nerve antiinflammatory drugs (NSAIDs), diuretics and cardioac-
endings, may increase the amount of noradrenaline in the tive drugs. Lithium is excreted via the kidney, and caution
synaptic cleft. Tryptophan is an amino acid precursor for should be used in patients with renal impairment.
serotonin. Adverse effects—Lithium has a long plasma half-life and a
Contraindications—The contraindications for atypical narrow therapeutic window; therefore side effects are com-
antidepressants are similar to those for TCAs. mon and plasma concentration monitoring is essential. Early
Adverse effects—Atypical antidepressants generally cause side effects include thirst, nausea, diarrhoea, tremor and
less autonomic side effects and are less dangerous in over- polyuria; late side effects include weight gain, oedema, acne,
dose, owing to their lower cardiotoxicity compared with nephrogenic diabetes insipidus and hypothyroidism. Toxicity/
TCAs. Mirtazapine may cause agranulocytosis. Tryptophan overdose (serum level > 2–3 mmol/L) effects include vomit-
is associated with eosinophilic myalgia syndrome. ing, diarrhoea, tremor, ataxia, confusion and coma.
Therapeutic notes—Mirtazapine is a sedative, and it is, there- Therapeutic notes—Careful monitoring after initiation
fore used in depression when a degree of sedation is ­desirable. of treatment is essential.

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 Psychotic disorders 8

Carbamazepine auditory (hearing voices) and occur in 60% to 70% of

patients with schizophrenia, but they can be visual,
Carbamazepine is as effective as lithium in the prophylaxis tactile or olfactory.
of bipolar affective disorder and acute mania, particularly in • Thought alienation and disordered thought:
rapidly alternating bipolar affective disorder. However, it is belief that one's thoughts are under the control of
most commonly prescribed as an anticonvulsant (see later). an outside agency (e.g. aliens, MI5). This type of
Mechanism of action—Carbamazepine is a GABA ago- belief is common, and thought processes are often
nist, and this may be the basis of its antimanic properties. incomprehensible.
The relevance of its effect in stabilising neuronal sodium
Negative symptoms include:
and calcium channels is unclear.
Adverse effects—Drowsiness, diplopia, nausea, ataxia, • Poverty of speech: restriction in the amount of
rashes and headache; blood disorders such as agranulocyto- spontaneous speech
sis and leukopenia; and drug interactions with lithium, an- • Flattening of affect: loss of normal experience and
tipsychotics, TCAs and MAO inhibitors. Many other drugs expression of emotion
can be affected by the effect of carbamazepine on inducing • Social withdrawal
hepatic enzymes. Diplopia, ataxia, clonus, tremor and seda- • Anhedonia: inability to experience pleasure
tion are associated with acute carbamazepine toxicity. • Apathy: reduced drive, energy, and interest
Therapeutic notes—At the start of treatment with carba- • Attention deficit: inattentiveness at work or at home
mazepine, plasma concentrations should be monitored to The distinction between the positive and negative symp-
establish a maintenance dose. toms found in schizophrenia is of importance because
neuroleptic drugs tend to have the most effect on positive
symptoms, whereas negative symptoms are fairly refractory
to treatment and carry a worse prognosis.
PSYCHOTIC DISORDERS
Theories of schizophrenia
Psychotic disorders are characterized by a mental state that
The cause of schizophrenia remains mysterious. Any the-
is out of touch with reality, involving a variety of abnormal-
ory of the cause of schizophrenia must take into account
ities of perception, thought and ideas.
the strong, although not invariable, hereditary tendency
Psychotic illnesses include the following.
(50% concurrence in monozygotic twins), as well as the
• Schizophrenia environmental factors known to predispose towards its
• Schizoaffective disorder development.
• Delusional disorders Many hypotheses have been suggested to explain
• Some depressive and manic illnesses. the manifestations of schizophrenia at the level of neu-
Neuroleptics, or antipsychotics, are drugs used in the rotransmitters in the brain. The potential role of exces-
treatment of psychotic disorders. sive dopaminergic activity, in particular, has attracted
considerable attention. Evidence for this theory includes
Schizophrenia the following.
• Most antipsychotic drugs block dopamine receptors,
Epidemiology the clinical dose being proportional to the ability to
Schizophrenia characteristically develops in people aged 15 block D2 receptors.
to 45 years; it has a relatively stable cross-cultural incidence • Single photon emission computed tomography
affecting 1% of the population, with a greater proportion (SPECT) ligand scans show that there are increased D2
being male. receptors in the nucleus accumbens of patients with
schizophrenia.
Symptoms and signs • Psychotic symptoms can be induced by drugs that
Schizophrenia is a psychotic illness characterized by multi- increase dopaminergic activity, (e.g. antiparkinsonian
ple symptoms affecting thought, perceptions, emotion and agents).
volition. However, there is much evidence that the dopaminergic
Symptoms fall into two groups (positive and negative) theory fails to explain. Current research indicates a likely
that may have different underlying causes. role for other neurotransmitters in schizophrenia, includ-
Positive symptoms include: ing 5-HT, GABA and glutamate. Although the dopamine
• Delusions: false personal beliefs held with absolute theory cannot explain many of the features and findings
conviction in schizophrenia, most current pharmacological treatment
• Hallucinations: false perceptions in the absence of (typical neuroleptics) is aimed at dopaminergic transmis-
a real external stimulus; most commonly, these are sion (Table 8.4).

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 Central nervous system

Table 8.4 Classes of dopamine receptor

2nd messenger +
Type cellular effects Location in CNS and postulated function
D1 cAMP increase Mainly postsynaptic inhibition
Functions unclear
D2 cAMP decrease K+ Mainly presynaptic inhibition of dopamine synthesis/release in nigrostriatal,
conductance up Ca2+ mesolimbic and tuberoinfundibular systems
conductance down Affinity of neuroleptics for D2 receptors correlates with antipsychotic potency
D3 Unknown Localized mainly in limbic and cortical structures concerned with cognitive
functions and emotional behaviour
Not clear whether antipsychotic effects of neuroleptics are mediated by the D3
type
D4 Unknown Similar to D3 type; clozapine has particular affinity for D4 receptors
cAMP, Cyclic adenosine monophosphate; CNS, central nervous system.

Neuroleptics take days or weeks to work, suggesting that

CLINICAL NOTE secondary effects (e.g. increases in the number of D2 recep-
tors in limbic structures) may be more important than a di-
Mr Sarhan is a 28-year-old postman who was
rect effect of D2 receptor block.
found at 5 AM standing on the edge of Tower
Most neuroleptics also block other monoamine recep-
Bridge and shouting “Freedom is through flying”. tors, and this is often the cause of some of the side effects
He was previously seen erratically throwing of these drugs.
his mailbag into the River Thames. The police The distinction between typical and atypical groups is
managed to grab him just before he jumped and not clearly defined, but it rests partly on the incidence of
took him to A&E. The on-call psychiatrist sees extrapyramidal motor side effects, and partly on receptor
him. Mr Sarhan is very agitated and shouting specificity. Atypical neuroleptics are less prone to producing
“They gave me powers to fly! Let me prove it! I can motor disorders than other drugs, and they tend to have dif-
prove it! Don't try to steal my powers, go away!” A ferent pharmacological profiles with respect to dopamine
and other receptor specificity.
mental state examination supports a diagnosis of
Route of administration—All the neuroleptic drugs can
schizophrenia. A collateral history is obtained from
be given orally, although some of the typical drugs can be
his parents, who say that he has been acting more
given by the intramuscular route, which prolongs their re-
and more bizarrely over the past year, but they lease and aids drug compliance.
just thought it was caused by stress. Shortly after
admission, he began shouting abuse and pushing Typical neuroleptics
past staff with the intention of leaving despite their
discouragement. He was rapidly tranquillized using Phenothiazines
haloperidol and sectioned under section 2 of the This class of compounds is subdivided into three groups by
Mental Health Act. the type of side chain attached to the pharmacophore (the
phenothiazine ring) (see Table 8.5). Side-effect patterns
vary with the different side chains.
• Propylamine side chains: for example, in
Treatment of schizophrenia chlorpromazine, produce strong sedation, a moderate
The treatment of schizophrenia and all other psychotic muscarinic block, and moderate motor disturbance.
illnesses involves the use of antipsychotic medication, Indicated for violent patients, owing to their sedative
the neuroleptic drugs. Neuroleptic drugs produce a gen- effect.
eral improvement in all the acute positive symptoms of • Piperidine side chains: for example, in thioridazine,
schizophrenia, but it is less clear how effective they are produce moderate sedation, strong muscarinic block
in the treatment of chronic schizophrenia and negative and low motor disturbance. Favoured for use in elderly
symptoms. patients.
Mechanism of action—Antipsychotic drugs have a vari- • Piperazine side chains: for example, in fluphenazine,
ety of structures and fall into various classes (Tables 8.4 and produce low sedation, low muscarinic block and strong
8.5). There is a strong correlation between clinical potency motor disturbance. Contraindicated for use in elderly
and affinity for D2 receptors among the typical neuroleptics. patients, owing to the motor effects.

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 Psychotic disorders 8

Table 8.5 Classes of neuroleptic drugs

Class Chemical classification Examples
Typical antipsychotics Phenothiazines: Chlorpromazine
propylamine side chains Thioridazine
piperidine side chains Fluphenazine
piperazine side chains Haloperidol
Butyrophenones Flupentixol
Thioxanthines
Atypical antipsychotics Dibenzodiazepines Clozapine,
Dopamine/5-HT blockers: olanzapine
diphenylbutylpiperidines Pimozide
substituted benzamides Sulpiride
benzixasoles Risperidone
5-HT, 5-Hydroxytryptamine

Butyrophenones and thioxanthenes Dopamine/5-HT blockers

The butyrophenone and thioxanthene groups of com- Examples of dopamine/5-HT blockers include the diphen-
pounds have the same profile of low sedation, low musca- ylbutylpiperidines (e.g. pimozide and sulpiride) and the
rinic block and high incidence of motor disturbance. benzoxazoles (e.g. risperidone).
An example of a butyrophenone compound is haloperi- Sulpiride, and the newer agent pimozide show high se-
dol; flupentixol is an example of the thioxanthenes. lectivity for D2 receptors compared with D1 or other neu-
rotransmitter receptors. Both drugs are effective in treating
Atypical neuroleptics schizophrenia but sulpiride is claimed to have less tendency
to cause adverse motor effects. Pimozide appears to be sim-
Dibenzodiazepines ilar to conventional neuroleptic agents, but it has a longer
Dibenzodiazepines such as clozapine and olanzapine have a duration of action, allowing once-daily medication.
low affinity for the D2 receptor and a higher affinity for D1 Benzoxazoles such as risperidone show a high affin-
and D4 receptors. ity for 5-HT receptors and a lower affinity for D2 re-
Indications—Olanzapine is recommended as first-line ceptors. With this class of drugs, extrapyramidal motor
treatment of patients with schizophrenia. Clozapine is pre- side effects occur with less frequency than with “classic”
scribed in refractory cases given the 1% risk of potentially neuroleptics.
fatal neutropenia. Quetiapine fumarate is a dibenzothiazepine derivative that
Adverse effects—Clozapine has a low incidence of adverse acts as an antagonist at the D1, D2, 5-HT1A and 5-HT2 receptors.
motor effects because of its low affinity for the D2 receptor. Aripiprazole appears to mediate its antipsychotic effects
Side effects of dibenzodiazepines include hypersalivation, primarily by partial agonism at the D2 receptor. It is also a
sedation, weight gain, tachycardia and hypotension. partial agonist at 5-HT1A receptors, and similar to the other
Therapeutic notes—Olanzapine is similar to clozapine, atypical antipsychotics, aripiprazole displays an antagonist
although it carries less risk of agranulocytosis. profile at the 5-HT2A receptor, as well as a moderate affinity
for histamine and α-adrenergic receptors.
Zotepine has good efficacy against negative symptoms of
schizophrenia. This is thought to be caused by its noradren-
aline reuptake inhibition. It also has a high affinity for the
HINTS AND TIPS dopamine D1 and D2 receptors. It also affects the 5-HT2A,
Antipsychotic medications are used in the 5-HT2C, 5-HT6 and 5-HT7 receptors.
treatment of acute mania and schizophrenia.
Olanzapine, quetiapine, risperidone and Adverse effects of neuroleptics
haloperidol are commonly prescribed. If a Neuroleptic drugs cause a variety of adverse effects
combination of two antipsychotics is ineffective (Box 8.1). The majority of the unwanted effects of neuro-
or not tolerated, then lithium is added. In cases leptics can be inferred from their pharmacological actions,
where lithium is inappropriate, sodium valproate is such as the disruption of dopaminergic pathways (the ma-
sometimes used. jor action of most neuroleptics) and the blockade of mono-
amine and other receptors, including muscarinic receptors,
α-adrenoceptors and histamine receptors.

127
 Central nervous system

BOX 8.1 ADVERSE EFFECTS OF THE

.
Psychological effects
NEUROLEPTICS . antipsychotic

• Acute neurological effects: acute dystonia,

. impaired performance
sedation

akathisia, parkinsonism
• Chronic neurological effects: tardive dyskinesia,
tardive dystonia Cortex/
limbic system
• Neuroendocrine effects: amenorrhoea,
galactorrhoea, infertility
• Idiosyncratic: neuroleptic malignant syndrome
• Anticholinergic: dry mouth, blurred vision,
constipation, urinary retention, ejaculatory
failure Mesolimbic pathway
• Antihistaminergic: sedation No
• Antiadrenergic: hypotension, arrhythmia
entry
• Miscellaneous: photosensitivity, heat sensitivity,
cholestatic jaundice, retinal pigmentation
D2
receptor
blockade
(Modified from Page et al. 2006.)
Tuberoinfundibular Nigrostriatal pathway
pathway
In addition, individual drugs may cause immunolog-
ical reactions or have their own characteristic side-effect
profile.

Adverse effects on the dopaminergic pathways

There are three main dopaminergic pathways in the brain Pituitary gland
(Fig. 8.6). Basal ganglia/
striatum
• Mesolimbic and/or mesocortical dopamine pathways
running from groups of cells in the midbrain to the
nucleus accumbens and amygdala. This pathway affects
.
Neuroendocrine effects
.
Movement disorders
thoughts and motivation. . hyperprolactinaemia
.parkinsonism

• Nigrostriatal dopamine pathways running from . amenorrhoea

.dystonia

. galactorrhoea
.akathisia
the midbrain to the caudate nuclei. This pathway is
. gynaecomastia tardive dyskinesia

•
important in smooth motor control.
Tuberoinfundibular neurones running from the
. infertility
weight gain

hypothalamus to the pituitary gland, the secretions of Fig. 8.6 Effect of D2 dopamine receptor blockade on the
which they regulate. dopaminergic pathways in the brain.

Antagonism of dopamine receptors leads to interference

with the normal functioning of these pathways, bringing
Blocking of dopamine receptors in the basal ganglia
about unwanted side effects, as well as the desired antipsy-
(corpus striatum) frequently results in distressing and dis-
chotic effect. This antagonism is the cause of the most seri-
abling movement disorders. Two main types of movement
ous side effects associated with neuroleptic use.
disorder occur. Acute reversible parkinsonian-like symp-
• Psychological effects because of D2 receptor blockade toms (tremor, rigidity and akinesia) are treated by dose re-
of the mesolimbic/mesocortical pathway. duction, anticholinergic drugs or switching to an atypical
• Movement disorders because of D2 receptor blockade neuroleptic. Slowly developing tardive dyskinesia, often
of the nigrostriatal pathways. irreversible, and manifesting as involuntary movements of
• Neuroendocrine disorders because of D2 receptor the face, trunk and limbs, appear months or years after the
blockade of the tuberoinfundibular pathway. start of neuroleptic treatment. It may be a result of prolif-
Neuroleptics are thought to exert their antipsychotic effects eration or sensitization of dopamine receptors. Incidence
by antagonism of dopaminergic nerves in the mesolimbic is unpredictable, and it affects approximately 20% of long-
mesocortical pathway. However, as a side effect of mesolim- term users of neuroleptics. Treatment is generally unsuc-
bic and mesocortical dopaminergic inhibition, sedation and cessful. The newer atypical neuroleptics may be less likely
impaired performance are common. to induce tardive dyskinesia.

128
 Epilepsy 8

By reducing the negative feedback on the anterior pi- Route of administration—Oral.

tuitary, oversecretion of prolactin can result (hyperprolac- Indications—Used to treat attention deficit hyperactiv-
tinaemia). This can lead to gynaecomastia, galactorrhoea, ity disorder (ADHD) in children. Occasionally used in the
menstrual irregularities, impotence and weight gain in treatment of narcolepsy.
some patients (see Fig. 8.6). Contraindications—Moderate to severe hypertension,
structural cardiac disease, hyperthyroidism.
Adverse effects from nonselective receptor Adverse effects—Gastrointestinal upset, palpitations and
blockade weight loss. Hallucinations, paranoia and aggressive be-
The adverse effects of neuroleptics from nonselective recep- haviour can also occur if taken for a long time.
tor blockade include the following.
• Anticholinergic effects caused by muscarinic-receptor Methylphenidate
antagonism, such as dry mouth, urinary retention, Methylphenidate is also given orally in the treatment of
constipation, blurred vision, and so on. ADHD. It produces a profound and sustained elevation of
• Adverse effects caused by α-adrenoceptor antagonism. extracellular noradrenaline and dopamine.
Many neuroleptics have the capacity to block
α-adrenoceptors and cause postural hypotension.
• Adverse effects caused by antagonism of central
histamine H1 receptors may contribute to sedation. EPILEPSY
Adverse effects caused by individual drugs or
Epilepsy is a chronic disease, in which seizures result from
immune reactions
the abnormal high-frequency discharge of a group of neu-
The neuroleptic drug clozapine can cause neutropenia
rones, starting focally and spreading to a varying extent
as a result of toxic bone marrow suppression, whereas
to affect other parts of the brain. According to the focus
pimozide can cause sudden death secondary to cardiac
and spread of discharges, seizures may be classified in
arrhythmia.
two ways.
Immune reactions to neuroleptic drugs can include
dermatitis, rashes, photosensitivity and urticaria. Such re- • Partial (focal), which originate at a specific focus and
actions are more common with the phenothiazines, which do not spread to involve other cortical areas.
can also cause deposits in the cornea and lens. • Generalized, which usually have a focus (often in the
temporal lobe) and then spread to other areas.
Neuroleptic malignant syndrome Different epileptic syndromes can be classified on the ba-
This is the most lethal adverse effect of neuroleptic use. It sis of seizure type and pattern, with other clinical features
is an idiosyncratic reaction of unknown pathophysiology. (such as age of onset), anatomic location of focus, and aeti-
Symptoms include fever, extrapyramidal motor disturbance, ology taken into account.
muscle rigidity and coma. Urgent treatment is indicated.

Common types of epileptic

HINTS AND TIPS syndrome
Epileptic syndromes result from either generalized seizures
Neuroleptics have many side effects, some related
or focal seizures (Table 8.6).
to their principal mechanism of action (dopamine
Generalized seizures involve loss of consciousness, and it
receptor antagonism) and some unrelated to may be convulsive or nonconvulsive.
this. Learn these well because they are a popular
• Tonic-clonic (grand-mal seizures): convulsive generalized
examination topic.
seizures characterized by periods of tonic muscle rigidity
followed later by jerking of the body (clonus).

Drugs used for attention deficit

hyperactivity disorder Table 8.6 Classification of common epileptic syndromes
Partial (local, focal)
Amphetamines seizures Generalized seizures
Dexamphetamine is an example.
Mechanism of action—Amphetamines act by releasing Psychomotor (temporal Tonic-clonic seizure or grand-
lobe) epilepsy mal epilepsy
monoamines (dopamine and noradrenaline) in the brain.
The main central effects of amphetamine-like drugs are in- Partial motor epilepsy Absence seizure or petit-mal
creased stamina, anorexia and insomnia. epilepsy

129
 Central nervous system

• Absence (petit-mal seizures): generalized seizures Inhibition of ion channels involved in neuronal
characterized by changes in consciousness lasting less excitability
than 10 seconds. They occur most commonly in children, Drugs such as phenytoin, carbamazepine and valproate in-
where they can be confused with day-dreaming. hibit the “fast” sodium current. These drugs bind preferen-
The effect on the body of focal seizures depends on the loca- tially to inactivated (closed) sodium channels, preventing
tion of the abnormal signal focus: for example, involvement them from opening. The high-frequency repetitive depolar-
of the motor cortex will produce convulsions whereas in- isation of neurones during a seizure increases the propor-
volvement of the brainstem can produce unconsciousness. tion of sodium channels in the inactivated state susceptible
Psychomotor or temporal lobe epilepsy results from a par- to the blockade. Eventually, sufficient sodium channels be-
tial seizure with cortical activity localized to the temporal come blocked so that the fast neuronal sodium current is
lobe. Such seizures are characterized by features including insufficient to cause a depolarization. Note that neuronal
impaired consciousness or confusion, amnesia, emotional transmission at normal frequencies is relatively unaffected
instability, atypical behaviour and outbursts. because a much smaller proportion of the sodium channels
Partial motor seizures have their focus in cortical motor re- are in the inactivated state.
gions and they present with convulsive or tonic activity corre- Absence seizures involve oscillatory neuronal activity
sponding to the neurones involved, for example, the left arm. between the thalamus and the cerebral cortex. This oscil-
Another type of epileptic syndrome is status epilepticus. lation involves “T-type” calcium channels, which produce
This is a state in which seizures follow each other without low-threshold spikes and consequently cause groups of cells
consciousness being regained or if a seizure is prolonged. to fire in bursts. Ethosuximide inhibits T-type low-threshold
Status epilepticus constitutes a medical emergency because and reduces the fast-inactivating calcium current, dampen-
of the risk of respiratory arrest and hypoxia. ing the thalamocortical oscillations that are critical in the
generation of absence seizures.

Causes of epilepsy Inhibition of excitatory transmission

Drugs that block excitatory amino acid receptors (NMDA
The aetiology of epilepsy is unknown in 60% to 70% of cases, antagonists) have been shown to be antiepileptic in an-
but a family history is an important factor. Damage to the imal models. Such drugs may prove useful in the clinical
brain, for example, by tumours, head injury, infections or treatment of epilepsy in the future. Lamotrigine, one of the
cerebrovascular accident, may subsequently cause epilepsy. newer antiepileptic agents, inhibits the release of glutamate
The neurochemical basis of the abnormal discharges as one of its actions, and this may contribute to its antiepi-
in epilepsy is not known, but it may involve altered GABA leptic activity.
metabolism.
Enhancement of GABA-mediated inhibition
This can take any of the following forms.
HINTS AND TIPS
• Enhancement by direct GABA agonist properties,
Remember that epilepsy is simply aberrant for example, by gabapentin, another of the newer
electrical activity spreading throughout an area of, antiepileptics, agent which has been designed to mimic
or the whole of, the brain. Antiepileptic medications GABA in the CNS.
limit the propagation of this spread and inhibit the • Potentiation of chloride currents through the GABAA/
development of symptoms. Cl– channel complex, for example, by benzodiazepines
and barbiturates. The increased postsynaptic inhibitory
chloride current at GABAA receptors hyperpolarizes
neurones and makes them refractory to excitation (see
Table 8.1).
Treatment of epilepsy • Inhibition of GABA degradation in the CNS, for
example, by vigabatrin, which is an irreversible
Drugs used to treat epilepsy are termed antiepileptics; the inhibitor of GABA transaminase (GABAT), the enzyme
term anticonvulsant is also used. normally responsible for the metabolism of GABA in
The aim of pharmacological treatment of epilepsy is to the neurone. Inhibition of GABAT, therefore leads to an
minimize the seizure activity/frequency, without producing increase in synaptic levels of GABA and so enhances
adverse drug effects. GABA-mediated inhibition.

Mechanisms of action of antiepileptics Antiepileptic drugs (anticonvulsants)

Antiepileptic drugs act generically to inhibit the rapid, re- Antiepileptic drugs can be classified according to their
petitive neuronal firing that characterizes seizures. There mechanism of action (see Fig. 8.7), but in clinical prac-
are three established mechanisms of action by which the tice, it is useful to think of the drugs according to their use
antiepileptic drugs achieve this (Fig. 8.7). (Table 8.7).

130
 Epilepsy 8

Seizure spread

Epileptic
focus

1 2
Na+ channels
Inhibition of ionic channels Inhibition of excitatory

.
involved in neuronal excitation
inhibition of 'fast' Na+ channels .
transmission
inhibition of glutamate release
e.g. phenytoin e.g. lamotrigine
carbamazepine
valproate
−
− . glutamate receptor antagonism
. inhibition of 'T-type' calcium e.g. future drugs?

currents
Inhibitory GABA
e.g. ethosuximide
nerve terminal

Glu Glu
GAD +
−
Glutaminergic excitatory GABA
nerve terminal

Metabolites
Glutamate release
GABA GABA-
Glu GABA transaminase
−
receptor
site Cl− −

3
Glutamate receptor Cl− receptor Enhancement of GABA-mediated
+
.
site inhibition
+ + − direct GABA agonist properties
Ca2
+ Cl− e.g. gabapentin
GABA/Cl−

Ca2
+
+
Depolarization
of neuron and
receptor
complex
. potentiation of Cl− currents
−
Ca2 through the GABA/Cl complex
+ propagation
Ca2 + + e.g. benzodiazepines
Ca2 of seizure
(clonazepam/diazepam)
barbiturates
(phenobarbital/primidone)
+
T-type Ca2 channel
. inhibition of GABA degradation in
the central nervous system
e.g. vigabatrin

Fig. 8.7 Mechanism and site of action of antiepileptic drugs. GABA, γ-Aminobutyric acid; GAD, glutamic acid
decarboxylase; Glu, glutamate.

131
 Central nervous system

Table 8.7 Drugs used for epilepsy classified Sodium valproate

by clinical use Mechanism of action—Sodium valproate has two mech-
anisms of action: similar to phenytoin, it causes a use-
Seizure type Primary drugs Secondary drugs
dependent block of voltage-gated sodium channels; it also
Partial and/or Sodium Phenytoin increases the GABA content of the brain when given over a
generalized valproate Vigabatrin prolonged period.
tonic-clonic Carbamazepine Gabapentin
Route of administration—Oral, intravenous.
seizures Lamotrigine
Phenobarbital Indications—Sodium valproate is useful in all forms of
epilepsy.
Absence Ethosuximide Phenobarbital
Contraindications—Sodium valproate should not be
seizures Sodium
valproate given to people with acute liver disease or a history of he-
Lamotrigine patic dysfunction.
Adverse effects—Sodium valproate has fewer side effects
Status Lorazepam Diazepam
epilepticus Clonazepam than other antiepileptics; the main problems are gastroin-
testinal upset and, importantly, liver failure. Hepatic toxicity
appears to be more common when sodium valproate is used
in combination with other antiepileptics.
Therapeutic notes—Sodium valproate is well absorbed
Phenytoin
orally and has a half-life of 10 to 15 hours. Sodium valproate
Mechanism of action—Phenytoin blocks use-dependent,
is now the first-line drug for most types of seizure syndromes.
voltage-gated sodium channels. Phenytoin reduces the
spread of a seizure. However, it does not prevent the initi-
ation of an epileptic discharge, but it does stop it spreading Antiepileptic medication should be avoided in
and causing overt clinical symptoms. pregnancy unless there is no safer alternative and
Route of administration—Oral, intravenous.
only after the risks have been discussed with the
Indications—Phenytoin is indicated in all forms of epilepsy.
patient. Prescribers should ensure that women of
Contraindications—Phenytoin has many contrain-
dications, mainly because it induces the hepatic cyto- childbearing age are using effective contraception
chrome P450 oxidase system, increasing the metabolism of throughout treatment because of the risk of major
oral contraceptives, anticoagulants, dexamethasone and congenital malformations.
pethidine.
Adverse effects—Dose-related effects of phenytoin in-
clude ataxia, blurred vision and hyperactivity secondary
to the cerebellovestibular system being affected. Acute Carbamazepine
toxicity causes sedation and confusion. The nondosage- Mechanism of action—Similar to phenytoin, carbamaze-
related effects include effects on collagen such as gum pine causes a use-dependent block of voltage-gated sodium
hypertrophy and coarsening of facial features; allergic channels. Oxcarbazepine, another antiepileptic, is structur-
reactions, for example, rash, hepatitis and lymphadenop- ally a derivative of carbamazepine. It has an extra oxygen
athy; haematological effects, for example, megaloblastic atom on the dibenzazepine ring, which helps reduce the im-
anaemia; endocrine effects, for example, hirsutism (hair pact on the liver of metabolising the drug, and also prevents
growth); and teratogenic effects (it may cause congenital the serious forms of anaemia occasionally associated with
malformations). carbamazepine. It is thought to have the same mechanism
Therapeutic notes—The use of phenytoin is further com- of action as carbamazepine.
plicated by its zero-order pharmacokinetics, characteristic Route of administration—Oral, rectal.
toxicities, and the necessity for long-term administration. Indications—Carbamazepine can be used in the treat-
Phenytoin has a narrow therapeutic index, and the relation- ment of all forms of epilepsy except absence seizures. It can
ship between dose and plasma concentration is nonlinear. also be used to treat neuralgic pain (p. 150, Chapter 10.).
This is because phenytoin is metabolized by a hepatic enzyme Contraindications—Like phenytoin, carbamazepine is
system saturated at therapeutic levels. Small dosage increases a strong enzyme inducer in the liver and so causes similar
may therefore produce large rises in plasma concentrations drug/drug interactions.
with acute side effects. Monitoring of plasma concentration Adverse effects—Ataxia, nystagmus, dysarthria, vertigo,
of phenytoin greatly assists dosage adjustment. Because of sedation.
its adverse effects and narrow therapeutic window, phenyt- Therapeutic notes—Carbamazepine is well absorbed
oin is no longer a first-line treatment for any of the seizure orally with a long half-life (25–60 hours) when first given.
syndromes. Enzyme induction subsequently reduces this half-life.

132
 Epilepsy 8

Ethosuximide Adverse effects—Somnolence, dizziness, ataxia, fatigue

Mechanism of action—Ethosuximide exerts its ef- and, rarely, cerebellar signs.
fects by inhibition of low-threshold calcium currents
(T-currents). Barbiturates
Route of administration—Oral. Examples of barbiturates include phenobarbital and prim-
Indications—Ethosuximide is the drug of choice in sim- idone (which itself, is largely converted to phenobarbital).
ple absence seizures and is particularly well tolerated in Mechanism of action—Barbiturates cause potentiation of
children. chloride currents through the GABAA/Cl– channel complex.
Contraindications—Ethosuximide may make tonic- Route of administration—Oral, intravenous.
clonic attacks worse. Indications—Barbiturates are used in all forms of epi-
Adverse effects—The adverse effects of ethosuximide lepsy (except absence seizures), including status epilepticus.
include gastrointestinal upset, drowsiness, mood swings Contraindications—Barbiturates should not be used
and skin rashes. Rarely, it causes serious bone marrow in children, elderly people, and people with respiratory
depression. depression.
Adverse effects—The main side effect of barbiturates is
Vigabatrin sedation, which limits their use clinically, along with the
Mechanism of action—Vigabatrin exerts its effects by ir- danger of potentially fatal CNS depression in overdose.
reversible inhibition of GABA transaminase. Phenobarbital is an inducer of cytochrome P450, and so in-
Route of administration—Oral. teracts with many medications.
Indications—Vigabatrin is indicated in epilepsy not sat- Therapeutic notes—Only the long-acting barbiturates
isfactorily controlled by other drugs. are antiepileptic. Phenobarbital has a plasma half-life of 10
Contraindications—Vigabatrin should not be used in hours. The strong sedating nature of these drugs now limits
people with a history of psychosis because of the side effect their use in the management of epilepsy.
of hallucinations.
Adverse effects—Drowsiness, dizziness, depression, vi- Benzodiazepines
sual hallucinations and visual field defects. Examples of benzodiazepines include lorazepam, diazepam,
Therapeutic notes—Vigabatrin is a new drug, used as an midazolam, clonazepam and clobazam.
adjunct to other therapies. It should be prescribed by a spe- Mechanism of action—Benzodiazepines cause potentia-
cialist and not given in patients with absence seizures be- tion of chloride currents through the GABAA/Cl– channel
cause it can worsen this type of epilepsy. complex (see Table 8.1). Clonazepam is unique in that it
acts at the GABAA receptor and inhibits T-type calcium
Lamotrigine channels.
Mechanism of action—Lamotrigine appears to act via an Route of administration—Oral, intravenously.
effect on sodium channels and inhibits the release of excit- Indications—Clonazepam is occasionally used for
atory amino acids. tonic-clonic and partial seizures. Lorazepam and diaze-
Route of administration—Oral. pam are effective in the management of status epilepticus
Indications—Monotherapy and adjunctive treatment of because they act very rapidly when compared with other
partial seizures, and generalized tonic-clonic seizures. antiepileptics.
Contraindications—Hepatic impairment. Contraindications—Benzodiazepines should not be used
Adverse effects—Rashes, fever, malaise and drowsiness. in people with respiratory depression.
Rarely, hepatic dysfunction and bone marrow failure. Adverse effects—The most common adverse ef-
fect of the benzodiazepines is sedation and respiratory
Gabapentin depression.
Mechanism of action—Gabapentin is a lipophilic drug Therapeutic notes—The repeated seizures of status
that was designed to mimic GABA in the CNS (agonist), epilepticus can damage the brain and be potentially life-
although it does not appear to have GABA-mimetic ac- threatening, so they should be controlled by administration
tions. Its mechanism of action remains elusive, but its an- of a benzodiazepine (e.g. rectal diazepam, buccal midaz-
tiepileptic action almost certainly involves voltage-gated olam or intravenous lorazepam). Note that lorazepam has a
calcium-channel blockade. longer half-life than diazepam.
Route of administration—Oral.
Indications—Monotherapy and adjunctive therapy in Other anticonvulsants
partial epilepsy with or without secondary generalisation, Other agents used as antiepileptics include tiagabine, topi-
and in the treatment of neuropathic pain. ramate, acetazolamide and piracetam. Their indications
Contraindications—Avoid sudden withdrawal, in elderly and side-effect profiles can be obtained from the British
patients and in those with renal impairment. National Formulary (BNF).

133
 Central nervous system

• The pigment epithelium

CLINICAL NOTE • The retina (neural tissue containing photoreceptors).
Emmett Hezz, a 19-year-old student car mechanic Light entering the eye is focused by the lens onto the retina,
is brought to A&E following a collapse while waiting and the signal reaches the brain via the optic nerve.
for a taxi. His fiancée was with him at the time and
tells staff that he fell to the ground suddenly and Glaucoma
that his breathing appeared to stop for about 30 Glaucoma describes a group of disorders characterized by a
seconds. He then developed jerking movements loss in the visual field associated with cupping of the optic
of his arms and legs and by this time, his face had disc and optic nerve damage. Glaucoma is the second most
turned blue. He was incontinent of urine and on common cause of blindness in the world and the most com-
regaining consciousness was drowsy, confused mon cause of irreversible blindness. Glaucoma is generally
and complaining of aching muscles. In hospital, associated with raised intraocular pressure (IOP) but can
he was able to explain that 8 months ago, he occur when the IOP is within normal limits.
experienced a similar episode when in a park, but
There are two types of glaucoma: open-angle and
closed-angle.
was too embarrassed to tell anybody.
Open-angle glaucoma is the most common type of glau-
On examination, his pulse is 76 beats per minute coma and it may be congenital. It is caused by pathology of
and regular. No abnormalities are found, other than the trabecular meshwork that reduces the drainage of the
a bleeding tongue. The history is very indicative of aqueous humour into the canal of Schlemm. Treatment in-
a tonic-clonic (grand mal) seizure. He is admitted volves either reducing the amount of aqueous humour pro-
for 24 hours and sent for blood investigations, duced (Fig. 8.9) or increasing its drainage.
electrocardiogram (ECG), head computed In closed-angle glaucoma, the angle between the iris and
tomography (CT) and electroencephalogram (EEG). the cornea is very small, and this results in the forward bal-
EEG reveals generalized spike-and-wave activity, looning of the iris against the back of the cornea.
Chronic open-angle glaucoma is of insidious onset
but no other abnormality. He is warned not to drive
and often picked up at a routine check-up, whereas acute
or operate heavy machinery until he has been
closed-angle glaucoma symptoms include painful, red eyes
seizure-free for a year. Emmett agrees to start and blurred vision. Acute closed-angle glaucoma is a medi-
taking the anticonvulsant sodium valproate and cal emergency and requires admission to save sight. It is dif-
return for a follow-up appointment. ficult for the patient to notice a gradual loss of visual fields
associated with chronic open-angle glaucoma and so regular
check-ups are vital for at-risk groups, such as elderly people.

Treatment of open-angle glaucoma

Status epilepticus The most effective way of preventing damage to the eye is
Intravenous benzodiazepines (lorazepam or diazepam) by lowering the IOP. Most drugs used to treat eye disease
are first-line drugs in the treatment of status epilepticus. can be given topically in the form of drops and ointments.
If these fail to bring an end to seizure activity, intravenous To enable these drugs to penetrate the cornea, they must be
phenytoin should be administered. Alternatively, intrave- lipophilic or uncharged.
nous fosphenytoin, a prodrug of phenytoin, can be given
more rapidly but requires ECG monitoring. Thiopental Drugs used to inhibit aqueous production
(and other muscle relaxants) can be used as a final option. Beta-adrenoceptor antagonists and prostaglandin ana-
logues are the current choice for first-line treatment.
Beta-adrenoceptor antagonists
Timolol and betaxolol are examples of beta-adrenoceptor
THE EYE antagonists used in glaucoma.
Mechanism of action—Beta-adrenoceptor antagonists
The eyeball is a 25-mm sphere made up of two fluid-filled block β2-receptors on the ciliary body and on ciliary blood
compartments (the aqueous humour and the vitreous hu- vessels, resulting in vasoconstriction and reduced aqueous
mour) separated by a translucent lens, all encased within four production (see Fig. 8.9).
layers of supporting tissue (Fig. 8.8). There are four layers. Route of administration—Topical.
• The cornea and sclera Indications—Open-angle glaucoma. beta-adrenoceptor
• The uveal tract, comprising the iris, ciliary body and antagonists are also used in the treatment of cardiovascular
choroid disease (Chapter 4).
134
 The eye 8

Bulbar conjunctiva
Eyelid
Palpebral
Superior rectus conjunctiva
muscle
Eyelash
Retinal arteries
and veins

Canal of Schlemm
Fovea
Auspensory ligament

Optic disc Aqueous humour

(blind spot)

Optic nerve Visual axis Light

Pupil

Lens
Iris
Cornea

Retina

Pigment epithelium

Choroid

Sclera Ciliary body

Vitreous humour
Inferior rectus muscle

Fig. 8.8 Anatomy of the eye. (Modified from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds) Integrated Pharmacology,
3rd edn. Mosby, 2006.)

Aqueous Lens Vitreous Adrenaline

humour humour brimonidine
Aqueous flow +
Timolol

–
Iris β2-receptor
α2-receptor

α1-receptor

Cornea Carbonic
Ciliary body anhydrase

Ciliary
blood supply
Trabecular –
meshwork
Canal of Schlemm
Ciliary muscle
Acetazolamide

+ Latanaprost

Episcleral vein Uveoscleral outflow

Fig. 8.9 Production and drainage of the aqueous humour. (Modified from Page, C., Curtis, M. Walker, M, Hoffman, B. (eds)
Integrated Pharmacology, 3rd edn. Mosby, 2006.)

135
 Central nervous system

Contraindications—Beta-adrenoceptor antagonists should Drugs used to increase the drainage of

not be given to patients with asthma, bradycardia, heart block aqueous humour
or heart failure.
Adverse effects—Systemic side effects include bron- Miotics–muscarinic agonists
chospasm in asthmatic patients, and potentially bradycar- Pilocarpine is a muscarinic agonist.
dia owing to their nonselective action on beta-receptors. Mechanism of action—Pilocarpine causes contraction
Other side effects include transitory dry eyes and allergic of the constrictor pupillae muscles of the iris, constricting
blepharoconjunctivitis. the pupil, and allowing aqueous to drain from the anterior
chamber into the trabecular meshwork (see Fig. 8.9).
Prostaglandin analogues Route of administration—Topical.
Examples include latanoprost and travoprost. Indications—Open-angle glaucoma.
Mechanism of action—Promote outflow of aqueous from Contraindications—Acute iritis, anterior uveitis.
the anterior chamber via an alternative drainage route, Adverse effects—Eye irritation, headache and brow ache,
called the uveoscleral pathway. blurred vision, hypersalivation. May exacerbate asthma.
Indications—Open angle glaucoma, ocular hypertension.
Contraindication—Pregnancy.
Adverse effects—Brown pigmentation of the iris may occur. Treatment of closed-angle
Sympathomimetics (adrenoceptor agonists)
glaucoma
Adrenaline, dipivefrine and brimonidine are commonly Drugs to treat closed-angle glaucoma are used in emergen-
used sympathomimetics. cies as a temporary measure to lower IOP.
Mechanism of action—Agonism at α-adrenoceptors is Pilocarpine and a CAI are often first-line treatments,
thought to be the principal means by which these agents re- with mannitol and glycerol being administered systemically
duce aqueous production from the ciliary body. Adrenaline to reduce IOP for resistant or more serious cases.
may also increase drainage of aqueous humour (see Fig. 8.9). YAG (yttrium-aluminium-garnet) laser surgery pro-
Route of administration—Topical. vides a permanent cure for closed-angle glaucoma. A hole
Indications—Open-angle glaucoma. Sympathomimetics is made in the iris (iridectomy) to allow increased flow of
are also used in the management of cardiac (Chapter 4) and aqueous humour.
anaphylactic emergencies and in the treatment of reversible
airways disease (Chapter 3).
Contraindications—Closed-angle glaucoma, hyperten- HINTS AND TIPS
sion, heart disease.
Adverse effects—Pain and redness in the eye. Stimuli that cause the pupils to dilate, such as
Therapeutic notes—Adrenaline is not very lipophilic, sitting awake in a dark room, increase the tightness
and therefore it does not penetrate the cornea effectively. of the angle between the iris and the cornea and
This can be overcome by administering dipivefrine hydro- can thus precipitate an attack of acute closed-
chloride, a prodrug that crosses the cornea and that is me- angle glaucoma.
tabolized to adrenaline once inside the eye.
Carbonic anhydrase inhibitors
Acetazolamide and dorzolamide are carbonic anhydrase in-
hibitors (CAIs). Examining the eye
Mechanism of action—CAIs inhibit the enzyme carbonic
anhydrase, which catalyses the conversion of carbon diox- Mydriatic drugs dilate the pupil, that is, cause mydriasis,
ide and water to carbonic acid, which dissociates into bi- whereas cycloplegic drugs cause paralysis of the ciliary
carbonate and H+. Bicarbonate is required by the cells of muscle, that is, cycloplegia. Mydriatic and cycloplegic drugs
the ciliary body, and underproduction of bicarbonate limits are used in ophthalmoscopy to allow a better view of the
aqueous secretion (see Fig. 8.9). CAIs given systemically interior of the eye.
also have a weak diuretic effect (Chapter 5). Mydriasis and cycloplegia reduce the drainage of the
Route of administration—Oral, topical, intravenous. aqueous humour, and they should therefore be avoided in
Indications—Open-angle glaucoma. patients with closed-angle glaucoma.
Contraindications—Hypokalaemia, hyponatraemia, re-
nal impairment. These effects can be reduced if the drug is Muscarinic antagonists
given in a slow-release form. The most effective mydriatics are the muscarinic receptor
Adverse effects—Irritation of the eye, nausea, vomiting, antagonists. These block the parasympathetic control of the
diarrhoea, diuresis. iris sphincter muscle.

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 The eye 8

Table 8.8 Mydriatic and cycloplegic effects of the commonly used muscarinic antagonists
Drug Duration (h) Mydriatic effect Cycloplegic effect
Tropicamide 1–3 ++ +
Cyclopentolate 12–24 +++ +++
Atropine 168–240 +++ +++

The type of muscarinic receptor antagonist chosen will sympathetic system does not control the ciliary muscle,
depend on the length of the procedure and on whether or however, and, therefore these drugs do not produce cy-
not cycloplegia is required. cloplegia. The α-agonist most commonly used to produce
The most commonly used muscarinic receptor antago- mydriasis is phenylephrine.
nists, their duration of action, and their mydriatic and cy-
cloplegic effects are summarized in Table 8.8. Muscarinic agonists and α-antagonists
A muscarinic agonist such as pilocarpine, or an α-receptor
α-Adrenoceptor agonists antagonist such as moxisylyte may be used to reverse mydri-
α-Adrenoceptor agonists can cause mydriasis by stimulat- asis at the end of an ophthalmic examination, although this
ing the sympathetic control of the iris dilator muscle. The is not usually necessary.

Chapter Summary

• Medications used in Parkinson disease correct the imbalance between the dopaminergic
and cholinergic systems within the basal ganglia
• Benzodiazepines and hypnotic drugs should only be prescribed as a short course in the
treatment of insomnia or anxiety
• Beta-blockers are useful in the treatment of somatic symptoms associated with anxiety
• SSRIs are the most commonly prescribed antidepressant, but patients must be informed
that their effect can take up to 4 weeks
• Tricyclic antidepressants are harmful in overdose and can cause muscarinic blocking side
effects including a dry mouth, blurred vision and constipation
• Lithium is an effective mood stabilizer but has a narrow therapeutic window and patients
require substantial monitoring whilst taking it
• Beta-adrenoceptor antagonists and prostaglandin analogues are used to reduce the
intraocular pressure associated with glaucoma

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 Drug misuse
9
DEFINITIONS DRUGS OF MISUSE

Drug misuse Drugs with a high potential for misuse fall into many dis-
tinct pharmacological categories. They may or may not
Drug misuse is defined as the use of drugs that cause ac- be used therapeutically, and they may be illegal or legal
tual physical or mental harm to an individual or to society, (Table 9.1). Controlled drugs are categorized into three
or that is illegal. Therefore drug misuse includes alcohol, classes (Table 9.2).
nicotine, and prescription medications taken in excess, as
well as the more obvious illicit drugs such as ecstasy, heroin,
cocaine or amphetamines. HINTS AND TIPS

Always use the correct chemical name when

Drug dependence describing drugs of misuse, for example,
Drug dependence is defined as the compulsion to take amphetamines rather than lay street terms such as
a drug repeatedly, with distress being caused if this is whizz or speed.
prevented. Dependence on drugs is often caused by the
rewarding effects but is also related to psychological and
physical effects. These are not exclusive and there is a
mixture of both in most people who are dependent on Central stimulants
drugs. Psychological dependence is when the rewarding
effects (positive reinforcement) predominate to cause a Amphetamines
compulsion to continue taking the drug. Physical depen- Other names—“Speed”, “whizz”, “billy”, “base”.
dence is when the distress on stopping the drug (nega- Mechanism of action—Amphetamines cause the release
tive reinforcement) is the main reason for continuing to of monoamines and the inhibition of monoamine reuptake,
take it, that is, avoidance of symptoms associated with the especially of dopamine and noradrenaline in neurones.
withdrawal. Route of administration—Amphetamines are adminis-
tered orally, or “snorted” as a powder nasally; sometimes
Drug tolerance used intravenously.
Effects—Increased motor activity; euphoria and excite-
Drug tolerance is the necessity to increase the dose of an ment; anorexia and insomnia; peripheral sympathomimetic
administered drug progressively to maintain the effect pro- effects, such as hypertension and inhibition of gut motility;
duced by the (smaller) original doses. Drug tolerance is a stereotyped behaviour and psychosis, which develop with
phenomenon that develops with chronic administration of prolonged usage. Stimulant effects last for a few hours and
certain drugs. are followed by depression and anxiety.
Many different mechanisms can give rise to drug tol- Clinical uses—The clinical uses of amphetamines are for
erance, although they are rather poorly understood. They narcolepsy and for attention deficit hyperactivity disorder
include the following. in children.
• Downregulation of receptors Tolerance, dependence and withdrawal—Tolerance to
• Changes in receptor coupling the peripheral sympathomimetic stimulant effects of am-
• Exhaustion of biological mediators or transmitters phetamines develops rapidly, but it develops much more
• Increased metabolic degradation (enzyme induction) slowly to other effects such as locomotor stimulation.
• Physiological adaptation. Amphetamines cause strong psychological dependence but
no real physical dependence. After stopping chronic use,
the individual will usually enter a deep, long sleep (“REM
Withdrawal rebound”) and awake feeling tired, depressed and hungry.
Withdrawal is the term used to describe the syndrome of This state may reflect the depletion of the normal mono-
effects caused by stopping administration of a drug. It re- amine stores.
sults from the change of (neuro) physiological equilibrium Adverse effects—Acute amphetamine toxicity causes car-
induced by the presence of the drug. diac arrhythmias, hypertension and stroke. Chronic toxicity

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 Drug misuse

Table 9.1 Drugs with high potential for misuse volatile, and which does not decompose on heating. It can,
therefore be smoked, producing a brief intense “rush”.
Drug class Examples
Effects—The behavioural effects produced by cocaine
Central stimulants Cocaine are similar to those produced by amphetamines, such as
Amphetamines euphoria. The euphoric effects may be greater, and there is
less of a tendency for stereotypic behaviour and paranoid
MDMA (ecstasy)
delusions.
Nicotine The effects of cocaine hydrochloride (lasting about an
Central depressants Alcohol hour) are not as long lasting as those of amphetamine,
Benzodiazepines whereas those obtained from crack are brief (minutes).
Clinical uses—Cocaine is no longer used clinically
Barbiturates
Tolerance, dependence and withdrawal—Cocaine causes
Opioid analgesics Morphine strong psychological dependence but no real physical depen-
Heroin (diamorphine) dence. Withdrawal causes a marked deterioration in motor
Methadone
performance, which is restorable on the provision of the drug.
Adverse effects—Acute cocaine toxicity causes toxic
Cannabinoids Cannabis psychosis, cardiac arrhythmias, hypertension and stroke.
Tetrahydrocannabinoids Chronic toxicity causes paranoid psychosis, vasocon-
(THCs) striction, tissue anoxia and damage at sites of injection or
Hallucinogens LSD snorting. Cocaine used by pregnant mothers impairs foetal
Mescaline development and damages the foetal brain.
Psilocybin
Dissociative anaesthetics Ketamine
CLINICAL NOTE

Phencyclidine Cocaine can cause cardiac toxicity because

LSD, Lysergic acid diethylamide; MDMA, it has a direct effect on the heart. Cocaine will
methylenedioxymethamphetamine increase myocardial contractility as a result
of sympathomimetic effects mediated by B1
receptors, but the heart is unable to meet the
Table 9.2 Classes of controlled drugs
demand because of a decrease in coronary artery
Class A drugs Class B drugs Class C drugs blood flow (caused by sympathomimetic effects
Cocaine MDMA Amphetamines Benzodiazepines on α1 receptors). First-line treatment of cocaine-
(ecstasy) Barbiturates Cannabis induced arrhythmias is usually benzodiazepines,
Diamorphine Some weak Androgenic and
which moderate the effects of cocaine on the
(heroin) and other opioids anabolic steroids
strong opioids Others Human chorionic central nervous system (CNS) and cardiovascular
LSD class B gonadotrophin system. The use of β-blockers are contraindicated
substance when Others because the resultant unopposed alpha effect
prepared for
can precipitate a dangerous hypertensive crisis in
injection
Others patients who have cocaine induced chest pain.
LSD, Lysergic acid diethylamide; MDMA,
methylenedioxymethamphetamine

Methylenedioxymethamphetamine
Other names—“Ecstasy”, “E”, “disco biscuits”, “pills”.
causes paranoid psychosis, vasoconstriction, tissue anoxia, Mechanism of action—Methylenedioxymethamphet-
damage at sites of injection or snorting and damage to the amine (MDMA) is an amphetamine derivative that has a
foetal brain in utero. mechanism of action similar to that of amphetamines (re-
lease of monoamines, inhibition of monoamine reuptake).
Cocaine MDMA also acts on serotonergic neurones, potentiating
Other names—“Coke”, “Charlie”, “snow”, “crack”. the effects of serotonin (5-HT).
Mechanism of action—Cocaine strongly inhibits the re- Route of administration—MDMA is usually taken as a
uptake of catecholamines into noradrenergic neurones, and pill containing other psychoactive drugs, such as amphet-
thus strongly enhances sympathetic activity. amine or ketamine.
Route of administration—Cocaine hydrochloride is usu- Effects—MDMA has mixed stimulant and hallucino-
ally snorted nasally. Crack is the free base, which is more genic properties, especially in its pure form. Euphoria,

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 Drugs of misuse 9

arousal and perceptual disturbances are common. Uniquely, Tolerance, dependence and withdrawal—Tolerance to
MDMA has the effect of creating a feeling of euphoric em- nicotine occurs rapidly, first to peripheral effects but later
pathy, so that social barriers are reduced. to central effects.
Clinical uses—MDMA has no clinical use. Nicotine is highly addictive, causing both physical and
Tolerance, dependence and withdrawal—It is not cur- psychological dependence. Withdrawal from tobacco often
rently known to what extent tolerance and dependence oc- leads to a syndrome of craving, irritability, anxiety and in-
cur with MDMA. The withdrawal syndrome is similar to creased appetite for approximately 2 to 3 weeks.
that with amphetamines. Adverse effects—Acute nicotine toxicity causes nausea and
Adverse effects—The most serious acute consequences vomiting. Chronic toxicity caused by smoking leads to more
of acute MDMA toxicity appear to be hyperthermia and morbidity in the United Kingdom than all other drugs com-
exhaustion caused indirectly by the hyperexcitability
­ bined, predisposing to all the following diseases, often greatly so.
that is induced. Acute hyperthermia results in damage to • Cardiovascular diseases, including atherosclerosis,
skeletal muscle and renal failure. MDMA causes users to hypertension and coronary heart disease
consume large amounts of water and in addition, MDMA • Cancer of the lung, bladder and mouth
causes inappropriate secretion of antidiuretic hormone • Respiratory diseases such as bronchitis, emphysema
leading to overhydration and hyponatraemia (“water (chronic obstructive pulmonary disease) and asthma
intoxication”). • Foetal growth retardation
The most successful treatments for nicotine addiction com-
Ketamine bine psychological and pharmacological treatments.
Other names—“Special K”, “Cat valium”
Pharmacological options largely rely on nicotine replace-
Mechanism of action—N-methyl-D aspartic acid
ment, once the patient has stopped smoking, with a gradual
(NMDA) receptor antagonist.
reduction in nicotine. The latest drug to be used to help cig-
Route of administration—Ketamine is typically injected
arette smokers is bupropion (Zyban), which is derived from
or snorted when misused.
an antidepressant.
Effects—Ketamine causes an overwhelming feeling
of relaxation, “a full body buzz” and out of body experi-
ence, as well as hallucinations. It is known as a dissociative CLINICAL NOTE
anaesthetic.
Clinical uses—Ketamine is sometimes used as a general Note that nicotine consumption during pregnancy
anaesthetic. is associated with miscarriage, ectopic and foetal
Tolerance, dependence and withdrawal—Ketamine can growth restriction, placental abruption, stillbirth
cause users to develop cravings and dependence on the drug. and premature delivery. Patients should be advised
Adverse effects—Ketamine eliminates pain therefore sev- to stop smoking if they are trying to conceive or if
eral misusers cause themselves significant injuries. In ad- they are already pregnant. This would also include
dition, depression, amnesia and hallucinations can occur. the cessation of using the newer e-cigarettes
Importantly, ketamine causes thickening of the bladder and because the vaporized nicotine causes similar
urinary tract. Long-term addicts can develop problems with
problems, in addition to nicotine toxicity.
passing urine and severe bladder dysfunction.

Nicotine
Nicotine is found in cigarettes, cigars, pipes and chewing Nicotine replacement products
tobacco. Mechanism of action—Measured doses of nicotine are
Mechanism of action—Nicotine exerts its effects by act- used to replace nicotine derived from cigarettes once the
ing as an agonist at nicotinic receptors, thus mimicking patient has stopped smoking, meeting the physical nicotine
some of the actions of acetylcholine, both in the CNS and needs. The dose of nicotine is gradually reduced over 10 to
in the periphery. 12 weeks.
Route of administration—Nicotine is usually inhaled, al- Route of administration—Oral (chewing gum, sublingual
though it can be chewed or applied topically via “patches” as tablets), transdermal (patches), nasal (spray), inhalation.
part of treating nicotine withdrawal. Indications—Adjunct to smoking cessation.
Effects—Nicotine has both stimulant and relaxant Contraindications—Severe cardiovascular disease, re-
properties. Physiologically, nicotine increases alertness, cent cerebrovascular accident, pregnancy, breastfeeding.
decreases irritability and relaxes skeletal muscle tone. Adverse effects—Nausea, dizziness, headache and cold,
Peripheral effects caused by ganglionic stimulation include influenza-like symptoms, palpitations.
tachycardia, increased blood pressure and decreased gastro- Therapeutic notes—Nicotine replacement products are
intestinal motility. available over the counter or General Practitioners (GPs)
Clinical uses—Nicotine has no clinical use. can prescribe them for patients intending to stop smoking.

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 Drug misuse

Bupropion (Zyban) There are two stages of alcohol withdrawal.

Mechanism of action—Bupropion is a selective inhibitor • Early stage (“hangover”), which is common and starts
of the neuronal uptake of noradrenaline and dopamine. 6 to 8 hours after cessation of drinking. It involves
This is believed to reduce nicotine craving and withdrawal tremulousness, nausea, retching and sweating.
symptoms. • Late stage (delirium tremens), which is much less common
Route of administration—Oral. and starts 48 to 72 hours after cessation of drinking. It
Indications—Adjunct to smoking cessation. involves delirium, tremor, hallucinations and confusion.
Contraindications—History of epilepsy (bupropion
Management of these late withdrawal symptoms involves
lowers seizure threshold) and eating disorders, pregnancy,
benzodiazepines (such as chlordiazepoxide).
breastfeeding.
Adverse effects—Acute ethanol toxicity causes ataxia,
Adverse effects—Dry mouth, gastrointestinal distur-
nystagmus, coma, respiratory depression and death.
bances, insomnia, tremor and impaired concentration.
Chronic ethanol toxicity causes neurodegeneration (po-
Therapeutic notes—Bupropion is available on the
tentiated by vitamin deficiency), dementia, liver damage,
National Health Service.
pancreatitis, and so on, and accompanying psychiatric
Varenicline (Champix) ­illness-depression/psychosis is common.
Mechanism of action—A partial agonist at nicotinic
acetylcholine receptors. The stimulatory effect produces a
CLINICAL NOTE
weak nicotine-like effect, which reduces the craving for nic-
otine itself, while the blocking effect inhibits the pleasurable Wernicke encephalopathy is a classic triad of
effect derived from smoking. Hence varenicline is thought confusion, ataxia and ophthalmoplegia caused
to mediate the rewarding effects of smoking. by thiamine deficiency related to alcohol abuse.
Route of administration—Oral
On admission to hospital, patients who consume
Indication—Cessation of smoking, prevent relapse.
excess alcohol are prescribed vitamins, including
Contraindication—Pregnancy, history of psychiatric ill-
ness as increased risk of suicidal thoughts. thiamine to reduce the risk of this occurring.
Adverse effects—Nausea, abnormal dreams, headaches,
flatulence.
Irritability, depression, insomnia can occur on abrupt
cessation of varenicline. Supportive treatment for ethanol dependency
Therapeutic notes—Should be started 1 to 3 weeks before Disulfiram is an aldehyde dehydrogenase inhibitor taken as
the target stop date and should be prescribed alongside psy- tablets.
chological support. Available only on prescription. Mechanism of action—Alcohol is usually broken down
into acetaldehyde and then removed from the body.
Disulfiram blocks aldehyde dehydrogenase enzyme which
Central depressants breaks down the acetaldehyde which leads to high levels of
acetaldehyde in the blood, causing a number of unpleasant
Ethanol effects. These include a throbbing headache, flushed face,
Mechanism of action—Ethanol, or alcohol, acts in a sim- vomiting and palpitations.
ilar way to volatile anaesthetic agents, as a general CNS Indication—It should be prescribed alongside psycho-
depressant. The cellular mechanisms involved may include logical support and must only be given to patients who have
inhibition of calcium entry, hence the reduction in trans- stopped drinking and who require a deterrent to drinking
mitter release, as well as potentiation of inhibitory gamma- further alcohol.
aminobutyric acid (GABA) transmission.
Route of administration—Ethanol is administered orally. Benzodiazepines
Effects—The familiar effects of ethanol intoxication Mechanism of action—Benzodiazepines exert their ef-
range from increased self-confidence and motor in- fects by potentiation of inhibitory GABA transmission.
coordination through to unconsciousness and coma. Route of administration—Benzodiazepines are adminis-
Peripheral effects include a self-limiting diuresis and tered orally.
vasodilatation. Effects—Benzodiazepines are widely abused drugs as
Clinical uses—Ethanol is used as an antidote to methanol they induce a feeling of calm and reduced anxiety, creating
poisoning. a “dream-like” effect.
Tolerance, dependence and withdrawal—Tolerance and Clinical uses—Benzodiazepines are prescribed as anxio-
physical and psychological dependence all occur with lytics and hypnotics.
ethanol, such that there were 100,000 hospital admissions Tolerance, dependence and withdrawal—Benzodiaze-
relating to alcohol consumption where an alcohol related pines have a potential for misuse; tolerance and dependence
disease, injury or condition was the primary reason. are common.

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 Drugs of misuse 9

A physical withdrawal syndrome can occur in patients There is a definite physical withdrawal syndrome in
given benzodiazepines, even for short periods. Symptoms addicts following cessation of drug treatment with opi-
include rebound anxiety and insomnia with depression, oids. This syndrome comprizes a complex mixture of
nausea and perceptual changes that may last from weeks to irritable and sometimes aggressive behaviour, combined
months. with autonomic symptoms such as fever, sweating, yawn-
Adverse effects—The adverse effects of acute benzodiaze- ing, pupillary dilatation, and piloerection that gives the
pine toxicity include hypotension and confusion. Cognitive state its colloquial name of cold turkey. Patients are ex-
impairment occurs in chronic benzodiazepine toxicity. tremely distressed and restless and strongly crave the
drug. Symptoms are maximal at 2 days and largely disap-
pear in 7 to 10 days.
CLINICAL NOTE
Treatment of withdrawal—Methadone is a long-acting
Mr Alrum, a 45-year-old male is brought to A&E opiate, active orally, used to wean addicts from their ad-
following a fall in the road. He is confused and diction. The withdrawal symptoms from this longer-acting
smells strongly of alcohol. Some minor cuts compound are more prolonged but less intense than, for
example, those of heroin. Treatment usually involves sub-
and bruises are noted on his right arm and leg.
stitution of methadone followed by a slow reduction in dose
Blood tests reveal a macrocytic anaemia,
over time.
elevated γ-glutamyl transferase and alanine Clonidine, an α2-adrenoceptor agonist, inhibits firing of
aminotransferase (liver transaminases) locus coeruleus neurones, and it is effective in suppressing
indicating alcohol misuse. Given that he is some components of the opioid withdrawal syndrome, es-
disorientated, sweating and trembling, he is given pecially nausea, vomiting and diarrhoea.
chlordiazepoxide and vitamins. He is seen by the Adverse effects—Acute opioid toxicity causes the
alcohol specialist nurse who discovers that Mr following.
Alrum has recently lost his job because of poor • Confusion, drowsiness and sedation. Initial excitement
performance and that he is feeling low in mood and is followed by sedation and finally coma on overdose.
hopeless. A set of screening questions confirms a • Shallow and slow respiration caused by a reduction of
diagnosis of alcohol dependence and Mr Alrum is sensitivity of the respiratory centre to carbon dioxide.
offered psychological support. • Vomiting caused by stimulation of the chemoreceptor
trigger zone.
• Autonomic effects such as tremor and pupillary
constriction.
Opioid analgesics • Bronchospasm, flushing and arteriolar dilatation
caused by histamine release.
Diamorphine (heroin) and other opioids Acute toxicity may be countered by use of an opioid antag-
Other names—“Smack”, “H”, “gear”, “junk”, “jack”, onist such as naloxone. The adverse effects of direct chronic
“brown”. toxicity are minor (see Chapter 10).
Mechanism of action—Opioids show agonist action at
opioid receptors. Strong opioids produce a sense of eupho-
ria and wellbeing by reducing anxiety and stress. These HINTS AND TIPS
effects contribute to their analgesic effect in the clinical
management of pain but also account for the illicit use of Heroin addicts are able to tolerate 300- to 600-
these drugs by addicts. mg doses several times per day. This is 30 to 60
Route of administration—Opioids are generally taken times the normal dose needed to produce an
intravenously by misusers because this produces the most analgesic effect. A nonaddict given this would die
intense sense of euphoria (rush). of respiratory depression.
Effects—Opioids produce feelings of euphoria and well-
being. Other effects are mentioned in Chapter 10.
Clinical uses—Opioids are used as analgesia for moder-
ate to severe pain. Cannabinoids
Tolerance, dependence and withdrawal—Tolerance to
opioid analgesics develops quickly in addicts and results in Cannabis
larger and larger doses of the drug being needed to achieve There are two forms of cannabis: marijuana is the dried
the same effect. leaves and flowers of the cannabis plant, and hashish is the
Dependence involves both psychological factors and extracted resin of the cannabis plant.
physical factors. Psychological dependence is based on the Other names—“Hash,” “weed”, “skunk”, “pot”, “dope”,
positive reinforcement provided by euphoria. “gear”, “grass”, “ganja”, “blow”.

143
 Drug misuse

Mechanism of action—How cannabis exerts its effects is Psychotomimetic drugs or

not clearly defined, but it includes both depressant, stim-
ulant and psychomimetic effects. The active constituent of
hallucinogens
cannabis is D9-tetrahydrocannabinol (THC), although me- Examples of psychotomimetic drugs include lysergic acid
tabolites that also have activity may be important. diethylamide (LSD), mescaline and psilocybin.
Route of administration—Cannabis is usually smoked, Street names—“Acid”, “trips”, “magic mushrooms”.
although it may be eaten. Mechanism of action—How LSD, mescaline and psi-
Effects—Cannabis has several effects. locybin produce changes in perception is not well under-
• Subjectively, users feel relaxed and mildly euphoric. stood, but it seems to involve serotonin. LSD appears to
• Perception is altered, with the apparent sharpening of affect serotonergic systems by acting on 5-HT2 inhibitory
sensory experience. autoreceptors on serotonergic neurones to reduce their
• Appetite is enhanced. firing. Whether LSD is an agonist, an antagonist or both is
• Peripheral actions include vasodilatation and not clear.
bronchodilation, and a reduction in intraocular Route of administration—Psychotomimetic drugs are ad-
pressure. ministered orally as a liquid, pills or paper stamps.
Effects—Psychotomimetic drugs cause a dramatically
Clinical uses—Cannabis is not currently licensed for
altered state of perception-vivid and unusual sensory expe-
use in the United Kingdom. However, cannabis extract is
riences combined with euphoric sensations. Hallucinations,
used to treat spasticity in patients with multiple sclerosis. In
delusions and panic can occur; this is known as a “bad trip”
some patients with chronic disease or malignancy, cannabis
and it can be terrifying.
is used as an antiemetic.
Clinical uses—Psychotomimetic drugs have no clinical
Tolerance, dependence and withdrawal—Tolerance to
uses.
cannabis occurs to a minor degree. It is not dangerously
Tolerance, dependence and withdrawal—Tolerance to,
addictive, with only moderate physical and psychological
dependence on, and withdrawal from psychotomimetic
withdrawal effects noted, such as mild anxiety/dysphoria
drugs are not significant.
and sleep disturbances.
Adverse effects—Acute toxicity from psychotomimetic
Adverse effects—Acute cannabis toxicity causes con-
drugs causes frightening delusions or hallucinations that
fusion and hallucinations. Chronic toxicity may cause
can lead to accidents or violence. In chronic toxicity, “flash-
flashbacks, memory loss and “demotivational syndrome”.
backs” (a recurrence of hallucination) may occur long after
There is a clear correlation between cannabis use and
the “trip”. Other psychotic symptoms may also occur.
schizophrenia.

Chapter Summary

• Dependence is defined as the compulsion to take a drug repeatedly

• Physical dependence is the result of avoiding symptoms associated with drug
withdrawal
• Drug tolerance is the necessity to increase the dose of an administered drug
progressively to maintain the desired effect
• Amphetamines, taken orally or snorted nasally, cause the release of monoamines,
resulting in stereotypical behaviours and paranoid delusions
• Cocaine strongly inhibits the reuptake of catecholamines into neurones causing
euphoria
• MDMA acts on serotonergic neurones, potentiating the effects of 5-HT and creates a
feeling of euphoric empathy
• MDMA causes water intoxication and exhaustion
• Opioid withdrawal results in cold turkey symptoms including fever, piloerection and
irritability
• Nicotine replacement products are available to help patients stop smoking
• Ethanol abuse can result in Wernicke encephalopathy

144
 Pain and anaesthesia
10
BASIC CONCEPTS Activation of nociceptors in the peripheral
tissues
Pain, which may be acute or chronic, is defined as an un- Noxious thermal, chemical or mechanical stimuli can trigger
pleasant sensory and emotional experience associated with the firing of primary afferent fibres (type C/Aδ), through the
actual or potential tissue damage. Pain is a subjective expe- activation of nociceptors in the peripheral tissues (Fig. 10.2).
rience, as a patient’s experience of pain is individual.
An analgesic drug is one that effectively removes (or at Transmission of pain information
least lessens) the sensation of pain. The principles of pain Transmission of pain information from the periphery to the
relief are as follows. dorsal horn of the spinal cord is inhibited or amplified by
a combination of local (spinal) neuronal circuits and de-
1. Careful assessment scending tracts from higher brain centres. This constitutes
2. Diagnosis of the cause of the pain the “gate-control mechanism”.
3. Use of analgesics in accordance with the analgesic
ladder (Fig. 10.1) • The primary afferent fibres synapse in lamina I and II
4. Regular review of the effectiveness of the prescribed drug of the dorsal horn of the spinal cord.
• Transmitter peptides (substance P, calcitonin gene-
related peptide, bradykinin, glutamate) and nitric oxide
Pain perception are involved in the ascending pain pathways.
Pain perception is best viewed as a three-stage process; acti- • The activity of the dorsal horn relay neurons is
vation of nociceptors (pain-specific receptors), followed by modulated by several inhibitory inputs. These include:
the transmission and onward passage of pain information. local inhibitory interneurons, which release opioid
peptides; descending inhibitory noradrenergic fibres
from the locus ceruleus area of the brainstem, which are
activated by opioid peptides; and descending inhibitory
Step 3 serotonergic fibres from the nucleus raphe magnus and
severe pain or
pain persisting/ periaqueductal grey areas of the brainstem, which are
increasing also activated by opioid peptides (see Fig. 10.2).
strong opioid
+ non-opioid Onward passage of pain information
± adjuvants
The onward passage of pain information is via the spinotha-
lamic tract, to the higher centres of the brain. The higher
Step 2 centres of the brain coordinate the cognitive and emotional
pain persists or aspects of pain and control appropriate reactions. Opioid
increases
weak opioid peptide release in both the spinal cord and the brainstem
+ non-opioid can reduce the activity of the dorsal horn relay neurons and
± adjuvants cause analgesia (see Fig. 10.2).

Step 1
Opioid receptors
pain All opioids, whether endogenous peptides, naturally occurring
non-opioid
± adjuvants drugs, or chemically synthesized drugs, interact with specific
opioid receptors to produce their pharmacological effects.
Drugs interact with opioid receptors as either full ago-
nists, partial agonists, mixed agonists (full agonists on one
opioid receptor but partial agonists on another) or as antag-
onists. Opioid analgesics are agonists.
There are three major opioid receptor subtypes: μ,
δ and κ.
• μ receptors are thought to be responsible for most of the
analgesic effects of opioids and for some major adverse
Fig. 10.1 The World Health Organization (WHO) analgesic effects for example, respiratory depression. Most of the
ladder for chronic pain. analgesic opioids in use are μ receptor agonists.
145
 Pain and anaesthesia

Higher sensory areas

Descending serotonergic fibre

+ from periaqueductal grey (PAG)
Opioid matter (inhibitory, activated by
receptor opioids)

+
3 Descending serotonergic fibre
from nucleus raphe magnus
Relay neuron +
(inhibitory, activated by opioids)
in lateral
spinothalamic
tract Pain stimuli

2
5-HT 'Gate control'
mechanism in
dorsal horn of 1
Sub P Glu spinal cord

NA
− −
Primary afferent
+ EnC neuron
3 (Aδ-/C-fibre)
−

− EnC
Local encephalinergic interneuron (inhibitory)
− Descending inhibitory noradrenergic fibre
(activated by opioids)
Ascending pathway neuron

Fig. 10.2 Nociceptive pathways and sites of opioid action. (1) Activation of nociceptors in the peripheral tissues; (2)
transmission of pain information; (3) onward passage of pain information to higher centres. 5-HT, 5-Hydroxytryptamine
(serotonin); Glu, glutamate; NA, noradrenaline; Sub P, substance P.

• δ receptors are probably more important in • σ receptors are not selective opioid receptors, but
the periphery, but they may also contribute to they are the sites of action of psychomimetic drugs,
analgesia. such as phencyclidine (PCP). They may account for
• κ receptors contribute to analgesia at the spinal level, the dysphoria produced by some opioids.
and may elicit sedation and dysphoria, but they Opioid receptor activation has an inhibitory effect on syn-
produce relatively few adverse effects, and do not apses in the central nervous system (CNS) and in the gut
contribute to physical dependence. (Table 10.1).

Table 10.1 Actions mediated by opioid receptor subtypes

Action μ/δ κ σ
Analgesia Supraspinal and spinal Spinal —
Respiratory depression Marked Slight —
Pupil Constricts — Dilates
GIT mobility Reduced (constipating) — —
Mood/effect Euphoria inducing but also Dysphoria inducing mildly Marked dysphoric and
sedating sedating psychomimetic actions
Physical dependence +++ + —
GIT, Gastrointestinal tract.

146
 Opioid analgesic drugs 10

Secondary-messenger systems associated with opioid re- Table 10.2 Endogenous opioid peptides
ceptor activity include the following.
Precursor Relative opioid
• μ/δ receptors, the activation of which causes molecules Products receptor affinity
hyperpolarisation of a neuron by opening potassium
Pro- Endorphins e.g. μ
channels and inhibiting calcium channels
opiomelanocortin β-endorphin and
• κ receptors, the activation of which inhibits calcium (POMC) other nonopioid
channels peptides e.g. ACTH
Activation of all opioid receptors by endogenous or exoge- Proenkephalin Enkephalins e.g. δ
nous opioids results in the following. Leu5 enkephalin, μ
Met5 enkephalin, μ
• Inhibition of the enzyme adenylate cyclase and thus a
extended Met5
reduction in cyclic adenosine monophosphate (cAMP) enkephalins
production
Prodynorphin Dynorphins, e.g. κ
• Inhibition of voltage-gated calcium-channel opening
dynorphin A
• Potassium-channel activation, which causes
ACTH, adrenocorticotrophic hormone.
hyperpolarisation of the cell membrane

Endogenous opioids
Physiologically, the CNS has its own “endogenous opioids”
that are the natural ligands for opioid receptors. There are OPIOID ANALGESIC DRUGS
three main families of endogenous opioid peptides occur-
ring naturally in the CNS. Opioid analgesics are drugs, either naturally occurring (e.g.
morphine) or chemically synthesized, that interact with
• Endorphins
specific opioid receptors to produce analgesia.
• Dynorphins
Mechanism of action—Opioid analgesic drugs work by
• Enkephalins
agonist action at opioid receptors (see earlier).
They are derived from three separate gene products (pre- The sense of euphoria produced by strong opioids con-
cursor molecules), but all possess homology at their amino tributes to their analgesic activity by helping to reduce the
end. The expression and anatomic distribution of the prod- anxiety and stress associated with pain. This effect also ac-
ucts of these three precursor molecules within the CNS are counts for the illicit use of these drugs.
varied, and each has a distinct range of affinities for the Route of administration—Oral, rectal, intravenous, intra-
different types of opioid receptor (Table 10.2).Although it muscular, transdermal and transmucosal (as lozenges).
is known that the endogenous opioids possess analgesic ac- Oral absorption is irregular and incomplete, necessi-
tivity, they are not used therapeutically. tating larger doses; 70% is removed by first-pass hepatic
metabolism. Fentanyl is available in a transdermal drug
delivery system as a self-adhesive patch, which is changed
every 72 hours. Transdermal fentanyl is particularly
useful in patients prone to nausea, sedation or severe
CLINICAL NOTE
constipation with morphine. Fentanyl is also useful for
Mrs Moore is a 60-year-old patient with bone breakthrough pain when given as lozenges and helpful in
pain secondary to advanced metastatic breast patients with renal impairment because it is mainly me-
cancer, while receiving chemotherapy. She has tabolized by the liver. Morphine is the drug of choice for
severe nociceptive pain.
been on several analgesics for the pain, including
Indications—Strong opioids (Table 10.3) are used in
nonsteroidal antiinflammatory drugs (NSAIDs).
moderate to severe pain. They are commonly used preoper-
NSAIDs were effective initially, but over the atively and postoperatively in patients with cancer, myocar-
following months, the pain increased. In addition dial infarction or acute pulmonary oedema.
to regular NSAIDs, she was given co-codamol, Weak opioids (see Table 10.3) are used in the relief of
a compound analgesic containing codeine and mild to moderate pain, as antitussives (Chapter 3) and as
paracetamol. Compound analgesics contain both antidiarrhoeal agents (Chapter 6), taking advantage of the
an opioid and a nonopioid and can be effective side effects of opioid analgesics.
in controlling pain. Nevertheless, a palliative care Contraindications—Opioid analgesics should not be
specialist is asked to review Mrs Moore’s pain and given to people in acute respiratory depression, with acute
advise that she may require morphine in the future. alcohol intoxication, or with head injuries before neuro-
logical assessment (because they can affect a patient’s con-
scious level).

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 Pain and anaesthesia

Table 10.3 Opioid analgesics Dependence involves μ receptors and is both physical
and psychological in nature and is discussed in Chapter 9.
Weak opioid analgesics Strong opioid analgesics
If physical dependence develops, it is characterized by a
Pentazocine Morphine definite withdrawal syndrome following cessation of the
Codeine Diamorphine drug. This syndrome comprises a complex mixture of ir-
ritable, and sometimes aggressive behaviour combined
Dihydrocodeine Phenazocine
with extremely unpleasant autonomic symptoms such as
Dextropropoxyphene Pethidine fever, sweating, yawning and pupillary constriction. The
Buprenorphine withdrawal syndrome is relieved by the administration of
Nalbuphine μ receptor agonists (e.g. naloxone) and worsened by the ad-
ministration of μ receptor antagonists.
Psychological dependence of opioid analgesics is based
on the positive reinforcement provided by euphoria.
Adverse effects—Opioid analgesics share many adverse In the clinical context, especially in terminal care, where
effects. These can be subdivided into central and peripheral tolerance and dependence can be monitored, they are not
adverse actions. inevitably problematic. However, the fear of tolerance and
Central adverse actions include the following. dependence often leads to overcaution in the use of opioid
• Drowsiness and sedation, in which initial excitement is analgesics, and inadequate pain control in some patients.
followed by sedation and finally a coma Therapeutic notes—Strong opioid analgesics include mor-
• Reduction in sensitivity of the respiratory centre to phine, diamorphine (heroin), pethidine and buprenorphine.
carbon dioxide, leading to shallow and slow respiration • Morphine remains the most valuable drug for severe
• Tolerance and dependence (Chapter 9) pain relief, although it frequently causes nausea and
• Suppression of a cough, an effect exploited clinically in vomiting. It is the drug of choice for severe pain in
antitussives (Chapter 3) terminal care. Morphine is the standard against which
• Vomiting caused by stimulation of the chemoreceptor other opioid analgesics are compared.
trigger zone (CTZ) • Diamorphine (heroin) is twice as potent as morphine,
• Pupillary constriction caused by stimulation of the owing to its greater penetration of the blood–brain
parasympathetic third cranial nerve nucleus barrier. It is metabolized to 6-acetylmorphine and
• Hypotension and reduced cardiac output, which are thence morphine in the body. Diamorphine causes
partly caused by reduced hypothalamic sympathetic less nausea and hypotension than morphine, but more
outflow euphoria. It has a rapid onset of action and thus is
Peripheral adverse actions include the following. useful for breakthrough pain.
• Constipation, is partly caused by stimulation of • Pethidine is more lipid soluble than morphine, and it
cholinergic activity in the gut wall ganglia which results has a rapid onset and short duration of action, making
in smooth wall spasm it useful in labour. Pethidine is equianalgesic compared
• Contraction of smooth muscle in the sphincter of Oddi with morphine, but it produces less constipation.
and in the ureters, which results in an increase in blood Interaction with monoamine inhibitors is serious, causing
amylase and lipase caused by pancreatic stasis fever, delirium and convulsions or respiratory depression.
• Histamine release, which produces bronchospasm, • Buprenorphine has both agonist and antagonist actions
flushing and arteriolar dilatation at opioid receptors, and it may precipitate withdrawal
• Lowered sympathetic discharge and direct arteriolar symptoms in patients dependent on other opioids. It
dilatation, which results in lowered cardiac output and has a longer duration of action than morphine and
hypotension its lipid solubility allows sublingual administration.
Buprenorphine is commonly given as a patch for patients
Adverse effects of opioids tend to limit the dose that can be
with long-term opioid analgesic requirements. Unlike
given, and the level of analgesia that can be maintained. The
most opioid analgesics, the effects of buprenorphine are
most serious of all these effects is respiratory depression, which
only partially antagonized by naloxone owing to its high-
is the most common cause of death from opioid overdose.
affinity attraction to opioid receptors.
Constipation and nausea are also common problems and
clinically it is common to coadminister laxatives and an an- Weak opioid analgesics include pentazocine, codeine, dihy-
tiemetic (Chapter 6). drocodeine and dextropropoxyphene.
Tolerance and dependence—Tolerance to opioid analge- • Pentazocine has both κ/σ receptor agonist and μ
sics can be detected within 24 to 48 hours from the onset of antagonist actions, and it may precipitate withdrawal
administration, and it results in increased doses of the drug symptoms in patients dependent on other opioids.
being needed to achieve the same clinical effect. Pentazocine is weak orally, but, by injection, it has a

148
 Headache and neuralgic pain 10

potency between that of morphine and codeine. It is • Tension-type headache

not recommended because of the side effects of thought • Migraine
disturbances and hallucinations, which probably are • Headache associated with eye or sinus disease
caused by its action on σ receptors. More sinister causes of a headache (including meningitis
• Codeine has about one-twelfth of the analgesic potency of and tumours) are less common, and these can often be ex-
morphine but is commonly prescribed as a weak opioid cluded by the history and examination.
analgesic. The incidence of nausea and constipation limit The pathophysiology underlying a headache is unclear,
the dose and duration that can be used. Codeine is also although symptomatic relief is often obtained from NSAIDs
used for its antitussive and antidiarrhoeal effects. and paracetamol. Some headaches are related to stress and
• Dihydrocodeine has an analgesic efficacy similar to that anxiety, and these patients may benefit from antidepressant
of codeine. It may cause dizziness and constipation. drugs (Chapter 8).
• Dextropropoxyphene has an analgesic efficacy about The management of a migraine includes the treatment
one-half that of codeine (i.e. very mild), and so it is often and prophylaxis of acute attacks. Drugs used for acute mi-
combined with aspirin or paracetamol. Such mixtures grainous attacks.
can be dangerous in overdose, with dextropropoxyphene
• NSAIDs and paracetamol (see p. 159)
causing respiratory depression and acute heart failure and
• Antiemetics (Chapter 6)
the paracetamol being hepatotoxic.
• Serotonin (5-HT1) agonists
Drugs used in migraine prophylaxis include the
CLINICAL NOTE following.
Opioids are renally excreted so should be used • Histamine (H1)/5-HT antagonists
• β-receptor antagonists (Chapter 4)
cautiously in patients with renal impairment. If
• Tricyclic antidepressants (Chapter 8)
opioid analgesia is required, oxycodone or fentanyl
is safer to prescribe.
Serotonin agonists
Sumatriptan and rizatriptan are 5-HT1 agonists.
Mechanism of action—Serotonin agonists are believed
Opioid antagonists to reverse the dilatation of cerebral blood vessels in the
Examples of opioid antagonists include naloxone and acute attack, which may be responsible for some of the
naltrexone. symptoms of a migraine.
Mechanism of action—These drugs act by specific antag- Route of administration—Oral, intranasal,
onism at opioid receptors: μ, δ and κ receptors are blocked subcutaneous.
more or less equally. They block the actions of endogenous Indications—Acute migraine attacks.
opioids as well as of ­morphine-like drugs. Contraindications—Caution in coronary artery disease
Naloxone is short acting (half-life: 2–4 hours) whereas (may cause vasoconstriction of coronary vessels), hepatic
naltrexone is long acting (half-life: 10 hours). impairment, pregnancy and breastfeeding.
Route of administration—Intravenous. Adverse effects—Sensations of tingling, heat, chest
Indications—Opioid antagonists are given to reverse tightness.
­opioid-induced analgesia and respiratory depression rapidly,
mainly after overdose, or to improve the breathing of newborn
babies who have been affected by opioids given to the mother. H1 receptor/serotonin antagonists
Adverse effects—Precipitation of withdrawal in those Pizotifen is the main drug in this class.
with physical dependence on opioids. Reversal of analgesic Mechanism of action—Unlike the serotonin ago-
effects of opiate agonist. nists, pizotifen appears to limit the initial proinflam-
matory and vascular changes which precede migrainous
episodes.
Route of administration—Oral.
HEADACHE AND NEURALGIC PAIN Indications—Prevention of migraine and cluster
headache.
Contraindications—To be used cautiously in patients
Headache with urinary retention, angle-closure glaucoma, renal im-
A headache is a very common presenting symptom, yet one pairment, pregnancy, breastfeeding.
which can be difficult to manage. The most common causes Adverse effects—Antimuscarinic effects (urinary reten-
of a headache include the following. tion, dry mouth), drowsiness, increased appetite.

149
 Pain and anaesthesia

HINTS AND TIPS

Headache is a common complaint, and more often O O

than not, it does not represent a sinister pathology. R C O R R NH C R

Analgesia will simply help control the symptoms
so, if a patient frequently returns with pain, ensure Ester bond : COO Amide bond : CONH
to look for a treatable underlying cause.

Fig. 10.3 General structure of ester-linked and amide-

Neuralgic pain linked local anaesthetics.

Neuralgic pain is a pain in the distribution of a particular

nerve or nerve root. The most common pathologies are sci- • Local anaesthetics with ester bonds are inactivated by
atica, herpetic neuralgia and trigeminal neuralgia. plasma cholinesterases.
Neuralgia commonly occurs because of compression or • Local anaesthetics with amide bonds are degraded by
entrapment of the nerve or nerve root, and definitive man- N-dealkylation in the liver.
agement relies on the surgical release of the nerve. Metabolites can often be pharmacologically active.
Pharmacological options can be used when surgery is
ill advised, or ineffective, or as an adjunct. NSAIDs are not Mechanism of block
effective for neuralgic pain. Antidepressants, in particular,
amitriptyline, often have an “analgesic” effect in neuralgic Importance of pH and ionization
pain, and often at a dose lower than their antidepressant ef- Local anaesthetics are weak bases (pKa = 8–9). Only the un-
fect (Chapter 8). charged form can penetrate lipid membranes; thus, quaternary
The other main class of drug used orally in neuralgic pain ammonium compounds, which are fully protonated, must be
are the anticonvulsants, notably carbamazepine, phenytoin injected directly into the nerve axon if they are to work.
and more recently lamotrigine (Chapter 8). These potentially The proportion of uncharged local anaesthetic is gov-
stabilize the neurones involved and limit their activation. erned by the pH, the pKa and the Henderson–Hasselbalch
Local anaesthesia of the nerve in question can provide equation (Chapter 1).
relief for some patients, although nerve ablation with drugs
(e.g. bupivacaine) or by surgical means can be performed to B + H + = BH +
alleviate symptoms. pK a = pH + log BH +  / B

A local anaesthetic with a pKa of 8 will be 10% uncharged at

pH 7, 50% uncharged at pH 8, and 5% uncharged at pH 6.
LOCAL ANAESTHESIA

Basic concepts Routes of block

Most local anaesthetics block by two routes (Fig. 10.4).
Local anaesthetics are drugs used to inhibit pain sensation.
These drugs work by reversibly blocking nerve conduction. • The hydrophobic route, the uncharged form enters the
membrane and blocks the channel from a site in the
protein membrane interface.
Chemistry • The hydrophilic route, the uncharged form crosses the
All local anaesthetics have the same basic structure.
membrane to the inside where the charged form blocks
• An aromatic group (lipophilic end) linked to a basic
side chain (hydrophilic end) by an ester or amide bond
(Fig. 10.3) B BH+ B
• The basic side chain (usually a secondary or tertiary Outside
H+
Hydrophobic
amine) is important because only the uncharged
molecule can enter the nerve axoplasm. BH+ B
Potency and duration of action are correlated with high
lipid solubility.
Inside
B
Pharmacokinetics Hydrophilic
Elimination of local anaesthetics depends on the nature of Fig. 10.4 Hydrophobic and hydrophilic routes of the block
the chemical bond. for local anaesthesia.

150
 General anaesthesia 10

the channel. This pathway depends on the channel cord itself. Problems arise from the block of preganglionic
being open and, therefore this type of block is use sympathetic fibres supplying the vasculature (causing vaso-
dependent. Use dependency is especially important in dilatation) and the heart (causing bradycardia), both lead-
the antiarrhythmic action of local anaesthetics. ing to hypotension. Rostral spread can lead to the blocking
• Nerve block occurs when the number of noninactivated of intercostal and phrenic nerves and result in respiratory
channels (those unaffected by the drug) is insufficient depression. Tilting the patient can control the amount the
to bring about depolarisation to the threshold. anaesthetic spreads.

CLINICAL NOTE HINTS AND TIPS

Mr Hadeed is a 34-year-old metal grinder who In inflamed tissues, the pH is acidic, resulting in
presents to an Eye Hospital A&E with an acute a greater proportion of the charged form of the
onset of left eye pain, which occurred while at anaesthetic, thus delaying or preventing its onset
work. He has never had any pain like this before. of action.
Slit-lamp examination revealed a fairly superficial
foreign body in his left eye. To remove the foreign
body, the eye is prepared with the application of
Unwanted effects
lidocaine (local anaesthetic) eye drops and then the
foreign body is removed with a needle. Unwanted effects of local anaesthetics are mainly associated
with the spread of the drug into the systemic circulation.
• Effects on the CNS, such as restlessness, tremor,
confusion, agitation. At high doses, CNS depression can
Routes of administration occur. Procaine is worse than lidocaine or bupivacaine
for causing CNS depression and is seldom used.
Surface anaesthesia • Respiratory depression
In surface anaesthesia, the local anaesthetic is applied di- • Possible effects on the cardiovascular system, including
rectly to the skin and mucous membranes, for example, myocardial depression and vasodilatation
cornea, bronchial tree, oesophagus and genitourinary tract. • Visual disturbances and twitching
The local anaesthetic, for example, lidocaine, must be able • Severe toxicity causes convulsions and coma
to penetrate the tissues easily. Problems occur when large
areas, for example, the bronchial tree, are anaesthetized.
HINTS AND TIPS

Infiltration anaesthesia Fentanyl should not be used in patients who have

Infiltration anaesthesia involves direct injection of a local been on monoamine inhibitors in the previous
anaesthetic into tissue. Often, a vasoconstrictor such as 14 days. The interaction between these drugs can
adrenaline is used with the local anaesthetic to prevent the produce an accumulation of serotonin and the
spread of the local anaesthetic into the systemic circulation. patient may become delirious and violent, or may
Vasoconstrictors must never be used at extremities as isch- develop severe hypertension, dysrhythmias or fatal
aemia could result. respiratory depression.

Nerve block anaesthesia

In nerve block anaesthesia, a local anaesthetic is injected
close to the appropriate nerve trunk, for example, the bra-
Properties and uses
chial plexus. The injection must be accurate in location. Table 10.4 shows the properties and uses of the main lo-
Nerve block anaesthesia can be useful in the reduction of cal anaesthetics, and Table 10.5 lists other compounds that
limb dislocations or fractures. block sodium channels.

Spinal and epidural anaesthesia

Spinal anaesthesia involves the injection of a local anaesthetic GENERAL ANAESTHESIA
into the cerebrospinal fluid (CSF) in the subarachnoid space.
In epidural anaesthesia, the local anaesthetic is injected
into the space between the dura mater and the spinal cord.
Basic concepts
In both spinal and epidural anaesthesia, the local anaes- General anaesthesia is the absence of sensation associated
thetic acts by blocking spinal roots, as opposed to the spinal with a reversible loss of consciousness.

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 Pain and anaesthesia

Table 10.4 Properties and uses of the main local anaesthetics

Rate of onset Duration Tissue penetration Chemistry Common use
Cocaine Rapid Moderate Rapid Ester bond ENT
Procaine Moderate Short Slow Ester bond Little used, CNS effects
Tetracaine Slow Long Moderate Ester bond Topical, prevenepuncture
(amethocaine)
Oxybuprocaine Rapid Short Rapid Ester bond Surface, ophthalmology
(benoxinate)
Benzocaine Very slow Very long Rapid Ester bond, no Surface ENT
basic side chain
Lidocaine Rapid Moderate Rapid Amide bond Widely used in all
(lignocaine) applications, EMLA
Prilocaine Moderate Moderate Moderate Amide bond Many uses, IVRA, EMLA.
Low toxicity
Bupivacaine Slow Long Moderate Amide bond Epidural and spinal
anaesthesia
CNS, Central nervous system; EMLA, eutectic mixture of local anaesthetics; ENT, ear, nose and throat; IVRA, intravenous regional
anaesthetic.

Table 10.5 Naturally occurring and synthetic sodium Some may argue that a fourth stage exists, in which
channel blockers drugs are used to reverse the action of agents given in the
previous three stages.
Compound Source Type of block
Tetrodotoxin Puffer fish Outside only
Premedication
Saxitoxin Plankton Outside only
Premedication is often given on the ward before the patient
μ-Conotoxins Piscivorous Affects inactivation
marine snail
is taken to the operating theatre (Table 10.6), and it has four
component aims.
μ-Agatoxins Funnel web spider Affects inactivation
• Relief from anxiety
α-, β- and Scorpions Complex • Reduction of parasympathetic bradycardia and
γ-toxins
secretions
QX314 and Synthetic, Inside only • Analgesia
QX222 permanently (hydrophobic • Prevention of postoperative emesis.
charged local pathway)
anaesthetics
Benzocaine Synthetic, From within
Table 10.6 General anaesthetic agents
uncharged local the membrane
anaesthetic (hydrophilic Induction/ Maintenance/
pathway) intravenous inhalation
Local Plant (cocaine), Inside and Premedication agents agents
anaesthetics others synthetic from within the Relief from anxiety, e.g. Barbiturates, Nitrous oxide
membrane diazepam, lorazepam e.g. thiopental Halothane
Reduction of Nonbarbiturates, Enflurane
General anaesthetics are used as an adjunct to surgical parasympathetic e.g. propofol, Isoflurane
procedures to render the patient unaware of, and unrespon- bradycardia and ketamine Sevoflurane
sive to, painful stimuli. Modern anaesthesia is characterized secretions, e.g.
atropine, hyoscine
by the so-called balanced technique, in which drugs and an-
aesthetic agents are used specifically to produce analgesia, Analgesia, e.g.
sleep/sedation and muscle relaxation and the abolition of NSAIDs, fentanyl
reflexes. Postoperative
No one drug or anaesthetic agent can produce all these antiemesis, e.g.
effects, and so a combination of agents is used in the three metoclopramide,
prochlorperazine
clinical stages of surgical general anaesthesia. The three
stages are premedication, induction and maintenance. NSAIDs, Nonsteroidal antiinflammatory drugs.

152
 General anaesthesia 10

Relief from anxiety s­ ensitivities to anaesthetics, and the reticular activating sys-
Oral benzodiazepines, for example, diazepam and midaz- tem, which is responsible for consciousness, is among the
olam (Chapter 8), are most effective and they perform three most sensitive. Hence, it is possible to use anaesthetics at a
useful functions. concentration that produces unconsciousness without un-
• Relieve apprehension and anxiety before anaesthesia duly depressing the cardiovascular or respiratory centres of
• Lessen the amount of general anaesthetic required to the brain or the myocardium. However, for the majority of
achieve and to maintain unconsciousness anaesthetics, the margin of safety is small.
• Possibly, sedate postoperatively.
Intravenous anaesthetics
Reduction of parasympathetic Intravenous anaesthetics, for example, thiopental, propofol
and ketamine, are all CNS depressants. They produce an-
bradycardia and secretions aesthesia by relatively selective depression of the reticular
Muscarinic antagonists, for example, atropine and hyoscine activating system of the brain. They may be used alone for
(Chapter 2), are used to prevent salivation and bronchial se- short surgical procedures, but they are used mainly for the
cretions, and importantly to protect the heart from arrhyth- induction of anaesthesia, and, therefore, it is rapidity of on-
mias, particularly bradycardia caused by some inhalation set that is the desirable feature.
agents and neuromuscular blockers. Intravenous anaesthetics are all highly lipid-soluble
agents and cross the blood–brain barrier rapidly; their
Analgesia rapid onset (< 30 seconds) results from this rapid transfer
Opioid analgesics, for example, fentanyl, are often given into the brain and high cerebral blood flow. Duration of
before an operation: although the patient is unconscious action is short (minutes) and terminated by redistribution
during surgery, adequate analgesia is important to stop of the drug from the CNS into less-well-perfused tissues
physiological stress reactions to pain. NSAIDs are useful al- (Fig. 10.5); drug metabolism is irrelevant to recovery.
ternatives and adjuncts to opiates, although are likely to be
inadequate for severe postoperative pain used alone. Thiopental
Mechanism of action—Thiopental is a highly lipophilic
Postoperative antiemesis member of the barbiturate group of CNS depressants that
Drugs that provide postoperative antiemesis include meto- act to potentiate the inhibitory effect of GABA on the
clopramide and prochlorperazine. Nausea and vomiting GABAA/Cl– receptor channel complex.
are common after general anaesthesia, often because of the Route of administration—Intravenous.
administration of opioid drugs perioperatively and postop- Indications—Rapid induction of general anaesthesia.
eratively. Antiemetic drugs can be given with the premedi-
cation to inhibit this.

Induction
Intravenous agents (see Table 10.6) are used to produce a
rapid induction of unconsciousness. Patients, in general,
prefer intravenous agents because some patients find having
% of dose

a mask placed over the face unpleasant.

Prevention of acid aspiration in emergency and obstetric
operations is crucial, and it relies on the administration of
either an H2-receptor antagonist or a proton-pump inhibi-
tor before induction (Chapter 6).

Maintenance Time (min)

Inhalation anaesthetic agents (see Table 10.6) are used to Intravenous

injection
maintain a state of general anaesthesia after induction in
most patients, although intravenous agents can be used via Blood
a continuous pump. Brain
Less-well-perfused tissues
Fat
Anaesthetic agents
Fig. 10.5 Redistribution of intravenous anaesthetic
Anaesthetic agents depress all excitable tissues including agents to less-well-perfused tissues causes a short
central neurones, cardiac muscle and smooth and stri- central duration of action. (Modified from Rang HP, et al.
ated muscle. Different parts of the CNS have different Pharmacology, 7th edition. Churchill Livingstone 2012.)

153
 Pain and anaesthesia

Contraindications—Thiopental should not be given to a Etomidate

patient with a previous allergy to it or who has porphyria. Mechanism of action—The mechanism of action of eto-
Adverse effects—Respiratory depression, myocardial midate is similar to that of thiopental.
depression (bradycardia), vasodilatation and anaphylaxis. Route of administration—Intravenous.
There is a risk of severe vasospasm if thiopental is acciden- Indications—Rapid induction of general anaesthesia.
tally injected into an artery. Contraindications—Etomidate should not be given to
Therapeutic notes—Thiopental is a widely used induc- patients with a previous allergy to it.
tion agent, but it has no analgesic properties. It provides Adverse effects—Extraneous muscle movement and pain
smooth and rapid (< 30 seconds) induction but, owing to on injection, possible adrenocortical suppression.
its narrow therapeutic margin, overdosage with consequent Therapeutic notes—Etomidate is an induction agent that
cardiorespiratory depression occur. Thiopental is given as gained favour over thiopental because of its larger therapeu-
the sodium salt, which is unstable in solution and so it must tic margin and faster metabolism leading to fewer hangover
be made up immediately before use. effects. Etomidate is more prone to causing extraneous mus-
cle movement and pain on injection compared with other
Propofol agents.
Mechanism of action—Propofol is similar to thiopental
in its mechanism of action.
Route of administration—Intravenous. Ketamine
Indications—Induction or maintenance of general an- Mechanism of action—Ketamine produces full surgical
aesthesia or sedation in intensive care units. anaesthesia, but the form of the anaesthesia is known as dis-
Contraindications—Propofol should not be given to pa- sociative anaesthesia because the patient may remain con-
tients with a previous allergy to it. scious although amnesic and insensitive to pain. This effect
Adverse effects—Convulsions, anaphylaxis, and delayed is probably related to an action on N-methyl-D-aspartate
recovery from anaesthesia have occasionally been reported (NMDA)-type glutamate receptors. Ketamine is a derivative
as side effects. of the street drug PCP (angel dust) (Chapter 9).
Therapeutic notes—Propofol is associated with rapid Route of administration—Intravenous, intramuscular.
recovery without nausea or hangover, and it is very widely Indications—Ketamine is used in the induction and
used. Propofol is the drug of choice if an intravenous agent is maintenance of anaesthesia, especially in children.
to be used to maintain anaesthesia by a continuous infusion. Contraindications—Ketamine should not be given to
people with hypertension or psychosis.
Adverse effects—These include cardiovascular stimula-
CLINICAL NOTE tion, tachycardia and raised arterial blood pressure, as well
as transient psychotic sequelae such as vivid dreams and
Dina is a 17-year-old student who presents to hallucinations.
A&E, looking very unwell and with severe pain in Therapeutic notes—Ketamine is not often used as an in-
her right iliac fossa. She reports that the pain had duction agent, owing to the high incidence of dysphoria and
originally started around her belly button a couple hallucinations during recovery in adults. These effects are
of hours ago and that she has vomited twice much less marked in children, and ketamine, in conjunction
with a benzodiazepine, is often used for minor procedures in
since. Examination reveals a tender abdomen with
paediatrics.
guarding. A computed tomography scan shows
an inflamed appendix. She is rushed to theatre.
Midazolam is given as sedation because she is Inhalation anaesthetics
rather anxious about the sudden forthcoming Examples of inhalation anaesthetics include halothane, en-
operation. Hyoscine is given before the operation flurane, isoflurane, sevoflurane and desflurane. Nitrous ox-
because it dries bronchial and salivary secretions. ide also has anaesthetic properties.
Domperidone is also given beforehand for Inhalation anaesthetics may be gases or volatile liquids.
antiemesis. General anaesthesia is induced with They are commonly used for the maintenance of anaesthe-
propofol and maintained with isoflurane. The muscle sia after induction with an intravenous agent.
relaxant rocuronium and the analgesic fentanyl
(intravenous) are also given for the operation. Mechanism of action
Rocuronium is stopped before completion of the It is not known exactly how inhalation anaesthetic agents
operation, but a small dose of neostigmine is produce their effects. Unlike most drugs, inhalation anaes-
required to fully reverse the effect of rocuronium. thetics do not all belong to one recognizable chemical class.
It seems that the pharmacological action of inhalation an-
aesthetics is dependent on the physiochemical properties of

154
 General anaesthesia 10

the molecule. Anaesthetic potency is closely linked to lipid 100 Nitrous oxide (0.47)*
solubility–anaesthetics dissolve in the membrane lipid and
90
cause volume expansion. There is evidence to suggest that
anaesthetics may also act by binding to discrete hydrophobic 80
domains of membrane proteins. Anaesthetics are thought

(% of inspired concentration)
Arterial anaesthetic tension
70
to enhance the activity of inhibitory GABAA receptors and
Halothane (2.4)*
other ion gated channels, particularly potassium channels. 60

50

40

HINTS AND TIPS 30 Ether (12.0)*

20
Similar to the benzodiazepines and barbiturates,
thiopental and propofol act via the GABAA/Cl– 10
receptor in causing CNS depression.
0 10 20 30 40 50

Time (min)
Fig. 10.6 Rate of equilibrium of inhalation anaesthetics in
humans. (Modified from Papper EM, Kitz R. Uptake and
Distribution of Anaesthetic Agents. McGraw-Hill 1963).
Pharmacokinetic aspects
The depth of anaesthesia produced by inhalation anaes- Nitrous oxide
thetics is directly related to the partial pressure (tension) Mechanism of action—See earlier.
of the agent in the arterial blood because this determines Route of administration—Inhalation.
the concentration of an agent in the CNS. The concentra- Indications—Nitrous oxide is used in the maintenance
tion of anaesthetic in the blood is in turn determined by of anaesthesia (in combination with other agents), and for
the following. analgesia (50% mixture in oxygen: Entonox).
• The concentration of anaesthetic in the inspired gas Contraindications—Pneumothorax. Nitrous oxide dif-
(alveolar concentration) fuses into air containing closed spaces resulting in an
• The solubility of the anaesthetic in the blood (blood/ ­increased pressure, in the case of pneumothorax, which
gas partition coefficient) may compromize breathing.
• Cardiac output Adverse effects—Nitrous oxide has been associated with
• Alveolar ventilation. bone marrow suppression if used long-term.
Rapid induction and recovery are important proper- Therapeutic notes—Nitrous oxide cannot produce surgi-
ties of an anaesthetic agent, allowing flexible control cal anaesthesia when administered alone, because of a lack
over the arterial tension (and hence brain tension) and, of potency. It is commonly used as a nonflammable carrier
therefore the depth of anaesthesia. The speed at which gas for volatile agents, allowing their concentration to be re-
induction of anaesthesia occurs is determined by two duced. As a 50% mixture in oxygen, nitrous oxide is a good
properties of the anaesthetic: its solubility in blood analgesic and is commonly prescribed during childbirth or
(blood/gas partition coefficient) and its solubility in fat for painful dressing changes.
(lipid solubility). Halothane
• Agents of low blood solubility (e.g. nitrous oxide, Mechanism of action—See earlier.
enflurane) produce rapid induction and recovery Route of administration—Inhalation.
because relatively small amounts are required to Indications—Halothane is used in the maintenance of
saturate the blood, and so the arterial tension (and anaesthesia.
hence brain tension) rises and falls quickly (Fig. 10.6). Contraindications—Halothane should not be given to
• Agents of high blood solubility (e.g. halothane) have people with a previous reaction to halothane or exposure to
much slower induction and recovery times because halothane in the previous 3 months.
much more anaesthetic solution is required before Adverse effects—Halothane causes cardiorespiratory
the arterial anaesthetic tension approaches that of the depression.
inspired gas (see Fig. 10.6). Respiratory depression results in elevated carbon di-
• Agents with high lipid solubility (e.g. ether) accumulate oxide partial pressure. Halothane also depresses cardiac
gradually in the body fat during prolonged anaesthesia muscle fibres and may cause bradycardia and ventricular ar-
and so may produce a prolonged hangover if used for a rhythmias. The result of this is a concentration-­dependent
long surgical procedure (see Fig. 10.6). hypotension.

155
 Pain and anaesthesia

The most significant toxic effect of halothane is severe

hepatic necrosis, which occurs in 1 in 35,000 cases. Lesser CLINICAL NOTE
degrees of liver damage may occur more frequently. The Patients who are genetically susceptible may
damage is caused by metabolites of the 20% of administered
develop malignant hyperthermia when given a
halothane that is biotransformed in the liver (80% of an ad-
number of anaesthetics, particularly halothane
ministered dose is excreted by the lungs).
Therapeutic notes—Halothane is a halogenated and suxamethonium. Patients present with muscle
hydrocarbon. rigidity, tachycardia, flushed skin, hypercapnia and
a raised temperature (> 40°C).
Enflurane
Mechanism of action—See earlier.
Route of administration—Inhalation.
Indications—Enflurane is used in the maintenance of Sevoflurane
anaesthesia. Mechanism of action—See earlier.
Contraindications—Enflurane should not be given to Route of administration—Inhalation.
people with epilepsy. Indications—It is used both in the gas induction and in
Adverse effects—Enflurane causes cardiorespiratory de- the maintenance of anaesthesia.
pression similar to that with halothane, although the inci- Contraindications—Susceptibility to malignant
dence of arrhythmias is much lower than with halothane. hyperthermia.
Enflurane undergoes only 2% metabolism in the liver, so Adverse effects—Similar to isoflurane.
it is much less likely than halothane to cause hepatotoxicity. Therapeutic notes—Sevoflurane is probably the most
The disadvantage of enflurane is that it may cause muscle widely used inhalation agent.
twitching, and special caution is needed in epileptic subjects.
Therapeutic notes—Enflurane is a volatile anaesthetic
similar to, but less potent than, halothane, about twice the HINTS AND TIPS
concentration is necessary for maintenance. Induction and
recovery times are faster than for halothane. Nitrous oxide is used as an adjunct to other inhaled
agents because it reduces the dose required to
Isoflurane maintain anaesthesia, thus limiting side effects and
Mechanism of action—See earlier.
allowing more rapid recovery.
Route of administration—Inhalation.
Indications—It is used in the maintenance of anaesthesia.
Contraindications—Susceptibility to malignant
hyperthermia.
Adverse effects—Isoflurane has actions similar to those Use of neuromuscular blockers in
of halothane, but it has fewer effects upon the cardiorespi-
ratory system. Hypotension is caused by a dose-related de-
anaesthesia
crease in systemic vascular resistance rather than a marked For some operations, for example, intraabdominal, com-
fall in cardiac output. Less hepatic metabolism (0.2%) oc- plete relaxation of skeletal muscle is essential. Some general
curs than with enflurane, so hepatotoxicity is even rarer. anaesthetic agents have significant neuromuscular blocking
Therapeutic notes—Isoflurane is an isomer of enflurane. actions, but drugs that specifically block the neuromuscular
It has a potency intermediate between that of halothane and junction are frequently used, for example, suxamethonium,
enflurane. rocuronium, vecuronium and atracurium (Chapter 2).

156
 General anaesthesia 10

Chapter Summary

• Pain is a subjective experience and management requires a careful assessment and use
of the analgesic ladder
• Activation of nociceptors via primary afferent fibres results in pain
• Opioids are commonly prescribed analgesics but have several side effects, including
respiratory depression
• Sumatriptan is used prophylactically in the management of a migraine
• Neuralgic pain is managed with low-dose antidepressants and anticonvulsants
• Potency and duration of action of local anaesthetics is dependent on lipid solubility
• Intravenous anaesthetics are used for induction and maintenance of anaesthesia
• Inhalational anaesthetics are typically used for maintenance of anaesthesia but can trigger
malignant hyperthermia in susceptible individuals
 Desflurane has a faster onset and recovery; useful for day case surgery
• Isoflurane is an irritant to the respiratory tract, causing cough and laryngospasm
 Sevoflurane is similar to desflurane but is less of a respiratory irritant
• The speed at which induction of anaesthesia occurs is determined by two properties of the
anaesthetic: its solubility in blood (blood/gas partition coefficient) and its solubility in fat (lipid
solubility)

157
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Inflammation, allergic diseases
and immunosuppression 11
Both these classes of antiinflammatory drug exert their
INFLAMMATION effect by inhibiting the formation of eicosanoids (see
Fig. 11.1).
Inflammation describes the changes seen in response to tis-
In addition, there are a number of other drug classes that
sue injury or insult including pain, redness, heat, swelling
have more restricted antiinflammatory actions.
and loss of function. These changes occur because of dil-
atation of local blood vessels, which lead to increased per- • Disease-modifying antirheumatic drugs (DMARDs)
meability and increased receptiveness for leucocytes. This • Drugs used to treat gout
results in the accumulation of inflammatory cells at the site • H1-receptor antagonists
of injury. The main cells seen in an acute inflammatory • Drugs used to treat skin disorders
response are neutrophils and macrophages. Lymphocytes,
basophils and eosinophils can also accumulate depending Nonsteroidal antiinflammatory drugs
on the insult. NSAIDs all possess the ability to inhibit both forms of
Inflammatory responses are produced and controlled by the enzyme cyclooxygenase (COX-1 and COX-2) (see
the interaction of a wide range of inflammatory mediators, Fig. 11.1), an action that is responsible for their pharmaco-
some derived from leucocytes, some from the damaged tis- logical effects (Table 11.2).
sues. Examples include the following. The first drugs of this type were the salicylates (e.g.
• Histamine aspirin), extracted from the bark of the willow tree.
• Kinins (bradykinin) Subsequently, many synthetic and semisynthetic NSAIDs
• Neuropeptides (substance-P, calcitonin gene-related have been created. Chemically and structurally heteroge-
peptide) neous, they are related through their common mechanism
• Cytokines (e.g. interleukins [ILs]) of action (see Table 11.3).
• Arachidonic acid metabolites (eicosanoids). Mechanism of action—The main action of all the NSAIDs
is inhibition of the enzyme cyclooxygenase. This enzyme is
Arachidonic acid metabolites: involved in the metabolism of arachidonic acid to form the
prostanoids, that is, the classic prostaglandins, prostacyclin
the eicosanoids
and thromboxane A2. Inhibition of cyclooxygenase can oc-
Of the inflammatory mediators mentioned previously, the cur by several mechanisms.
eicosanoids are of special importance because they are in- • Irreversible inhibition; for example, aspirin causes
volved in the majority of inflammatory reactions and thus acetylation of the active site.
most antiinflammatory therapy is based on the manipula- • Competitive inhibition; for example, ibuprofen acts as a
tion of their biosynthesis. competitive substrate.
The eicosanoids are a family of polyunsaturated fatty • Reversible, noncompetitive inhibition, for example,
acids formed from arachidonic acid. The biosynthetic paracetamol has a free radical trapping action that
pathway is shown in Fig. 11.1. Arachidonic acid is derived interferes with the production of hydroperoxidases,
mainly from phospholipids of cell membranes, from which which are believed to have an essential role in
it is mobilized by the action of the enzyme phospholipase cyclooxygenase activity.
A2. Arachidonic acid is then further metabolized by cycloo- Cyclooxygenase exists in two enzyme isoforms.
xygenase to produce the “classic prostaglandins”, thrombox-
• COX-1: Expressed in most tissues, especially platelets,
ane and prostacyclin, collectively known as the proteinoids,
gastric mucosa and renal vasculature, and involved in
and by lipoxygenase to produce the leukotrienes.
physiological cell signalling. Most adverse effects of
The actions of eicosanoids in inflammatory reactions are
NSAIDs are caused by inhibition of COX-1.
listed in Table 11.1.
• COX-2: Induced at sites of inflammation and produces
the prostanoids involved in inflammatory responses.
Antiinflammatory drugs Analgesic and antiinflammatory effects of NSAIDs are
These are the main drugs used for their broad-spectrum an- largely caused by inhibition of COX-2.
tiinflammatory effects. COX-2-specific inhibitors (e.g. celecoxib) have a reduced
• Nonsteroidal antiinflammatory drugs (NSAIDs). incidence of gastric side effects. However, they are associ-
• Steroidal antiinflammatory drugs (glucocorticoids) ated with an increased incidence of adverse cardiovascular
(Chapter 7). events (such as myocardial infarction).

159
 Inflammation, allergic diseases and immunosuppression

Corticosteroid
Membrane phospholipid
Induce
Lipocortin
−
Phospholipase A2

Arachidonic acid

Cyclooxygenase 5-lipoxygenase
−
NSAIDs
Cyclic endoperoxides 5-HPETE

12-lipoxy- 15-lipoxy- Prostacyclin Isomerases Thromboxane LTA4

genase genase synthetase synthetase
Non-enzymatic
formation

12-HETE Lipoxins Prostacyclin PGF2a PGD2 PGE2 thromboxane LTC4 LTB4

A&B (PGI2) A2 (TXA2)
Classic
LTD4
prostaglandins

LTE4

Leukotrienes
Fig. 11.1 Biosynthetic pathway of the eicosanoids. HETE, Hydroxyeicosatetraenoic acid; HPETE,
hydroperoxyeicosatetraenoic acid; LT, leukotrienes; NSAID, nonsteroidal antiinflammatory drug; PG, prostaglandin.

Table 11.1 Actions of the eicosanoids in the Not all NSAIDs possess these three actions to exactly the
inflammatory reaction same extent, an example being the lack of antiinflammatory
Eicosanoid Actions in inflammation
activity possessed by paracetamol (see Table 11.3).
In addition, aspirin has a pronounced effect on inhib-
Prostanoids iting platelet aggregation, caused by reduced thromboxane
“Classic Produce increased synthesis. Aspirin irreversibly inhibits cyclooxygenase in
prostaglandins” e.g. vasodilatation, vascular platelets, and because platelets do not have a nucleus, they
PGD2, PGE2, PGF2 permeability and oedema are unable to resynthesize a new enzyme, thus platelets are
in an inflammatory reaction;
inhibited for their lifespan. Aspirin is therefore used in the
prostaglandins also sensitize
nociceptive fibres to stimulation primary and secondary prevention of cardiovascular and
by other inflammatory cerebrovascular events (Chapter 4).
mediators Indications—NSAIDs are widely used for a variety of
Thromboxane A2 Platelet aggregation and complaints. They are available on prescription and “over the
(TXA2) vasoconstriction counter”. Their use includes musculoskeletal and joint dis-
eases (strains, sprains, rheumatic problems, arthritis, gout,
Prostacyclin (PGI2) Inhibition of platelet
aggregation and vasodilatation etc.), analgesia for mild to moderate pain relief and symp-
tomatic relief of fever.
Leukotrienes
Contraindications—NSAIDs should not be given to peo-
E.g. LTB4, LTC4 Increase vascular permeability, ple with gastrointestinal ulceration or bleeding or a previ-
promote leucocyte chemotaxis ous hypersensitivity to any NSAID. Caution should be used
(and cause contraction of
in asthma and when renal function is impaired.
bronchial smooth muscle)
Adverse effects—Generalized adverse effects of NSAIDs
are common, especially in the elderly and in chronic users,
and mostly arise from the nonselective inhibition of COX-1
Clinical effects—NSAIDs work by the inhibition of cy- and COX-2 (Table 11.4).
clooxygenase and resulting inhibition of prostaglandin syn- Less commonly, liver disorders and bone marrow de-
thesis, producing three major clinical actions of potential pression are seen. Other unwanted effects that are rel-
therapeutic benefit: analgesia, an antiinflammatory action atively specific to individual compounds are also seen
and an antipyretic action (see Table 11.2). (see later).

160
 Inflammation 11

Table 11.2 Three major clinical actions of nonsteroidal antiinflammatory drugs

Clinical action Mechanism of action
Analgesic action The analgesic effect is largely a peripheral effect caused by the inhibition of prostaglandin synthesis
at the site of pain and inflammation
Prostaglandins do not produce pain directly, but sensitize nociceptive fibre nerve endings to
other inflammatory mediators (bradykinin, histamine, 5-HT), amplifying the basic pain message;
prostaglandins of the E and F series are implicated in this sensitizing action
Thus NSAIDs are most effective against pain where there is an inflammatory component
A small component of the analgesic action of NSAIDs is a consequence of a central effect in
reducing prostaglandin synthesis in the CNS; paracetamol especially works in this manner
Antiinflammatory Prostaglandins produce increased vasodilatation, vascular permeability and oedema in an
action inflammatory reaction
Inhibition of prostaglandin synthesis therefore reduces this part of the inflammatory reaction
NSAIDs do not inhibit the numerous other mediators involved in an inflammatory reaction; thus
inflammatory cell accumulation, for example, is not inhibited
Antipyretic action During a fever, leucocytes release inflammatory pyrogens (e.g. interleukin-1) as part of the immune
response; these act on the thermoregulatory centre in the hypothalamus to cause an increase in
body temperature
This effect is believed to be mediated by an increase in hypothalamic prostaglandins (PGEs), the
generation of which is inhibited by NSAIDs
NSAIDs do not affect temperature under normal circumstances or in heat stroke
5-HT, Serotonin; CNS, central nervous system; NSAIDs, nonsteroidal antiinflammatory drugs.

Table 11.3 Classes of nonsteroidal antiinflammatory drugs and comparison of their main actions
Chemical class Examples Analgesic Antipyretic Antiinflammatory
Salicylic acids Aspirin + + +
Propionic acids Ibuprofen Fenuprofen + + +
Acetic acids Indometacin + + ++
Oxicams Piroxicam + + ++
Pyrazolones Phenylbutazone +/− + ++
Fenemates Mefenamic acid + + +/−
para-Aminophenols Paracetamol + + −

Table 11.4 General adverse effects of nonsteroidal antiinflammatory drugs

System Adverse effect Cause
GI Dyspepsia, nausea, vomiting Inhibition of the normal protective actions of
prostaglandins on the gastric mucosa
Ulcer formation and potential haemorrhage risk in PGE2 and PGI2 normally inhibit gastric acid
chronic users secretion, increase mucosal blood flow, and have a
cytoprotective action
Renal Renal damage/nephrotoxicity Inhibition of PGE2- and PGI2-mediated vasodilatation
Renal failure can occur after years of chronic misuse in the renal medulla and glomeruli
Other Bronchospasm, skin rashes, other allergic-type Hypersensitivity reaction/allergy to drug
reactions
GI, Gastrointestinal; PG, prostaglandin.

Therapeutic notes on individual

Its antiplatelet action is used in the management of a
nonsteroidal antiinflammatory drugs myocardial infarction and ischaemic stroke.
Salicylic acids, for example, aspirin. • Aspirin suppresses the production of prostaglandins
• Aspirin irreversibly blocks the formation of thromboxane because of its irreversible inactivation of
A2, producing an inhibitory effect on platelet aggregation. cyclooxygenase enzyme. Thus it is an inexpensive

161
 Inflammation, allergic diseases and immunosuppression

drug to use in the management of mild pain despite a bowel conditions, asthma (see Chapter 3) and inflamma-
relatively high incidence of gastrointestinal side effects. tory conditions of the skin.
• Aspirin produces tinnitus in toxic doses. Their profound generalized inhibitory effects on inflam-
Propionic acids, for example, ibuprofen. matory responses result from the effects of corticosteroids in
altering the activity of certain corticosteroid-responsive genes.
• Ibuprofen has a lower incidence of side effects.
• The antiinflammatory action results from reduced
Acetic acids, for example, indomethacin.
production of acute inflammatory mediators, especially
• Indomethacin is a highly potent nonselective inhibitor the eicosanoids (see Fig. 11.1). Corticosteroids
of cyclooxygenase that is effective but associated with a prevent the formation of arachidonic acid from
high incidence of side effects. membrane phospholipids by inducing the synthesis
• It may cause neurological effects such as dizziness and of a polypeptide called lipocortin. Lipocortin inhibits
confusion, as well as gastrointestinal upsets. phospholipase A2, the enzyme normally responsible
Oxicams, for example, piroxicam. for mobilising arachidonic acid from cell membrane
• Piroxicam is a potent drug used for chronic inflammatory phospholipids and thus inhibits the subsequent
conditions, but it should only be prescribed by formation of both prostaglandins and leukotrienes.
specialists because it causes a high incidence of severe • Corticosteroids reduce the number and activity of
gastrointestinal problems and skin reactions. circulating immunocompetent cells, neutrophils and
macrophages.
Fenemates, for example, mefenamic acid.
• Corticosteroids decrease the activity of macrophages
• Mefenamic acid is a moderately potent drug. and fibroblasts involved in the chronic stages of
• It commonly causes gastrointestinal upset and inflammation, leading to decreased inflammation and
occasionally skin rashes. decreased healing. Glucocorticoids are discussed in
para-Aminophenols, for example, paracetamol. detail in Chapter 7.
• The mechanism of action of paracetamol is not
completely understood, but it is not considered an
antiinflammatory drug because it does not appear
to inhibit the cyclooxygenase enzyme outside of the INFLAMMATORY DISEASES
central nervous system (CNS).
• It is effective for pain, especially headaches and fever. Rheumatoid arthritis
This is probably as a result of its mechanism of action
in trapping free radicals and interfering with the Disease modifying antirheumatic drugs
production of hydroperoxidases, which are believed DMARDs are a diverse group of agents mainly used in the
to have an essential role in cyclooxygenase activity. In treatment of rheumatoid arthritis, which is a chronic, pro-
areas of inflammation, phagocytic cells produce high gressive and destructive inflammatory disease of the joints
levels of peroxide that swamp this effect. It does appear (Table 11.5).
to have some selective inhibition of cyclooxygenase The mechanism of action of the DMARDs is often un-
within the CNS and can reduce the production of IL-1, clear; they appear to have a long-term depressive effect on
which probably accounts for its antipyretic effect. the inflammatory response as well as possibly modulating
other aspects of the immune system.
COX-2 specific inhibitors, for example, lumiracoxib and
All DMARDs have a slow onset of action, with clinical
celecoxib.
improvement not becoming apparent until 4 to 6 months
• These preferentially inhibit the inducible COX-2
after the initiation of treatment. DMARDs have been shown
enzyme, limiting COX-1–mediated side effects
observed with other, nonspecific NSAIDs.
The COX-2 inhibitors are licensed in the United Kingdom
Table 11.5 Disease-modifying antirheumatic drugs
for symptomatic relief in osteoarthritis and rheumatoid
arthritis. They are contraindicated in inflammatory bowel Class Example
disease, ischaemic heart disease or cerebrovascular disease. Gold salts Sodium aurothiomalate,
auranofin
Steroidal antiinflammatory drugs Penicillamine Penicillamine
(glucocorticoids) Antimalarials Chloroquine, hydroxyquinine
There are two main groups of corticosteroids: the glucocor-
ticoids and the mineralocorticoids. It is the glucocorticoids Sulfasalazine Sulfasalazine
(such as cortisone and cortisol), which possess powerful Immunosuppressants Cytotoxic drugs:
antiinflammatory actions that make them useful in several methotrexate, azathioprine,
diseases, for example, rheumatoid arthritis, inflammatory cyclosporine

162
 Inflammatory diseases 11

to improve symptoms and reduce disease activity. They are Mechanism of action—The mechanism of antimalarials is
believed to slow erosive damage at joints. unclear. They interfere with a wide variety of leucocyte func-
DMARDs are generally indicated for use in severe, active, tions, including IL-1 production by macrophages, lymphop-
progressive rheumatoid arthritis when NSAIDs alone have roliferative responses and T-cell cytotoxic responses.
proved inadequate. DMARDs are frequently used in com- Route of administration—Oral.
bination with an NSAID and/or low-dose glucocorticoids. Adverse effects—At the low doses currently recom-
mended for antimalarials, toxicity is rare. The major ad-
verse effect is retinal toxicity.
HINTS AND TIPS Therapeutic notes—People on antimalarials should have
their vision monitored.
DMARDS are also used in the management of
other severe, chronic inflammatory conditions (e.g. Sulfasalazine
inflammatory bowel disease or psoriasis). Mechanism of action—Sulfasalazine is broken down in
the gut into its two component molecules, 5-­aminosalicylate
(5-ASA) and sulfapyridine. The 5-ASA moiety is believed to
be a free radical scavenger and responsible for most of the
Methotrexate antirheumatic effects of this drug.
Mechanism of action—Acts as a competitive inhibitor Route of administration—Oral.
of dihydrofolate reductase. Cytotoxic and immunosuppres- Adverse effects—Side effects of sulfasalazine are mainly
sant activity results from folic acid antagonism. caused by sulfapyridine; they are common but rarely seri-
Route of administration—Oral. ous. These include nausea, vomiting, headache and rashes.
Adverse effects—Potential blood dyscrasias and liver Rarely, blood disorders and oligospermia are reported.
cirrhosis. Therapeutic notes—People on sulfasalazine should have
Therapeutic notes—Has a rapid onset of action and is their blood counts monitored.
a common first choice drug for rheumatoid arthritis. It is
superior to most other DMARDS in terms of efficacy and
patient tolerance. CLINICAL NOTE
Gold salts Mrs Arlington, a 50-year-old secretary, attends
Examples of gold salts include sodium aurothiomalate and
her General Practitioner (GP) with worsening
auranofin.
pain in both her wrists and fingers, causing her
Mechanism of action—The mechanism of action of gold salts
is unknown; they may be taken up by, and inhibit, mononuclear increasing difficulty to type. Tender swelling is
macrophages, or may affect the production of free radicals. noted at those joints. A diagnosis of rheumatoid
Route of administration—Sodium aurothiomalate is arthritis is made following an X-ray showing
given by intramuscular injection, and auranofin orally. erosions and blood tests indicating that she is
Adverse effects—Rashes, proteinuria, ulceration, diar- positive for IgM rheumatoid factor. Initially, she is
rhoea, bone marrow suppression. given daily ibuprofen with omeprazole
Therapeutic notes—Careful patient monitoring, includ- (a proton-pump inhibitor) to protect her stomach.
ing blood counts and urine analysis, is necessary. If any se- This helps to begin with, however, 3 months later
rious adverse effects develop, treatment must be stopped. she presents with worsening symptoms.
Penicillamine A diagnosis of progressive rheumatoid arthritis is
Mechanism of action—The mechanism of action of made. She is given a short course of prednisolone
penicillamine is unknown. It chelates metals and has im- (a glucocorticoid) and started on a DMARD,
munomodulatory effects, including suppression of immuno- sulfasalazine by the rheumatology specialist.
globulin (Ig) production and effects on immune complexes.
Penicillamine may also decrease the synthesis of IL involved
in the immune response associated with rheumatoid arthritis.
Route of administration—Oral.
Adverse effects—Rashes, proteinuria, ulceration, gastro-
Other Immunosuppressants
Certain drugs with immunosuppressive actions have been shown
intestinal upsets, fever, transient loss of taste, bone marrow
to be effective in autoimmune or inflammatory conditions
suppression.
(e.g. rheumatoid arthritis). These include three main groups.
Therapeutic notes—As for gold salts.
• Drugs that inhibit IL-2 production or action
Antimalarials ○ Cyclosporine is an example and is used in the
Examples of antimalarials include chloroquine and hy- management of rheumatoid arthritis as well as to
droxychloroquine (Chapter 12). suppress the rejection of transplanted organs (see later)

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 Inflammation, allergic diseases and immunosuppression

• Drugs that inhibit cytokine gene expression (e.g. like a sponge to remove most of the TNF-α molecules from
corticosteroids) (see Chapter 7) the joints and blood.
• Drugs that inhibit purine or pyrimidine synthesis Indications—Moderate to severe rheumatoid arthritis af-
○ Azathioprine interferes with purine synthesis and is ter DMARDs have not provided an adequate response.
widely used for immunosuppression and to control Contraindications—Pregnancy, breastfeeding, severe in-
autoimmune diseases. The drug is metabolized fections and heart failure.
to mercaptopurine, an analogue that inhibits Route of administration—Subcutaneous injection.
deoxyribonucleic acid (DNA) synthesis. The main Adverse effects—Predisposition to infections, exacerbation of
unwanted side effect is bone marrow suppression. heart failure or demyelinating CNS disorders, blood disorders.
Other effects include nausea, vomiting, skin rashes Interactions—Avoid concomitant use of live vaccines.
and mild hepatotoxicity. Therapeutic notes—Monitor for infections.

HINTS AND TIPS

HINTS AND TIPS
The “-mab” of adalimumab and infliximab stands
DMARDs are prescribed by a specialist. Patients
for their being monoclonal antibodies. The “-rcept”
taking these agents need regular blood tests to
of etanercept is a useful clue to remember it is the
assess their renal and liver function and to monitor
soluble receptor for TNF-α.
their red and white blood cell counts.

Cytokine inhibitors Gout

Cytokine inhibitors are also thought to retard destruction of
joints caused by rheumatoid arthritis. They are usually used for Gout is a condition in which uric acid (monosodium urate)
highly active rheumatoid arthritis in those who have failed to crystals are deposited in tissues, especially in the joints,
respond to at least two standard DMARDs. The primary proin- provoking an inflammatory response that manifests as an
flammatory cytokines are tumour necrosis factor (TNF)-α and extremely painful acute arthritis. Uric acid crystallizes in
IL-1. Thus their inflammatory role in diseases, such as rheu- the tissues when plasma urate levels are high, because of
matoid arthritis can be reduced via cytokine inhibitors. either excessive production or reduced renal excretion.
There are two treatment strategies for gout: treatment
of an acute attack and prophylaxis against further attacks
Monoclonal antibodies (Table 11.6).
Examples of monoclonal antibodies include adalimumab,
tocilizumab and infliximab.
Mechanism of action—The monoclonal antibodies bind
Treatment of an acute attack
TNF-α, preventing its interaction with cell surface receptors Nonsteroidal antiinflammatory drugs
and the subsequent proinflammatory events. At the onset of an acute attack of gout, NSAIDs are used for
Indications—Moderate to severe rheumatoid arthritis, their general antiinflammatory and analgesic effects.
after DMARDs have not provided an adequate response. Aspirin and other salicylates are not used in gout
Contraindications—Pregnancy, breastfeeding, severe in- because they inhibit uric acid excretion in the urine,
fections, heart failure. exacerbating serum concentrations. However, indometha-
Route of administration—Subcutaneous injection. cin can often be effective.
Adverse effects—Reemergence of tuberculosis, septicae-
mia, gastrointestinal disturbance, worsening heart failure,
hypersensitivity reactions, blood disorders. Table 11.6 Drugs used in the treatment of gout
Interactions—Avoid concomitant use of live vaccines. Treatment of an acute attack Example
Therapeutic notes—Monitor for infections, discontinue
NSAIDs Indometacin
if active tuberculosis is suspected.
Immunosuppressive Colchicine
Prophylaxis against recurrent attacks (reduction of plasma
Soluble tumour necrosis uric acid concentration)
factor-α blocker Agents that reduce uric acid synthesis Allopurinol
An example is etanercept.
Agents that increase uric acid Sulfinpyrazone,
Mechanism of action—Contains the ligand-binding
excretion (uricosurics) probenecid
component of the human TNF receptor. It, therefore
NSAIDs, Nonsteroidal antiinflammatory drugs
­competes with the patient's own receptors, thereby acting

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 Inflammatory diseases 11

Colchicine Therapeutic notes—Uricosurics should not be used during

Mechanism of action—Colchicine helps in gouty arthri- an acute attack of gout. NSAIDs or colchicine should be co-
tis by inhibiting the migration of leucocytes, such as neu- administered for the first 3 months of treatment because the
trophils, into the inflamed joint. This effect is achieved as initiation of treatment may precipitate an acute attack.
a result of the action of colchicine binding to tubulin, the
protein monomer of microtubules, resulting in their depo- Skin disorders
lymerisation. The result is that cytoskeletal movements and
cell motility are severely inhibited. The most common skin diseases are eczema, acne, psori-
The inhibition of microtubular function inhibits mi- asis, skin cancer (usually managed surgically), viral warts
totic spindle formation, giving colchicine a cytotoxic effect and urticaria.
on dividing cells. This cytotoxic effect is also responsible for
side effects of colchicine. Eczema (dermatitis)
Route of administration—Oral, rarely intravenously. Eczema is an inflammatory disease of the skin, defined by
Adverse effects—Side effects of colchicine include gastro- the presence of epidermal intercellular oedema or spongio-
intestinal toxicity, with nausea, vomiting and diarrhoea, oc- sis. It can occur because of several factors.
curring in 80% of people. Rarely, bone marrow suppression • Exogenous irritants and contact allergens
and renal failure occur. • Infections
Therapeutic notes—Colchicine is rapidly effective. It is • Atopy
given for the first 24 hours of an attack and then for no more • Drugs
than 7 days. Nausea and vomiting are common side effects. • Certain environmental conditions such as low
humidity and ultraviolet light
Prophylaxis against recurrent attacks Drugs used to treat eczema and their targets are shown in
Preventative management of gout includes diet and lifestyle Fig. 11.2.
changes, as well as the use of drugs that reduce plasma uric
acid concentration. These drugs should not be used during Acne
an acute attack because they will initially worsen symptoms. Acne affects the pilosebaceous unit and occurs where these are
Indomethacin or colchicine should be coadministered for numerous, such as on the face, back and chest. It is characterized
the first 3 months of treatment because the initiation of pro- by the presence of keratin plugs in the sebaceous duct openings,
phylactic treatment may precipitate an acute attack. known as comedones. Other signs of worsening acne include
inflammatory papules, pustules, nodules, cysts and scars.
Agents that reduce uric acid synthesis
Acne is stimulated by androgens, which is why it is re-
Allopurinol and febuxostat (xanthine oxidase inhibitors)
lated to puberty, and why the antiandrogen cyproterone is
are examples of a drug that reduces uric acid synthesis.
often used in females with acne (Chapter 7).
Mechanism of action—Allopurinol inhibits the en-
The drugs used to treat acne and their targets are shown
zyme xanthine oxidase, which converts purines (from
in Fig. 11.3.
DNA breakdown) into uric acid, thus reducing uric acid
production.
Route of administration—Oral. Parakeratosis
Adverse effects—Headaches, dyspepsia, diarrhoea, rash,
drug interactions and acute exacerbation of gout initially.
Rarely, life-threatening hypersensitivity occurs. Acanthosis
Therapeutic notes—Febuxostat is indicated in hyperuri- Spongiosis
caemia where urate deposition has occurred (in the form of Emollients
tophi or arthritis).
Secondary
Agents that increase uric acid excretion infection
Inflammation Lymphocyte Antibiotics
Uricosurics are drugs that increase uric acid excretion. Glucocorticosteroids e.g. tetracycline,
Examples of uricosurics include sulfinpyrazone and benzoylperoxide
Eosinophil
probenecid. Antiseptics
Mechanism of action—Uricosurics compete with uric
acid for reabsorption in the proximal tubules, preventing
uric acid reabsorption and resulting in uricosuria.
Route of administration—Oral. Fig. 11.2 Characteristics of eczema and point of action
Adverse effects—Gastrointestinal upset, deposition of of its drug treatment. (Modified from Page, C., Curtis, M.
uric acid crystals in the kidney, interference with excretion Walker, M, Hoffman, B. (eds) Integrated Pharmacology, 3rd
of certain drugs, and acute exacerbation of gout initially. edn. Mosby, 2006.)

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 Inflammation, allergic diseases and immunosuppression

Poral occlusion • Dilated capillaries in the dermis (these might

Keratolytics
Retin A
act to initiate psoriasis or as nourishment for
Isotretinoin hyperproliferating skin)
Azelaic acid • An infiltrate of inflammatory cells, especially
lymphocytes and neutrophils, in the epidermis and
dermis, respectively
Drugs used to treat psoriasis and their targets are shown
in Fig. 11.4.

Treatment of skin disorders

Preparations of drugs for use on skin
Drugs applied to the skin are delivered by a variety of vehi-
cles such as ointments, creams, pastes, powders, aerosols,
gels, lotions and tinctures. Factors affecting the choice of the
vehicle include the following.
• The solubility of the active drug
• The ability of the drug to penetrate the skin
Rudimentary hair
• The stability of the drug–vehicle complex
Rancid sebum Glandular hyperplasia
• The ability of the vehicle to delay evaporation, this
Antibiotics
being greatest for ointments and least for tinctures
Isotretinoin

Nicotinamide Oral contraceptive pill

Emollients
Fig. 11.3 Characteristics of acne and point of action of its Emollients are used to soothe and hydrate the skin. A sim-
drug treatment. (Modified from Page, C., Curtis, M. Walker, ple preparation is an aqueous cream, which is often as effec-
M, Hoffman, B. (eds) Integrated Pharmacology, 3rd edn. tive as more complex drugs.
Mosby, 2006.) Most creams are thin emollients, whereas a mixture
of equal parts soft white paraffin and liquid paraffin is a
Psoriasis thick emollient. Camphor, menthol and phenol prepa-
Psoriasis is a genetic skin disorder that manifests under rations have antipruritic effects, whereas zinc-based and
certain conditions including stress, infection, damage from titanium-based emollients have mild astringent (contract-
ultraviolet light, or trauma. In psoriasis, the turnover rate of ing) effects.
skin is much greater than normal. Psoriasis is characterized Mechanism of action—Emollients hydrate the skin and
by the following. reduce transepidermal water loss.
• Thickened skin plaques Route of administration—Topical. Many emollients can
• Superficial scales be added to bath water.

Parakeratosis
Hyperkeratosis
Keratolytics

Inflammatory cell
infiltration
Ciclosporin

Hyperproliferation
of keratinocytes

Topical Systemic
Coal tar Methotrexate
Dithranol Hydroxyurea
Vitamin D
analogues

Fig. 11.4 Characteristics of psoriasis and point of action of its drug treatment. (Modified from Page, C., Curtis, M. Walker,
M, Hoffman, B. (eds) Integrated Pharmacology, 3rd edn. Mosby, 2006.)

166
 Inflammatory diseases 11

Indications—Emollients are used for the long-term treat- Mechanism of action—Dithranol modifies keratinisation
ment of dry scaling disorders. and has an immunosuppressive effect (see Fig. 11.4).
Contraindications—None. Route of administration—Topical.
Adverse effects—Some ingredients, such as lanolin or an- Contraindications—Dithranol should not be given to
tibacterials, may induce an allergic reaction. people with hypersensitivity or acute and pustular psoriasis.
Therapeutic notes—The use of emollients lessens the Adverse effects—Local skin irritation, staining of skin
need for topical corticosteroids, therefore limiting potential and hair.
side effects. They should be used liberally in the manage-
ment of eczema and psoriasis. Vitamin D analogues
Calcipotriol and tacalcitol are vitamin D analogue
Corticosteroids derivatives.
Examples of corticosteroids include clobetasol propionate, Vitamin D analogues are keratolytics, although also used
betamethasone, clobetasol butyrate and hydrocortisone in vitamin D deficiency related to gastrointestinal/biliary
(Table 11.7). disease and renal failure (Chapter 6).
Mechanism of action—Corticosteroids suppress compo- Mechanism of action—The exact mechanism of action
nents of the inflammatory reaction (see Chapter 7 and see is still unclear, but several effects of vitamin D analogues
Fig. 11.2). have been observed. These include inhibition of epidermal
Route of administration—Topically; orally, intradermally proliferation and induction of terminal keratinocyte differ-
or intravenously in severe disease. entiation (see Fig. 11.4).
Indications—Corticosteroids are used for the relief of The antiinflammatory properties of vitamin D analogues
symptoms attributed by inflammatory conditions of the skin include inhibition of T-cell proliferation and of cytokine re-
other than those caused by infection, for example, they are lease, decreased the capacity of monocytes to stimulate T-cell
applied topically to affected areas in patients with eczema. proliferation and to stimulate cytokine release from T cells,
Contraindications—Rosacea, untreated skin infections. and inhibition of neutrophil accumulation in psoriatic skin.
Adverse effects—Most likely to occur with prolonged, or Route of administration—Topical.
high dose therapy. Local: spread or worsening of infection, Indications—Psoriasis.
thinning of the skin, impaired wound healing, irreversible Contraindications—Vitamin D analogues should not be
striae atrophicae. Systemic: immunosuppression, peptic ul- given to people with disorders of calcium metabolism. They
ceration, osteoporosis, hypertension, cataracts. should not be used on the face because irritation may occur.
Therapeutic notes—Withdrawal of corticosteroids after Adverse effects—Side effects of vitamin D analogues in-
high doses or prolonged use should be gradual (Chapter 7), clude local irritation and dermatitis. High doses may affect
even when used topically. calcium homoeostasis.
Dithranol Tar preparations
Dithranol is the most potent topical drug for the treatment Coal tar, made up of about 10,000 components, is kerato-
of psoriasis. lytic that is more potent than salicylic acid. It also has anti-
inflammatory and antipruritic properties.
Mechanism of action—Coal tar modifies keratinization,
but the mechanism is unclear (see Fig. 11.4).
Table 11.7 Potency of some topical steroids (UK Route of administration—Topical.
classification and nomenclature) Indications—Psoriasis and occasionally eczema.
Contraindications—Coal tar should not be given to peo-
Group Approved name Proprietary name
ple with acute or pustular psoriasis or in the presence of an
I (very potent) Clobetasol Dermovate infection. It should not be used on the face or on broken or
propionate inflamed skin.
II (potent) Betametasone Betnovate Adverse effects—Skin irritation and acne-like eruptions,
valerate 0.1% Propaderm photosensitivity, staining of the skin and hair.
Beclometasone Locoid
dipropionate Salicylates
Hydrocortisone
Salicylic acid is keratolytic at a concentration of 3% to 6%.
17-butyrate
Mechanism of action—Salicylic acid causes desquama-
III (moderately Clobetasone Eumovate tion via the solubilization of cell-surface proteins that main-
potent) butyrate
tain the integrity of the stratum corneum.
IV (mild) Hydrocortisone 1% Various Route of administration—Topical.
Hydrocortisone 2% Various Indications—Hyperkeratosis, eczema, psoriasis (com-
(Modified from Graham-Brown et al. Mosby’s Color Atlas and Text bined with coal tar or dithranol preparations) and acne,
of Dermatology, 1st edition. 1998.) wart and callus eradication.

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 Inflammation, allergic diseases and immunosuppression

Table 11.8 Other drugs used in skin disease, their indications and mechanisms of action
Drug Indication Mechanism of action
Benzoyl peroxide Acne vulgaris Antibacterial, keratolytic
Retinoids (vitamin A derivatives) Acne vulgaris, psoriasis Keratolytic, cytoinhibitory
Psoralen Psoriasis Mutates DNA/cytotoxic
Methotrexate Psoriasis Cytotoxic
Cyclosporine Psoriasis Immunosuppressant
Antibacterial, antiviral, antifungal Skin infections, warts Antimicrobial
preparations
Antiparasite preparations Skin/hair infestations Parasite toxins
Tacrolimus ointment Atopic eczema, psoriasis Calcineurin inhibitor
Apremilast Psoriasis Phosphodiesterase 4 and TNF α
inhibitor
Imiquimod BCC, actinic keratosis, genital warts Immune response modifier
Efudix (5-fluorouracil) Benign and malignant skin lesions Inhibits DNA replication
(e.g. BCC or SCC)
BCC, Basal cell cancer; DNA, deoxyribonucleic acid; SCC, squamous cell cancer; TNF, tumour necrosis factor.
(Modified from Graham-Brown et al. Mosby’s Color Atlas and Text of Dermatology, 1st edition. 1998.)

Contraindications—Sensitivity to the drug or broken or reactions that occur in a previously sensitized person reex-
inflamed skin. High concentrations, such as those needed posed to the sensitising antigen. Type I immediate hypersen-
to treat warts, should not be given to people with diabetes sitivity reactions are also known as atopic disorders.
mellitus or peripheral vascular disease because ulceration Patients with atopic diseases have an inherited predisposi-
may be induced. tion to develop IgE antibodies to allergens that are normally
Adverse effects—Side effects of salicylic acid include ana- innocuous and nonantigenic in healthy subjects. These spe-
phylactic shock in those sensitive to the drug, skin irritation cific IgE antibodies become bound to high-­affinity IgE re-
and excessive drying, and systemic effects if used long-term. ceptors (FceRI) on the surface of tissue mast cells and blood
basophils. The cross-linking of this cell-surface-bound IgE
Other drugs used in skin disease by antigens (allergens), on subsequent exposure, induces de-
Many other drugs are used in the management of skin dis- granulation and release of mediators such as histamine, leu-
ease. Some of the more common drugs are summarized in kotrienes and prostaglandins (Fig. 11.5).
Table 11.8. The released vasoactive and inflammatory mediators
The future produce many local and systemic effects, including vaso-
Specific immunosuppressant drugs that selectively tar- dilatation, increased vascular permeability, smooth muscle
get interleukins (e.g. ustekinumab that targets IL-12 for contraction, oedema, glandular hypersecretion and inflam-
psoriasis) and monoclonal antibodies used in the manage- matory cell infiltration.
ment of severe eczema have recently been developed and Depending on the site of this reaction and release of me-
licensed for use by specialists. In addition, specialists can diators, a variety of disorders can result (Table 11.9).
prescribe apremilast, an orally active phosphodiesterase 4
inhibitor, for the treatment of severe psoriasis and psoriatic Allergen IgE Histamine Vasodilatation and
arthritis. Similarly using immunotherapy for the treatment FcεRI vascular
of melanoma is increasing. permeability

Mediator
PGD2 Bronchoconstriction
release

ALLERGIC DISORDERS AND DRUG Mast cell LTC4

Urticaria/angioedema
Mucosal oedema
THERAPY LTD4
Bronchoconstriction
Fig. 11.5 Mechanism of type 1 hypersensitivity (allergic)
Allergic reactions occur when the immune system mounts an reaction. FceRI, Cell surface IgE receptor; LT, leukotriene;
inappropriate response to an innocuous foreign substance. PG, prostaglandin. (Modified from Page, C., Curtis, M.
Most common allergic disorders are caused by immuno- Walker, M, Hoffman, B. (eds) Integrated Pharmacology, 3rd
globulin E (IgE)-mediated type I immediate hypersensitivity edn. Mosby, 2006.)

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 Allergic disorders and drug therapy 11

Table 11.9 Type I hypersensitivity/allergic disorders

Disorder Site of reaction Response Common allergens
Anaphylaxis Circulation Oedema, circulatory collapse, Venoms, drugs
death
Allergic rhinitis/ hay fever Nasal passages Irritation, oedema, mucosal Pollen, dust
Conjunctiva hypersecretion
Asthma Bronchioles Bronchoconstriction, mucosal Pollen, dust
secretion, airway inflammation
Food allergy GIT Vomiting, diarrhoea, urticaria Seafood, milk, etc.
(hives)
Wheal and flare Skin Vasodilatation and oedema Insect venom
GIT, gastrointestinal tract.

Drug therapy of allergic disorders Table 11.10 Drug therapy in allergic disorders
The most effective therapy in hypersensitivity reactions is Mechanism of
avoidance of the offending antigen or environment. When Disorder Drugs used action
this is not possible, drug therapy can be of use (Table 11.10). Anaphylaxis Adrenaline Vasoconstriction (α2)
Antihistamines Bronchodilation (β2)
Glucocorticoids Proinflammatory
CLINICAL NOTE mediator
antagonism
Adam, a 6-year-old boy, is rushed to A&E with a Antiinflammatory
blood pressure of 65/30 mm Hg. He is clearly in Allergic rhinitis/ Antihistamines Proinflammatory
distress, breathless and vomiting. Swollen lips and hay fever Mast-cell mediator
stabilizers antagonism
blisters around his mouth are also noted. His father Glucocorticoids Inhibition of
tells the doctor that he had been fine previously Sympathomimetic mast-cell
and had just started having his lunch, peanut vasoconstrictors degranulation
butter sandwiches. Suddenly, he became severely Antiinflammatory
Decongestion of
unwell. The doctors acted quickly to diagnose nasal mucosa
anaphylactic shock. Adam is given oxygen and
Asthma (see Ch. 3) (see Ch. 3)
250 μg adrenaline intramuscularly. Afterwards,
Food allergies Antihistamines Proinflammatory
he is also given chlorphenamine (H1-receptor
mediator
antagonist) and hydrocortisone to prevent relapse. antagonism
He and his father are advised about the allergic
Wheal and flare Antihistamines Proinflammatory
reaction and the need to avoid peanuts. Adam is mediator
taught to carry prefilled adrenaline syringes and antagonism
given a MedicAlert bracelet.

H1-receptor antagonists: antihistamines

There are two types of H1-receptor antagonists.
Histamine and H1-receptor antagonists • “Old” sedative types, for example, chlorphenamine and
(antihistamines) promethazine
Histamine is a basic amine that is stored in mast cells and • “New” nonsedative types, for example, cetirizine and
in circulating basophils; it is also found in the stomach and loratadine
CNS. The effects of histamine are mediated by three differ- Mechanism of action—Antagonism of histamine H1-
ent receptor types found on target cells (Table 11.11). receptors (see Table 11.11). In the periphery, their action
As the major chemical mediator released during an al- can inhibit allergic reactions where histamine is the main
lergic reaction, histamine produces a number of effects, mediator involved.
mainly via action on H1-receptors. Therefore H1 antago- The old-style antihistamines can cross the blood–brain
nists (antihistamines) are of potential benefit in the treat- barrier where both specific and nonspecific actions in the
ment of allergic disorders. CNS produce sedation and antiemetic effects.

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 Inflammation, allergic diseases and immunosuppression

Table 11.11 Effects at histamine receptors • To suppress host immune rejection responses to donor
organ grafts or transplants
Histamine
• To suppress donor immune responses against host
receptor Effect
antigens (prevention of graft-versus-host disease after
H1 Responsible for most of the actions of bone marrow transplant [GVHD])
histamine in a type I hypersensitivity
reaction: The main pharmacological agents used for immunosup-
- capillary and venous dilatation (producing pression are as following.
‘flare’ or systemic hypotension) • Calcineurin inhibitors
- increased vascular permeability
• Antiproliferatives
(producing ‘wheal’ or oedema)
- contraction of smooth muscle (producing • Glucocorticoids (Chapter 7).
bronchial and gastrointestinal contraction) Solid organ transplant patients require immunosuppres-
H2 Regulation of gastric acid secretion: sion to prevent organ rejection. They are usually maintained
- H2-receptors respond to histamine on a corticosteroid combined with a calcineurin inhibitor
secreted from the enterochromaffin-like (cyclosporine) or with an antiproliferative drug (azathio-
cells that are adjacent to the parietal cell prine or mycophenolate mofetil), or with both.
H3 Involved in neurotransmission:
- the exact physiological role is not clear
but there may be presynaptic inhibition of CLINICAL NOTE
neurotransmitter release in the central and
autonomic nervous system affecting itch Mr Isaac, a 40-year-old man has end-stage
and pain perception renal failure caused by diabetic nephropathy.
He fortunately receives a renal transplant.
After a successful operation, he is started
Indications—The main use of H1-receptor antagonists is on cyclosporine, mycophenolate mofetil and
in the treatment of seasonal allergic rhinitis (hay fever). They prednisolone immunosuppression to prevent organ
are also used for the treatment and prevention of allergic skin rejection. When he is discharged, he is also given
reactions such as urticarial rashes, pruritus and insect bites,
cotrimoxazole (a mixture of the antibacterials,
and in the emergency treatment of anaphylactic shock.
sulfamethoxazole and trimethoprim) and nystatin
The old-style H1-receptor antagonists can also be used
as mild hypnotics (Chapter 8), and to suppress nausea in (antifungal) prophylactically. However, 2 months
motion sickness, owing to their actions on the CNS. later, he develops an infection. Cytomegalovirus
Route of administration—Oral, topical, transnasal. (CMV) is identified as the cause of his symptoms,
Intravenous chlorphenamine can be used in anaphylaxis. chest X-ray and detection of CMV DNA by
Adverse effects—Old-style antihistamines produce quite polymerase chain reaction test.
pronounced sedation or fatigue, as well as anticholinergic Mr Isaac is treated by two methods.
effects such as dry mouth. The newer agents do not do this.
• A reduction in his immunosuppression
Rare hazardous arrhythmias are associated with a few
H1-receptor antagonists (e.g. terfenadine), especially at (mycophenolate mofetil treatment is
high plasma levels or when in combination with imidaz- suspended). This is vital to allow a better
ole antifungal agents or macrolide antibiotics (Chapter 12). immune response to clear the CMV. Close
Hypersensitivity reactions, especially to topically applied surveillance of graft function is important during
H1-receptor antagonists, may occur. this period.
Mast-cell stabilizers, the antiinflammatory glucocorti- • Specific antiviral therapy (ganciclovir).
coids, and sympathomimetic decongestants are all used in Mr Isaac responds to this therapy and his
allergy (see Chapter 3).
symptoms resolve after 6 days.

IMMUNOSUPPRESSANTS Calcineurin inhibitors

The main drug in this class is cyclosporine.
Deliberate pharmacological suppression of the immune sys- Mechanism of action—Cyclosporine is a cyclic peptide,
tem is used in the following three main clinical areas. derived from fungi, that has powerful immunosuppres-
• To suppress inappropriate autoimmune responses (e.g. sive activity. It has a selective inhibitory effect on T cells
systemic lupus erythematosus or rheumatoid arthritis), by inhibiting the T-cell receptor (TCR)-mediated signal-­
where the host immune system is “attacking” host tissue transduction pathway. It is believed to exert its actions after

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 Immunosuppressants 11

Antigen-presenting cell

MHC class II
Antigen-presenting
cell plasma membrane

Ag

α β CD4
Ciclosporin A Ciclosporin/ T-cell
cyclophilin T-cell plasma
complex receptor membrane
complex
egzp ed
Cyclophilin CD3 family CD3

NF-ATc − T-cell-receptor
activation
T-cell cytoplasm
Dephosphorylation
Ca2+

Calcineurin

Nuclear envelope

NF-ATn

NF-AT
Transcription IL-2 gene etc. T-cell nucleus

Key
NF-ATc = nuclear factor of activated T cells–cytoplasmic component
NF-ATn = nuclear factor of activated T cells–nuclear component
NF-AT = nuclear factor of activated T cells–complete
IL-2 = interleukin-2
Ag = antigen
MHC class II= major histocompatibility complex class II

Fig. 11.6 Cyclosporine and T-cell suppression.

entering the T cell and preventing the transcription of spe- Inhibition of calcineurin by the cyclosporine-cyclophilin
cific genes (Fig. 11.6). complex therefore prevents the nuclear translocation of NF-
After entry into the T cell, cyclosporine specifically ATc and the transcription of certain genes essential for the ac-
binds to its cytoplasmic binding protein, cyclophilin. This tivation of T cells. Hence the production of IL-2 by T-helper
cyclosporine-cyclophilin complex then binds to a serine/ cells, the maturation of cytotoxic T cells and the production of
threonine phosphatase called calcineurin, inhibiting its some other cytokines, such as interferon-γ, are all inhibited.
phosphatase activity. Calcineurin is normally activated The overall action of cyclosporine is to suppress revers-
when intracellular calcium ion levels rise following TCR ibly both cell-mediated and antibody-specific adaptive im-
binding to the appropriate major histocompatibility com- mune responses.
plex: antigen complex. When calcineurin is active, it de- Indications—Cyclosporine is used for the prevention of
phosphorylates the cytoplasmic component of the nuclear graft and transplant rejection, and prevention of GVHD.
factor of activated T cells (NF-ATc) into a form that mi- Route of administration—Oral, intravenous.
grates to the nucleus and induces transcription of genes Adverse effects—Unlike most immunosuppressive
such as IL-2 that are involved in T-cell activation. agents, cyclosporine does not cause myelosuppression.

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 Inflammation, allergic diseases and immunosuppression

However, it is markedly nephrotoxic to the proximal tubule Therapeutic notes—Azathioprine is used as part of
of the kidney, and renal damage almost always occurs. This a posttransplantation triple therapy regimen with oral
may be reversible or permanent. Hypertension occurs in corticosteroids.
50% of people.
Less serious side effects include mild hepatotoxicity, an- Mycophenolate mofetil
orexia, lethargy, gastrointestinal upsets, hirsutism and gum Mechanism of action—Mycophenolate mofetil is rap-
hypertrophy. idly hydrolysed to mycophenolic acid, which is the active
Therapeutic notes—Cyclosporine is often used as part metabolite. Mycophenolic acid is a potent, uncompetitive
of a posttransplantation “triple therapy” regimen with oral and reversible inhibitor of iosine monophosphate dehy-
corticosteroids and azathioprine. drogenase, and therefore inhibits the pathway critical for
T- lymphocyte and B-lymphocyte proliferation. It is se-
Antiproliferatives lective because other cells are not solely reliant on this en-
zyme and so are able to maintain their rapid proliferation.
Azathioprine Indications—Prophylaxis of acute renal, cardiac or he-
Mechanism of action—Azathioprine is a prodrug that is patic transplant rejection (in combination with cyclospo-
converted into the active component 6-mercaptopurine in rine and corticosteroids).
the liver. Mercaptopurine is a “fraudulent” purine nucleo- Contraindications—Pregnancy and those with hypersen-
tide that impairs DNA synthesis and has a cytotoxic action sitivity to the drug.
on dividing cells. Route of administration—Oral, intravenous.
Indications—Azathioprine is used for the prevention of Adverse effects—Side effects of mycophenolate mofetil
graft and transplant rejection, and autoimmune conditions include bone marrow suppression, which can lead to leu-
when corticosteroid therapy alone is inadequate. copoenia, thrombocytopenia and sometimes anaemia.
Route of administration—Oral, intravenous. Increased susceptibility to infections (often opportunistic
Adverse effects—Side effects of azathioprine include pathogens), and to certain cancers (lymphomas) can occur.
bone marrow suppression, which can lead to leucopoenia, Common side effects include gastrointestinal disturbances,
thrombocytopenia and sometimes anaemia. This is often nausea, vomiting and diarrhoea. Alopecia may be partial or
the dose-limiting side effect. complete but is usually reversible.
Increased susceptibility to infections (often opportu-
nistic pathogens), and to certain cancers (lymphomas) can
occur. Common side effects include gastrointestinal distur- Glucocorticoids
bances, nausea, vomiting and diarrhoea. Alopecia may be The use of glucocorticoids as immunosuppressant agents
partial or complete but is usually reversible. involves both their antiinflammatory actions and their
Drug interaction with allopurinol necessitates lowering ­effects on the immune system (Chapter 7).
the dose of azathioprine.

Chapter Summary

• Erythema, heat, oedema and tenderness indicate inflammation

• Inflammatory mediators include histamine, bradykinin, cytokines, eicosanoids and
neuropeptides
• NSAIDs inhibit cyclooxygenase and inhibit prostaglandin synthesis
• Because of the unspecific nature of NSAIDs, they have wide ranging, severe
adverse effects
• DMARDS have a slow onset of action but reduce inflammation in chronic disease
• H1-receptor antagonists are used in the management of allergic reactions
• Intramuscular adrenaline is given to counteract the type I hypersensitivity reaction that
occurs in anaphylactic shock
• Emollients are the mainstay of treatment of inflammatory, dry skin conditions
• Topical steroids can cause systemic side effects if used long-term and should be
withdrawn slowly
• Bone marrow suppression is common with systemic immunosuppressants (e.g.
azathioprine or methotrexate)
• Colchicine and NSAIDs are used to treat acute attacks of gout, allopurinol is used to
prevent acute attack

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 Infectious diseases
12
This chapter reviews the drugs used in the treatment of Acquired resistance
bacterial, fungal, viral and helminth infections. Malaria, Acquired resistance is when bacteria that were sensitive to
tuberculosis and human immunodeficiency virus (HIV) an antibiotic become resistant. Biochemical mechanisms re-
medications are also reviewed. sponsible for resistance to an antibiotic include the following.
• Production of enzymes that inactivate the drug
• Alteration of drug binding site
• Reduction in drug uptake and accumulation
ANTIBACTERIAL DRUGS • Development of altered metabolic pathways
The major stimulus for the development of acquired re-
Concepts of antibacterial sistance is the over use or inappropriate use of antibiotics.
chemotherapy Antibiotic use exerts selective pressure on bacteria to “ac-
quire” resistance to survive. Acquired resistance to antibi-
Bacteria are prokaryotic organisms. Some bacteria are otics can develop in bacterial populations in many ways,
pathogenic to humans and responsible for a number of although all involve genes that code for the resistance
medically important diseases. mechanism located either on the bacterial chromosome or
The principal treatment of infections is with antibiotics. on plasmids. The acquisition of resistance by a bacterium
These antibacterial agents can be: can either be achieved de novo by spontaneous mutation or
• bacteriostatic (i.e. they inhibit bacterial growth but do by being transferred from another bacterium.
not kill the bacteria), or The development of clinical antibiotic drug resistance is
• bactericidal (i.e. they kill bacteria). a major problem imposing serious constraints on the med-
Note that the distinction is not clear cut because the ical treatment of many bacterial infections. Methicillin-
ability of an antibacterial agent to inhibit or kill bacte- resistant Staphylococcus aureus (MRSA) and some strains
ria is partially dependent on its concentration and both of Mycobacteria tuberculosis are examples of multidrug-­
are used frequently. Patients who are immunocompro- resistant bacteria.
mized often require bactericidal agents because their
immune system is not capable of eliminating bacteria Prescribing antibiotics
completely.
Similar to most drugs, many antibiotics have side effects.
When prescribing antibiotics, there are many consider-
Classification of antibiotics ations determining which antibiotic to use, by which route,
There are three main ways of classifying antibiotics. for how many days, and so on. One should consider the fol-
lowing points when treating an infection.
• Whether they are bactericidal or bacteriostatic
• By their site of action (Table 12.1 and Fig. 12.1) • Identify the organism responsible for, or likely to be
• By their chemical structure responsible for the symptoms
• Assess the severity of illness
In this chapter, antibiotics have been described accord- • Previous antibiotic therapy
ing to their site of action. • Previous adverse/allergic response to antibiotics
• Other medications being taken and their possible
Antibiotic resistance interactions
• Ongoing medical considerations
When an antibiotic is ineffective against a bacterium, that
bacterium is said to be resistant. Resistance to antibiotics
can be acquired or innate.
HINTS AND TIPS

Innate resistance Always try to get a sample (e.g. blood, urine

Innate resistance is a long-standing characteristic of a par- or sputum) for microbial culture before starting
ticular species of bacteria. For instance, Pseudomonas aeru- antibiotics, unless there is a threat to life by
ginosa has always been resistant to treatment with several withholding antibiotics.
antibiotics, including benzylpenicillin, vancomycin and
fusidic acid.

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 Infectious diseases

Table 12.1 Sites of action of cytotoxic drugs that act on dividing cells
Site Exploitable difference Antibacterial drug
Peptidoglycan Peptidoglycan cell walls are a uniquely prokaryotic feature not shared Penicillins
cell wall by eukaryotic (mammalian) cells. Drugs that act here are therefore very Cephalosporins
selective Glycopeptides
Cytoplasmic Bacteria possess a plasma membrane within the wall which is a Polymyxins
membrane phospholipid bilayer, as in eukaryotes. However, in bacteria the plasma
membrane does not contain any sterols and this results in differential
chemical behaviour that can be exploited.
Protein synthesis The bacterial ribosome (50S + 30S subunits) is sufficiently different from Aminoglycosides
the mammalian ribosome (60S + 40S subunits) that sites on the bacterial Tetracyclines
ribosome are good targets for drug action. Chloramphenicol
Macrolides Fusidic acid
Nucleic acids The bacterial genome is in the form of a single circular strand of DNA Antifolates
plus ancillary plasmids unenclosed by a nuclear envelope, in contrast to Quinolones
the eukaryotic chromosomal arrangement within the nucleus. Drugs may Rifampicin
interfere directly or indirectly with microbial DNA and RNA metabolism,
replication and transcription.
DNA, Deoxyribonucleic acid; RNA, ribonucleic acid.

Cell wall synthesis DNA replication

Penicillins Quinolones
Cephalosporins DNA
Glycopeptides

Folinic acid DNA-dependent

mRNA
RNA polymerase
Nucleotide metabolism Rifampicin
antifolates Ribosomes
Folic acid
50 50 50
Protein synthesis
30 30 30 Aminoglycosides
Cell membrane
Tetracyclines
polymyxins
Chloramphenicol
Macrolides
Fusidic acid
PABA
Fig. 12.1 Sites of action of different types of antibiotic agent. DNA, Deoxyribonucleic acid; PABA, para-aminobenzoic
acid, RNA, ribonucleic acid.

Antibacterial drugs that inhibit cell Penicillins bind to penicillin-binding proteins on sus-
wall synthesis ceptible microorganisms. This interaction results in inhibi-
tion of peptide cross-linking within the microbial cell wall,
Penicillins and indirect activation of autolytic enzymes. The combined
Examples of penicillins include benzylpenicillin, phe- result is lysis (see Fig. 12.1).
noxymethylpenicillin, flucloxacillin, amoxicillin and Spectrum of activity—Penicillins exhibit considerable di-
ampicillin. versity in their spectrum of activity (Table 12.2).
Combinations exist to help minimize resistance; co-­ Benzylpenicillin is active against aerobic gram-positive
amoxiclav is a combination of amoxicillin and clavulanic acid, and gram-negative cocci and many anaerobic organisms.
whereas tazocin is a combination of piperacillin and tazobactam. Many staphylococci are now resistant to benzylpenicillin.
Mechanism of action—Penicillins are bactericidal. Flucloxacillin is used against penicillin-resistant staphy-
Structurally, they possess a thiazolidine ring connected to lococci because it is not inactivated by their β-lactamase.
a β-lactam ring. The side chain from the β-lactam ring de- Phenoxymethylpenicillin is similar to benzylpenicillin but
termines the unique pharmacological properties of the dif- less active. Amoxicillin and ampicillin are broad-spectrum
ferent penicillins. penicillins. The penicillins are useful for treating lung and

174
 Antibacterial drugs 12

Table 12.2 Drugs of choice and alternatives for selected common bacterial pathogens
Bacterium Drug(s) of choice Alternatives Comments
Streptococcus Penicillin First-generation A few strains are penicillin resistant, especially
species cephalosporins some S. Pneumoniae
Erythromycin Erythromycin is only for mild infections
Clindamycin Vancomycin is only for serious infections
Vancomycin
Enterococcus Penicillin or ampicillin Vancomycin plus There are some strains for which streptomycin is
species plus gentamicin gentamicin synergistic but gentamicin is not
Some strains are resistant to synergy with any
aminoglycoside
Staphylococcus Antistaphylococcal First-generation Vancomycin is required for methicillin-resistant
species penicillin, e.g. cephalosporins strains
flucloxacillin Vancomycin Rifampicin is occasionally used to eradicate the
nasal carriage state
Neisseria Penicillin Chloramphenicol Rare strains are penicillin resistant
meningitidis Third-generation
cephalosporins
Neisseria Cefixime Ciprofloxacin Some strains are fluoroquinolone resistant
gonorrhoeae Third-generation (especially in Asia)
cephalosporins
Bordetella Erythromycin Trimethoprim with
pertussis sulfamethoxazole
Haemophilus Aminopenicillin Cefuroxime Approximately 30% are aminopenicillin-
influenzae (ampicillin, amoxicillin) Third-generation resistant: aminopenicillins should not be
cephalosporins used empirically in serious infections until
Chloramphenicol susceptibility results are available
Rifampicin is used to eradicate the nasal
carriage state
Enterobacteria Trimethoprim with Ciprofloxacin β-lactams are less effective than trimethoprim
in urine sulfamethoxazole Gentamicin with sulfamethoxazole or fluoroquinolones for
Nitrofurantoin the treatment of urinary tract infection
Enterobacteria in Third-generation Trimethoprim with In neonates only, aminoglycosides are equivalent
cerebrospinal fluid cephalosporin sulfamethoxazole to third-generation cephalosporins
Experience with trimethoprim with
sulfamethoxazole in meningitis is limited
Enterobacteria Gentamicin Trimethoprim with Two-drug therapy is sometimes used in serious
elsewhere (blood, Third-generation sulfamethoxazole infection
lung, etc.) cephalosporins Monotherapy with a third-generation
Ciprofloxacin cephalosporin should be avoided if the pathogen
is E. cloacae, E. aerogenes, Serratia marcescens
or Citrobacter freundii
Pseudomonas Antipseudomonal Ceftazidime Two-drug therapy recommended except for
aeruginosa penicillin plus Ciprofloxacin urinary tract infection
aminoglycoside
Bacteroides fragilis Metronidazole or Imipenem Penicillin B. fragilis is usually involved in polymicrobial
clindamycin β-lactamase infections; therefore another antibiotic active
inhibitors against Enterobacteriaceae is often required
Mycoplasma Macrolides, e.g. Tetracycline Although tetracyclines are as effective as
penumoniae erythromycin macrolides, the latter are recommended because
of better activity against Pneumococcus, which
can mimic this infection
Chlamydia Tetracycline Azithromycin Azithromycin is the only therapy effective in a
trachomatis Erythromycin single dose
Erythromycin is used in pregnancy
(Continued)

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 Infectious diseases

Table 12.2 Drugs of choice and alternatives for selected common bacterial pathogens—cont’d
Bacterium Drug(s) of choice Alternatives Comments
Rickettsial species Tetracycline Chloramphenicol
Listeria Ampicillin plus Vancomycin plus
monocytogenes gentamicin gentamicin
Legionella species Erythromycin Tetracycline Rifampicin is occasionally used as a second
agent in severe cases
Clostridium difficile Metronidazole Vancomycin (oral)
Mycobacterium Isoniazid plus rifampicin Streptomycin Directly observed therapy is recommended
tuberculosis plus pyrazinamide plus Fluoroquinolones Isoniazid is used alone for preventive therapy
ethambutol Cycloserine
Clarithromycin
Capreomycin
Mycobacterium Dapsone plus rifampicin ± Clarithromycin Thalidomide is useful for erythema nodosum
leprae clofazimine leprosum

skin infections. Neutropenic sepsis is commonly treated Cephalosporins

with tazocin. The cephalosporins comprise a large group of drugs. There
Route of administration—Benzylpenicillin must be ad- are three main subgroups.
ministered parenterally because it is inactivated when given • First-generation drugs, for example, cefadroxil (oral)
orally. Phenoxymethylpenicillin, flucloxacillin, amoxicillin and cefradine (parenteral).
and ampicillin are active when given orally. • Second-generation drugs, for example, cefuroxime
Contraindications—Known hypersensitivity to penicil- (oral) and cefamandole (parenteral).
lins or cephalosporins. • Third-generation drugs, for example, cefixime (oral)
Adverse effects—In general, very specific and safe an- and cefotaxime (parenteral).
tibiotics. Hypersensitivity reactions are the main adverse
effect, including rashes (common) and anaphylaxis (rare). Mechanism of action—Cephalosporins are bactericidal.
Neurotoxicity occurs at excessively high cerebrospinal fluid They are β-lactam-containing antibiotics and inhibit bac-
concentrations. Diarrhoea is common, owing to distur- terial cell wall synthesis in a manner similar to the penicil-
bance of normal colonic flora. lins. Structurally cephalosporins possess a dihydrothiazine
Therapeutic notes—Resistance to penicillins is often ring connected to the β-lactam ring that makes them
caused by the production of β-lactamase by some micro- more resistant to hydrolysis by β-lactamases than are the
organisms, which hydrolyses the β-lactam ring. This re- penicillins.
sistance gene is located in a plasmid and is transferable. Spectrum of activity—The cephalosporins are broad-
Flucloxacillin is resistant to β-lactamase. spectrum antibiotics that are second-choice agents for many
infections (see Table 12.2), including meningitis.
Route of administration—Oral, intravenous, intramuscu-
CLINICAL NOTE lar. Consult the British National Formulary (BNF).
Contraindications—Known hypersensitivity to cephalo-
A 55-year-old male presents to the hospital to sporins or penicillins.
have his pacemaker upgraded. The surgery is Adverse effects—Side effects of the cephalosporins in-
uneventful and completed successfully. On routine clude hypersensitivity reactions, which occur in a similar
observation, the wound is found to be weeping and cross-reacting fashion to the penicillins. Diarrhoea is
and the skin around the incision is noted to be common, owing to disturbance of normal colonic flora.
Nausea and vomiting may also occur.
red, swollen and tender to touch. A swab of the
Therapeutic notes—The cephalosporins can be inac-
pus is taken and sent to microbiology for cultures
tivated by the β-lactamase enzyme, although the later-­
and he is started on intravenous flucloxacillin and generation drugs are more resistant to hydrolysis.
cefuroxime. The following day his temperature is
noted to be 37.8°C and he reports general malaise
and lethargy. The wound is still weeping with no Glycopeptides
improvement in appearance. MRSA is suspected, Vancomycin and teicoplanin are the classic glycopeptides.
and he is started on intravenous vancomycin. Mechanism of action—Glycopeptides are bactericidal.
They inhibit peptidoglycan synthesis, with possible effects
on ribonucleic acid (RNA) synthesis (see Fig. 12.1).

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 Antibacterial drugs 12

Spectrum of activity—Vancomycin is active only Contraindications—Pregnant women because there is

against aerobic and anaerobic gram-positive bacteria. a theoretic teratogenic risk with antifolates. Neonates be-
Glycopeptides are reserved for resistant staphylococcal cause bilirubin displacement can damage the neonatal brain
infections and Clostridium difficile in antibiotic-associated (kernicterus).
pseudomembranous colitis (see Table 12.2). Adverse effects—Nausea, vomiting and hypersensitiv-
Route of administration—Glycopeptides are usually ity reactions, for example, rashes, fever, Stevens-Johnson
administered intravenously as they are not well absorbed syndrome. The sulphonamides are relatively insoluble and
orally. Oral administration is reserved for when a local gas- can cause crystalluria, whereas trimethoprim can cause
trointestinal tract effect is required, for example, in colitis. myelosuppression/agranulocytosis.
Adverse effects—Side effects of glycopeptides include Therapeutic notes—Antifolates are often used in com-
ototoxicity and nephrotoxicity at high plasma levels, and fe- bined preparations because they have synergistic effects.
ver, rashes (“red man syndrome”) and local phlebitis at the Resistance is common and is caused by the production of
site of infection. enzymes that have reduced affinity for the drugs. Resistance
Therapeutic notes—Acquired resistance to vancomycin can be acquired on plasmids in gram-negative bacteria.
is rare, but reports of vancomycin-resistant enterococci are
becoming more common. Quinolones
Ciprofloxacin and levofloxacin are quinolones.
Monobactam and carbapenems Mechanism of action—Quinolones are bactericidal. They
Aztreonam is a monobactam antibiotic, which is less likely act by inhibiting prokaryotic DNA gyrase. This enzyme
to cause hypersensitivity reactions in penicillin-sensitive packages DNA into supercoils and is essential for DNA rep-
patients. Carbapenems have the broadest spectrum of lication and repair (see Fig. 12.1).
activity of all the β-lactams and include ertapenem, imi- Spectrum of activity—Ciprofloxacin has a broad spec-
penem (used with cilastatin to increase the duration of ac- trum of activity but works best against gram-negative or-
tion) and meropenem. Both groups contain β-lactam rings, ganisms (see Table 12.2). Quinolones are typically used
although they are resistant to many β-lactamases. For indi- for pyelonephritis and atypical respiratory infections (e.g.
cations, the spectrum of activity and adverse effects consult pseudomonas, legionella and mycoplasma).
the BNF. Route of administration—Oral, intravenous. Ciprofloxacin
is so well absorbed orally that intravenous administration is
rarely required unless the patient is unable to tolerate oral
Antibacterial drugs that inhibit medication.
bacterial nucleic acids Contraindications—Quinolones should not be given
with theophylline because theophylline toxicity may be
Antibacterial drugs that inhibit bacterial nucleic acids (see
precipitated.
Fig. 12.1).
Adverse effects—Gastrointestinal upset. Rarely, hy-
• The antifolates, which affect deoxyribonucleic acid persensitivity and central nervous system (CNS) distur-
(DNA) metabolism bances (e.g. hallucinations) occur. Quinolones can also
• The quinolones, which affect DNA replication and cause tendon damage and increase the risk of C. difficile
packaging infection.
• Rifampicin, which affects transcription (see later)
Antibacterial drugs that inhibit
Antifolates
Examples of antifolates include the sulphonamides (e.g. protein synthesis
sulfadiazine) and trimethoprim. Antibacterial drugs that inhibit protein synthesis include
Mechanism of action—Folate is an essential cofactor in the following.
the synthesis of purines and hence of DNA. Bacteria, un- • Aminoglycosides
like mammals, must synthesize their own folate from para-­ • Tetracyclines
aminobenzoic acid (see Fig. 12.1). This pathway can be • Chloramphenicol
inhibited at two points: the sulphonamides inhibit dihydro- • Macrolides
folate synthetase, whereas trimethoprim inhibits dihydrofo- • Lincosamides
late reductase but both are bacteriostatic. • Fusidic acid.
Spectrum of activity—The sulphonamides are used for
“simple” urinary tract infections (UTIs). Trimethoprim The site of action of these drugs is summarized in Fig. 12.2.
and co-trimoxazole (trimethoprim and sulfamethoxaz-
ole) are used for UTIs and respiratory tract infections (see Aminoglycosides
Table 12.2). Examples of aminoglycosides include gentamicin, strepto-
Route of administration—Oral, intravenous. mycin, and amikacin.

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 Infectious diseases

Growing polypeptide

Fusidic acid Chloramphenicol

prevents binding of tRNA to binds to 50S portion inhibiting
the ribosome formation of peptide bond

50S
portion

Tetracycline
interferes with attachment of
tRNA to mRNA−ribosome complex

Macrolides
bind to 50S portion preventing
tRNA translocation movement of
ribosome along mRNA

mRNA

30S Direction of
portion ribosome travel
Aminoglycosides
bind to 30S portion inhibiting
translation and causing code
on mRNA to be read incorrectly
70S bacterial
ribosome
Fig. 12.2 Site of action of the antibiotics which inhibit bacterial protein synthesis. mRNA, Messenger ribonucleic acid;
tRNA, transfer ribonucleic acid.

Mechanism of action—Aminoglycosides are bactericidal. of active bacterial transport systems not possessed by mam-
They bind irreversibly to the 30S portion of the bacterial malian cells. The tetracycline then binds reversibly to the
ribosome. This inhibits the translation of messenger RNA 30S subunit of the bacterial ribosome, interfering with the
(mRNA) to protein and causes more frequent misreading of attachment of transfer RNA (tRNA) to the mRNA ribosome
the prokaryotic genetic code (see Fig. 12.2). complex (see Fig. 12.2).
Spectrum of activity—Aminoglycosides have a broad Spectrum of activity—Tetracyclines have broad-­
spectrum of activity but with low activity against anaer- spectrum activity against gram-positive and gram-negative
obes, gram-negative organisms, streptococci and pneu- bacteria, as well as intracellular pathogens (see Table 12.2).
mococci (see Table 12.2). Streptomycin is used against They are typically used for atypical chest infections, acne
M. tuberculosis, whereas gentamicin is used to treat bacte- and as malaria prophylaxis.
rial endocarditis. Route of administration—Oral, intravenous. Oral ab-
Route of administration—Parenteral only. sorption is incomplete and can be impaired by calcium (e.g.
Contraindications—Acute neuromuscular blockade can milk), and magnesium or aluminium salts (e.g. antacids).
occur if an aminoglycoside is used in combination with an- Contraindications—Tetracyclines should not be given to
aesthesia or other neuromuscular blockers. children or pregnant women.
Adverse effects—Dose-related ototoxicity and nephro- Adverse effects—Gastrointestinal disturbances (espe-
toxicity at high plasma levels. cially reflux) are common after oral administration. In
Therapeutic notes—Resistance to aminoglycosides is in- children, tetracyclines depress bone growth and produce
creasing and is primarily caused by plasmid-borne genes permanent discolouration of teeth.
encoding degradative enzymes. Therapeutic notes—In the majority of cases, resis-
tance is caused by decreased uptake of the drug and is
Tetracyclines plasmid-borne.
Examples of tetracyclines include tetracycline, minocycline,
doxycycline. Chloramphenicol
Mechanism of action—Tetracyclines are bacteriostatic. Mechanism of action—Chloramphenicol is both bacteri-
They work by selective uptake into bacterial cells because cidal and bacteriostatic, depending on the bacterial ­species.

178
 Antibacterial drugs 12

It reversibly binds to the 50S subunit of the bacterial ri- Fusidic Acid
bosome, inhibiting the formation of peptide bonds (see Mechanism of action—Fusidic acid is a steroid that pre-
Fig. 12.2). vents binding of tRNA to the ribosome (see Fig. 12.2).
Spectrum of activity—Chloramphenicol has a broad Spectrum of activity—Fusidic acid has a narrow spec-
spectrum of activity against many gram-positive cocci trum of activity, particularly against gram-positive bacteria
and gram-negative organisms (see Table 12.2). Despite its (see Table 12.2). It is most useful for skin infections caused
toxicity, it is used in the treatment of typhoid fever in the by staphylococcal infections.
developing world, where the organism is sensitive to it. Route of administration—Oral, intravenous.
Chloramphenicol eye drops are typically used for bacterial Adverse effects—Gastrointestinal disturbance. Skin erup-
conjunctivitis. tions and jaundice may occur.
Route of administration—Oral, topical, intravenous. Therapeutic notes—Resistance to fusidic acid can occur
Contraindications—Chloramphenicol should not be via mutation or by plasmid-borne mechanisms.
given to pregnant women or neonates.
Adverse effects—Myelosuppression, reversible anaemia. Lincosamides
Neutropenia and thrombocytopenia may occur during Clindamycin is a lincosamide.
chronic administration. Fatal aplastic anaemia is rare. Mechanism of action—Similar to the macrolides.
Neonates cannot metabolise chloramphenicol and “grey Spectrum of activity—Clindamycin is active against
baby syndrome” may develop, which comprises pallor, ab- gram-positive cocci, including penicillin-resistant staphy-
dominal distension, vomiting and collapse. lococci, and many anaerobes.
Therapeutic notes—Resistance to chloramphenicol is Route of administration—Oral, parenteral.
caused by a plasmid-borne gene encoding an enzyme that Adverse effects—Antibiotic-associated (pseudomembra-
inactivates the drug by acetylation. Blood monitoring is nous) colitis; greater risk than for other antibiotics.
necessary. Therapeutic notes—Clindamycin is used for staphylo-
coccal joint and bone infections.
Macrolides
Erythromycin, clarithromycin and azithromycin are exam- Miscellaneous antibacterials
ples of macrolides.
Mechanism of action—Macrolides are bacteriostatic/ Other antibacterial drugs include the following.
bactericidal. They reversibly bind to the 50S subunit of the • Metronidazole
bacterial ribosome, preventing the translocation movement • Nitrofurantoin
of the ribosome along mRNA (see Table 12.2). • Bacitracin
Spectrum of activity—Erythromycin is effective against • Polymyxins
most gram-positive bacteria and spirochetes. Clarithromycin
is active against Haemophilus influenzae, Mycobacterium Metronidazole and tinidazole
avium cellulare and Helicobacter pylori. Mechanism of action—Metronidazole is bactericidal.
Route of administration—Oral, intravenous. It is metabolized to an intermediate that inhibits bacterial
Adverse effects—Side effects of erythromycin include DNA synthesis and degrades existing DNA. Its selectivity is
gastrointestinal disturbance, which is common after oral caused by the fact that the intermediate toxic metabolite is
administration. Liver damage and jaundice can occur after not produced in mammalian cells.
chronic administration. Spectrum of activity—Metronidazole is antiprotozoal
Therapeutic notes—Resistance to erythromycin results and has antibacterial activity against anaerobic bacteria
from a mutation of the binding site on the 50S subunit. (see Table 12.2). Metronidazole is particularly helpful in the
Erythromycin has a similar spectrum of activity to peni- treatment of intraabdominal sepsis, C. difficile and giardia,
cillin and is an effective alternative in penicillin-sensitive as well as aspiration pneumonia.
patients. Azithromycin can be given as a one-off dose for Route of administration—Oral, rectal, intravenous, topical.
uncomplicated chlamydial infections of the genital tract Contraindications—Metronidazole should not be given
and has been shown to be effective in reducing exacerba- to pregnant women.
tions of asthma and chronic obstructive pulmonary disease. Adverse effects—Mild headache, gastrointestinal distur-
bance. Adverse drug reactions occur with alcohol.
Therapeutic notes—Acquired resistance to metronida-
HINTS AND TIPS
zole is rare. Tinidazole is similar to metronidazole but has a
Macrolides are cytochrome p450 enzyme longer duration of action.
inhibitors. Care should be taken if they are
coprescribed with warfarin or statins.
Nitrofurantoin
Mechanism of action—The mechanism of action of ni-
trofurantoin is uncertain although it possibly interferes

179
 Infectious diseases

with bacterial DNA metabolism through the inhibition of orally. Adverse effects are infrequent but can be serious,
nucleic acid synthesis. for example, hepatotoxicity and “toxic syndromes”.
Spectrum of activity—Nitrofurantoin is active against Orange discolouration of the urine is a common side
gram-positive bacteria and Escherichia coli (see Table 12.2), effect. There are many drug interactions because
therefore useful in the treatment of UTIs. rifampicin is a cytochrome p450 enzyme inhibitor, and
Route of administration—Oral; it reaches high therapeu- therefore resistance can develop rapidly.
tic concentrations in the urine. • Ethambutol: This drug is bacteriostatic. The
Contraindications—Third trimester of pregnancy as risk mechanism of action is uncertain, involving the
of neonatal haemolysis. impaired synthesis of the mycobacterial cell wall.
Adverse effects—Gastrointestinal disturbance. Impaired Ethambutol is administered orally. Adverse effects are
renal function, pulmonary fibrosis (if chronically used). uncommon but reversible optic neuritis may occur.
Therapeutic notes—Rarely, chromosomal resistance to Resistance often develops.
nitrofurantoin can occur. • Pyrazinamide: Its mechanism of action is uncertain
but may involve metabolism of the drug within M.
Polymyxins tuberculosis to produce a toxic product, pyrazinoic
Colistin is an example of a polymyxin, although this class is acid, which works as a bacteriostatic agent in the low
seldom prescribed because of its toxicity. Nonetheless, colis- pH environment of the phagolysosome. It is active
tin is sometimes the last antibiotic available for ­patients with orally. Adverse effects are hepatotoxicity and raised
multidrug resistance because resistance to colistin is rare. plasma urate levels that can lead to gout. Resistance can
Mechanism of action—Polymyxins are bactericidal. They develop rapidly.
are peptides that interact with phospholipids on the outer The second-line drugs used for tuberculosis infections
plasma cell membranes of gram-negative bacteria, disrupt- when first-line drugs have been discontinued owing to re-
ing their structure. This disruption destroys the bacteria's sistance or adverse effects include the following.
osmotic barrier, leading to lysis (see Fig. 12.1).
• Capreomycin: A peptide drug given intramuscularly. It
Spectrum of activity—Polymyxins are active only
can cause ototoxicity and kidney damage.
against gram-negative bacteria including P. aeruginosa (see
• Cycloserine: A broad-spectrum drug that inhibits
Table 12.2).
peptidoglycan synthesis. This drug is administered
Route of administration—Intravenous, intramuscular,
orally and can cause CNS toxicity.
inhalation. Oral polymyxins are given to sterilize the bowel
• New macrolides, for example, azithromycin and
in neutropenic patients.
clarithromycin.
Adverse effects—Perioral and peripheral, paraesthesia,
• Quinolones, for example, ciprofloxacin.
vertigo, nephrotoxicity, neurotoxicity.
Therapeutic notes—Resistance to polymyxins is rare. To reduce the emergence of resistant organisms, compound
drug therapy is used to treat tuberculosis, involving the fol-
Antimycobacterial drugs lowing phases.
• An initial phase, designed to reduce the bacterial
The mycobacteria are slow-growing intracellular ba- population as quickly as possible and prevent the
cilli that cause tuberculosis (M. tuberculosis) and leprosy emergence of drug-resistance, lasts about two months
(Mycobacterium leprae) in humans. and consists of three drugs: isoniazid, rifampicin
Mycobacteria differ in their structure and lifestyle from and pyrazinamide. Ethambutol is added where
gram-positive and gram-negative bacteria and are treated there may be resistance to isoniazid (e.g. those who
with different drugs. have previously been treated for tuberculosis or the
immunocompromized).
Antituberculosis therapy • Continuation phase of four months consisting of two
The first-line drugs used in the treatment of tuberculosis. drugs: isoniazid and rifampicin. Longer treatment
• Isoniazid: Inhibits the production of mycolic acid, a regimens may be needed for patients with meningitis
component of the cell wall unique to mycobacteria, or bone/joint involvement.
and is bactericidal against growing organisms. Taken
orally, it penetrates tuberculous lesions well. Adverse Antileprosy therapy
effects occur in about 5% of patients and include • Tuberculoid leprosy is treated with dapsone and
peripheral neuropathy, hepatotoxicity, agranulocytosis rifampicin for 6 months.
and autoimmune phenomena. Pyridoxine (vitamin B6) • Lepromatous leprosy is treated with dapsone,
is given to help reduce the risk of peripheral neuritis rifampicin and clofazimine for up to 2 years.
associated with isoniazid. Dapsone resembles sulphonamides chemically and may in-
• Rifampicin: Inhibits DNA-dependent RNA polymerase, hibit folate synthesis in a similar way. It is active orally. Adverse
causing a bactericidal effect. It is a potent drug, active effects are numerous, and some fatal. Consult the BNF.

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 Antibacterial drugs 12

Clofazimine is a chemically complex dye that accumu- Nevertheless, antiviral chemotherapy is clinically effec-
lates in macrophages, possibly acting on mycobacterial tive against some viral diseases (identified with an asterisk
DNA. As a dye, clofazimine can discolour the skin and urine in Table 12.3). The viruses include the following.
red. Other adverse effects are numerous. It is active orally. • Herpesviruses (herpes simplex virus [HSV], varicella-
zoster virus [VZV] and cytomegalovirus [CMV])
Antiviral drugs • Influenza virus A and more recently virus B
• Respiratory syncytial virus, arenaviruses
Concepts of viral infection • HIV-1
Viruses are obligate intracellular parasites that lack inde-
The selective inhibition of these viruses by drugs
pendent metabolism and can only replicate within the host
­depends on either:
cells they enter and infect. A virus particle, or virion, con-
sists essentially of DNA or RNA enclosed in a protein coat • Inhibition of unique steps in the viral replication
(capsid). In addition, certain viruses may possess a lipopro- pathways, such as adsorption of the virion to the cell
tein envelope and replicative enzymes (Fig. 12.3). receptor, penetration, uncoating, assembly and
Viruses are classified largely according to the architec- release.
ture of the virion and the nature of their genetic material. • Preferential inhibition of steps shared with the host cell,
Viral nucleic acid may be single stranded (ss) or double which includes transcription and translation.
stranded (ds) (Table 12.3). In addition to chemotherapy, immune-based therapies,
such as the use of immunoglobulins and cytokines in viral
infection, are also mentioned subsequently.
Antiviral agents
Because viruses have an intracellular replication cycle and Inhibition of attachment to or penetration
share many of the metabolic processes of the host cell, it of host cells
has proved extremely difficult to find drugs that are selec-
tively toxic to them. In addition, by the time a viral infection Amantadine
becomes detectable clinically, the viral replication process Mechanism of action—Amantadine blocks a primitive
tends to be very far advanced, making chemotherapeutic ion channel in the viral membrane (named M2) prevent-
intervention difficult. All current antiviral agents are virus- ing fusion of a virion to host cell membranes, and inhibits
tatic rather than virucidal and thus rely upon host immuno- the release of newly synthesized viruses from the host cell
competence for a complete clinical cure. (Fig. 12.4).

Nucleic acid
(DNA or RNA
Capsomere
ds or ss) Nucleo-
(protein subunits
of coat) capsid

Coat (capsid)

Viral enzyme in core Viral glycoprotein

in envelope Lipoprotein
phospholipid bilayer envelope (not
(derived from host always present)
cell plasma membrane)

Fig. 12.3 Diagrammatic representation of the components of a virion. DNA, deoxyribonucleic acid; ds, double-stranded;
RNA, ribonucleic acid; ss, single-stranded.

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 Infectious diseases

Table 12.3 Classification of selected medically important viruses and the diseases they cause
Family ss/ds Viruses Diseases
DNA viruses
Herpes viruses Ds Herpes simplex (HSV)a Cold sores, genital herpes
Varicella zoster (VZV)a Chickenpox, shingles
Cytomegalovirus (CMV)a Cytomegalic disease
Epstein-Barr virus (EBV)a Infectious mononucleosis
Poxviruses Ds Variola Smallpox
Adenoviruses Ds Adenoviruses Acute respiratory disease
Hepadnaviruses Ds Hepatitis B Hepatitis
Papovaviruses Ds Papilloma Warts
Parvoviruses Ss B19 Erythema infectiosum
RNA viruses
Orthomyxoviruses Ss Influenza Aa and Ba Influenza
Paramyxoviruses Ss Measles virus Measles
Mumps virus Mumps
Parainfluenza Respiratory infection Respiratory
Respiratory syncytiala infection
Coronaviruses Ss Coronavirus Respiratory infection
Rhabdoviruses Ss Rabies virus Rabies
Picornaviruses Ss Enteroviruses Meningitis
Rhinoviruses Colds
Hepatitis A Hepatitis
Calciviruses Ss Norwalk virus Gastroenteritis
Togaviruses Ss Alphaviruses Encephalitis, haemorrhagic fevers
Rubivirus Rubella
Reoviruses Ds Rotavirus Gastroenteritis
Arenavirus Ss Lymphocytic choriomeningitis Meningitis
Lassavirusa Lassa fever
Retroviruses Ss HIV I, IIa AIDS
a
Viruses for which effective chemotherapy exists.
ds, Double stranded; ss, single stranded.

Route of administration—Oral. Route of administration—Zanamivir is delivered by inhala-

Indications—Amantadine is used for the prophylaxis tion, although its sister drug oseltamivir may be given orally.
and treatment of acute influenza A in groups at risk. It is Indications—Treatment of influenza A or B virus within
not effective against influenza B. 48 hours after onset of symptoms when influenza is en-
Adverse effects—Some patients (5%–10%) report nonse- demic in the community.
rious dizziness, slurred speech and insomnia. Neurological Contraindications—Breastfeeding.
side effects and renal failure can occur at high concentrations. Adverse effects—Gastrointestinal disturbances.
Therapeutic notes—Resistance has been reported in 25%
to 50% of patients. Amantadine is not used widely because Immunoglobulins
of problems with resistance, its narrow spectrum of activity Examples of immunoglobulins include human normal im-
and because influenza vaccines are often preferred. munoglobulin (HNIg/gamma globulin) and specific immu-
noglobulins, for example, hepatitis B (HBIg), rabies (RIg),
Neuraminidase inhibitors varicella zoster (VZIg) and cytomegalovirus (CMVIg)
Zanamivir belongs to the neuraminidase inhibitor class of immunoglobulins.
drugs. Mechanism of action—Immunoglobulins bind specifi-
Mechanism of action—Zanamivir inhibits the release of cally to antigenic determinants on the outside of virions. By
newly synthesized viruses from the host cell by inhibiting specifically binding to a virus, the immunoglobulins may
the enzyme neuraminidase, which is responsible for cleav- neutralize it by coating the virus and preventing its attach-
ing the peptide links between virus and host. ment and entry into host cells.

182
 Antibacterial drugs 12

Infecting virus

Envelope Attachment
Capsid

Receptor
Nucleic acid
By cytosis
No envelope Host
Nucleus cell
Nucleus

By budding Penetration
Forming envelope

Release

Uncoating

Assembly
Capsids form
around nucleic acid

Capsid
shed

Replication
Synthesis of viral messenger RNA
(direct or via host machinery),
synthesis of viral protein for
new capsids
Synthesis of viral nucleic acid
Fig. 12.4 Stages in the infection of a host's cell and replication of a virus. Several thousand virus particles may be formed
from each cell. RNA, Ribonucleic acid. (From Mims et al. Medical Microbiology, 2nd edn. Mosby, 1998).

HNIg is prepared from pooled plasma of ~1000 donors Therapeutic notes—Protection with immunoglobulins is
and contains antibodies to measles, mumps, varicella and immediate and lasts several weeks. HNIg may interfere with
hepatitis A. vaccinations for 3 months.
Specific immunoglobulins are prepared by pooling the
plasma of selected donors with high levels of the antibody Inhibition of nucleic acid replication
required.
Route of administration—Intramuscular, although im- Acyclovir and related drugs
munoglobulins can be given intravenously. Acyclovir, famciclovir and valaciclovir are all closely related
Indications—HNIg is administered for the protec- antiviral drugs.
tion of susceptible contacts against hepatitis A, measles, Mechanism of action—Acyclovir and related drugs
mumps and rubella. Specific immunoglobulins may at- are characterized by their selective phosphorylation in
tenuate or prevent hepatitis and rabies following known ­herpes-infected cells. This takes place by a viral thymidine
exposure, and before the onset of signs and symptoms, kinase rather than inhibiting host kinases, as a first step.
for example, following exposure to a rabid animal. VZIg Phosphorylation yields a triphosphate nucleotide that
and CMVIg are indicated for prophylactic use to prevent inhibits viral DNA polymerase and viral DNA synthesis.
chickenpox and cytomegalic disease in immunosup- These drugs are selectively toxic to infected cells be-
pressed patients at risk. cause, in the absence of viral thymidine kinase, the host ki-
Contraindications—Immunoglobulins should not be nase activates only a small amount of the drug. In addition,
given to people with a known antibody against IgA. the DNA polymerase of herpes virus has a much higher
Adverse effects—Malaise, chills, fever and (rarely) affinity for the activated drug than has cellular DNA poly-
anaphylaxis. merase (see Fig. 12.4).

183
 Infectious diseases

Route of administration—Topical, oral, parenteral. Potential targets for antiviral agents

Indications—Acyclovir and related drugs are used
for the prophylaxis and treatment of HSV and VZV in-
fections, superficial and systemic, particularly in the
immunocompromized.
Adverse effects—Side effects are minimal. Rarely, renal
impairment and encephalopathy occur.
Therapeutic notes—The herpes genome in latent (non-
replicating) cells is not affected by acyclovir therapy and so
1. Block binding
recurrence of infection after cessation of treatment is to be
expected. Reverse
2. Inhibit uncoating transcription
CMV is resistant to acyclovir because its genome does
not encode thymidine kinase. 3. Inhibit reverse
transcription
Ganciclovir
Mechanism of action—Ganciclovir is a synthetic nu-
cleoside analogue, structurally related to acyclovir. It also
Integration
requires conversion to the triphosphate nucleotide form, al-
though by a different kinase. Ganciclovir acts as a substrate
for viral DNA polymerase and as a chain terminator abort-
ing virus replication.
Route of administration—Oral, intravenous. 4. Block translation Transcription
Indications—Although as active as acyclovir against
HSV and VZV, ganciclovir is reserved for the treatment of
severe CMV infections in immunocompromized people, 5. Inhibit polyprotein Viral
processing precursor
owing to its side effects. Polyprotein
Adverse effects—Reversible neutropenia in 40% of pa- processing
tients. There is occasional rash, nausea and encephalopathy.
Therapeutic notes—Maintenance therapy with ganciclo- 6. Inhibit assembly Assembly
vir at a reduced dose may be necessary to prevent recur-
rence of CMV.

Ribavirin (tribavirin)
Mechanism of action—Ribavirin is a nucleoside analogue 7. Interfere with budding Budding
that selectively interferes with viral nucleic acid synthesis in
a manner similar to acyclovir. Release
Route of administration—For respiratory syncytial virus
(RSV) by inhalation; for Lassa virus intravenously. Fig. 12.5 The human immunodeficiency virus replicative
Indications—Severe RSV bronchiolitis in infants. Lassa cycle and potential sites of antiviral drug action.
fever.
Adverse effects—Reticulocytosis, respiratory depression.
Therapeutic notes—The necessity of aerosol administra- Route of administration—Oral.
tion for RSV limits the usefulness of this effective drug. Indications—NRTIs are used for the management of as-
ymptomatic and symptomatic HIV infections, and the pre-
Nucleoside analogue reverse transcriptase vention of maternal-foetal HIV transmission.
inhibitors Adverse effects—Side effects of AZT are uncommon at
Examples of nucleoside reverse transcriptase inhibitors the recommended low dosage in patients with asymptom-
(NRTI) include zidovudine (AZT), and the newer drugs, atic or mild HIV infections, but more common in acquired
abacavir, didanosine (ddI), lamivudine (3TC), stavudine immune deficiency syndrome (AIDS) patients on higher
(d4T) and zalcitabine (ddC). dosage regimens.
Mechanism of action—These nucleotide analogues all Toxicity to human myeloid and erythroid progenitor
require intracellular conversion to the corresponding tri- cells commonly causes anaemia and neutropenia, that is,
phosphate nucleotide for activation. The active triphos- bone marrow suppression. Other common side effects in-
phates competitively inhibit reverse transcriptase and cause clude nausea, insomnia, headaches and myalgia.
termination of DNA chain elongation once incorporated. The major dose-limiting effects of ddI are pancreatitis
Affinity for viral reverse transcriptase is 100 times that for and peripheral neuropathy, and of ddC and d4T, peripheral
host DNA polymerase (Fig. 12.5, site 3). neuropathy.

184
 Antibacterial drugs 12

Therapeutic notes—Drug resistance evolves to all the The mechanism of the antiviral effect of IFNs varies for
current NRTIs by the development of mutations in reverse different viruses and cells. IFNs have been shown to bind
transcriptase, although the kinetics of resistance develop- to cell-surface receptors and signal a cascade of events that
ment varies for the different drugs (e.g. 6–18 months for interfere with viral penetration, uncoating, synthesis, or
AZT). Combined therapies have a place in increasing ef- methylation of mRNA, translation of viral protein, viral
ficacy synergistically and reducing the emergence of resis- assembly and viral release (see Fig. 12.4). IFNs induce en-
tant strains. zymes in the host cell that inhibit the translation of viral
mRNA.
Nonnucleoside reverse transcriptase inhibitors The relatively recent production of IFNs in large quan-
Efavirenz and nevirapine are examples of drugs within this tities by cell culture and recombinant DNA technology
class. has allowed their evaluation and prescription as antiviral
Mechanism of action—Efavirenz and nevirapine both agents.
bind to reverse transcriptase near the catalytic site, Route of administration—Intravenous, intramuscular.
leading to a conformational change that inactivates this Indications—The exact role of IFNs in the treatment
enzyme. of viral infections remains unclear. They have a wide
Route of administration—Oral. spectrum of activity and have been shown to be effective
Contraindications—Breastfeeding. in the treatment of chronic hepatitis (B and C) among
Adverse effects—In general, well tolerated. Rash, dizzi- others.
ness and headache may occur. Adverse effects—Influenza-like syndrome with fatigue,
Therapeutic notes—Resistance can develop quickly when fever, myalgia, nausea and diarrhoea is the most common
subtherapeutic doses are used. side effect. Chronic administration can cause bone marrow
depression and neurological effects.
Inhibition of posttranslational events Therapeutic notes—The role of IFNs remains to be
clearly established. Their usefulness has been limited by
Protease inhibitors
the need for repeated injections and dose-limiting adverse
Examples of protease inhibitors include saquinavir, and
effects.
the newer drugs, ritonavir, indinavir, nelfinavir and
amprenavir.
Mechanism of action—Protease inhibitors prevent the Drugs used in human immunodeficiency
­virus-specific protease of HIV cleaving the inert polypro- virus infection
tein product of translation into various structural and func- Infection with the HIV ultimately results in progression to
tional proteins (see Fig. 12.5, site 5). AIDS.
Route of administration—Oral. There are a variety of potential sites for antiviral drug
Indications—Protease inhibitors are used for the man- action in the HIV-1 replicative cycle (see Fig. 12.5).
agement of asymptomatic and symptomatic HIV infections, The four main classes of drug used in the treatment
in combination with NRTI. of HIV have already been discussed, but consist of the
Adverse effects—Protease inhibitors are well tolerated. following.
Nausea, vomiting and diarrhoea are common. In addition,
• Nucleoside reverse transcriptase inhibitors, for
indinavir and ritonavir may cause taste disturbances, and
example, zidovudine, prevent DNA chain elongation
saquinavir may cause buccal and mucosal ulceration.
and have a competitive inhibitory effect on reverse
Therapeutic notes—Combination treatment with
transcriptase (see Fig. 12.5, site 3).
protease inhibitors and NRTI produces additive antivi-
• Nonnucleoside reverse transcriptase inhibitors, for
ral effects and reduces the incidence of resistance. Such
example, nevirapine, inactivate reverse transcriptase
combination therapy is termed highly active antiretroviral
(see Fig. 12.5, site 3).
therapy (HAART). Note that all protease inhibitors inhibit
• Protease inhibitors, for example, ritonavir, prevent viral
the cytochrome p450 enzyme leading to multiple drug
assembly and budding (see Fig. 12.5, site 5).
interactions.
• Fusion inhibitors, for example, enfuvirtide,
prevent cell infection by preventing fusion of
Immunomodulators the HIV virus with the host cell
Interferons (see Fig 12.5, site 1).
Mechanism of action—Interferons (IFNs) are endog- Recently licensed drugs include raltegravir, an HIV-1 in-
enous cytokines with antiviral activity that are normally tegrase inhibitor that may be used to treat HIV-1 which
produced by leucocytes and other cells in response to viral is either resistant to other drugs or to treat patients show-
infection. Three major classes have been identified (α, β and ing viral replication. Maraviroc has similar indications but
γ) and have been shown to have immunoregulatory and an- blocks the interaction between HIV-1 and the chemokine
tiproliferative effects. receptor CCR5 on host cells.

185
 Infectious diseases

CLINICAL NOTE ANTIFUNGAL DRUGS

Dr Hiroshimi, a 28-year-old man, presents with Concepts of fungal infection
a 3-week history of persistent influenza-like
symptoms. He denies any foreign travel, but he Fungi are members of a kingdom of eukaryotic organisms
admits having unprotected sexual intercourse, that live as saprophytes or parasites. A few species of fungi are
pathogenic to humans. Fungal infections are termed mycoses
last summer, with a number of homosexual men.
and may be superficial, affecting the skin, nails, hair, mucous
On examination, his temperature is 39°C. He is
membranes, or systemic, affecting deep tissues and organs.
counselled for the possibility of HIV and wishes to Three main groups of fungi cause disease in humans
have an HIV test. (Table 12.4). Fungal pathogenicity results from mycotoxin
Two years on his CD4+ T-lymphocyte count is production, allergenicity/inflammatory reactions and tis-
found to be low and his viral count raised. A sue invasion. Opportunistic fungal infections are important
decision is made to commence HAART, causes of disease in the immunosuppressed.
consisting of zidovudine, lamivudine and
nevirapine. Antifungal drugs
He continued to have regular follow-ups. Then There are four main classes of antifungal drugs.
years later he is found to have a sore and painful • Polyene macrolides
throat. On examination, he has whitish velvety • Imidazole antifungals
plaques on the mucous membranes of the • Triazole antifungals
mouth and tongue. The pattern on the tongue is • Other antifungals
distinctive of oral candidiasis. He is given nystatin The sites of action of the antifungal drugs are summarized
(antifungal) mouthwash and a chance to rediscuss in Fig. 12.6.
his antiretroviral therapy.
Polyene macrolides
Examples of polyene macrolides include amphotericin B
and nystatin.
Mechanism of action—Polyene macrolides bind to ergos-
terol in the fungal cell membrane, forming pores through
Future antihuman immunodeficiency virus which cell constituents are lost. This results in fatal damage
drug therapy (Fig. 12.7). These drugs are selectively toxic because in hu-
A number of strategies are being pursued in research labo- man cells, the major sterol is cholesterol, not ergosterol.
ratories across the world in the quest for effective drugs to Route of administration—Amphotericin B is adminis-
treat HIV infection.: tered topically and intravenously. Nystatin is too toxic for
• Drugs which interrupt HIV binding to host cells, intravenous use. It is not absorbed orally at all and so is
notably the gp120 envelope protein applied topically as a cream or vaginal pessaries, or tablets
• Drugs designed specifically to “smother” and prevent sucked so as to deliver the drug via the oral membranes.
its entry into cells Indications—Amphotericin is a broad-spectrum anti-
• Antisense oligonucleotides to complement specific fungal used in potentially fatal systemic infections. Nystatin
portions of the viral genome and inhibit transcription is used to suppress candidiasis (thrush) on the skin and mu-
and replication cous membranes (oral and vaginal).

Table 12.4 Main groups of fungi causing disease in humans

Fungal class Form Example Disease caused
Moulds Filamentous branching Dermatophytes, e.g. Tinea Athlete’s foot, ringworm and
mycelia spp. Aspergillus fumigatus other superficial mycoses
Pulmonary or disseminated
aspergillosis
True yeasts Unicellular (round or oval) Cryptococcus neoformans Cryptococcal meningitis
and lung infections in the
immunocompromized
Yeast- like fungi Similar to yeasts but can also Candida albicans Oral and vaginal thrush,
form long (nonbranching) endocarditis and
filaments septicaemias

186
 Antifungal drugs 12

Cell wall

Cell membrane
• polyenes (amphotericin) − bind to membrane
ergosterol, altering membrane integrity
• imidazoles (ketoconazole) − inhibit cytochrome P-450; leads to membrane
disruption
• triazoles (fluconazole) − inhibit cytochrome P-450; leads to membrane
disruption
• allyamine (terbinafine) − inhibits squalene oxidase leading to membrane
disruption

Nuclear division
• griseofulvin − inhibits fungal mitosis by binding to intracellular microtubular
mRNA
protein
Nucleic acid synthesis
• flucytosine − converted in fungal cells into 5-fluorouracil, a potent inhibitor
of DNA synthesis

Fig. 12.6 Sites of action of antifungal drugs. DNA, Deoxyribonucleic acid; mRNA, messenger ribonucleic acid.

Outside cell Uncontrolled loss of chains of phospholipids, inhibiting growth and interfering
Ions
intracellular ions with membrane-bound enzyme systems.
Fungal cell membrane Pore formed by drug
Route of administration—Intravenous, topical.
Ketoconazole is given orally because, unlike the other im-
idazoles, it is well absorbed by this route.
Indications—Candidiasis and dermatophyte mycoses.
Miconazole can also be used intravenously as an alternative
to amphotericin in disseminated mycoses. Ketoconazole is
active orally and can be used for systemic mycoses.
Adverse effects—Topical use of imidazoles tends to be
unproblematic. Intravenous miconazole is often limited by
Inside cell side effects of nausea, faintness and haematological disor-
ders. Oral ketoconazole can cause serious hepatotoxicity
and adrenosuppression.
Therapeutic notes—Resistance rarely develops to imidazoles.
Ergosterol Hydrophobic side Hydrophilic side
of amphotericin of amphotericin Triazoles
Examples of triazoles include fluconazole and itraconazole.
Fig. 12.7 Mechanism of action of polyene antifungal Mechanism of action—Triazoles are similar to imidazoles
agents. (see earlier), although they have greater selectivity against
fungi and cause fewer endocrinological problems.
Route of administration—Oral.
Adverse effects—Fever, chills and nausea. Long-term
Indications—Fluconazole can be used for a wide range of
therapy invariably causes renal damage. Nystatin may cause
systemic and superficial infections, including cryptococcal
oral sensitisation.
meningitis, because it reaches the cerebrospinal fluid in high
Therapeutic notes—Creatinine clearance must be mon-
concentrations. Itraconazole is similarly indicated, although
itored during amphotericin therapy to exclude renal dam-
unlike fluconazole, it can be used against Aspergillus.
age. Resistance can develop in vivo to amphotericin, but not
Adverse effects—Nausea, diarrhoea and rashes. Itraconazole
to nystatin.
is well tolerated, although nausea, headaches and abdomi-
nal pain can occur, but should not be given to patients with
Imidazoles liver damage.
Examples of imidazoles include clotrimazole, miconazole Therapeutic notes—Resistance rarely develops to the
and ketoconazole. triazoles.
Mechanism of action—Imidazoles have a broad spec-
trum of activity. They inhibit fungal lipid (especially er- Other antifungals
gosterol) synthesis in cell membranes. Interference with
fungal oxidative enzymes results in the accumulation of Allylamines
14α-methyl sterols, which may disrupt the packing of acyl Terbinafine is an example of an allylamine.

187
 Infectious diseases

Mechanism of action—Terbinafine prevents ergosterol

synthesis by inhibiting the enzyme squalene oxidase, result-
ANTIPROTOZOAL DRUGS
ing in squalene accumulation, which leads to membrane
disruption and cell death. It is lipophilic and penetrates su- Concepts of protozoal infection
perficial tissues well, including the nails. Protozoa are members of a phylum of unicellular organ-
Route of administration—Oral, topical. isms, some of which are parasitic pathogens in humans,
Indications—Terbinafine has been recently introduced causing several diseases of medical and global importance.
against dermatophyte infections including ringworm, Parasitic protozoa replicate within the host's body and are
where oral therapy is appropriate because of the site and se- usually divided into four subphyla according to their type of
verity of extent of infection. locomotion (Table 12.5).
Adverse effects—Mild nausea, abdominal pain, skin reac-
tions. Loss of taste has been reported.
Therapeutic notes—Resistance rarely develops. Malaria
Flucytosine Malaria is responsible for 2 million deaths per year and 200
Mechanism of action—Flucytosine is imported into million people worldwide are infected. Malaria is caused by
fungal, but not human, cells, where it is converted into four species of plasmodial parasites that are transmitted by
5-­fluorouracil, a potent inhibitor of DNA synthesis. female anopheline mosquitoes.
Route of administration—Intravenous. Antimalarial drugs target different phases of the life cy-
Indications—Flucytosine is most active against yeasts cle of the malarial parasite (Fig. 12.8). This life cycle pro-
and is indicated for use in systemic candidiasis and as an ceeds as follows.
adjunct to amphotericin in cryptococcal meningitis. • When an infected mosquito feeds on a human, it
Adverse effects—Nausea and vomiting are common. injects sporozoites into the bloodstream from its
Rare side effects include hepatotoxicity, hair loss and bone-­ salivary glands.
marrow suppression. • The sporozoites rapidly penetrate the liver where they
Therapeutic notes—Weekly blood counts of patients on flu- transform and grow into tissue schizonts containing
cytosine are necessary to monitor bone marrow suppression. large numbers of merozoites. In the case of Plasmodium
vivax and Plasmodium ovale, some schizonts remain
Griseofulvin
dormant in the liver for years (hypnozoites), before
Mechanism of action—The mechanism of action of gris-
rupturing to cause a relapse.
eofulvin is not fully established, but it probably interferes
• The large tissue schizonts rupture after 5 to 20 days,
with microtubule formation or nucleic acid synthesis and
releasing thousands of merozoites that invade
polymerization. It is selectively concentrated in keratin and
circulating red blood cells (RBCs), and multiply inside
therefore is suitable for treating dermatophyte mycoses.
the cell.
Route of administration—Oral.
• The host's RBCs rupture, leading to the release of more
Indications—Griseofulvin is the drug of choice for wide-
merozoites. These then invade and destroy more RBCs.
spread or intractable dermatophyte infections, where topi-
This cycle of invasion/destruction causes the episodic
cal therapy has failed.
chills and fever that characterize malaria.
Adverse effects—Hypersensitivity reactions, headaches,
• Some merozoites develop into gametocytes. If these
rashes, photosensitivity.
are taken up by a feeding mosquito, the insect becomes
Therapeutic notes—Because griseofulvin is fungistatic
infected, thus completing the cycle.
rather than fungicidal, treatment regimens are long,
amounting to several weeks or months. Griseofulvin is The clinical features and severity of malaria depend upon
more effective for skin than nail infections. the species of parasite and the immunological status of the
person infected. Clinically significant malaria is less com-
mon in adults who have always lived in endemic areas, as
HINTS AND TIPS partial immunity develops.
There are four types of plasmodium causing malaria.
Superficial mycoses (e.g. athlete's foot/thrush) are • Plasmodium falciparum: Widespread and causes
common and usually easily treated with topical malignant tertian (fever every third day) malaria. There
drugs (e.g. terbinafine) that have few adverse is no exoerythrocytic stage, so that, if the erythrocytic
effects. Deep mycoses are rare (except in the forms are eradicated, relapses do not occur.
immunocompromized), serious and may be fatal • P. vivax: Widespread and causes benign, tertian
despite therapy with systemic drugs, which often relapsing malaria. Exoerythrocytic forms may persist in
the liver for years and cause relapses.
have adverse effects.
• Plasmodium malariae: Rare and causes benign
quartan (fever every fourth day) malaria. There is no

188
 Antiprotozoal drugs 12

Table 12.5 Classification of medically important protozoan species causing disease in humans
Medically important
Subphyla Defining characteristics species Disease
Amoebae (sarcodina) Amoeboid movement with Entamoeba histolytica Amoebiasis (amoebic
pseudopods dysentery)
Flagellates (mastigophora) Flagella that produces a Giardia lamblia Giardiasis
whip-like movement Trichomonas vaginalis Trichomonal vaginitis
Leishmania spp. Leishmaniasis
Trypanosoma spp. Trypanosomiasis (sleeping
sickness and Chagas
disease)
Ciliates (ciliophora) Cilia beat to produce — —
movement
Sporozoans (sporozoa) No locomotor organs in Plasmodium spp. Malaria
adult stage

In mosquito In human Clinical malaria

Fast blood schizontocides
tissue schizontocides
* chloroquine
* proguanil * quinine, quinidine
* pyrimethamine * mefloquine
* primaquine
* tetracycline Slow blood schizontocides
* pyrimethamine and primaquine
* sulphonamides and dapsone
Sporontocides
* primaquine Exo-red blood cell
* proguanil schizogony
* pyrimethamine (in hepatocytes) Merozo
ite
Hypnozoites s
(P. vivax and P. ovale)

48 h (P. falciparum,
Sporogony Red blood cell
vivax and ovale)
schizogony
72 h (P. malariae)
Hypnozoitocides
* primaquine

Gametocytes ( , )

Gametocytocides
* primaquine

Fig. 12.8 Life cycle of the malarial parasite and point of action of chemotherapeutic agents.

exoerythrocytic stage, so that, if the erythrocytic forms They are used to protect against or cure malaria or to pre-
are eradicated, relapses do not occur. vent transmission.
• P. ovale: Mainly African and causes a rare form of
benign relapsing malaria. Exoerythrocytic forms may Prophylactic use
persist in the liver for years and cause relapses. The aim of prophylactic use is to prevent the occurrence of
infection in a previously healthy individual who is at poten-
tial exposure risk.
Approaches to antimalarial Suppressive prophylaxis involves the use of blood schizon-
chemotherapy ticides to prevent acute attacks; causal prophylaxis involves
Antimalarial drugs are usually classified in terms of their the use of tissue schizonticides or drugs against the sporo-
action against different stages of the parasite (see Fig. 12.8). zoite to prevent the parasite becoming established in the liver.

189
 Infectious diseases

Curative (therapeutic use) Route of administration—Quinine is administered orally

Antimalarial drugs can be used curatively (therapeutically) or by rate-controlled infusion in severe cases. Mefloquine is
against an established infection. only given orally.
Suppressive treatment aims to control acute attacks, usu- Indications—Quinine is the drug of choice for treating
ally with blood schizonticides; radical treatment aims to kill the acute clinical attack of falciparum malaria resistant to
dormant liver forms, usually with a hypnozonticide, to pre- chloroquine. Mefloquine is effective against all malarial
vent relapsing malaria. species including multidrug-resistant P. falciparum and can
also be used for chemoprophylaxis.
Antimalarial drugs Adverse effects—Quinine may cause tinnitus, headache,
nausea, blurring of vision, hypoglycaemia and, rarely, blood
4-aminoquinolines disorders. Overdose results in profound hypotension be-
Chloroquine is an example of a 4-aminoquinoline. cause of peripheral vasodilatation and myocardial depres-
Mechanism of action—Chloroquine is a rapidly acting sion (see Chapter 4). Quinine is safe in pregnancy.
blood schizonticide (see Fig. 12.8). It is concentrated 100- Mefloquine may cause nausea, vomiting, gastrointestinal
fold in erythrocytes that contain plasmodial parasites; this disturbance and postural hypotension. Rarely, acute neuro-
occurs because of ferriprotoporphyrin IX, a degradation pathic conditions may occur. Mefloquine may cause foetal
product of haemoglobin digestion by the parasites, acts as a abnormalities.
chloroquine receptor. It is unclear how the high ­chloroquine Therapeutic notes—The quinoline-methanols are used
concentrations kill the parasites; possibly, the digestion of in combination therapy with other agents such as the sul-
haemoglobin is inhibited. phonamides or tetracyclines.
Route of administration—Oral. In severe falciparum ma- Monitoring for hypoglycaemia should occur in patients
laria infections, injections or infusions can be used. with malaria because the malarial parasite consumes glu-
Indications—Suppressive chemoprophylaxis and treat- cose and quinine can stimulate insulin release, causing a
ment of susceptible strains of plasmodium. reduction in blood glucose levels.
Adverse effects—Nausea, vomiting, headache, rashes
and, rarely, neurological effects and blurred vision.
Therapeutic notes—Chloroquine is considered safe HINTS AND TIPS
for use in pregnant women. It rapidly controls fever (24–
Quinine is usually given orally as a 7-day course
48 hours) but cannot produce a lasting radical cure in
P. vivax and P. ovale strain infections, because it does not af- but can be given intravenously for severe
fect hypnozoites. P. Falciparum malaria or in patients who are
In most areas, P. falciparum is resistant to chloroquine, vomiting. In some areas of the tropics, quinine
necessitating combination chemoprophylaxis with antifo- was incorporated into tonic waters to help protect
lates (see later). against malaria, giving the water a bitter taste.

HINTS AND TIPS

Chloroquine is the drug of choice for the treatment

Antifolates
of all nonfalciparum malaria. It is highly effective Examples of antifolates include type 1 drugs, for exam-
against P. Malariae, P. Ovale and P. Vivax. Quinine, ple, sulphonamides and dapsone, and type 2 drugs, for
artemether with lumefantrine can be used as example, pyrimethamine and proguanil. Both types are
second line. Primaquine is used to destroy liver useful.
stage parasites and prevent relapse. Mechanism of action—Antifolates are slow-acting (in
comparison with chloroquine, quinine and mefloquine)
blood schizonticides, tissue schizonticides and sporon-
ticides. These drugs inhibit the formation of folate com-
Quinoline-methanols pounds and thus inhibit DNA synthesis and cell division.
Examples of quinoline-methanols include quinine and All growing stages of the malarial parasite are affected.
mefloquine. The sulphonamides and dapsone are known as type 1
Mechanism of action—Quinoline-methanols are rapidly antifolate drugs. They compete with para-aminobenzoic
acting blood schizonticides (see Fig. 12.8). It is not precisely acid for the enzyme dihydropteroate synthetase, which is
known how the quinoline-methanols work but, similar to found only in the parasites.
chloroquine, they are known to bind to a product of haemo- Proguanil and pyrimethamine are known as type 2 anti-
globin digestion. It has no effect on exoerythrocytic forms folate drugs. They selectively inhibit malarial dihydrofolate
or on the gametocytes of P. falciparum. reductase.

190
 Antiprotozoal drugs 12

These two groups of drugs act on the same pathway but

at different points; they are used in combination as their CLINICAL NOTE
synergistic blockade is more powerful than any one drug A 25-year-old student, presents with a 4-day
acting alone.
history of high fever (40°C), general malaise, feeling
Route of administration—Oral.
intensely cold and shaky followed by profuse
Indications—Antifolates are used in combination for
the causal chemoprophylaxis of malaria, or in combina- sweating. He denies any homosexual contacts,
tion with quinine for the treatment of acute chloroquine-­ unprotected sexual intercourse or intravenous
resistant malaria. drug use. He returned from Nigeria 3 weeks ago
Adverse effects—Antifolates have almost no side effects and was completing his proguanil with atovaquone
if used in therapeutic doses. In toxic doses, type 2 antifo- malarial prophylaxis treatment. On examination, he
lates can inhibit mammalian dihydrofolate reductase and looked unwell. His pulse was 98 beats per minutes
cause a megaloblastic anaemia. Skin rashes occasionally with a blood pressure of 132/72 mm Hg. There are
occur. no heart murmurs. There are no enlarged lymph
Therapeutic notes—Common chemoprophylactic com- nodes.
binations include chloroquine plus pyrimethamine with a
sulphonamide or dapsone. Blood tests reveal raised bilirubin with normal liver
Monitoring of a patient’s full blood count is key when enzymes, mild anaemia and a low platelet count.
taking antifolate medication. Light microscopy of a Giemsa-stained blood smear
shows approximately 1% of red blood cells are
8-aminoquinolines infected with Plasmodium parasite.
Primaquine is an example of an 8-aminoquinoline. He is kept well hydrated and treated with oral
Mechanism of action—Primaquine is an hypnozonicide quinine for 7 days, after which his fever resolves,
and gametocide. It is unclear how the drug works, but it and he starts to improve.
may cause oxidative damage to the parasite. It is effective
against the nongrowing stages of malaria, that is, hypno-
zoites and gametocytes (see Fig. 12.8).
Route of administration—Oral.
Indications—Primaquine is used for the radical cure of
Treatment of other protozoal
relapsing malarias (P. ovale and P. vivax) and prevention of infections
transmission of P. falciparum.
Contraindications—Pregnancy. Amoebiasis
Adverse effects—Nausea, vomiting, bone marrow depres- Amoebic dysentery is caused by infection with Entamoeba
sion. Intravenous haemolysis can occur in people with glu- histolytica, which is ingested in a cystic form. Dysentery
cose 6-phosphate deficiency. results from invasion of the intestinal wall by the parasite.
Therapeutic notes—Primaquine is usually used in com- Occasionally, the organism encysts in the liver, forming
bination with chloroquine. Resistance is rare. abscesses.
Metronidazole is the drug of choice for acute invasive
amoebic dysentery, it kills the trophozoites although has no
Artemisinin
activity against the cyst forms. Diloxanide and tinidazole
Artemisinin is given with the antimalarial lumefantrine
are also used to treat amoebiasis.
because together they are much more effective than either
drug given individually. There is a synergistic effect. This
medication is effective at treating resistant P. Falciparum Giardiasis
cerebral malaria. Giardiasis is a bowel infection caused by the flagellate
Mechanism of action—A peroxide (trioxane) struc- Giardia lamblia. Infection follows ingestion of contami-
ture is responsible for its blood schizontocide activity nated water or food and involves flatulence and diarrhoea.
against plasmodium, including multiresistant strains of P. Metronidazole is the drug of choice for giardiasis.
falciparum.
Route of administration—Oral. Trichomonas vaginitis
Indications—Treatment of uncomplicated falciparum Trichomonas vaginitis is caused by the flagellate
malaria. Trichomonas vaginalis. It is a sexually transmitted inflam-
Contraindications—Breastfeeding, congestive heart fail- matory condition of the female vagina and, occasionally,
ure, congenital Q-T interval prolongation, arrhythmias. male urethra.
Adverse effects—Nausea, vomiting, abdominal pain, di- Metronidazole is the drug of choice for trichomonas
arrhoea, dizziness, arthralgia, myalgia. vaginitis.

191
 Infectious diseases

Trypanosomiasis and leishmaniasis There are three groups of helminths that parasitize
humans.
Trypanosomiasis
• Cestoda (tapeworms)
African trypanosomiasis (sleeping sickness) and South
• Nematoda (roundworms)
American trypanosomiasis (Chagas disease) are caused by
• Trematoda (flukes).
species of flagellate trypanosome.
Insect vectors introduce the parasites into the human Table 12.6 lists medically important helminth infections
host, where they reproduce, causing bouts of parasitaemia and the main drugs used in their treatment.
and fever. Toxins released cause damage to organs. The CNS
is affected in sleeping sickness and the heart, liver, spleen, The anthelmintic drugs
bone and intestine in Chagas disease.
The drug suramin kills the African trypanosomiasis To be effective, an anthelmintic drug must be able to pene-
parasite, possibly related to an ability to reversibly inhibit a trate the cuticle of the worm, or gain access to its alimentary
number of enzymes (in the host and parasite). However, it tract, so that it may exert its pharmacological effect on the
does not penetrate into the CNS and thus its use is restricted physiology of the worm.
to early trypanosomiasis. Anthelmintic drugs act on parasitic worms by a number
Melarsoprol is used to treat the late CNS form of African of mechanisms. These include the following.
trypanosomiasis. It may act by inactivating pyruvate kinase, • Damaging or killing the worm directly
a critical enzyme in the metabolism of trypanosomes. • Paralysing the worm
Nifurtimox and benznidazole are used to treat acute • Damaging the cuticle of the worm so that host
American trypanosomiasis. defences, such as digestion and immune rejection, can
affect the worm
Leishmaniasis • Interfering with worm metabolism
Leishmania species are flagellated parasites that are trans-
Because there is great diversity across the different helminth
mitted by a sandfly vector, assuming a nonflagellated intra-
classes, drugs highly effective against one species of worm
cellular form that resides within macrophages on infecting
are often ineffectual against another species.
humans. Clinical infections range from simple, resolving
Mechanism of action—Niclosamide, a salicylamide de-
cutaneous infections to systemic “visceral” forms with hep-
rivative, is the most used drug for tapeworm infestations.
atomegaly, splenomegaly, anaemia and fever.
It blocks glucose uptake at high concentrations, irreversibly
Leishmaniasis can usually be treated with stibogluco-
damaging the scolex (attachment end) of the tapeworm,
nate, a trivalent antimonial compound that reacts with thiol
leading to the release and expulsion of the tapeworm. It is a
groups and reduces adenosine triphosphate (ATP) produc-
safe, selective drug because very little is absorbed from the
tion in the parasite.
gastrointestinal tract.
Route of administration—Oral.
Pneumocystis pneumonia Indications—Tapeworm infestation (see Table 12.6).
Pneumocystis pneumonia is most often associated with Adverse effects—Mild gastrointestinal disturbance.
HIV infection and is now considered an AIDS-defining Therapeutic notes—Patients fast before treatment with
illness. The infective agent Pneumocystis jiroveci (previ- niclosamide. Purgatives to expel the dead worm segments
ously called Pneumocystis carinii) is not truly a protozoa, (proglottides) can be used, but are probably unnecessary be-
although it has similarities with both protozoa and fungi, cause the worm may be digested after the effects of the drug.
and remains difficult to classify.
Signs and symptoms of P. jiroveci pneumonia are similar
to other pneumonias, but culture is not possible, and the Praziquantel
microorganism must be visualized on direct microscopy. Mechanism of action—Praziquantel increases the perme-
High-dose oral or parenteral co-trimoxazole (trimetho- ability of the helminth plasma membrane to calcium. At low
prim and sulfamethoxazole) is the drug of choice. Dapsone concentrations, this causes contraction and spastic paralysis
with trimethoprim is given as an alternative treatment. and, at higher concentrations, vesiculation and vacuoliza-
tion damage is caused to the tegument of the worm.
Route of administration—Oral.
Indications—Praziquantel is the drug of choice for all
ANTHELMINTIC DRUGS schistosome infections (see Table 12.6), and for cysticerco-
sis (a rare cestode condition caused by encystation of larvae
of the tapeworm Taenia solium in human organs).
Concepts of helminthic infection Adverse effects—Mild gastrointestinal disturbance, head-
Helminth is derived from the Greek helmins, meaning ache and dizziness may occur shortly after administration.
worm. Anthelmintic drugs are therefore medicines acting Therapeutic notes—Praziquantel should be taken after
against parasitic worms. meals 3 times a day for 2 days only.

192
 Anthelmintic drugs 12

Table 12.6 Classification of medically important helminth infections and the main drugs in their treatment
Helminth species Drugs used in treatment
Cestodes
Beef tapeworm Taenia saginata Niclosamide, praziquantel
Pork tapeworm Taenia solium Niclosamide, praziquantel
Fish tapeworm Diphyllobothrium latum Niclosamide, praziquantel
Hydatid tapeworm Echinococcus granulosus Albendazole
Nematodes
Intestinal species
Common round worms Ascaris lumbricoides Mebendazole, piperazine
Threadworms/pin worms Enterobius vermicularis Mebendazole, piperazine
Threadworms (USA) Strongyloides stercoralis Thiabendazole, albendazole
Whipworms Trichuris trichiura Mebandazole
Hookworms Necator americanus Mebendazole
Ankylostoma duodenale Mebendazole
Tissue species
Trichinella Trichinella spiralis Thiabendazole
Guinea worm Dracunculus medinesis Metronidazole
Filarioidea Wuchereria bancrofti Diethylcarbamazine
Loa loa Diethylcarbamazine
Brugia malayi Diethylcarbamazine
Onchocerca volvulus Ivermectin
Trematodes
Blood flukes/schistosomes Schistosoma japonicum Praziquantel
Schistosoma mansoni Praziquantel
Schistosoma haematobium Praziquantel

Piperazine ­ olymerisation of microtubules. Subsequent depolymerisa-

p
Mechanism of action—Piperazine is a reversible neuro- tion leads to complete breakdown of the microtubule.
muscular blocker that causes a flaccid paralysis in worms, The selectivity of benzimidazoles arises because they are
leading to their expulsion by gastrointestinal peristalsis. It 250 to 400 times more potent in helminth than in mamma-
has very little effect on the host. lian tissue. The process takes time to have an effect, and the
Route of administration—Oral. worm may not be expelled for days.
Indications—Piperazine is used for roundworm and Route of administration—Oral.
threadworm gastrointestinal infestation. Indications—Benzimidazoles are used in the treatment
Adverse effects—Gastrointestinal disturbance and neuro- of hydatid disease, and many nematode infestations (see
toxic effects (dizziness) may occur. Table 12.6).
Therapeutic notes—A single dose of piperazine is usually Contraindications—Benzimidazoles should not be given to
effective for treating roundworm infection; threadworm in- pregnant women because they are teratogenic and embryotoxic.
festation may require a longer course (7 days). Adverse effects—Occasional gastrointestinal disturbance.
Thiabendazole causes more frequent gastrointestinal dis-
Benzimidazoles turbance, headache and dizziness. Serious hepatotoxicity
Examples of benzimidazoles include mebendazole, thiaben- rarely occurs.
dazole and albendazole. Therapeutic notes—Dosage regimens of benzimidazoles
Mechanism of action—Benzimidazoles bind with high range from a single dose for pinworm infestation to multi-
affinity to a site on tubulin dimers, thus preventing the ple doses for up to 5 days for trichinosis.

193
 Infectious diseases

Diethylcarbamazine Route of administration—Oral.

Mechanism of action—it is not clear exatly how dieth- Indications—Treatment of choice for Ascaris lumbri-
ylcarbamazine exerts its filaricidal effect. It has been sug- coides roundworm infection (see Table 12.6).
gested that it damages or modifies the parasites in such a Adverse effects—Mild nausea and vomiting.
way as to make them more susceptible to host immune de-
fences. Diethylcarbamazine kills both microfilariae in the
peripheral circulation and adult worms in the lymphatics
Route of administration—oral VACCINATIONS
Indications—diethylcarbamazine is the drug of choice
for lymphatic filariasis caused by Wucheria Bancrofti, Loa Artificial immunity is achieved by giving a vaccine (active
Loa and Brugia malayia. See Table 12.6 immunisation) or immunoglobulin (passive immunisation).
Adverse effects—gastrointestinal disturbance, headache, Active immunity is the stimulation of the immune
lassitude. Material from the damaged and dead worms causes mechanism to produce antibodies by giving an antigen as
allergic side effects, including skin reactions, lymph gland en- a vaccine.
largement, dizziness and tachycardia, lasting from 3 to 7 days. - Live attenuated viruses (e.g. rubella, measles, mumps,
Therapeutic notes—to minimise the dangerous sudden oral polio)
release of dead worm material, the initial dose of diethyl- - Inactivated viruses (e.g. parenteral polio, hepatitis A)
carbamazine is started low and then increased and then - Inactivated bacterial toxins (e.g. diphtheria and
maintained for 21 days. tetanus)
- Genetically engineered (e.g. hepatitis B)
Ivermectin The body is then able to generate an immune response (ei-
Mechanism of action—Ivermectin immobilizes the tape- ther humoral or cell-mediated) and have protection against
worm Onchocerca volvulus by causing tonic paralysis of the the bacteria/virus that they are inoculated against.
peripheral muscle system. It does this by potentiating the effect
of γ-aminobutyric acid at the worm's neuromuscular junction.
Route of administration—Oral. Precautions before vaccination
Indications—Ivermectin is the drug of choice for O. volvu- Avoid giving vaccinations to patients with allergies or previ-
lus, which causes river blindness and may be the most effec- ous reactions. Similarly, patients with an acute febrile illness
tive drug for chronic Strongyloides infection (see Table 12.6). should not be given a vaccine. Live vaccines should not be
Adverse effects—Ocular irritation, transient electrocardio- given to patients on chemotherapy and immunosuppres-
graphic changes and somnolence. An immediate immune re- sive medications (including corticosteroids). Likewise, they
action to dead microfilariae (Mazzotti reaction) can be severe. should not be given to patients who have had a recent bone
marrow transplant.
Levamisole
Mechanism of action—Levamisole stimulates nicotinic
receptors at the neuromuscular junction and results in a
spastic paralysis, which causes faecal worm expulsion.

Chapter Summary

• Bactericidal (kill bacteria) antibiotics often have to be used in immunocompromized

individuals
• Acquired resistance occurs when bacteria produce enzymes that inactive the antibiotic
• Broad-spectrum antibiotics include penicillins, tetracyclines and cephalosporins
• Antibiotics are either protein synthesis inhibitors (e.g. tetracyclines), cell wall synthesis
inhibitors (e.g. glycopeptides) or nucleic acid synthesis (e.g. quinolones)
• Treatment of tuberculosis involves four drugs for two months (rifampicin, isoniazid,
pyrazinamide and ethambutol) and then two drugs for four months (rifampicin and isoniazid)
• Treatment of HIV involves four main classes of drug; nucleoside reverse transcriptase
inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors and fusion
inhibitors
• Vaccines can be live attenuated viruses, inactivated viruses, inactivated bacterial toxins
or genetically engineered

194
 Cancer
13
Cancers are malignant neoplasms (new growths) occurring • Cytotoxic therapy (which is the main approach)
when cells no longer differentiate in an orderly fashion but • Endocrine therapy
multiply in a haphazard way. Despite their variability, can- • Immunotherapy
cers share these characteristics. Cancers differ in their sensitivity to chemotherapy, from
• Uncontrolled proliferation the very sensitive (e.g. lymphomas, testicular carcinomas)
• Local invasiveness where complete clinical cures can be achieved, to the resis-
• Tendency to spread (metastasis) tant (generally solid tumours, e.g. colorectal, squamous cell
• Changes in some aspects of original cell morphology/ bronchial carcinoma).
retention of other characteristics A diagnosis of cancer carries a significant social and
Cancer accounts for 20% to 25% of deaths in the Western emotional impact. Hair loss and sickness are more often
world. Management options include surgery, radiotherapy the initial concern for patients, rather than other potentially
and chemotherapy. These methods are not mutually exclu- serious side effects of chemotherapy. Nausea and vomiting
sive, often being used in combination, for example, adjuvant should be taken seriously in cancer management, as these
chemotherapy after surgical removal of a tumour. can have a devastating impact on quality of life; antiemetic
drugs are discussed in Chapter 6.

CONCEPTS OF CANCER HINTS AND TIPS

CHEMOTHERAPY
Adjuvant chemotherapy is given after successful
treatment of cancer, where no remaining disease is
Chemotherapy found, or for prophylaxis against reoccurrence.
Cancer chemotherapy is the use of drugs to inhibit the rate
of growth of or to kill cancerous cells. The ideal anticancer
drugs target malignant cells in preference to nonmalignant
cells. This is achieved by exploiting the molecular differ-
ences between them. CYTOTOXIC CHEMOTHERAPY

CLINICAL NOTE
Mechanisms of action
Most cytotoxic drugs affect deoxyribonucleic acid (DNA) syn-
A 60-year-old man presents with a 6-week history thesis and thus cell division. They can be classified according to
of the passage of fresh blood from his rectum their site of action affecting the process of DNA synthesis within
and looser stool. He also admits to low appetite, the cancer cell (Fig. 13.1). Cytotoxic drugs are therefore most
significant weight loss and feeling fatigued. He effective against actively cycling/proliferating cells, both normal
is referred for investigative colonoscopy, which and malignant, and least effective against nondividing cells.
reveals an abnormal growth in the descending Some drugs are only effective at killing cycling cells
colon. A biopsy confirms an adenocarcinoma. during specific parts of the cell cycle. These are known as
Staging computed tomography scans show phase-specific drugs (Fig. 13.2). Other drugs are cytotoxic
no other areas of disease. He is managed by
towards cycling cells throughout the cell cycle (e.g. alkylat-
ing agents) and are known as cycle-specific drugs.
surgical resection of the tumour. Following this, he
undergoes adjuvant chemotherapy.
Selectivity
Cytotoxic drugs are not specifically toxic to cancer cells, and
The most striking difference between cancerous and the selectivity they show is marginal at best.
noncancerous cells is their accelerated rate of cell division. Cytotoxic drugs affect all dividing tissues, both normal
This remains a common target for therapeutic intervention. and malignant, and thus are likely to have a wide range of
The chemotherapeutic techniques currently used in- toxic side effects (Table 13.1), most often related to the in-
clude the following. hibition of division of noncancerous host cells, namely in

195
 Cancer

Precursors Precursors

Methotrexate 5-fluorouracil
Mercaptopurine inhibits dihydrofolate inhibits thymidylate
inhibits purine reductase and therefore reductase and therefore
synthesis and nucleotide inhibits purine and pyrimidine synthesis
interconversions pyrimidine synthesis

Purine Pyrimidine
biosynthesis biosynthesis

ribonucleotides
Hydroxyurea
inhibits ribonucleotide
reductase, hence formation of
deoxyribonucleotides
deoxyribonucleotides

Cytarabine
inhibits DNA polymerase
Alkylating agents
e.g. melphalan,
cyclophosphamide, chlorambucil Procarbazine
covalently cross-link DNA DNA inhibits DNA and RNA
production by unclear
mechanism

Cytotoxic antibiotics mRNA

e.g. dactinomycin
intercalates between base
pairs of DNA and inhibits Amino acids
RNA synthesis
e.g. doxorubicin, amsacrine
inhibit topoisomerase II and
inhibit RNA synthesis Crisantaspase
destroys exogenous
asparagine and inhibits
protein synthesis
Proteins

Mitotic inhibitors
e.g. vincristine, vinblastine
etoposide
bind tubulin, block spindle to
arrest mitosis

Enzymes etc. Microtubules

Fig. 13.1 Sites of action of cytotoxic drugs that act on dividing cells. DNA, Deoxyribonucleic acid; mRNA, messenger
ribonucleic acid; RNA, ribonucleic acid.

the gut, in the bone marrow and in the reproductive and • Normal cells seem to recover from chemotherapeutic
immune systems. inhibition faster than some cancer cells.
Relative selectivity can occur with some cancers. • Knowledge of these principles and knowing that
• In malignant tumours, a higher proportion of cells cytotoxic drugs kill a constant fraction, not a constant
are undergoing proliferation than in normal number, of cells, lays down the foundation for
proliferating tissues. chemotherapeutic dosing schedules (Fig. 13.3).

196
 Cytotoxic chemotherapy 13

G2 phase (19%)
Antimetabolites pre-mitosis
5-fluorouracil (synthesis of components
methotrexate DNA synthesis needed for mitosis)
mercaptopurine
cytarabine
M-phase (2%)
%) mitosis
39
s e(
S-phase
−

ha
specific

Sp
Mitotic inhibitors
vincristine, vinblastine
− etoposide
M-phase specific

− G
Cycle-specific drugs 1 phase (40%)
e.g. alkylating agents and G0 resting phase
cytotoxic antibiotics:
cytotoxic throughout the
cell cycle, but still do not
affect resting (non-cycling) Pre-DNA synthesis
cells in Go (synthesis of components
needed for DNA synthesis)

Fig. 13.2 Cell cycle and point of action of phase-specific drugs. DNA, Deoxyribonucleic acid.

Table 13.1 General adverse effects of cytotoxic drugs

Site Effects
Bone marrow Myelosuppression can lead to leucopoenia, thrombocytopenia and sometimes anaemia, this is
often the dose-limiting side effect; there is a high risk of haemorrhage, immunosuppression and
infection as a result
Gastrointestinal Inhibition of mucosal cell division may produce anorexia, ulceration or diarrhoea; nausea and
tract vomiting are common, especially with alkylating agents and cisplatin
Skin Loss of hair (alopecia) may be partial or complete but is usually reversible
Wounds Impaired wound healing results from cell reproduction inhibition
Reproductive Sterility, teratogenesis and mutagenicity are all possible
system
Secondary Many cytotoxic drugs are carcinogenic, additionally the immunosuppression resulting from
cancers myelosuppression may reduce immune surveillance of emerging dysplastic cells, leading to an
increased risk of development of some cancers after chemotherapy

Resistance to cytotoxic drugs

Bone marrow Genetic resistance to cytotoxic drugs can be inherent
Number of cells (log)

cells to the cancer cell line or acquired during the course of

chemotherapy, as a result of selection induced by the
­
­chemotherapeutic agent.

Mechanisms of genetic resistance

Cancer cells
to cytotoxic drugs
The mechanisms of genetic resistance to cytotoxic drugs.
0 Treatment Treatment Treatment • Abnormal transport
1 Treatment 3 Treatment 5 • Decreased cellular retention/active transport out of
2 4
Time cells
Fig. 13.3 Theoretical anticancer cytotoxic dosing schedule, • Increased cellular inactivation (binding/metabolism)
allowing recovery of normal tissues. • Altered target protein

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 Cancer

Table 13.2 Summary of cancer therapies

Important side
Class of drug Drug Mechanism of action Use effects
Alkylating agent Cyclophosphamide Pronounced effect Haematological N&V
on lymphocytes malignancy Bone marrow
Immunosuppressant depression
Intrastrand cross-linking Haemorrhagic cystitis
of DNA
Alkylating agent Procarbazine Inhibits DNA and RNA Hodgkin disease Hypertension Flushing
synthesis reaction
Interferes with mitosis
Platinum compound Cisplatin Intrastrand cross-linking Solid tumours Nephrotoxic
of DNA (especially testes and Severe N&V
ovary)
Antimetabolite Fluorouracil Inhibition of DNA Basal cell carcinoma Gastrointestinal upset
synthesis Myelotoxicity
Antimetabolite Cytarabine Pyramidine analogue— Acute myeloid Gastrointestinal upset
inhibits DNA leukaemia Myelotoxicity
polymerase
Cytotoxic antibiotic Doxorubicin Inhibits DNA and RNA Bladder cancer N&V Myelosuppression
synthesis, through Hair loss
interference with Cardiotoxic in high
topoisomerase II doses
Vinca alkaloids Vincristine Bind to tubulin Haematological Mild myelosuppression
(mitotic inhibitor) and inhibit its malignancy Neurotoxic →
polymerisation, causing paraesthesia and
arrest at metaphase weakness
inhibiting mitosis Abdominal pain
Mitotic inhibitor Etoposide Inhibits DNA Haematological Vomiting
synthesis by action on malignancy Alopecia
topoisomerase II Myelosuppression
Inhibits mitochondrial
function
Monoclonal antibody Rituximab It binds to CD20 protein Lymphoma Hypotension
→ lyses B lymphocytes Chills and fever
Hypersensitivity
reaction
Monoclonal antibody Trastuzumab Binds to oncogenic Breast cancer that
(Herceptin) protein HER2 overexpress HER2
Protein kinase Imatinib Inhibits oncogenic Chronic myeloid Gastrointestinal upset
inhibitor cytoplasmic kinase leukaemia Headaches
(BCR/ABL) & platelet- Rashes
derived growth factor (can get resistance)
DNA, Deoxyribonucleic acid; N nausea and vomiting; RNA, ribonucleic acid.

• Enhanced repair of DNA The theory is that multiple attacks with cytotoxic agents act-
• Altered processing ing at different biochemical sites will increase efficacy while
Some tumours are relatively resistant to chemotherapy be- reducing the likelihood of resistance.
cause they exist in so-called “pharmacological sanctuaries”.
These occur when a tumour is in a privileged compartment, Cytotoxic agents
for example, inside the blood–brain barrier, or in large solid
tumours when poor blood supply and diffusion limit the Cytotoxic agents, the major group of anticancer drugs,
penetration of the drug. ­include the following (see Table 13.2).
In clinical practice, cancers may be treated more success- • Alkylating agents
fully with combinations of cytotoxic drugs simultaneously. • Antimetabolites

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 Cytotoxic chemotherapy 13

• Cytotoxic antibiotics Antimetabolites

• Mitotic inhibitors Examples of antimetabolites include the folic acid antago-
• Platinum compounds nists (e.g. methotrexate), antipyrimidines (e.g. fluoroura-
• Miscellaneous agents cil and cytarabine) and antipurines (e.g. mercaptopurine).
Mechanism of action—Antimetabolites are analogues of
normal metabolites and act by competition, replacing the
CLINICAL NOTE natural metabolite and then subverting cellular processes
(see Fig. 13.1).
A 58-year-old female presents to her General • Methotrexate competitively antagonizes dihydrofolate
Practitioner (GP) following increasing vague reductase and prevents the regeneration of
abdominal pain and discomfort for the past intermediates (tetrahydrofolate) essential for the
4 months and abdominal distension for the past synthesis of purine and thymidylate, thus inhibiting the
1 month. She is referred to A&E and admitted. synthesis of DNA. Methotrexate should therefore be
A CT scan is done and an ascitic drain inserted, prescribed with folic acid.
from which a sample of the fluid is sent for • Fluorouracil is converted into a fraudulent pyrimidine
nucleotide, fluorodeoxyuridine monophosphate,
cytology. CT shows ovarian and omental masses.
that inhibits thymidylate synthetase, impairing DNA
Cytological examination of ascitic fluid indicates
synthesis.
adenocarcinoma. • Cytarabine is converted intracellularly to a triphosphate
Laparotomy is done allowing peritoneal biopsy, form that inhibits DNA polymerase.
which shows ovarian malignancy. The management • Mercaptopurine is converted into a fraudulent purine
includes removal of her uterus, ovaries and nucleotide that impairs DNA synthesis.
omentum. After surgery, she is started on a Route of administration
6-month course of carboplatin. - Methotrexate is administered orally, intravenously,
intramuscularly and intrathecally.
- Fluorouracil is usually given intravenously, although it
can be given orally and topically.
Alkylating agents - Cytarabine is given subcutaneously intravenously and
Examples of alkylating agents include melphalan, cyclo- intrathecally.
phosphamide and chlorambucil. - Mercaptopurine is given orally.
Mechanism of action—Alkylating agents act via a re- Indications—Methotrexate is used for acute lymphoblas-
active alkyl group that reacts to form covalent bonds with tic leukaemia and non-Hodgkin lymphoma. It is also used
nucleic acids. There follows either cross-linking of the two in the treatment of psoriasis and rheumatoid arthritis (see
strands of DNA, preventing replication, or DNA strand Chapter 11).
breakage (see Fig. 13.1). Fluorouracil is used for the treatment of solid tumours
Route of administration and some malignant skin conditions.
- Melphalan and cyclophosphamide orally and Cytarabine is used for the treatment of acute myeloblas-
intravenously. tic leukaemia.
- Chlorambucil orally. Mercaptopurine is used as maintenance therapy for
Indications acute leukaemias.
- Melphalan is used in myeloma and in some solid Adverse effects—A common side effect of antimetabo-
tumours. lites is generalized cytotoxicity (see Table 13.1).
- Cyclophosphamide is used to treat a variety of Methotrexate can cause liver cirrhosis, pulmonary fibro-
leukaemias, and lymphomas, and some solid tumours. sis and bone marrow suppression.
- Chlorambucil is used for leukaemias, lymphomas and Contraindications—Methotrexate is contraindicated
ovarian cancers. in acute infections and in pregnancy because it is a
Adverse effects—Generalized cytotoxicity is common teratogenic.
with alkylating agents (see Table 13.1). A urinary metabo- Therapeutic notes—Methotrexate should not be given to
lite of cyclophosphamide, acrolein, may cause serious hae- people with significant hepatic or renal impairment. Folic
morrhagic cystitis. This effect may be reduced by high fluid acid should be prescribed alongside methotrexate.
intake (4 L/day).
Damage to gametogenesis and the development of
secondary acute nonlymphocytic leukaemias is a particu- Cytotoxic antibiotics
lar problem with these alkylating agents. Alopecia is also Dactinomycin (actinomycin D), bleomycin and doxorubi-
common. cin are examples of cytotoxic antibiotics.

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 Cancer

Mechanism of action—Cytotoxic antibiotics work

mainly by preventing cell division either through direct CLINICAL NOTE
­action on DNA itself or by blocking the enzymes involved A 66-year-old painter, who presents to his GP with
in DNA replication.
a 4-month history of increasing shortness of breath
Dactinomycin prevents transcription by interfering with
and significant weight loss, with a 2-week history
ribonucleic acid (RNA) polymerase.
Doxorubicin inhibits transcription and DNA replication of haemoptysis 4–5 times per day. The patient
by inhibiting topoisomerase II. Bleomycin acts to fragment also complains of lethargy, breathlessness on lying
DNA chains. down and increasing pain in his spine. He has
Route of administration—Intravenous. Doxorubicin can smoked 20 cigarettes per day for the past 50 years.
be given intravesically for bladder cancer. On examination, breath sounds are absent and
Indications—Dactinomycin is principally used in pae- there is stony dullness to percussion. He also has
diatric cancers. Doxorubicin is used for acute leukaemias, right axillary lymphadenopathy. He is referred for
lymphomas and a variety of solid tumours. Bleomycin is urgent investigation. Chest X-ray reveals a large
used for lymphomas and certain solid tumours. pleural effusion on the right. Aspiration of the
Adverse effects—Generalized cytotoxicity (see Table 13.1).
pleural effusion shows malignant cells. Tissue
Doxorubicin produces dose-dependent cardiotoxicity,
obtained at bronchoscopy confirms squamous
because of irreversible free radical damage to the myocar-
dium. Bleomycin may cause pulmonary fibrosis, but has cell carcinoma of the bronchus. Staging scans
virtually no myelosuppression, unlike doxorubicin and show liver and bone metastases. His management
dactinomycin. includes cisplatin and vinorelbine chemotherapy.

Mitotic inhibitors
Examples of mitotic inhibitors include the vinca alkaloids,
vincristine, vinblastine and vinorelbine, ixabepilone and Platinum compounds
etoposide. Cisplatin (first-generation drug), carboplatin (second gen-
Mechanism of action—Mitotic inhibitors act by binding eration), and lastly oxaliplatin (third generation).
tubulin and inhibiting the polymerization of microtubules, Mechanism of action—Cross-linking of DNA subunits,
which is necessary to form the mitotic spindle. This pre- thus inhibiting DNA synthesis, transcription and function.
vents mitosis and arrests dividing cells at metaphase (see They can act in any cell cycle.
Fig. 13.1). Indications
Route of administration—The vinca alkaloids are - Cisplatin is mainly used for lung, cervical, bladder,
administered intravenously, and etoposide orally or testicular and ovarian cancers (although carboplatin is
intravenously. preferred for ovarian cancer).
Indications—Mitotic inhibitors are used for acute leu- - Carboplatin is mainly used for advanced ovarian and
kaemias, lymphomas and some solid tumours. lung cancer (particularly small cell type).
Adverse effects—Side effects of mitotic inhibitors result - Oxaliplatin is used in combination with 5-fluorouracil
from the fact that tubulin polymerization is relatively indis- and folinic acid to treat metastatic colorectal cancer
criminate, inhibiting other cellular processes that involve and as colon cancer adjuvant treatment.
microtubules, as well as cell division. Contraindications—Pregnancy, breastfeeding.
Generalized cytotoxicity occurs (see Table 13.1), except Route of administration—Intravenous.
that vincristine is unusual in producing little or no bone Adverse effects—Cisplatin may cause nausea, vomiting,
marrow suppression. nephrotoxicity, ototoxicity, peripheral neuropathy, hypo-
Neurological and neuromuscular effects occur, espe- magnesaemia, myelosuppression.
cially with vincristine, and include peripheral neuropa- Carboplatin has the same adverse effects as cispla-
thy leading to paraesthesia, loss of reflexes and weakness. tin, but all to a lesser extent, with the exception of greater
Recovery from these effects occurs but is slow. myelosuppression.
Therapeutic notes—Intrathecal administration of vinca Oxaliplatin may cause neurotoxicity, gastrointestinal
alkaloids is contraindicated as it is usually fatal. Vinorelbine disturbances, myelosuppression.
is used for the treatment of advanced breast cancer when Therapeutic note—Ondansetron (5-HT3 antagonist) is
other treatments have failed, and for advanced nonsmall effective against severe nausea and vomiting associated with
cell lung cancer. platinum salts.

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 Endocrine therapy 13

Crisantaspase
HINTS AND TIPS Mechanism of action—Some tumour cells lose the abil-
High oral fluid intake must be ensured when ity to synthesize asparagine, requiring an exogenous source
of the substance to grow; normal host cells can synthesize
cisplatin chemotherapy is prescribed to prevent
their own. Crisantaspase is a preparation of bacterial aspar-
kidney damage. A patient’s hearing should be
aginase that breaks down any circulating asparagine, hence
tested regularly because cisplatin damages the inhibiting the growth of some cancers, namely acute lym-
inner ear. Patients should be prescribed regular phoblastic leukaemia (see Fig. 13.1).
antiemetics when on chemotherapy because Route of administration—Intramuscular, subcutaneous.
nausea and vomiting are common, and often leads Indication—Acute lymphoblastic leukaemia.
to patients stopping the chemotherapy. Adverse effects—The most serious side effects of crisan-
taspase include severe toxicity to the liver and pancreas.
Central nervous system (CNS) depression and anaphylaxis
are also risks.
Multikinase inhibitors Therapeutic notes—Regular testing of patients given cri-
Multikinase inhibitors (pazopanib, sunitinib, sorafenib, santaspase is necessary to monitor organ functions.
imatinib) are used, for example, in advanced renal cell car- Many other anticancer agents are used in the manage-
cinoma. They inhibit cell signalling induced by the growth ment of malignant tumours, including mTOR kinase inhib-
factors; vascular endothelial growth factor and platelet-­ itors (temsirolimus, everolimus), amsacrine, altretamine,
derived growth factor. Imatinib is commonly used in the dacarbazine, mitotane, pentostatin, taxanes, thalidomide,
treatment of chronic myeloid leukaemia and acute lympho- topoisomerase I inhibitors, and tretinoin. Detailed infor-
blastic leukaemia that is Philadelphia chromosome positive. mation on these can be gained from the British National
If in advanced renal cell carcinoma multikinase inhibitors Formulary or specialist textbooks.
are not affective, mTOR (mammalian target of rapamycin)
kinase inhibitors (e.g. everolimus, temsirolimus) can be
considered. ENDOCRINE THERAPY
Miscellaneous agents Hormones and antihormones
Several chemotherapeutic cytotoxic agents do not fall into
any of the aforementioned groups. The growth of some cancers is hormone dependent and
can be inhibited by surgical removal of the source of the
Procarbazine driving hormone, such as the gonads, adrenals or pituitary.
Mechanism of action—Procarbazine is a methyl-­ Increasingly, however, administration of hormones or anti-
hydrazine derivative with monoamine oxidase inhibitor ac- hormones is preferred.
tions and cytotoxicity. It inhibits DNA and RNA synthesis Endocrine therapy can cause side effects, the nature of
by a mechanism that is unclear (see Fig. 13.1). which can normally be deduced from the physiological ef-
Route of administration—Oral. fects of the hormone being given or antagonized. Endocrine
Indication—Procarbazine is used in Hodgkin lymphoma. therapy generally has the advantage that it has far fewer se-
Adverse effects—Generalized cytotoxicity (see Table 13.1). rious adverse effects than cytotoxic therapy.
It causes an adverse reaction in combination with alcohol. Hormones used in endocrine therapy include the following.
Therapeutic notes—Procarbazine forms part of MOPP
(mechlorethamine [chlormethine], vincristine, procarba- • Adrenocortic steroids (Chapter 7), for example,
zine and prednisone) therapy for Hodgkin lymphoma. prednisolone, which inhibit the growth of cancers of
the lymphoid tissues and blood. In addition, they are
Hydroxyurea used to treat some of the complications of cancer (e.g.
Mechanism of action—Hydroxyurea causes the inhibi- oedema). They are also useful in the palliative care of
tion of ribonucleotide reductase and hence the formation of end-stage malignant disease because they elevate mood
deoxyribonucleotides (Fig. 13.1). and stimulate appetite.
Route of administration—Oral. • Oestrogens (Chapter 7), for example, diethylstilbestrol,
Indications—Hydroxyurea is used for chronic myeloid which has an antiandrogenic effect and can be used to
leukaemia. Polycythemia rubra vera. suppress androgen-dependent prostatic cancers.
Adverse effects—Generalized cytotoxicity (see • Progesterones (Chapter 7), which inhibit endometrial
Table 13.1). cancer and carcinomas of the prostate and breast.

201
 Cancer

Hormone antagonists Androgen antagonists

Androgen antagonists, for example, flutamide, bicalut-
Oestrogen antagonists amide, cyproterone acetate inhibit androgen-dependent
Mechanism of action—Tamoxifen and toremifene are prostatic cancers. Side effects include gynaecomastia,
competitive inhibitors at oestrogen receptors. Inhibition of weight loss and decreased libido.
the stimulatory effects of oestrogen suppresses the division Gonadotrophin-releasing hormone (GnRH) (e.g. go-
of breast cancer cells. nadorelin, goserelin, buserelin) analogues stimulate the pro-
Route of administration—Oral. duction of oestrogen and testosterone in a nonphysiological
Indication—Treatment of oestrogen receptor-positive manner, resulting in the disruption of endogenous hormonal
breast cancer with metastatic disease. feedback systems and in the downregulation of testosterone
Prevention of recurrences among women with early oes- and oestrogen production. They are used in the treatment of
trogen receptor-positive breast cancer. prostate and breast cancer. Side effects include gynaecomastia.
Adverse effects—Nausea, flushing, bone pain, oedema.
• Degarelix is a GnRH antagonist, which competes with
Increased risk of endometrial cancer,
endogenous GnRH and reversibly binds to the GnRH
thromboembolism
receptors in the pituitary gland. This blocks the release
Contraindications—Pregnancy and breastfeeding.
of luteinising hormone (LH) and follicle stimulating
Therapeutic notes—Tamoxifen increases the anticoagu-
hormone (FSH), suppressing the release of testosterone
lant effect of warfarin.
from the testes and subsequently reduces the growth of
Aromatase inhibitors prostate cancer.
Mechanism of action—Letrozole and anastrozole are
nonsteroidal aromatase inhibitors.
Exemestane is a steroidal aromatase inhibitor.
Aromatase inhibitors inhibit the action of the enzyme aro- IMMUNOTHERAPY
matase, which converts androgens into oestrogens. Oestrogen
stimulates breast tissue and subsequently cancer growth. Immunotherapy treatment for cancer is derived from the
Indications fact that bacterial infections sometimes provoked the re-
• Treatment of oestrogen receptor-positive breast cancer gression of cancer, that is, indirect immunostimulation.
in postmenopausal women. Immunotherapy involves using treatments that use the
• Treatment of advanced breast cancer in body’s immune system to stimulate a response to cancer
postmenopausal women. (i.e. the drug’s target is certain cells involved in the immune
Adverse effects—Hot flushes, vaginal dryness, anorexia, system: CD20 cells or interleukins).
gastrointestinal upset, bone fractures. Approaches of immunotherapy include the following.
Contraindications—Premenopausal women. When used • The use of vaccines for example, bacille Calmette Guérin
in premenopausal women, the decrease in oestrogen pe- (BCG) to provide nonspecific immunostimulation (e.g.
ripherally increases gonadotrophin secretion, which in turn in the treatment of bladder cancer).
stimulates the ovary to increase androgen production. This • The human papilloma virus (HPV) has been found to
increases the total amount of oestrogen, stimulating breast be a causative factor in most cases of cervical cancer.
tissue and cancer growth. HPV strains 6, 11, 16 and 18 have been implicated in
cervical cancer and therefore have been incorporated
into cervical cancer vaccines (Gardasil and Cervarix),
which have recently been introduced into a national
vaccination scheme and given to girls age 12 to 13 years.
• The use of specific vaccines prepared using tumour
cells from similar cancers, in an attempt to raise an
CLINICAL NOTE adaptive immune response against cancer. An example
of autologous cellular immunotherapy is sipuleucel-T,
In premenopausal women, the ovaries produce the the first approved “cancer vaccine” for the treatment of
majority of oestrogen whereas, in postmenopausal metastatic prostate cancer.
women, oestrogen is produced in the peripheral • Immunostimulation using drugs, for example, levamisole.
tissue through the conversion of androgens by the • The use of cytokines to regulate the immune response
aromatase enzyme. Therefore aromatase inhibitors so as to favourably target cancer. Cytokines used
should only be prescribed in postmenopausal include interferon α, interleukin (IL)-2, and tumour
women necrosis factor. Aldesleukin is an IL-2 drug used in
the treatment of metastatic renal cell carcinoma, via
subcutaneous injection.

202
 The future and personalized medicine 13

• The use of recombinant colony-stimulating factors • Basiliximab and daclizumab are both MAbs directed
to reduce the level and duration of neutropenia after against T lymphocytes, preventing them from proliferating.
cytotoxic chemotherapy. • Rituximab targets B lymphocytes and is used in the
• Recombinant human granulocyte colony-stimulating treatment of diffuse large B non-Hodgkin lymphoma
factor (rh-G-CSF; filgrastim) and granulocyte- • Rituximab lyses B lymphocyte by its effect on CD20
macrophage colony-stimulating factor (GM-CSF; protein and also sensitizes resistant cells to other
molgramostim) promote the development of their chemotherapeutic drugs. It is given via an infusion for
respective haemopoietic stem cells in the marrow. Their the treatment of lymphoma.
use to raise white blood cell counts after cytotoxic • Bevacizumab neutralizes vascular endothelial growth
chemotherapy is effective, although this has not been factor and therefore prevents angiogenesis that is
shown to alter overall survival rates. crucial to tumour survival. It is used for the treatment
• The use of tumour-specific monoclonal antibodies of colorectal cancer.
(MAbs) to target drugs specifically to cancerous cells; Contraindications—Severe dyspnoea at rest, breastfeeding.
the so-called “magic-bullet” approach (see later). Route of administration—Intravenous.
Adverse effects—Hypersensitivity reactions, chills, fevers,
cardiotoxicity, hypotension, gastrointestinal symptoms, air-
Monoclonal antibodies way obstruction, aches and pains.
Examples are: rituximab, alemtuzumab, cetuximab, trastu-
zumab, ofatumumab.
Mechanism of action—MAbs recognize specific pro-
teins found on the surface of the cancer cell and lock onto
them. It can then either trigger the body's immune system THE FUTURE AND PERSONALIZED
to destroy the cell or it may be attached to a cancer drug MEDICINE
or radioactive substance, which can target the selected cells.
The development of MAbs targeting ligands overexpressed Newer therapeutics that target certain oncogene and disease
on certain tumour types is a rapidly expanding area. By tar- pathways seem to be the future. Patients diagnosed with com-
geting factors overexpressed on tumour cells, the therapy mon cancers today can have further testing of their cancer
becomes more personalized for the patient and improves tissue receptors. Drug therapies that can target certain cancer
the chances of effective treatment with less unwanted ef- receptor types present in the cancerous tissue can then be used
fects, unlike most of the other cytotoxic drugs that have rather than generic cytotoxic medication used previously, re-
been more commonly used. This is because the biologics ducing the side-effect profile and improving cure rates and
should only be used in patients whose tumours are express- survival. These include noncytotoxic therapies (e.g. inhibitors
ing the particular target protein the antibody recognizes. of tyrosine kinase, MAbs to cell surface proteins and activat-
Antibody directed enzyme prodrug therapy (ADEPT) ing the patient’s own immunity to target cancer cells).
uses MAbs to carry enzymes directly to the cancer cells. A For example, patients with oestrogen-dependent breast
cytotoxic prodrug is then administered, which is only acti- cancer respond better than nonoestrogen-dependent breast
vated in cells with the enzyme, thus resulting in treatment cancer if treated with tamoxifen and aromatase inhibitors.
targeting cancer cells but not normal cells. Patients with HER2 receptor-positive breast cancer can be
Indications treated with trastuzumab, which is a form of immune target-
• Trastuzumab (herceptin) is licensed for metastatic breast ing. Similarly, patients with lung cancer that have the EGFR
cancer in patients with tumours overexpressing human mutation can be given erlotinib rather than treatment with
epidermal growth factor (EGFR) 2 (HER2) receptor. generic chemotherapy and the wide range of side effects
• Cetuximab (targets EGFR) in combination with this causes. Most recently, nivolumab, an anti-programmed
irinotecan, is licensed for metastatic colorectal cancers death ligand 1 (PDL1) antibody, has been approved for the
overexpressing epidermal growth factor receptors. treatment of advanced melanoma.
• Nonsmall cell lung cancer. Some overexpress EGFR These new immunotherapies are extremely promising in
and mutations of this receptor have been found and the the treatment of various cancers, particularly because they
MAb gefinitib is now used instead of chemotherapy in are less toxic than current cytotoxic therapy. However, they
patients with these mutations. are expensive, which limits their use.

203
 Cancer

Chapter Summary

• Cancer therapy intervention is aimed at inhibiting or reducing the accelerated growth of

cell division that leads to malignancy
• Cytotoxic chemotherapy causes side effects because of the inhibition of noncancerous
host cell division (especially gut, bone marrow and immune system)
• Cytotoxic antibiotics include doxorubicin and bleomycin
• Mercaptopurine is converted into a fraudulent purine nucleotide that impairs DNA synthesis
• Endocrine therapy is generally less toxic than chemotherapy
• Patients with certain receptors expressed within their cancer tissue can receive targeted
drug therapy

204
SELF-ASSESSMENT
Single best answer (SBA) questions����������������������� 207

Extended-matching questions (EMQs) ������������������ 219

SBA answers ������������������������������������������������������������ 227

EMQ answers������������������������������������������������������������ 243

This page intentionally left blank
 Single best answer (SBA)
questions
Chapter 1 Introduction to Pharmacology Chapter 2 Peripheral nervous system
1. A 30-year-old man is diagnosed with tuberculosis and 1. A 60-year-old man presents with dysuria,
is started on rifampicin and isoniazid treatment for frequency, loin pain and fever. He is diagnosed with
2 months. pyelonephritis and is started on antibiotics. However,
Which of the following medications will be affected he develops septic shock and has to be intubated
by the enzyme induction associated with this and taken to intensive care unit. Unfortunately, after
treatment? intubation with a neuromuscular blocker he remains
A. Allopurinol. paralysed. Which drug is responsible for this adverse
B. Cyclosporine. effect occurring?
C. Phenytoin. A. Ciprofloxacin.
D. Salbutamol. B. Co amoxiclav.
E. Warfarin. C. Gentamicin.
D. Paracetamol.
2. An 80-year-old woman presents with severe E. Trimethoprim.
sepsis secondary to a chest infection. She requires
antibiotics. Which is the most direct route of drug 2. A 52-year-old man is admitted for a routine surgical
administration? procedure. The anaesthetist gives him anaesthesia to
A. Intramuscular. ensure his muscles are paralysed for the surgery.
B. Intravenous. Which of the following medication is a depolarising
C. Per oral. neuromuscular blocking agent that is often used
D. Per rectum. during induction of anaesthesia?
E. Subcutaneous. A. Atracurium.
B. Botulinum.
3. A healthy male volunteer is keen to be involved in C. Hemicholinium.
the development of a novel drug. In which phase D. Suxamethonium.
of the drug development process will he be E. Vecuronium.
recruited into?
A. Preclinical. 3. A 35-year-old female presents with a 2-month history
B. Phase 1. of muscle weakness and early fatigue particularly at
C. Phase 2. the end of the day. She gets tired when brushing her
D. Phase 3. teeth in the evenings. Investigations so far have been
E. Phase 4. inconclusive. Which drug can be used to help aid the
diagnosis?
4. Which one of the following drugs is an agonist at β A. Alcuronium.
receptors? B. Edrophonium.
A. Isoprenaline. C. Neostigmine.
B. N-acetyl-P-aminophenol. D. Pancuronium.
C. Paracetamol. E. Suxamethonium.
D. Proguanil hydrochloride.
E. Syntometrine. 4. A 25-year-old woman presents with episodes of
anxiety, sweating, tremor and palpitations associated
5. Which one of these is an example of a G-protein- with severe hypertension. Currently her blood pressure
coupled receptor? is 190/90 mm Hg and her heart rate is 110 beats
A. B2 adrenergic receptor. per minute. You suspect a phaeochromocytoma.
B. Insulin receptor. What is the most appropriate way of managing her
C. Nicotinic acetylcholine receptor. hypertension acutely?
D. Platelet derived growth factor (PDGF) receptor. A. Oral propranolol.
E. Steroid receptor. B. Intravenous (IV) labetalol.

207
 Single best answer (SBA) questions

C. IV phentolamine. despite regular use of his salbutamol inhaler. He has

D. Oral phenoxybenzamine. been well otherwise. His regular medications include
E. IV atropine. salbutamol 100 mcg inhaler 2 puffs when he needs it
and beclomethasone 200 mcg inhaler 2 puffs twice a
5. A 60-year-old man is prescribed medication for day. On examination, his vital signs are within normal
his benign prostatic hyperplasia and his General limits and his chest is clear.
Practitioner notes show an improvement in his blood Which of the following is the most appropriate next
pressure. Which antihypertensive drug acts as an α1- step in the patient’s management?
adrenoreceptor antagonist? A. Continue salbutamol inhaler and add in a fixed
A. Clonidine. dose combination inhaler with budesonide and
B. Labetalol. formoterol and add in a short course of oral
C. Phenylephrine. antibiotics.
D. Prazosin. B. Continue salbutamol and beclometasone
E. Propranolol. inhaler.
C. Continue current inhalers and start antibiotics for a
6. A 24-year old female with asthma has recently been chest infection.
started on an inhaler containing ipratropium bromide. D. Continue salbutamol inhaler and increase dose of
Which of the following symptoms or signs can be related beclometasone inhaler.
to the mechanism of action of ipratropium bromide? E. Continue salbutamol inhaler and add in a fixed
A. Blurred vision. dose combination inhaler with fluticasone
B. Bradycardia. propionate and salmeterol.
C. Increase salivation.
D. Pin point pupils. 3. A 59-year-old woman who has been smoking
E. Urinary frequency. approximately 15 cigarettes a day for the past
40 years presents with intermittent breathlessness
Chapter 3 Respiratory system and a 3-month history of a cough, which is
productive of sputum. A diagnosis of COPD is made
1. A 40-year-old woman presents to the emergency
based on her history, examination and lung function
department with a 2-day history of worsening
tests. She is commenced on ipratropium. Over winter
breathlessness. She normally has an average
she has several exacerbations and presents to her
peak expiratory flow rate of 450 L per minute, is on
GP with persistent breathlessness. Her FEV1 is 55%.
regular salmeterol and fluticasone inhalers but she
Which of the following would not be an appropriate
ran out of all her medications a few days ago. On
option?
examination, she is alert with a respiratory rate of 30
breaths per minute. She has widespread bilateral A. Advice smoking cessation.
polyphonic wheeze and her peak expiratory flow is B. Offer a pneumococcal vaccination.
140 L per minute. She has already received nebulizers C. Add in a long-acting muscarinic antagonist
of salbutamol and ipratropium in the emergency (LAMA).
department with minimal response. D. Add in a long-acting B2 agonist (LABA).
E. Add in short-acting B2 agonist (SABA).
Which of the following is most appropriate next step in
this patient's management?
4. A 60-year-old woman is admitted with a cough
A. Inhaled budesonide and ipratropium.
productive of green sputum, breathless and wheeze.
B. Inhaled budesonide and intravenous (IV)
She is a current smoker and her regular medications
magnesium.
include ipratropium inhaler, fluticasone propionate and
C. Inhaled budesonide, IV magnesium and IV
salmeterol inhaler. She has had several admissions
theophylline.
to hospital with exacerbations and type II respiratory
D. Continue with nebulizers, add IV hydrocortisone
failure. Her GP has given her a dose of oral
and IV magnesium.
clarithromycin.
E. Inhaled salmeterol and ipratropium, IV
methylprednisolone and IV theophylline. On examination, she looks breathless, heart rate is
120 beats per minute, respiratory rate is 35 breaths
2. A 30-year-old man with asthma presents to his per minute, oxygen saturation 85%, temperature
General Practitioner (GP) because he is worried that 37.2 °C, blood pressure 135/80 mm Hg. Crackles are
he has been coughing at night at least 3 times per heard on the right base.
week over the past few months. Recently, he has also Which of the following is appropriate in the immediate
been wheezy and breathless when playing football, management?

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 Single best answer (SBA) questions

A. 15 L of oxygen, continue oral clarithromycin, add 3. A 60-year-old man presents to the emergency
in oral prednisolone and nebulized ipratropium. department with central, heavy chest pain, which
B. Controlled oxygen, continue oral clarithromycin, radiates down his left arm and started suddenly
add in oral prednisolone, nebulized ipratropium an hour ago. He feels nauseous and breathless
and intravenous (IV) theophylline. and grades the severity as 10/10. Medical history
C. Controlled oxygen, continue oral clarithromycin, includes angina, hypertension and high cholesterol.
add in oral prednisolone and nebulized He is not known to have any allergies. The patient
ipratropium. is diagnosed with a myocardial infarction (MI) and
D. 15 L of oxygen, continue oral clarithromycin, add prescribed the following medications.
in oral prednisolone, nebulized ipratropium and IV Which of the following medications’ mechanism of
theophylline. action is inhibition of ADP?
E. Continue oral clarithromycin, add in oral A. Aspirin.
prednisolone, nebulized ipratropium and IV B. Clopidogrel.
theophylline. C. Fondaparinux.
D. Morphine sulphate.
5. A 40-year-old male presents to the GP complaining E. Unfractionated heparin.
of itchy eyes, overproduction of nasal mucus and a
blocked nose every time he visits his girlfriend who 4. A 48-year-old Afro-Caribbean man attends his
owns a dog and has been a problem for the past GP for a routine medical examination for his
month. His medical history includes type 2 diabetes, work insurance and is noted to have a blood
hypertension and asthma. pressure (BP) measurement of 152/92 mm Hg. On
What medication would be inappropriate to prescribe subsequent measurements of his BP, it remains over
for this patient’s symptoms? 140/90 mm Hg. He has mild asthma.
A. Oral cetirizine. Which of the following medications would be
B. Oral chlorphenamine. appropriate to start as management of his
C. Oral ephedrine. hypertension?
D. Nasal ephedrine. A. ACE inhibitor.
E. Nasal glucocorticosteroid. B. ß-Blocker.
C. Calcium channel blocker.
D. Loop diuretic.
Chapter 4 Cardiovascular system
E. Thiazide diuretic.
1. A 29-year-old female presents in her second
trimester of pregnancy. She presents to the General 5. A 48-year-old man is commenced on lisinopril for
Practioner (GP) with high blood pressure. hypertension. Which of the following statements are
Which medication can be given to treat her true about ACE inhibitors?
hypertension? A. There is a risk of hypokalaemia.
A. Bisoprolol. B. Cough is an uncommon side effect.
B. Furosemide. C. Precaution needs to be taken if the patient
C. Losartan. develops diarrhoea and vomiting.
D. Methyldopa. D. ACE inhibitors cause liver failure.
E. Ramipril. E. Blood tests are required every 6 months.

2. A 75-year-old female presents acutely short of 6. A 65-year-old man presents to a hospital complaining
breath. She has a cough productive of pink frothy of general lethargy and weakness. He has
sputum. On examination, she has peripheral hypertension and takes regular ramipril and amlodipine.
oedema and a raised jugular venous pressure (JVP). He recently had a flare of his osteoarthritis and has
She had a myocardial infarction two weeks ago. been taking regular ibuprofen for the last week. He
She is diagnosed with acute pulmonary oedema attends his GP for a general review, and blood tests
secondary to right-sided heart failure. reveal he has raised potassium and an acute kidney
Which of the following medications will off load the injury. His blood results a month ago were normal.
fluid most effectively? What should the GP advise the patient to do?
A. Bendroflumethiazide. A. Stop amlodipine.
B. Bumetanide. B. Stop ibuprofen.
C. Furosemide. C. Stop Ramipril.
D. Glyceryl trinitrate. D. Stop ibuprofen and amlodipine.
E. Morphine. E. Stop ibuprofen and Ramipril.

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 Single best answer (SBA) questions

7. A 55-year-old woman who takes bisoprolol and 11. A 70-year-old woman presents with heart failure and
warfarin for atrial fibrillation has a routine blood test would like to know which medications have a proven
to check her international normalized ratio (INR). mortality benefit.
The INR result is 6.5 (target range 2–3). She denies Which of the following medications have this benefit
any bleeding and is well. However, she does admit in patients with heart failure?
that she drank more alcohol than normal over the A. ACE inhibitors.
weekend. B. Angiotensin-receptor blockers.
What is the most appropriate next step? C. Cardiac glycosides.
A. Stop bisoprolol and recheck INR. D. Calcium-channel blockers.
B. Give vitamin K and recheck INR. E. Loop diuretics.
C. Reduce dose of warfarin to 2 mg daily and
recheck INR.
Chapter 5 Kidney and urinary system
D. Increase warfarin to 5 mg daily and recheck INR.
E. Omit warfarin for at least 2 days and recheck INR. 1. Which part of the nephron is the main site of
potassium secretion?
8. A 60-year-old female presents with swollen A. Distal convoluted tubule.
ankles and feeling constipated. She takes ramipril B. Glomerulus.
for hypertension, verapamil for rate control C. Juxtaglomerular apparatus.
and rivaroxaban for anticoagulation as she has D. Loop of Henle.
atrial fibrillation and has recently been started E. Proximal tubule.
on furosemide for suspected heart failure, but
her echocardiogram is normal. She is also on 2. A 60-year-old man with hypertension is seen by his
simvastatin for hypercholesterolaemia. General Practitioner (GP) for review. He is currently
Which medication could be responsible for her taking amlodipine, but his blood pressure remains
symptoms? elevated. He is unable to tolerate an ACE inhibitor, so
A. Furosemide. his GP starts him on Bendroflumethiazide. Of which of
B. Ramipril. the following complications should the GP be aware?
C. Rivaroxaban. A. Hyperkalaemia.
D. Simvastatin. B. Hypernatraemia.
E. Verapamil. C. Hyperuricaemia.
D. Hypocalcaemia.
9. A 65-year-old female is noted to have high E. Hypomagnesaemia.
cholesterol and a 10-year cardiovascular disease
risk of greater than 20%. The GP would like to 3. A 60-year-old patient is admitted with worsening
start her on simvastatin. Which one of the following breathlessness, orthopnoea and leg swelling for
parameters would be the most important to monitor the last 3 days. She has no medical history and is
before prescribing simvastatin? taking no regular medications. She has crepitations
A. Blood pressure. to both midzones with a raised jugular venous
B. Creatinine kinase. pressure and pitting oedema in both legs. Her
C. Muscle biopsy. blood results are normal. Which of the following
D. Serum liver transaminases (alanine diuretics is the most appropriate to administer in the
aminotransferase/aspartate aminotransferase). initial management?
E. Weight. A. Amiloride.
B. Indapamide.
10. An 82-year-old female with a history of atrial C. Bumetanide.
fibrillation is prescribed warfarin and presents to A&E D. Furosemide.
with an episode of epistaxis. Her INR is 7.2. A week E. Spironolactone.
earlier she had commenced on a course of oral
antibiotics for a treatment of a chest infection. 4. A 74-year-old patient is recovering from an ischaemic
Which one of the following antibiotics do you stroke one week ago. He has hypertension and takes
suspect is most likely to have been prescribed? amlodipine. He also has heart failure for which he
A. Amoxicillin. takes furosemide and spironolactone. He has been
B. Augmentin. started on aspirin and simvastatin as secondary
C. Clarithromycin. management.
D. Co-amoxiclav. His blood results are the following:
E. Trimethoprim. Na 140 (135–145 mmol/L)

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 Single best answer (SBA) questions

K 6.2 (3.5–5 mmol/L)

Chapter 6 Gastrointestinal system
Urea 3.2 (3–7 mmol/L)
1. A 29-year-old man presents to his GP with epigastric
Creatinine 78 (60–125 umol/L)
abdominal pain and reflux with occasional vomiting.
Which is the most likely medication responsible for his
He has a 2-month history of loose stool with up to
hyperkalaemia?
5 episodes a day. He reports fatigue and a one-half
A. Amlodipine. stone weight loss over the past month. He drinks 15
B. Aspirin. to 20 units socially at the weekend and infrequently
C. Furosemide. smokes with friends. He recently took ibuprofen for
D. Spironolactone. a week for left ankle pain following a football injury. A
E. Simvastatin. year ago, he took triple therapy for a small peptic ulcer
in his stomach. When seen by a gastroenterologist,
5. A 66-year-old man comes to the clinic complaining he is found to have several various sized ulcers in his
of dizziness and unsteadiness on standing up in the stomach, duodenum and jejunum.
mornings. He has recently been started on treatment What is the underlying diagnosis?
for BPH after he reported poor urinary flow and
A. Alcohol induced peptic ulceration.
hesitancy associated with a normal prostate specific
B. Gastrinoma induced peptic ulceration.
antigen. A digital rectal examination identified a
C. H. pylori induced peptic ulceration.
smooth enlarged prostate. Which of the following
D. NSAID induced peptic ulceration.
medications is most likely to be responsible for his
E. Smoking induced peptic ulceration.
current symptoms?
A. Bethanechol. 2. A 65-year-old man is seen by his GP for a routine
B. Doxazosin. check-up. On examination, he is noted to have enlarged
C. Duloxetine. breast tissue. He denies drinking alcohol and is not
D. Finasteride. known to have any liver problems. He has been taking
E. Oxybutynin. regular medication for dyspepsia for many years. Which
medication is most likely to be responsible?
6. A 55-year-old female presents to clinic with symptoms A. Aluminium hydroxychloride.
of urge incontinence. Her GP discusses starting B. Amoxicillin.
oxybutynin and informs her of the side effects. Which C. Ranitidine.
of the following is a side effect of oxybutynin? D. Misoprostol.
A. Loose stool. E. Omeprazole.
B. Hypoglycaemia.
C. Blurred vision. 3. A 67-year-old woman is seen in A&E with epistaxis.
D. Hypotension. A week ago, she saw her GP who started her on
E. Excess saliva. some additional medication for treatment of her
longstanding GORD. She is known to have atrial
7. A 45-year-old diabetic presents with erectile fibrillation and takes warfarin.
dysfunction and requests treatment. Which of the Which medication is her GP likely to have started to
following is the most appropriate? cause this complication?
A. Intracavernous sildenafil. A. Bismuth chelate.
B. Oral alprostadil. B. Cimetidine.
C. Oral papaverine. C. Magnesium carbonate.
D. Oral sildenafil. D. Misoprostol.
E. Topical papaverine. E. Omeprazole.

8. A 62-year-old female with a history of a myocardial 4. A 65-year-old male who is undergoing treatment
infarction is diagnosed with mild heart failure and for pancreatic carcinoma presents with nausea and
commenced on furosemide. vomiting. He vomits undigested food and feels full
Which one of the following parameters is the most very quickly. Which of the following treatments is most
important to monitor in the community? useful for gastric outlet obstruction related emesis?
A. Blood pressure. A. Cyclizine.
B. Full blood count. B. Dexamethasone.
C. Heart rate. C. Levomepromazine.
D. Serum electrolytes. D. Metoclopramide.
E. Urinary sodium. E. Ondansetron.

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 Single best answer (SBA) questions

5. In acute chemotherapy induced nausea and vomiting, She has recently started taking medication for an
which of the following is the most useful antiemetic in overactive thyroid.
addition to dexamethasone? Which of the following investigations is most
A. Cyclizine. important to check?
B. Domperidone. A. Electrocardiogram (EKG).
C. Metoclopramide. B. Full blood count.
D. Ondansetron. C. Glucose.
E. Prochlorperazine. D. Liver function test.
E. Thyroid function test.
6. A 62-year-old man with Parkinson disease is seen
by his GP with nausea and vomiting associated with 2. A 62-year-old man presents to his GP feeling
vertigo. He is prescribed an antiemetic. A few days generally unwell. On direct questioning, he reports
later, his wife phones the surgery concerned that her a new tremor, feeling hot and sweaty and thinks he
husband is stiffer than normal and less mobile and may have lost some weight. He has recently been
has fallen twice. started on treatment by the cardiologists for atrial
Which of the following medications is contraindicated fibrillation. He has known structural heart disease.
in this patient? Which of the following medications is he most likely
A. Cimetidine. to have been started on which could account for his
B. Chlorpromazine. symptoms?
C. Cyclizine. A. Amiodarone.
D. Dexamethasone. B. Carbimazole.
E. Ondansetron. C. Iodide.
D. Levothyroxine.
7. A 25-year-old girl presents to her GP with a 4-week E. Propanalol.
history of frequent, bloody diarrhoea associated with
colicky abdominal pain and general malaise. She 3. A 55-year-old male is seen in the GP surgery. He has
is a nonsmoker. She denies any recent travel. Her type 2 diabetes and already takes maximum dose
maternal aunt is known to have ulcerative colitis. metformin but his HbA1c remains above 58 mmol/L.
On examination, she appears pale and unwell with He is commenced on gliclazide 40 mg once daily, in
generalized abdominal tenderness. She is referred addition to metformin.
to hospital. A faecal calprotectin result is positive. Which of the following statements should be
A colonoscopy confirms involvement of the bowel conveyed to the patient regarding gliclazide?
mucosa only. She is started on oral corticosteroids. A. Hypoglycaemia is not a risk when taking gliclazide.
Which of the following medications is used to maintain B. Drinking alcohol while on gliclazide should not
remission? cause any problems.
A. Azathioprine. C. Gliclazide can cause weight loss.
B. Cyclosporine. D. β-Blocker medication may mask the
C. Ispaghula husk. hypoglycaemic symptoms associated with
D. Infliximab. gliclazide.
E. Mesalazine. E. If a dose is missed then a double dose should
be taken the next day.
8. A 50-year-old patient who develops pain arising
from metastases is placed on opiate pain relief and 4. A mother brings her 14-year-old son to the GP clinic
subsequently develops constipation. Which of the because she is concerned that he has been passing
following medications is a stimulant laxative? urine more often than normal, over the past 2 to
A. Ispaghula husk. 3 weeks. He reports feeling thirsty all the time and
B. Lactulose. feels really tired. On direct questioning, he thinks
C. Methylcellulose. he has lost weight. A random venous glucose is
D. Peppermint oil. 12 mmol/L and he has glucose in his urine. Which
E. Senna. of the following options is the most appropriate
management?
A. Acarbose.
Chapter 7 Endocrine and reproductive B. Dietary modification
1. A 35-year-old woman presents to her GP feeling C. Gliclazide.
generally unwell with a sore throat. On examination, D. Insulin.
she has a red throat but otherwise appears well. E. Metformin.

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5. A 58-year-old male who is a known type 2 9. A 21-year-old female sees her GP regarding
diabetic is seen in the endocrine clinic because his contraception. Which of the following
glucose levels remain high despite dual therapy contraindicates the prescription of the combined oral
with metformin and gliclazide. He is started on contraceptive pill?
pioglitazone. Which of the following statements is A. Asthma.
true regarding pioglitazone? B. Hypotension.
A. Pioglitazone causes weight loss. C. Migraine.
B. Pioglitazone can reduce the need for exogenous D. Previous pregnancy.
insulin by 30%. E. Renal disease.
C. Pioglitazone can be given to patients with a
history of bladder cancer. 10. Which of the following medications reduce the
D. Pioglitazone can protect against bone effectiveness of the progestogen-only pill?
fractures. A. Amiodarone.
E. Pioglitazone is safe to use in patients with heart B. Ciprofloxacin.
failure. C. Erythromycin.
D. Phenytoin.
6. A 48-year-old man with type 2 diabetes attends his E. Sodium valproate.
GP with dysuria and offensive penile discharge. He
was recently reviewed by the diabetes clinic and 11. An 80-year-old female presents with pain in her left
commenced on an additional medication, as his thigh with no history of trauma. She is known to
glycaemic control remains poor despite therapy have osteoporosis and hypertension but is otherwise
started by his GP. well. An X-ray indicates an incomplete fracture of the
Which of the following antidiabetic femur shaft.
medications could be responsible for his Which of these drugs for osteoporosis can cause
symptoms? this complication?
A. Acarbose. A. Alendronate.
B. Dapagliflozin. B. Ergocalciferol.
C. Linagliptin. C. Raloxifene.
D. Liraglutide. D. Strontium ranelate.
E. Pioglitazone. E. Teriparatide.

7. A 32-year-old female attends her GP surgery 12. Mr. Simpson, a 65-year-old male visits his GP
complaining of general fatigue and weakness. She because he feels more lethargic and thirsty
also reports some abdominal pain and muscle compared with normal. His GP notes he has
cramps. Her GP notes that she has a postural drop glycosuria and a random blood glucose of 12.
in her blood pressure and appears slightly tanned. Mr. Simpson had normal blood sugars 3 months
She is diagnosed with primary adrenal insufficiency ago and has a normal body mass index. However,
by the endocrinologist. he has been started on several drugs for blood
Which medication is she most likely to be pressure and cholesterol control over the past year.
started on? He also takes medication for gout and osteoarthritis.
A. Beclometasone. Which of the following medications is associated
B. Dexamethasone. with inducing hyperglycaemia?
C. Fludrocortisone. A. Allopurinol.
D. Prednisolone. B. Bendroflumethiazide.
E. Triamcinolone. C. Celecoxib.
D. Paracetamol.
8. A 40-year-old male with inflammatory bowel E. Ramipril.
disease presents to the clinic. He requires long-term
steroids.
Which of the following symptoms or signs are side
effects of glucocorticosteroids? Chapter 8 Central nervous system
A. Hypoglycaemia. 1. Mr. Jeffers, a 56-year-old male attends his GP surgery
B. Muscle bulk. after noticing that his left-hand shakes when he is
C. Osteoporosis. watching television. His wife notes that he is unsteady
D. Thickened skin. when standing in the morning. On examination,
E. Weight loss. Mr. Jeffers appears to have a fixed facial expression

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 Single best answer (SBA) questions

with infrequent blinking and bradykinesia while 5. A psychiatrist wishes to prescribe lithium as second-
walking. His medical history includes hypertension line treatment for a patient with bipolar disorder. Which
only. He is referred to a neurologist and started on blood test, if any, is the most important to arrange,
new medication. Which of the following medications other than renal function?
inhibits dopa carboxylase in the periphery? A. Full blood count.
A. Carbidopa. B. Liver function tests.
B. Domperidone. C. No blood test required.
C. Entacapone. D. Parathyroid hormone.
D. Levodopa. E. Thyroid function tests.
E. Selegiline.
6. Which of the following medications is the most
2. A 29-year-old female with acute anxiety is prescribed appropriate antihypertensive for a patient who is
a short course of diazepam. Which of the following taking lithium for their bipolar disorder?
statements is correct regarding benzodiazepines? A. Amlodipine.
A. She is safe to drive while taking diazepam. B. Bendroflumethiazide.
B. She is safe to drink alcohol while taking C. Furosemide.
diazepam. D. Losartan.
C. She may experience drowsiness while taking E. Ramipril.
diazepam.
D. If she were to overdose on diazepam, there is no 7. A 24-year-old girl with depression is reviewed by her
reversal agent. GP. Despite taking fluoxetine for the past 2 months,
E. She can continue to take the diazepam for more she remains low in mood with biological symptoms
than 4 weeks and then stop taking them. of depression. Her GP wishes to start her on
moclobemide. Which of the following statements is
3. A 26-year-old female with known anxiety presents to true regarding this medication?
her GP. She is due to give a presentation at work to A. Fluoxetine can safely be prescribed alongside this
an important crowd of people and is worried about antidepressant.
sweating, flushing and shaking publically, and has B. This antidepressant can lower the seizure threshold.
asked for some medication. She is not known to have C. This antidepressant can safely be taken with
any medical history and has no drug allergies. cough mixtures.
Which of the following medication can provide D. This antidepressant can be prescribed to patients
the most appropriate symptomatic control of her who have had a recent myocardial infarction.
performance related anxiety? E. This antidepressant can cause weight gain and
A. Buspirone. teary red eyes.
B. Midazolam.
C. Pentobarbital. 8. A 21-year-old female presents to the neurologist after
D. Propranolol. having had two seizures (involving her body becoming
E. Zolpidem. rigid, followed by her limbs jerking) over the past
3 months. Her CT head scan is normal. Which of
4. A 29-year-old female presents to her GP with the following medication causes the use-dependent
low mood over the past 8 weeks, almost every blockade of voltage-gated sodium channels and is
day associated with a loss of energy. On direct used first line in the treatment of epilepsy?
questioning, she has a reduced ability to think A. Ethosuximide.
and is easily irritated by her colleagues at work. B. Lamotrigine.
She also admits to feelings of hopelessness C. Phenytoin.
and problems sleeping. The GP notes she has D. Sodium valproate.
recently started cognitive behavioural therapy. E. Vigabatrin.
Her past medical history includes hypertension.
Which of the following medications should she be
commenced on? Chapter 9 Drug misuse
A. Amitriptyline. 1. A 21-year-old male asks his friend who is a trainee
B. Citalopram. doctor what the effects of cannabis are. Which of the
C. Mirtazapine. following is true regarding cannabis?
D. Moclobemide. A. Cannabis reduces heart rate and constricts pupils.
E. Venlafaxine. B. Cannabis reduces appetite.

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 Single best answer (SBA) questions

C. Cannabis causes an apparent sharpening of Which one of the following options is the most
sensory experience. appropriate analgesic for “as required” use?
D. Cannabis is used clinically as an analgesic. A. Diamorphine subcutaneously.
E. Injecting cannabis enhances its effects. B. Fentanyl lozenges.
C. Methadone orally.
2. A 24-year-old female regularly takes heroin. However, D. Morphine sulphate orally.
she presents to A&E after being unable to buy any E. Oxycodone orally.
more. Which of the following symptoms are consistent
with the opioid withdrawal syndrome? 3. A 30-year-old male is brought to A&E with femur and
A. Euphoria. tibia fracture and multiple rib fractures, following a
B. Increased appetite. motorbike accident. He is given regular morphine to
C. Hypothermia. control the pain.
D. Pupillary constriction. Which of the following adverse effects are associated
E. Yawning. with opioids?
A. Cough.
3. A 35-year old female who has been a heavy smoker
B. Diarrhoea.
for the past 15 years attends her GP and would like
C. Dilated pupils.
to try a nicotine replacement product. Her medical
D. Fast respiratory rate.
history includes epilepsy and hay fever. She is
E. Flushing.
currently receiving psychological support from the
smoking cessation specialist nurse. 4. Miss Joules is reviewed by her GP. She has been
Which of the following medications should she be having episodes of unilateral, severe headaches
prescribed? associated with photophobia and vomiting for the
A. Bupropion. past 6 weeks. She has a family history of migraine.
B. Disulfiram. Despite treatment for her acute attacks, Miss Joules is
C. Flumazenil. concerned that her migraines are impacting negatively
D. Methanol. on her ability to work effectively. She has come to
E. Varenicline. discuss sumatriptan.
What is the mechanism of action of
Chapter 10 Pain and anaesthesia sumatriptan?
1. A 45-year-old man with lower back pain is seen by A. 5-HT1 receptor agonist.
his General Practitioner (GP) for a review. Sinister B. 5-HT1 receptor antagonist.
causes for his back pain have been excluded but he C. β-Receptor antagonist.
has extensive osteoarthritis. He is currently taking D. Nonsteroidal anti-inflammatory.
paracetamol and ibuprofen, but the pain is persisting. E. Serotonin-noradrenaline reuptake inhibitor.
His examination is normal, and his blood results are
unremarkable. He has no allergies. 5. A 45-year old female requires a general anaesthetic
Which of the following analgesia should he be for an appendectomy. Her past medical history
prescribed next? includes hypertension, epilepsy and hay fever.
She is given propofol during the induction stage of
A. Ibuprofen, paracetamol and aspirin.
anaesthesia.
B. Ibuprofen paracetamol and morphine.
C. Ibuprofen, paracetamol and codeine. Which of the following medication should she be given
D. Paracetamol and morphine. to maintain her anaesthesia during the surgery?
E. Ibuprofen and codeine. A. Enflurane.
B. Isoflurane.
2. Mr Jones, a 60-year-old male with a history of C. Halothane.
prostate cancer, is admitted with a short history of D. Etomidate.
back pain. He is in severe pain, particularly when E. Ketamine.
moving and it comes on very quickly. He is already
taking regular paracetamol and codeine phosphate
60 mg six hourly. A pelvic X-ray indicates a possible
Chapter 11 Inflammation, allergic diseases
metastatic deposit. His urea and electrolytes reveal a and immunosuppression
creatinine of 200 (one month previously 85) and his 1. A 65-year-old male attends his GP practice with
full blood count and liver function tests are normal. An a sprained ankle and informs his doctor that he
isotope bone scan and oncology review are arranged. has been taking ibuprofen over the counter but is

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 Single best answer (SBA) questions

concerned about what he has read in the patient C. Adrenaline acts at α2-receptors to cause
leaflet. Which of the following statements is correct vasoconstriction and β2-receptors to cause
regarding ibuprofen? bronchodilation.
Ibuprofen can be given to patients with: D. Promethazine is a new nonsedative H2 receptor
A. Renal impairment. antagonist.
B. Asthma. E. Intravenous adrenaline is required to treat this
C. Gastrointestinal ulceration. reaction.
D. Joint inflammation.
E. Liver failure. Chapter 12 Infectious diseases
1. Which of the following antibiotics acts as a protein
2. A patient with severe rheumatoid arthritis who
synthesis inhibitor?
has been taking regular ibuprofen and short
A. Co-amoxiclav.
courses of prednisolone is commenced on
B. Gentamicin.
hydroxychloroquine.
C. Meropenem.
Which of the following side effects is most associated D. Metronidazole.
with hydroxychloroquine? E. Trimethoprim.
A. Diarrhoea.
B. Oligospermia. 2. Which of the following antibiotics are known to cause
C. Thinning of the skin. ototoxicity, nephrotoxicity and red man syndrome?
D. Transient loss of taste. A. Erythromycin.
E. Visual loss. B. Levofloxacin.
C. Metronidazole.
3. Before commencing adalimumab, a history of which
D. Trimethoprim.
of the following should be excluded?
E. Vancomycin.
A. Chronic obstructive pulmonary disease.
B. Hypertension. 3. A 19-year-old man attends the walk-in sexual health
C. Ischaemic heart disease. clinic complaining of a painful, white discharge from
D. Recurrent urinary tract infections. his urethra and dysuria. He has a positive swab for a
E. Tuberculosis. gram-negative organism.
Which antibiotic can be given as a one-off dose to
4. A 30-year-old female has been referred to a
treat his symptoms?
dermatologist by her GP. She has several thickened
skin plaques on her elbows, knees and scalp A. Azithromycin.
with superficial scales. Her GP notes that she has B. Ciprofloxacin.
hyperlipidemia on her blood tests. C. Co-amoxiclav.
D. Meropenem.
Which of the following statements is true?
E. Trimethoprim.
A. Clobetasone butyrate is a very potent topical
steroid used on affected areas.
4. A 65-year-old man attends A&E with a productive
B. Methotrexate is used first-line in the treatment of
cough, fever and chest tightness. Past medical history:
psoriasis.
atrial fibrillation. DH: Warfarin (international normalized
C. Dithranol can be safely applied to pustular
ratio [INR] yesterday 2.6). Allergy: penicillin.
psoriasis.
He is started on an antibiotic for a presumed lower
D. Calcipotriol can be used in patients with disorders
respiratory tract infection. His repeat bloods show
of calcium metabolism.
an INR of 1.
E. Coal tar causes an acne like eruption and
photosensitivity Which of the following antibiotics was likely to have
been prescribed?
5. A 20-year-old female with a chest infection is A. Amoxicillin.
prescribed oral co-amoxiclav. Within a few minutes, B. Clarithromycin.
she experiences chest tightness, lip tingling and an C. Co-amoxiclav.
urticarial rash on her arms. D. Co-trimoxazole.
Which of the following statements is true? E. Levofloxacin.
A. The release of histamine causes
bronchoconstriction. 5. A 34-year-old 16/40 pregnant female is found to have
B. This reaction is mediated by IgA and is a type II asymptomatic bacteriuria of E. coli on screening.
hypersensitivity reaction. Which of the following is the most appropriate action?

216
 Single best answer (SBA) questions

A. None. D. Primaquine.
B. Trimethoprim. E. Sulphonamide.
C. Doxycycline.
D. Nitrofurantoin. Chapter 13 Cancer
E. Ciprofloxacin.
1. Which cytotoxic drug is an alkylating agent?
6. A 48-year-old male patient receiving treatment A. Cisplatin.
for tuberculosis attends his General Practitioner B. Dactinomycin.
complaining of orange tears and urine. Which of the C. Melphalan.
following antituberculosis medications is responsible D. Methotrexate.
for these side effects? E. Vinblastine.
A. Ethambutol.
B. Isoniazid. 2. Which of the following cytotoxic medication is known
C. Pyrazinamide. to cause haemorrhagic cystitis?
D. Pyridoxine. A. Chlorambucil.
E. Rifampicin. B. Cyclophosphamide.
C. Doxorubicin.
7. A 45-year old male is referred to the infectious D. Melphalan.
diseases team because he has recently been E. Methotrexate.
diagnosed with HIV. He is commenced on
antiretroviral therapy. Which of the following 3. A patient with lymphoma is started on chemotherapy,
antiretroviral agents is classed as a nonnucleoside given intravenously and complains of weakness
reverse transcriptase inhibitor? and loss of sensation in his hands and feet. On
A. Didanosine. examination, it is apparent that his power is reduced,
B. Lamivudine. and he has reduced reflexes. Which of the following
C. Nevirapine. chemotherapy agents is likely to be responsible?
D. Ritonavir. A. Bleomycin.
E. Zidovudine. B. Methotrexate.
C. Mercaptopurine.
8. A 28-year-old female attends a travel clinic for D. Rituximab.
vaccinations. She would like to know which of the E. Vincristine.
following vaccines include a live attenuated virus?
A. Diphtheria. 4. A patient is recently diagnosed with acute
B. Hepatitis A. lymphoblastic leukaemia that is Philadelphia
C. Hepatitis B. chromosome positive. Which of the following
D. Parenteral polio. chemotherapy agents is the most appropriate
E. Rubella. treatment given its underlying mechanism of
action?
9. Which of the following antihelminth medications A. Everolimus.
is most appropriately used in the treatment of B. Hydroxyurea.
pinworm? C. Imatinib.
A. Ivermectin. D. Oxaplatin.
B. Levamisole. E. Procarbazine.
C. Mebendazole.
D. Niclosamide. 5. A patient with lymphoma is given a MAb that targets
E. Praziquantel. the CD20 protein found on the surface of white blood
cells. Which of the following MAb acts in this way?
10. Which of the following antimalarial medications is A. Cetuximab.
safe to use in pregnancy for treatment of malaria? B. Erlotinib.
A. Chloroquine. C. Nivolumab.
B. Dapsone. D. Rituximab.
C. Mefloquine. E. Trastuzumab.

217
This page intentionally left blank
Extended-matching questions
(EMQs)
Each option may be used once, more than once 8. A patient has been on the oral contraceptive pill and
or not at all. is started on phenytoin to control her seizures. Two
months later she finds that she is pregnant because
Chapter 1 Introduction to Pharmacology of the pharmacokinetics of the two drugs.
9. A patient is currently taking ibuprofen (a nonsteroidal
Receptor interactions and pharmacokinetics antiinflammatory) and despite being given a diuretic,
A. Absorption of drug their blood pressure remains high.
10. An elderly patient with kidney disease should have
B. Activation of receptor linked to ion channel
their medication doses reviewed and perhaps
C. Activation of adenylyl cyclase
altered because of this pharmacokinetic property.
D. Adherence 11. A patient is taking their antibiotics at different times
E. Administration of drug on different days and is not getting better.
F. Agonist
G. Antagonist (competitive)
H. Antagonist (noncompetitive) Chapter 2 Peripheral nervous system
I. Distribution of drug
Medications – their actions and side effects
J. Excretion of drug
K. Inactivation of receptor linked to ion channel A. Atracurium
L. Inactivation of B. Atropine
M. Partial agonist C. Botulinum toxin A
N. Pharmacodynamics interaction D. Clonidine
O. Pharmacokinetic interaction E. Carbidopa
P. Phase 1 metabolic reaction F. Labetalol
Q. Phase 2 metabolic reaction G. Lidocaine
H. Methyldopa
For each subsequent scenario choose the most likely I. Neostigmine
corresponding option from the list given earlier. J. Phentolamine
K. Phenelzine
1. A patient presents with watery diarrhoea and L. Phenylephrine
is diagnosed with cholera and the underlying
M. Phenoxybenzamine
mechanism of the disease is this.
N. Physostigmine
2. A patient should not be given lidocaine orally
O. Pyridostigmine
because of this pharmacokinetic property.
3. A patient has taken a heroin overdose and is P. Reserpine
given naloxone. Through this action at the opiate Q. Salbutamol
receptor, the symptoms of respiratory depression R. Suxamethonium
are reversed.
4. A patient who has taken a paracetamol overdose For each subsequent scenario, choose the most likely
requires N-acetyl cysteine because this process is corresponding option from the list given earlier.
saturated.
5. A patient presents with a persistent whooping cough 1. A local anaesthetic is required to allow excision of a
because of this. small mole.
6. An anaesthetist must consider this pharmacokinetic 2. This drug can be used in the treatment of dystonia
property before giving a highly lipid soluble and spasticity.
medication to a patient. 3. A patient with asthma develops bronchospasm after
7. A patient should be given morphine by injection receiving this medication.
or delayed release capsules because of this 4. An α2-adrenoreceptor agonist used in the treatment
pharmacokinetic property. of hypertensive migraine.

219
 Extended-matching questions (EMQs)

5. An α1-adrenoreceptor agonist used in the treatment

of nasal decongestion.
Chapter 4 Cardiovascular system
6. A medication used intravenously to reverse the Mechanism of action of antiarrhythmics
effects of nondepolarising blockers.
A. Adenosine
7. A medication given to prevent bradycardia
B. Amiodarone
associated with muscarinic receptor activation
caused by depolarising blocking agents. C. Amlodipine
8. A medication used topically in the treatment of D. Bumetanide
glaucoma. E. Digoxin
9. A reversible nonselective α-adrenoreceptor F. Flecainide
antagonist that can be prescribed for the treatment G. Furosemide
of hypertension. H. Lidocaine
10. This medication is given to patients with Parkinson I. Metoprolol
disease and increases dopamine levels.
J. Procainamide
11. This drug acts presynaptically by preventing the
K. Spironolactone
accumulation of noradrenaline in vesicles.
12. This drug acts presynaptically to inhibit the L. Verapamil
breakdown of leaked noradrenaline stores.
For each subsequent scenario, choose the most likely
corresponding option from the list given earlier.
Chapter 3 Respiratory system
1. An antiarrhythmic drug that blocks voltage-gated
Respiratory system drugs and their side effects sodium channels which slows phase 0 of the cardiac
and contraindications action potential and therefore increases the effective
A. Aminophylline refractory period.
B. Chlorphenamine 2. An antiarrhythmic drug that slows phases 0 to 3 of the
cardiac action potential, prolonging the cardiac action
C. Ipratropium
potential duration and effective refractory period.
D. Montelukast
3. An antiarrhythmic drug that shortens phase 2 of the
E. Naloxone
cardiac action potential by calcium antagonism.
F. Oxygen
4. An antiarrhythmic and cardiac glycoside with positive
G. Prednisolone inotropic action that shifts the frank starling ventricular
H. Salbutamol function curve upward.
I. Salmeterol 5. An antiarrhythmic drug that blocks voltage-
J. Magnesium sulphate dependent sodium channels in their open
(activated) or refractory state. Their effects are to
For each subsequent scenario, choose the most likely slow phase 0 and phase 4 and to prolong action
corresponding option from the list given earlier. potential duration.
6. An antiarrhythmic that reduces the excitability of the
1. A 19-year-old girl seen in the emergency department myocardium and inhibits conduction through the His
is treated acutely. After 30 minutes of treatment, she Purkinje fibres, used in treatment of paroxysmal AF
develops a bilateral tremor. without left ventricular dysfunction.
2. A 20-year-old man with asthma complains of a dry 7. An antiarrhythmic that increases the refractory period
mouth, headache and gastrointestinal disturbance of the AV node and is used in the treatment of atrial
after taking this medication. fibrillation where there is sympathetic activation.
3. A 60-year-old man with benign prostatic 8. An antiarrhythmic that acts at A1 receptors to slow
hypertrophy and glaucoma cannot be prescribed the action potential rising and thus delays conduction
this medication for treatment of his obstructive
airways disease.
Side effects and contraindications of
4. A 20-year-old girl requires treatment after being
cardiovascular medications
admitted with a low respiratory rate and reduced
Glasgow Coma Scale following attendance at a party. A. Adenosine
5. A 15-year-old boy admitted with life-threatening B. Amiodarone
asthma is given this medication, and levels need to be C. Amlodipine
checked to ensure the dose is within range. D. Bumetanide

220
 Extended-matching questions (EMQs)

E. Digoxin For each subsequent scenario, choose the most likely

F. Enoxaparin corresponding option from the list given earlier.
G. Flecainide
1. In a cardiac arrest situation, this medication via this
H. Furosemide
route should be administered.
I. Glyceryl trinitrate
2. In managing a patient with an acute myocardial infarction,
J. Lidocaine this indirect factor Xa inhibitor should be prescribed.
K. Losartan 3. A 65-year-old female is admitted with fast ventricular
L. Metoprolol rate atrial fibrillation and has asthma. She is allergic to
M. Procainamide calcium channel blockers.
N. Spironolactone 4. A patient presents with facial flushing, sweating,
O. Verapamil tachycardia and paroxysmal hypertension and
requires immediate treatment.
For each subsequent scenario, choose the most likely 5. A patient presents with a 20-minute history of facial
corresponding option from the list given earlier. droop and arm weakness, consistent with a transient
ischaemic stroke. Aspirin and an additional medication
1. This antiarrhythmic causes transient flushing, chest is started.
pain and bronchospasm for approximately 30 6. A patient has ongoing raised cholesterol despite
seconds after administration. changes to his diet and on maximum dose statins.
2. This antiarrhythmic is contraindicated in patients with
systemic lupus erythematous.
Chapter 5 Kidney and urinary system
3. This antiarrhythmic can cause deranged thyroid
function tests and slate grey discolouration of skin. Mechanism of action and adverse effects of
4. This antiarrhythmic is contraindicated in patients with medications
Wolff-Parkinson-White syndrome. A. Alprostadil
5. This antihypertensive can cause hyperkalaemia.
B. Amiloride
6. A patient with profound hypertension associated
C. Amlodipine
with their myocardial infarction cannot be given this
medication. D. Desmopressin
7. This medication can reduce the glucose tolerance of E. Doxazosin
patients with diabetes. F. Duloxetine
8. A patient is started on a medication to slow their G. Eplerenone
heart rate and develops hypokalaemia while on a H. Finasteride
loop diuretic. I. Furosemide
9. A patient with severe heart failure is prescribed an J. Ibuprofen
additional potassium-sparing diuretic.
K. Indapamide
10. A patient is initiated on treatment for a deep vein
L. Lithium
thrombosis. He develops hyperkalaemia and
thrombocytopenia. M. Mannitol
N. Mirabegron
Appropriate management
O. Paracetamol
A. Adrenaline 1:10,000 intravenously
P. Sildenafil
B. Adrenaline 1:1000 intramuscularly
Q. Sodium Valproate
C. Bisoprolol
R. Solifenacin
D. Clopidogrel
E. Dipyridamole For each subsequent scenario, choose the most likely
F. Digoxin corresponding option from the list given earlier.
G. Ezetimibe
H. Fish oils 1. A patient with heart failure who takes isosorbide
mononitrate presents with erectile dysfunction. This
I. Fondaparinux
medication is contraindicated.
J. Nicotinic acid
2. This medication is a potassium-sparing diuretic
K. Phenoxybenzamine which acts through sodium-channel blockade and is
L. Rivaroxaban used in the treatment of heart failure in combination
M. Verapamil with other diuretics.

221
 Extended-matching questions (EMQs)

3. This medication is used in the treatment of bipolar X. Sulfasalazine

disorder. The patient may complain of excreting Y. Terlipressin
large volumes of urine because of this drug’s action Z. Ursodeoxycholic acid
on the kidney.
4. This diuretic acts on the early distal tubule and can For each subsequent scenario, choose the most likely
increase serum calcium levels. corresponding option from the list given earlier.
5. This medication used in the treatment of urge
incontinence is contraindicated in patients with 1. Gastrin exerts its acid secretory effect indirectly by
glaucoma. stimulating these cells.
6. This diuretic is used intravenously in the treatment of 2. This medication is commonly prescribed for the
raised intracranial pressure. dissolution of gallstones and causes diarrhoea as a
7. Coadministration of this medication can exacerbate side effect.
salt and water retention in patients with heart failure 3. This medication increases the volume of the
and precipitate heart failure. nonabsorbable solid residue in the gut.
8. Hypotension, flushing and headache are common 4. This medication irreversibly inhibits H+/K+-ATPase
side effects associated with this medication. that is responsible for H+ secretion from
9. The combination of this aldosterone antagonist parietal cells.
with Ramipril (an ACE inhibitor) can result in 5. An 18-year-old girl is admitted with nausea and
hyperkalaemia. vomiting associated with gastroparesis. She
10. A diuretic that can result in hyponatraemia, develops involuntary upward eye movements and
hypokalaemia, hypomagnesaemia and involuntary twisting of the neck.
hypocalcaemia. 6. A 40-year-old male is seen by his GP because of
11. This medication is an inhibitor of the enzyme 5α- worsening constipation. During the last few months,
reductase used in the treatment of benign prostate he has been taking large amounts of an antacid
hyperplasia. preparation to help relieve his dyspepsia.
12. This medication is a selective β-agonist that can be 7. This medication is a direct relaxant of smooth
used in urge incontinence. muscle and can be used in the management of
irritable bowel syndrome.
Chapter 6 Gastrointestinal system 8. This medication causes the vasoconstriction of
A. Aluminium hydroxide dilated splanchnic blood vessels and is used in
patients with raised portal hypertension.
B. Azathioprine
9. This medication increases gastrointestinal peristalsis
C. Biscodyl
and can be given via a suppository before a
D. Cholestyramine
procedure.
E. Cyclosporine 10. This medication is a pancreatic lipase inhibitor used
F. Cinnarizine in the management of obesity.
G. Cyclizine 11. This immunosuppressant medication is a purine
H. Docusate sodium analogue that is deactivated by TPMT.
I. Domperidone 12. This medication increases the water content of
J. Enterochromaffin-like paracrine cells the bowel and can be used in the prevention
K. Hyoscine of hepatic encephalopathy in patients with liver
disease.
L. Ispaghula Husk
13. A male patient with ulcerative colitis needs to be
M. Lactulose
counselled about the possibility of infertility before
N. Loperamide being prescribed this medication.
O. Magnesium salts
P. Mebeverine Chapter 7 Endocrine and reproductive
Q. Metoclopramide systems
R. Methylcellulose
S. Orlistat Adverse effects of endocrine drugs
T. Parietal cells A. Alendronate
U. Peptic cells B. Calcitonin
V. Pantoprazole C. Carbimazole
W. W.Propantheline D. Clomifene

222
 Extended-matching questions (EMQs)

E. Denosumab 2. This medication is a dopamine agonist selective for

F. Iodide the D2 receptor and is used in combination with
G. Levothyroxine L-dopa to reduce the on-off effect for patients with
Parkinson disease.
H. Metformin
3. A patient, recently prescribed a medication to help
I. Octreotide
reduce his disabling tremor, presents to his GP
J. Prednisolone
complaining of a dry mouth and blurred vision.
K. Tamoxifen
4. A patient with moderate Alzheimer dementia is
prescribed a selective NMDA receptor inhibitor.
For each subsequent scenario, choose the most likely
5. On routine optician review, a patient is noticed to have
corresponding option from the list given earlier.
raised intraocular pressure. He is warned of the risk of
his iris developing brown pigmentation.
1. A 50-year-old man presents with right upper quadrant
abdominal pain and jaundice. His ultrasound scan 6. A patient presents to A&E with a red, painful eye with
shows multiple gallstones and a dilated bile duct. He blurred vision. He is given a medication that causes
is noted to have an enlarged tongue, hands and feet. pupillary constriction.
2. A 27-year-old woman presents to the emergency
department with severe acute lower abdominal pain Medications used in the treatment of mood
and her ultrasound shows massive cystic enlargement disorders and insomnia
of both ovaries. She has recently started treatment for A. Buspirone
infertility. B. Chlordiazepoxide
3. A 55-year-old woman presents to her C. Clozapine
GP with retrosternal pain having started D. Flumazenil
treatment for osteoporosis. Gastroscopy E. Fluoxetine
reveals severe oesophageal erosions and
F. Melatonin
ulceration.
G. Mirtazapine
4. This medication can cause depression, insomnia
H. Olanzapine
and impotence if used long-term in the treatment of
hyperthyroidism. I. Reboxetine
J. Risperidone
K. Sertraline
Chapter 8 Central nervous system L. Zopiclone

Medications used in the treatment of Parkinson For each subsequent scenario, choose the most likely
disease, dementia and the eye corresponding option from the list given earlier.
A. Buspirone
B. Carbegoline 1. A patient with depression is prescribed an α2-
C. Domperidone adrenoceptor antagonist and advised to have an
urgent blood test if they develop a sore throat and feel
D. Donepezil
unwell.
E. Entacapone
2. This medication is thought to reduce 5-HT
F. Latanoprost transmission by acting as a partial agonist at 5-HT1A
G. Levodopa receptors and is used for the short-term relief of
H. Memantine generalized anxiety.
I. Melatonin 3. The doctor explains the risk of gynaecomastia,
J. Pilocarpine weight gain, tremor and risk of developing involuntary
K. Procyclidine movements of the face before prescribing medication
L. Selegiline to a patient with schizophrenia.
M. Timolol 4. This medication is prescribed in refractory cases of
schizophrenia, given the risk of fatal neutropenia.
For each subsequent scenario, choose the most likely 5. This medication binds to a site on GABAA receptors
corresponding option from the list given earlier. and potentiates the action of GABA and is used in the
treatment of acute alcohol withdrawal.
1. Patients with Parkinson disease taking this medication 6. A patient with severe insomnia is prescribed a MT1
are at risk of cardiac arrhythmias. receptor agonist.

223
 Extended-matching questions (EMQs)

7. This medication is an atypical neuroleptic that has a I. Ketamine

high affinity for D1 and D4 receptors and low affinity J. LSD
for D2 receptors and is used first line in the treatment K. MDMA
of schizophrenia.
L. Methadone
8. A patient presents with respiratory depression.
M. Methanol
He is known to have severe social anxiety and
N. Naloxone
takes medication. He requires an antidote to this
medication.
For each subsequent scenario, choose the most likely
Medications used in the treatment of epilepsy corresponding option from the list given earlier.
A. Carbamazepine
1. This drug of abuse can cause an altered state of
B. Clonazepam
perception with euphoric sensations.
C. Diazepam
2. The psychoactive constituent of cannabis.
D. Ethosuximide
3. This α2-adrenoceptor agonist drug is sometimes
E. Lamotrigine prescribed to suppress the effects of opioid
F. Phenobarbital withdrawal.
G. Phenytoin 4. A patient presents confused, with shallow and slow
H. Sodium Valproate breathing, constricted pupils and has a flushed face.
I. Vigabatrin He requires treatment for his drug overdose.
5. This commonly prescribed drug potentiates inhibitory
For each subsequent scenario, choose the most likely GABA transmission.
corresponding option from the list given earlier. 6. This drug, if taken in excess, can cause confusion,
ataxia and ophthalmoplegia, as well as memory
1. A patient on warfarin attends his GP practice for impairment and confabulation.
a routine international normalized ratio check. 7. This drug causes a throbbing headache, flushed face
The practice nurse reports that it is lower than and palpitations.
normal and not within the target range. He is
8. This drug causes bladder dysfunction and problems
known to have epilepsy and informs the nurse
passing urine.
that his anticonvulsant dose has recently been
9. This drug inhibits the reuptake of catecholamines
increased.
at noradrenergic neurones, enhancing sympathetic
2. Paramedics on route to hospital give a patient with
activity.
prolonged seizures this medication.
3. This medication is a GABA agonist and can cause
diplopia, nausea and agranulocytosis.
4. This medication inhibits T-type low-threshold calcium
Chapter 10 Pain and anaesthesia
current channels and dampens thalamocortical
Analgesia and anaesthesia
oscillations and is used in the treatment of absence
seizures. A. δ Receptors
5. This medication acts via sodium channels to inhibit the B. κ Receptors
release of glutamate and is used in the monotherapy C. μ Receptors
of partial seizures. D. Adrenaline
E. Amitriptyline
Chapter 9 Drug misuse F. Atropine
G. Etomidate
Drugs of misuse H. Halothane
A. Clonidine I. Ketamine
B. Cocaine J. Lidocaine
C. Delta-9-tetrahydrocannabinol (THC) K. Midazolam
D. Diazepam L. Morphine
E. Disulfiram M. Naloxone
F. Ethanol N. Naltrexone
G. Flumazenil O. Nitric oxide
H. Hashish P. Thiopental

224
 Extended-matching questions (EMQs)

For each subsequent scenario, choose the most likely For each subsequent scenario, choose the most
corresponding option from the list given earlier. likely corresponding option from the list given
previously.
1. A local anaesthetic (LA) used to aid the removal
of a mole. 1. This eicosanoid is involved in platelet aggregation
2. This inhaled anaesthetic is contraindicated in and vasoconstriction.
patients with a pneumothorax. 2. This antiinflammatory medication is a folic acid
3. Activation of these receptors account for the antagonist.
analgesic effects of opioids. 3. This isoform of cyclooxygenase is expressed
4. A lady presents with a shooting pain down her leg on platelets, gastric mucosa and renal
associated with tingling in her foot. She requires vasculature.
analgesia. 4. This antiinflammatory medication inhibits platelet
5. Activation of these opioid receptors accounts aggregation.
for the dysphoria associated with opioids. 5. This medication is a TNF-α blocker that competes
6. This medication is given to relieve apprehension with the patient’s own receptors.
before anaesthesia. 6. This medication is a xanthine oxidase inhibitor.
7. This induction anaesthetic can cause extraneous 7. This medication is used in the treatment of
muscle movement. basal cell carcinomas and inhibits DNA
8. This long-acting opioid receptor antagonist can be replication.
used to reverse opioid toxicity. 8. Histamine acting at this receptor results in a
9. This anaesthetic acting at NMDA-type receptors type 1 hypersensitivity reaction.
results in amnesia and insensitivity to pain. 9. This immunosuppressant inhibits calcineurin
10. This medication is given with LA to prevent the reducing IL-2 levels.
spread of the anaesthetic into the systemic 10. This immunosuppressant is converted to
circulation. 6-mercaptopurine in the liver and impairs DNA
11. This inhaled anaesthetic has a high blood synthesis.
solubility and has a much slower induction
time.

Chapter 12 Infectious diseases

Chapter 11 Inflammation, allergic diseases
Medications used in the treatment of
and immunosuppression inflammation and immunosuppression
Medications used in the treatment of A. Acyclovir
inflammation and immunosuppression B. Amantadine
A. Aspirin C. Benzylpenicillin
B. Azathioprine D. Ceftriaxone
C. Benzoyl peroxide E. Ciprofloxacin
D. Cyclosporine F. Clindamycin
E. Celecoxib G. Co-amoxiclav
F. Colchicine H. Doxycycline
G. COX-1 I. Enfuvirtide
H. COX -2 J. Flucloxacillin
I. Efudix K. Ganciclovir
J. Etanercept L. Indinavir
K. Febuxostat M. Metronidazole
L. H1-receptor N. Nevirapine
M. H2-receptor O. Nitrofurantoin
N. Methotrexate P. Nystatin
O. Penicillamine Q. Tazocin
P. Prostacyclin R. Trimethoprim
Q. Prostaglandin S. Zanamivir
R. Thromboxane A2 T. Ziduvidine

225
 Extended-matching questions (EMQs)

For each subsequent scenario, choose the most likely F. Degarelix

corresponding option from the list given earlier. G. Doxorubicin
H. Filgastrin
1. This is the antibiotic combination of piperacillin and
I. Fluorouracil
tazobactam.
J. Gardasil
2. This antibiotic is not inactivated by the β-lactamase
K. Gonadorelin
produced by penicillin resistant staphylococci and is
commonly used in the treatment of skin infections. L. Methotrexate
3. This antibiotic has cross-reactivity with penicillin and M. Prednisolone
is used in the treatment of meningitis. N. Sipuleucel T
4. This antibiotic should be avoided in children because O. Tamoxifen
of the effects on bone and teeth.
5. A commonly used antibiotic for the treatment of a For each subsequent scenario, choose the most likely
urinary tract infection that is teratogenic in the first corresponding option from the list given earlier.
trimester and can cause kernicterus in neonates.
6. This bactericidal antibiotic is used in the treatment of 1. This cytotoxic medication inhibits thymidylate
atypical respiratory infections but increase the risk of synthetase impairing DNA synthesis.
C. difficile infections. 2. This cytotoxic antibiotic inhibits topoisomerase II and
7. This protein synthesis inhibitor is used in the causes significant myelosuppression.
treatment of severe cellulitis but has a high risk of 3. This cytotoxic medication can cause severe nausea
causing C. difficile infections. and vomiting in association with acute kidney injury
8. This antibiotic is useful in the treatment of giardia. and myelosuppression.
9. This antiviral medication inhibits the release of newly 4. This cytotoxic medication contains bacterial
synthesized viruses from the host cell by inhibiting asparaginase and inhibits the growth of acute
the enzyme neuraminidase. lymphoblastic leukaemia.
10.This antiviral medication selectively phosphorylates viral 5. This medication can be used to elevate mood and
thymidine kinase and inhibits viral DNA synthesis. stimulate appetite in a patient with cancer.
11. This antiretroviral agent prevents DNA chain 6. This medication is used in the treatment of
elongation and has a competitive inhibitory effect to oestrogen receptor-positive breast cancer.
reverse transcriptase. 7. This medication competes with endogenous
12. This antiretroviral agent prevents viral assembly and GnRH.
budding. 8. This vaccine is given against the HPV.
13. This polyene macrolide is used in the treatment of 9. This medication is used to stimulate haematopoeitic
candidiasis on the skin and mucous membranes. stem cells in the bone marrow.
10. This medication is a GnRH agonist used in the
treatment of prostate cancer.
Chapter 13 Cancer

Medications used in the treatment of cancer

A. Aldesleukin
B. Bicalutamide
C. Bleomycin
D. Cisplatin
E. Crisantaspase

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 SBA answers

(answers A & E) and can be reversed by

Chapter 1 Introduction to Pharmacology
anticholinesterases (unlike depolarising blocking
1. E. Rifampicin is an enzyme inducer and will affect agents). Answer C (hemicholinium) blocks choline
the metabolism of Warfarin. Rifampicin induces uptake but is not used clinically. Answer B
the hepatic P450 system, therefore increasing the (botulinum) blocks acetylcholine release and is not
metabolism of several drugs, including warfarin. used during anaesthesia (refer to p. 22).
Therefore levels may be subtherapeutic, rendering 3. B. A young female presenting with muscle weakness
them ineffective. Drugs that inhibit enzymes affect the and early fatigue at the end of the day or with
other medications in the options list. repetitive activities should raise the possibility of
2. B. The intravenous route is the most direct route of myasthenia gravis. This is a disorder of neuromuscular
administering a drug because it avoids the need for transmission because of autoantibodies to the
absorption, which is the rate limiting step. acetylcholine receptors at the neuromuscular junction,
3. B. Preclinical phase involves laboratory animals or leading to “fatigability” and muscle weakness that
is in vitro. Phase 1 looks at drug metabolism and worsens with exercises but improves with rest.
bioavailability as well as evaluating the safety of the Edrophonium is a short-acting anticholinesterase,
drug and requires healthy individuals and/or patients. which is selective for the neuromuscular junction. It
Phases 2-4 involves patients. is sometimes administered intravenously to patients
4. A. Isoprenaline is a nonselective β-receptor agonist. with suspected myasthenia gravis. There should be a
Salbutamol and Salmeterol are other β-receptor transient improvement in muscle strength. However, it
agonists. Answers B and C are incorrect because is rarely done because it can result in life-threatening
N-acetyl-P-aminophenol is the nontrade name for bradycardia and requires resuscitation facilities.
paracetamol. Paracetamol is thought to be a weak Usually, the diagnosis is made if the patient is found
inhibitor of the synthesis of prostaglandins (PGs) and to have positive acetylcholine receptor antibodies
has some COX 2 inhibition. Proguanil hydrochloride (refer to p. 24). Answer C (neostigmine) is incorrect
is involved in the biosynthesis of pyrimidines required because it is used in the treatment of myasthenia
for nucleic acid replication and thus answer D is gravis. Answers A & D are incorrect because
incorrect. Answer E is incorrect because syntometrine pancuronium and alcuronium are anaesthetic agents
is a synthetic combination of oxytocin (hormone) and (nondepolarising neuromuscular blocking agents)
ergometrine, an alpha-adrenergic, dopaminergic and and answer E (suxamethonium) is a depolarising
serotonin (5-HT2) receptor agonist. neuromuscular blocking agent that has little effect in
5. A. B2 adrenergic receptors are an example of patients with myasthenia gravis (see Box 2.2).
G-protein-coupled receptor. Insulin receptor and 4. C. Medical management of phaeochromocytoma-
PDGF receptors are tyrosine linked receptors and induced hypertension relies on the powerful
steroid receptor is a DNA-linked receptor. α-adrenoceptor antagonist phentolamine.
α-Adrenoceptor blockade reduces peripheral
vascular resistance and lowers blood pressure. The
Chapter 2 Peripheral nervous system use of β-adrenoceptor antagonists is dangerous
1. C. When aminoglycoside antibiotics (e.g., (i.e., answers A and B are incorrect) because
gentamicin, streptomycin) are given concurrently with tumour-secreted sympathomimetics act unopposed
neuromuscular blocking agents, a rare but serious on α-adrenoceptors, increasing both peripheral
toxic reaction resulting in paralysis can occur. It results vascular resistance and blood pressure. Once the
from the aminoglycoside inhibiting calcium uptake patient is stabilized with IV phentolamine (which will
necessary for the exocytotic release of acetylcholine. It reduce the blood pressure safely) the patient can
can be reversed by the administration of calcium salts be given oral phenoxybenzamine (answer D). Then
(refer to p. 22). answer A (oral propanolol) can be added in. Answer
2. D. Suxamethonium is the main depolarising E is incorrect because atropine is a muscarinic
neuromuscular blocking agent used as an adjunct antagonist (refer to p. 30).
to general anaesthesia to permit intubation of the 5. D. Prazosin acts as an α1-adrenoreceptor antagonist
airway. Most other neuromuscular blocking agents and is used in the treatment of benign prostatic
used during anaesthesia are nondepolarising hyperplasia and hypertension. Side effects include

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 SBA answers

hypotension, tachycardia and nasal congestion 3. C. This woman’s symptoms are poorly controlled
(refer to Box. 2.12). Answer A is incorrect: Clonidine and therefore she requires a step up in her treatment.
is an α2-adrenoreceptor agonist used in the Because her FEV1 is above 50%, in line with NICE
treatment of resistant hypertension and migraine guidance, she needs to be given either a LABA or
(refer to Box 2.11). Answers B and E are incorrect a LAMA, but the LAMA is not appropriate unless
because they are antihypertensives that work at β the SAMA is stopped, which is not an option in
receptors in the main. Answer C is incorrect because the answer list. She could have been started on
phenylephrine is an α1 agonist that can be used in the a SABA initially as an alternative to ipratropium
treatment of hypotension but is more commonly used (SAMA) and then tiotropium (LAMA) would have been
as a nasal decongestant. appropriate at the next stage. A LABA plus an inhaled
6. A. Ipratropium bromide acts as a muscarinic corticosteroid would be appropriate if her symptoms
antagonist. Muscarinic antagonists can cause the are still inadequately controlled or her FEV1 falls below
following side effects: blurred vision, dry mouth and 50%.
skin, dilated pupils, and urinary retention. Therefore, 4. B. This case illustrates a woman who is likely to
answers B to E are incorrect (refer to pp. 30–31). have an exacerbation of COPD with an infective
component. She requires oxygen because her
saturations are low, but with COPD patients, caution
Chapter 3 Respiratory system needs to be exercised with regards to the amount
1. D. In the "rescue" of a patient with an acute of oxygen administered in case the patient relies on
exacerbation of asthma, only a few medications are a hypoxic drive to breathe and if they are chronic
helpful. The single most effective therapy in an acute retainers of carbon dioxide (CO2). The patient’s
exacerbation of asthma is systemic steroids. Inhaled saturations should be above 90% and should be
steroids are less effective in an acute exacerbation given enough oxygen to ensure this via a controlled
of asthma. Inhaled salmeterol is for long-term venturi oxygen mask. Because she is a chronic
management. If this patient does not respond to retainer of CO2, her target saturations should be 88%
oral/IV steroids and IV magnesium, the next step in to 92%. There is evidence to suggest that giving 15 L
management is theophylline infusion. Steroids can of high-flow oxygen to patients with COPD can cause
be given as oral or IV (there is no clear benefit of IV significant harm and should be avoided, provided that
therapy over oral therapy if the patient can take pills). the patient’s saturations are within the target range. If
Systemic steroids take 4 to 6 hours to start to work by this patient required IV theophylline, the clarithromycin
either route. would have to be switched to something other than a
2. E. This patient’s asthma symptoms are not controlled macrolide. Theophylline plasma concentrations would
on his current level of treatment. He is currently on increase enzymes involved in theophylline breakdown
stage 2 of the chronic asthma management guideline occupied by macrolide antibiotics and there is a
(see Table 3.1). Continuing only with his salbutamol significant risk of toxicity.
and beclometasone inhaler is not adequately 5. C. This patient has presented with allergic rhinitis. The
controlling his symptoms and therefore he needs his management of allergic rhinitis is with oral or nasal
treatment to be escalated to level 3. This would entail antihistamines (e.g., cetirizine and chlorphenamine)
prescribing an inhaled short-acting β2 agonist (e.g., and nasal glucocorticosteroids. Nasal decongestants
salbutamol), plus a long-acting β2 agonist (LABA) and (e.g., ephedrine) are available for the treatment of
a low-dose inhaled corticosteroid (can be given as a allergic rhinitis. However, they can only be used for 2
fixed dose combination inhaler of either fluticasone to 3 days a time and therefore are not recommended
propionate and salmeterol or budesonide and for long-term management. Oral ephedrine is not
formoterol). In this patient, you would need to stop used and would be contraindicated in this patient
the beclometasone inhaler. If the patient continued because he has diabetes and hypertension.
to have symptoms and had limited response to the Leukotriene modifiers may be used for patients with
LABA, then stop it and increase the dose of inhaled asthma or who cannot tolerate nasal sprays.
corticosteroid. If he had some benefit from the LABA
but his control remained inadequate, continue the
LABA and increase the inhaled corticosteroid to a Chapter 4 Cardiovascular system
moderate dose. Because there is no evidence of 1. D. Methyldopa is an α2-adrenoceptor agonist that
a chest infection in the case (e.g., no productive is safe to use in pregnancy. It should be avoided in
cough, no pyrexia, no crackles on the chest, normal patients with liver disease or depression (refer to
vital signs), we can assume that his asthma is poorly pp. 57–58). Bisoprolol is a β-adrenoceptor antagonist
controlled rather than him having an infective trigger of and it may cause intrauterine growth restriction
his symptoms; therefore antibiotics are not required. and neonatal bradycardia and thus is avoided in

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 SBA answers

pregnancy. Labetalol can, however, be used in incorrect because loop diuretics (e.g., furosemide) are
maternal hypertension if required. Furosemide, a loop not typically used in the management of hypertension.
diuretic, is not commonly used as an antihypertensive 5. C. ACE inhibitors reduce angiotensin II and
agent. It is more commonly prescribed in the aldosterone levels and thus cause vasodilation and
management of acute and chronic heart failure. a reduction in blood pressure. They also cause an
Losartan (angiotensin II receptor antagonist) and increase in bradykinin levels. Answer C is correct
ramipril (ACE inhibitor) are contraindicated because because ACE inhibitors are excreted renally and thus
they adversely affect foetal blood pressure control and if a patient is dehydrated secondary to diarrhoea
renal function. They can also cause oligohydramnios. and vomiting, there is an increased risk of acute
2. C. Furosemide (a loop diuretic) is the mainstay of kidney injury and they need to be stopped. Answer
treatment in acute heart failure and should be given A is incorrect because ACE inhibitors can increase
intravenously. Bumetanide is also a loop diuretic but is potassium levels, causing hyperkalaemia as an
given as a second-line treatment. Bendroflumethiazide adverse effect. Answer B is incorrect because a
is a thiazide diuretic used in the treatment of cough is a common side effect secondary to the
hypertension and uncommonly to manage chronic increased levels of bradykinin. Answer D is incorrect
heart failure. Glyceryl trinitrate is a nitrate and can because ACE inhibitors are not known to commonly
be helpful in the management of heart failure (dilates cause liver failure but there is an increased risk that
systemic veins, decreasing preload and thus the they cause acute renal failure, especially if there is
oxygen demand of the heart) but does not directly underlying renal artery stenosis. Blood tests (including
off load fluid (refer to p. 52). Morphine is an opiate urea and electrolytes) should be monitored following
which can help alleviate the uncomfortable feeling initiation of ACE inhibitors and after any dose change
of breathlessness associated with acute pulmonary (refer to p. 55).
oedema, but again does nothing to remove the fluid. 6. E. Answer A is incorrect because amlodipine
3. B. Clopidogrel inhibits ADP-induced platelet (calcium-channel blocker) has no effect on electrolyte
aggregation by irreversible inhibition of P2Y receptors levels nor renal function so can continue. Answers B
(refer to p. 66). It is used in the acute treatment of and C are partially correct because both ibuprofen
an MI. Aspirin is an antiplatelet like clopidogrel but (a nonsteroidal antiinflammatory) and ramipril (ACE
aspirin inhibits the synthesis of thromboxane A2 and inhibitor) need to be stopped. The issue in this
cyclooxygenase 1 (refer to p. 65). Fondaparinux is a scenario is the combination of these two medications
low-molecular-weight heparin and they increase the resulting in hyperkalaemia and acute kidney injury.
action of antithrombin III on factor Xa, thus limiting Ibuprofen decreases renal blood flow by inhibiting
the formation of blood clots. Fondaparinux is often prostaglandins that normally dilate blood vessels
used in the acute treatment of an MI (refer to p. 65). flowing to the kidney. Reduced blood flow to the
Morphine is an opiate used in the management of kidney can result in prerenal failure and, if prolonged,
the acute pain associated with an MI. Unfractionated causes intrarenal failure with raised urea, creatinine
heparin activates antithrombin III which inhibits and potassium. Adding ibuprofen to a medication that
thrombin and factor Xa and thus limits blood clotting. already increases the risk of hyperkalaemia and renal
It is used in the acute treatment of an MI if renal failure is dangerous if left unmonitored. ACE inhibitors
function is impaired (refer to p. 65). may cause hyperkalaemia directly through reduced
4. C. NICE guidance and evidence indicate that patients aldosterone production caused by the inhibition of the
aged over 55 years or who are Afro-Caribbean ACE. Renal failure can occur because efferent vessels
respond better to calcium channel blockers as leaving the kidney rely on angiotensin II to constrict.
first-line treatment of hypertension. Those younger Thus ACE inhibitors which decrease angiotensin II
than 55 years of age who are not of Afro-Caribbean production, reduce blood pressure and can cause
origin should be started on an ACE inhibitor (provided renal damage, particularly if there is underlying renal
they do not have contraindications – refer to p. 55). If artery stenosis, as is likely in this case (refer to p. 55).
second-line treatment is required, then a combination Answer D is incorrect because amlodipine can be
of an ACE inhibitor and a calcium-channel blocker can continued (refer to p. 52).
be used. Then third-line treatment is a thiazide diuretic 7. E. Answer A is incorrect because bisoprolol, a
(e.g., bendroflumethiazide). Therefore answer E would ß-adrenoceptor antagonist, is used as rate control in
be correct if the patient was already on an ACE atrial fibrillation. It has no effect on clotting and thus
inhibitor and calcium channel blocker. Answer B is the INR will be unaffected. In addition, she has been
incorrect because ß-blockers are not commonly used taking this without any problems until now and it
as first-line treatment of hypertension and importantly, should be continued to ensure rate control. Answer B
the patient is known to have asthma and ß-blockers is incorrect because there is no evidence of bleeding
are contraindicated (refer to p. 52). Answer D is and the INR is not over 8. Vitamin K reverses the

229
 SBA answers

effect of warfarin by allowing synthesis of factors presence of clarithromycin results in warfarin not being
II, VII, IX and X. Vitamin K is indicated and given metabolized thus increases the plasma levels and
intravenously if there is bleeding with any INR or orally consequently results in bleeding and a raised INR.
if the INR exceeds 8 without bleeding. Answer C is 11. A. Refer to p. 48, Hints and Tips box. ACE inhibitors,
incorrect because reducing the dose would only be β-blockers and nitrates with hydralazine and
appropriate if the INR was less than 6. Answer D is spironolactone have been found to have a proven
incorrect as increasing the dose would risk the INR to mortality benefit in patients with heart failure.
go up even further and the patient may start bleeding,
thus this option is dangerous. Answer E is correct
because the INR is greater than 6 and there is no
Chapter 5 Kidney and urinary system
evidence of bleeding. It is likely that the acute alcohol 1. A. The distal convoluted tubule is the main site of
consumption over the weekend has affected the potassium secretion because of the negative potential
metabolism of the warfarin. Acute alcohol intake is an difference that moves sodium into parietal cells and
enzyme inhibitor and thus the warfarin is not broken potassium out of cells. Answer B is incorrect as
down and its anticoagulant effects are potentiated, the glomerulus is the site where plasma is filtered
increasing the INR and risk of bleeding. Note that in general. Answer C is incorrect; juxtaglomerular
chronic alcohol consumption acts as an enzyme apparatus is where renin is secreted. Answer D is
inducer. incorrect; the loop of Henle is where approximately
8. E. Answer E is correct because verapamil, a calcium 25% of filtered sodium is reabsorbed. Answer E is
channel antagonist can cause peripheral oedema incorrect; the proximal tubule is where two-thirds
and constipation as side effects (refer to pp. 51–53). of the filtrate volume is reabsorbed, including
Answer A is incorrect bcause furosemide (loop bicarbonate (refer to pp. 70–72).
diuretic) is used in the treatment of heart failure and 2. C. Thiazide diuretics can cause hyperuricaemia and
should reduce the peripheral oedema. Answer B is therefore should be avoided in patients known to
incorrect. Ramipril is an ACE inhibitor and common have gout. They can also cause hyponatraemia,
side effects include a cough, muscle cramps and hypokalaemia, hypermagnesaemia and
hyperkalaemia (refer to p. 55). Answer C is incorrect. hypercalcaemia (refer to p. 74).
Rivaroxaban is a direct oral anticoagulant and its 3. D. Furosemide, a loop diuretic, causes the excretion
major side effect is haemorrhage. Answer D is of 25% of filtered sodium and can result in a profound
incorrect. Simvastatin is a HMG-COA reductase diuresis. Furosemide is the mainstay of treatment
inhibitor and common side effects include in acute heart failure and is usually administered
gastrointestinal upset and myalgia (refer to p. 61). intravenously. Answer C is incorrect. Bumetanide,
9. D. Statins are contraindicated in patients with liver although a loop diuretic, that acts at the thick
disease because they are metabolized by the liver. ascending segment of the loop of Henle, is usually
An increased level of serum transaminases (indicating reserved for patients who are resistant to furosemide.
hepatic impairment) increases the risk of side effects, Answer B is incorrect. Indapamide is a thiazide diuretic
importantly myopathy and myositis. These blood tests more commonly used as an antihypertensive. Answer
should be checked before starting statins, after starting A & E are both potassium-sparing diuretics used in the
and at 12 months. If at any point the transaminases are management of CHF (refer to pp. 74–75).
raised more than three times the normal range, then 4. D. Spironolactone is a potassium-sparing diuretic,
statins should be stopped (refer to p. 61). known to cause hyperkalaemia because of its action
Answer A, blood pressure, is important to know in at the late distal tubule and collecting duct (see
assessing cardiovascular risk but will not affect the Fig. 5.5). Spironolactone is a competitive antagonist at
prescription of simvastatin. Answer D is incorrect. A aldosterone receptors and reduces Na+ reabsorption
muscle biopsy is unnecessary and invasive. Answer and therefore K+ and H+ secretion. Answer A is
B is incorrect. A creatinine kinase can be useful to incorrect. Amlodipine is a calcium-channel blocker
check if an underlying myopathy is suspected. If raised, and has little effect on potassium (see Chapter 4).
then simvastatin should not be prescribed. However, Answer B is also incorrect because aspirin is an
creatinine kinase is not a blood test that is required to be antiplatelet with minimal effect on potassium. Answer
checked before starting a statin. Answer E is incorrect C is incorrect because furosemide is a loop diuretic
because simvastatin is not dosed according to weight. and, in fact, lowers serum potassium levels through
10. C. Clarithromycin is an inhibitor of the cytochrome inhibition of the Na+/K+/2Cl– cotransporter. Answer
P450 enzyme. This enzyme breaks down warfarin E is incorrect because simvastatin is a cholesterol-
and thus the combination of these two medications lowering medication with little effect on potassium (see
results in a potentially serious interaction. The Chapter 4).

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 SBA answers

5. B. Doxazosin is an α-blocker. It increases the flow urinary sodium is not routinely measured when
of urine by relaxing the smooth muscle around the patients are on furosemide.
urethra opening of the bladder. However, its vasodilator
properties can result in postural hypotension (refer
to p. 75). Answer A is incorrect. Bethanechol is Chapter 6 Gastrointestinal system
a parasympathomimetic that increases detrusor 1. B. A gastrinoma is a gastrin-secreting tumour found
muscle contraction and is not commonly used in the in the duodenum or pancreas, which causes multiple,
treatment of BPH. However, postural hypotension is refractory and recurrent peptic ulcers in the distal
not a common side effect associated with it, whereas duodenum and proximal jejunum. These gastrin-
bradycardia and intestinal colic are. Answer C is secreting tumours and subsequent excessive HCl
incorrect. Duloxetine is a serotonin noradrenaline secretion characterize Zollinger-Ellison syndrome.
reuptake inhibitor that is sometimes used in patients Patients with Zollinger-Ellison syndrome often
with stress incontinence and thus would not be have severe diarrhoea because of the HCl causing
prescribed in patients with BPH. Answer D is incorrect. hyperperistalsis and inhibition of the activity of
Finasteride is an inhibitor of the enzyme 5α-reductase, lipase. The answer is B because multiple ulcers
and although used in the treatment of BPH, it is not plus diarrhoea in a young man should highlight the
thought to cause postural hypotension (refer to p. 75). possibility of gastrin secreting tumours.
Answer E is also incorrect. Oxybutynin is a muscarinic Although he has risk factors for answers A, C, D and
receptor antagonist used in the treatment of urge E, they are unlikely to have caused several ulcers
incontinence, not BPH (refer to p. 75). throughout the gastrointestinal tract and diarrhoea
6. C. Oxybutynin is an antimuscarinic and is used (refer to p. 81).
to relax the detrusor muscle of the bladder. It has 2. C. Ranitidine is an H2 antagonist that works by
anticholinergical properties and thus causes the inhibiting parietal cell secretion of hydrochloric acid.
following constellation of symptoms: dry mouth, Ranitidine can cause nausea and diarrhoea and, in
constipation, blurred vision, urinary retention and the long-term gynaecomastia, because of its modest
nausea and vomiting. Answers A, B, D and E are affinity for androgen receptors. Answer A is incorrect
therefore all incorrect (refer to p. 76). because aluminium hydrochloride does not cause
7. D. Sildenafil is a selective inhibitor of gynaecomastia, although is used as an antacid for
phosphodiesterase type 5 and acts by enhancing dyspepsia (refer to p. 82). Answer B is incorrect
the vasodilator effects of nitrous oxide. This results because amoxicillin is an antibiotic that is not known
in maintenance of an erection if there is sexual to cause gynaecomastia. Answer D is incorrect
stimulation. It is administered orally. Therefore answer because misoprostol, a synthetic prostaglandin
E is incorrect. Alprostadil is a synthetic prostaglandin analogue used as prophylaxis against NSAID induced
E1 analogue administered as a direct injection into ulceration, is more likely to cause diarrhoea and,
the corpus cavernosum or applied to the urethra, in females, menstrual abnormalities (refer to p. 81).
it is not given orally and thus answer B is incorrect. Answer E is incorrect; omeprazole (a PPI) causes
Answers C & E are also incorrect because papaverine gastrointestinal upset and headaches (refer to p. 81).
is a nonselective phosphodiesterase inhibitor, which 3. B. Cimetidine inhibits the P450 enzyme, reducing the
is injected directly into the corpora cavernosa causing metabolism of drugs such as warfarin, potentiating
vasodilation and an erection (refer to pp. 75–77). its pharmacological effect. It is likely that this patient
8. D. When patients are on diuretic medication, it is was previously on a double dose PPI and then her
important to monitor their renal function and their GP added in a H2 receptor antagonist. Cimetidine
electrolytes. Diuretics affect the function of the is thought to be a more potent inhibitor of the P450
kidney and affect the excretion and reabsorption of enzyme than ranitidine. This patient was likely to be
potassium, sodium, calcium and magnesium. Answer overcoagulated, causing her to bleed. Answers A, C,
A, blood pressure, is incorrect. Although it would D and E are not known to inhibit the P450 enzyme
be important to check the blood pressure while the (refer to p. 81).
patient is taking furosemide, especially if the patient 4. D. Metoclopramide is a prokinetic and improves
becomes symptomatic, it is not the most important gastric motility and is, therefore, the most useful
parameter to monitor. Remember that furosemide antiemetic in patients with symptoms because of
can lower the blood pressure because water follows poor gastric emptying. Cyclizine (an H1-receptor
sodium and is excreted into the urine in larger antagonist) is useful in the treatment of motion
quantities, reducing the circulating volume. Answer C sickness and vestibulocochlear disease (refer to
is incorrect because furosemide does not affect the pp. 82–83) and therefore answer A is incorrect.
full blood count and answer E is incorrect because Answer B, dexamethasone is also incorrect. This is

231
 SBA answers

typically used in the treatment of nausea and vomiting has been resistant to steroids and/or the other
associated with cytotoxic therapy. Answer C is immunosuppressive drugs.
incorrect because levomepromazine is a dopamine 8. E. Senna is a stimulant laxative whereas lactulose
antagonist used usually for nausea and vomiting (answer B) is an osmotic laxative that increases the
in palliative care. Answer E, ondansetron, a 5-HT3 water content of the bowel. Answer A ispaghula
antagonist is not the preferred antiemetic in patients husk is a bulk forming laxative (refer to pp. 85–86)
with gastroparesis. and thus is incorrect. Answer C methylcellulose
5. D. Ondansetron has been recommended in guidelines is thought to be a bulk-forming agent but is
as an effective antiemetic in chemotherapy induced predominantly used in the management of obesity
nausea and vomiting. This is because it antagonizes and is therefore incorrect. Answer D peppermint oil is
5-HT3 receptors in the chemoreceptor trigger zone, incorrect. It is used as a smooth muscle relaxant and
which is stimulated by cytotoxic toxins associated antispasmodic (refer to p. 85).
with chemotherapy (refer to p. 84). Answers A, B, C
and E are incorrect because these antiemetics work
slightly differently. Metoclopramide and domperidone Chapter 7 Endocrine and reproductive
are dopamine receptor antagonists, whereas cyclizine 1. B. This question is related to the rare complication
is a histamine-receptor antagonist. Prochlorperazine of bone marrow suppression and neutropenia
antagonizes dopamine, histamine and muscarinic associated with carbimazole. A full blood count will
receptors. indicate whether there is a neutropenia, therefore
6. B. Chlorpromazine (an antiemetic) antagonizes answer B is the most important investigation to
several receptors including dopamine receptors. The because the patient is presenting with a sore throat.
reduction in dopamine in patients with Parkinson Before prescribing carbimazole, it is imperative
disease results in worsening symptoms and is that the physician informs the patient to report any
therefore contraindicated. Answer A is incorrect; symptoms of infection, including a sore throat, so
cimetidine is an H2-receptor antagonist that is used to that drug-induced neutropenia can be identified
reduce gastric acid secretion and is not typically used and if present, carbimazole stopped. Although
as an antiemetic. Answer C is incorrect; cyclizine is an carbimazole can cause hepatitis, and checking the
H1—receptor antagonist that is not known to affect liver function test would be sensible, hepatitis is rare
dopamine receptors and thus is not contraindicated and the patient has presented with a sore throat,
in patients with Parkinson disease. Answer D is and thus answer B is more appropriate than answer
incorrect; dexamethasone, a glucocorticosteroid is D (refer to p. 93). Answer A and E would be useful
used in the treatment of nausea and vomiting but has to do but as indicated are not the most important
no known effect on Parkinson symptoms. Similarly, investigation to do initially. There is no indication in
ondansetron is not known to cause problems in these the history that this patient is diabetic, so answer C
patients (refer to pp. 84–88). is not the most important to check.
7. E. Oral Mesalazine–5-ASA is the treatment of choice 2. A. Amiodarone is class III antiarrhythmic
for induction and maintenance of remission of mild (see Chapter 4) that blocks sodium and calcium
to moderate ulcerative colitis (UC). Mesalazine is channels. It is prescribed to patients with structural
also thought to reduce the risk of colorectal cancer heart disease who require treatment for atrial
associated with UC (refer to p. 88). Answer A fibrillation. Amiodarone is rich in iodine, which
azathioprine is incorrect because this medication is inhibits the conversion of T4 to T3 and inhibits
used when patients are intolerant to corticosteroids or hormone secretion. Amiodarone can cause either
who require several courses of steroids. Azathioprine hyperthyroidism (symptoms this gentleman presents
interferes with purine synthesis and depresses with) or hypothyroidism and thyroid function tests
antibody-mediated immune reactions thus dampening should be checked before prescribing it and
down the inflammation. Answer B cyclosporine is also 6 months thereafter (refer to Hints and Tips box
incorrect because it typically is prescribed in patients on p. 94). Answer B is incorrect. Carbimazole is
with severe refractory colitis. Answer C ispaghula used in the treatment of hyperthyroidism but is not
husk is used in the treatment of proximal constipation prescribed for the management of atrial fibrillation.
associated with ulcerative colitis because it is a Answer D is incorrect. Levothyroxine is used in the
stool bulking laxative but is not used in maintaining treatment of hypothyroidism. Answer E is incorrect.
remission. Answer D is incorrect because infliximab is Although β-receptor antagonists are used to rate
a monoclonal antibody used in inducing remission in control patients with atrial fibrillation, it does not
patients with moderate to severe UC whose disease cause symptoms of hyperthyroidism. In fact,
propranolol is prescribed to patients to relieve the
tachycardia, tremor and nervousness associated

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 SBA answers

with hyperthyroidism. Answer C is incorrect because and is contraindicated in patients with heart failure,
iodide is used in the treatment of thyrotoxicosis and therefore answer E is incorrect. Metformin is the
is not used in the treatment of atrial fibrillation. antidiabetic medication that is safe to give in heart
3. D. A β-blocker (e.g., atenolol) can mask the warning failure (refer to pp. 97–98). Pioglitazone can cause
signs (e.g., tremor, racing heart) of hypoglycaemia. liver failure and the prescriber should check liver
Patients taking gliclazide (a sulfonylurea) are at risk of function tests.
hypoglycaemia because they stimulate endogenous 6. B. Dapagliflozin is an SGLT-2 inhibitor. It is used in
insulin secretion through ATP-dependent sodium combination with other antidiabetic medications
channel blockade in pancreatic β-cells (refer to in the treatment of type 2 diabetes. In addition to
p. 98), therefore the combination of gliclazide and a causing polyuria, hypotension and hypoglycaemia,
β-blocker should be prescribed with caution. Answer one of its main side effects is urinary tract infections
A is incorrect. As indicated, gliclazide can cause (e.g., penile discharge and dysuria) hence B is
hypoglycaemia, particularly in the elderly and those the correct answer. Acarbose is an α-glucosidase
with renal impairment. Answer B is incorrect. Alcohol inhibitor and it causes flatulence and diarrhoea
can cause flushing if a patient is on gliclazide as as side effects and thus answer A is incorrect.
well as increasing the risk of severe hypoglycaemia. Linagliptin is a DPP4 inhibitor and its side effects
Answer C is incorrect. Gliclazide causes weight include gastrointestinal upset, worsening heart
gain (as do the other sulfonylureas). Answer E is failure and pancreatitis, hence answer C is incorrect.
incorrect. If a dose of gliclazide is missed, the patient Liraglutide is a GLP-1 agonist that also causes
should not take a double dose because the risk of gastrointestinal disturbances and pancreatitis.
hypoglycaemia is very high. Pioglitazone causes weight gain, fluid retention and
4. D. The case points towards type I diabetes as increases the risk of bladder cancer but does not
the most likely diagnosis. The patient, a child, is typically cause urinary tract infections. Therefore
presenting with polyuria, polydipsia and weight loss answers D and E are incorrect (refer to pp. 98–100).
with associated hyperglycaemia and glycosuria. The 7. C. Fludrocortisone (answer C) is used as
most appropriate management of type 1 diabetes mineralocorticoid replacement in primary adrenal
is subcutaneous insulin (refer to p. 96), because insufficiency. With regards to glucocorticoid
patients with type I diabetes do not produce enough replacement, hydrocortisone is used in patients with
insulin as a result of autoimmune destruction of Addison disease (refer to p. 104). Answers B and
their pancreas, therefore answer D is correct. D are incorrect. Dexamethasone and prednisolone
Answer A is incorrect. Acarbose is an α-glucosidase are glucocorticoids, but they are typically used in
inhibitor used in the treatment of type 2 diabetes the treatment of allergic and inflammatory diseases.
in combination with metformin and dietary control They are not first-line replacement in adrenal
(refer to p. 98). Type 2 diabetes typically affects older insufficiency (refer to p. 104). Answer A is incorrect.
patients who are overweight and inactive and is not Beclometasone is a very potent glucocorticoid drug
the diagnosis in this case. Answer B is incorrect. with no mineralocorticoid that is used topically to
Although it is important for all patients with diabetes treat allergic rhinitis and eczema (refer to
to avoid foods with a high fat or sugar content, p. 104). Answer E is incorrect. Triamcinolone is a
dietary modification is not sufficient treatment for the glucocorticoid used for the treatment of arthritis.
management of type I diabetes, and for patients who 8. C. Osteoporosis is a metabolic side effect of
have the inability to secrete insulin and who are at glucocorticosteroids long-term caused by the
risk of significant, uncontrolled hyperglycaemia that catabolism of protein matrix in bone. Answer
can lead to diabetic ketoacidosis and death. Answer A is incorrect. Glucocorticosteroids cause
C and E are both medications used in the treatment hyperglycaemia because of disturbed carbohydrate
of type 2 diabetes and are therefore incorrect. metabolism. Patients’ blood glucose levels should
5. B. Pioglitazone can be used second-line or third- be monitored when on steroids because they
line in the treatment of type 2 diabetes but can are at risk of diabetes mellitus. Answers B and D
take up to 3 months to have a maximum effect are incorrect. Glucocorticosteroids cause muscle
(refer to p. 98). Nevertheless, it can reduce the wasting and thinning of the skin because of
need for exogenous insulin by 30% so answer B altered protein metabolism. Answer E is incorrect.
is correct. Pioglitazone has been associated with Glucocorticoids cause fat redistribution and thus
an increased risk of bone fractures and bladder patients develop a characteristic moon face and
cancer and therefore answers C and D are incorrect. central obesity (refer to p. 102).
Pioglitazone causes weight gain and thus answer 9. C. The COCP contains both oestrogen and
A is incorrect. Pioglitazone causes fluid retention progestogen. It is an effective contraception but

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 SBA answers

must not be prescribed to patients with certain failure but it is not known to cause hyperglycaemia.
conditions. Patients with a migraine should not be Paracetamol (answer D) is used to manage pain and
prescribed the COCP, because of the risk of an is not known to cause hyperglycaemia. Ramipril,
ischaemic stroke, therefore answer C is the correct answer E, is an angiotensin-converting enzyme
answer. Answer A is incorrect. Asthma is not a inhibitor used in the treatment of hypertension but is
contraindication to the COCP. Answer B is incorrect. not known to cause hyperglycaemia. Statins (used in
It is hypertension that is a contraindication to the the treatment of hypercholesterolaemia) and steroids
COCP again because of the risk of a stroke. Answer (used in the treatment of inflammation) can also cause
D is incorrect. Having had a previous pregnancy is hyperglycaemia and blood glucose levels should be
not a contraindication to the COCP. Liver disease is monitored in patients started on these medications.
a contraindication to the COCP, not renal disease
thus answer E is incorrect (refer to p. 107).
10. D. Phenytoin is a cytochrome p450 inducer and
Chapter 8 Central nervous system
consequently, the metabolism of the progesterone- 1. A. Levodopa is usually given for symptom control
only pill is increased, reducing the contraceptive in patients with newly diagnosed Parkinson
effect. Answer A (amiodarone), B (ciprofloxacin), disease. However, it is an immediate precursor of
C (erythromycin) and E (sodium valproate) are all dopamine and penetrates the blood barrier. It is then
cytochrome P450 inhibitors and subsequently the carboxylated to dopamine by dopa decarboxylase
metabolism of the progesterone-only pill is reduced. and therefore answer D is incorrect (refer to p. 114).
11. A. Bisphosphonates, of which alendronate is an Carbidopa is the correct answer. This drug inhibits
example, are used first line for the prevention and dopa decarboxylase in the periphery and cannot
treatment of osteoporosis. It is contraindicated in cross the blood-brain barrier. This inhibits the
severe renal impairment. Atypical femoral fractures extracerebral conversion of L-dopa to dopamine. It
can develop if taking long-term bisphosphonate is often combined with levodopa as co-careldopa
treatment. This complication can also occur in and given to most patients to minimize adverse
patients taking denosumab (refer to p. 111). effects (refer to p. 115) and is an effective treatment
Answer B is incorrect. Ergocalciferol is the inactive for Parkinson disease. Answer B is incorrect.
form of vitamin D which helps the gastrointestinal Domperidone is a dopamine agonist that blocks the
tract absorb calcium. It is used in the treatment of stimulation of dopamine receptors in the periphery
osteoporosis but is not known to cause atypical (refer to p. 115). Answer C is incorrect. Entacapone is
fractures. Answer C is incorrect. Raloxifene a COMT inhibitor, which inhibits dopamine degradation
stimulates osteoblasts and inhibits osteoclasts and is in the CNS and does not affect dopa decarboxylase
used as third-line management of osteoporosis. It is (refer to p. 116). Answer E is incorrect. Selegiline is
contraindicated in patients who have had a previous a monoamine oxidase inhibitor. MAOB enzyme is
venous thromboembolism but is not known to cause normally responsible for the degradation of dopamine
atypical fractures. Answer D is incorrect. Strontium is but this is inhibited by selegiline (refer to p. 7).
prescribed by specialists for the treatment of severe 2. C. Benzodiazepines have several adverse effects;
osteoporosis. Answer E is incorrect. Teriparatide is drowsiness, ataxia and reduced psychomotor
a recombinant parathyroid hormone, which when performance are common. Therefore answer C is
given in small doses stimulates osteoblast activity. It correct. Given this, patients taking benzodiazepines
causes a headache and arthralgia but not atypical should take care when driving, so answer A is not
fractures (refer to p. 112). the correct answer. Answer B is incorrect. Taking
12. B. Bendroflumethiazide, a thiazide diuretic used in benzodiazepines with alcohol can potentiate
the management of hypertension and is known to the CNS depressants effects and can result in
cause hyperglycaemia, particularly in at-risk patients. respiratory depression. Answer D is incorrect. If
It is unclear how, but the current understanding is a patient takes a benzodiazepine only overdose,
that thiazide diuretics induce hypokalaemia. The this can be reversed with flumazenil. Answer E is
K+ deficiency is known to inhibit insulin secretion incorrect. Patients taking benzodiazepines for more
by the pancreas, thus blood sugar levels are not than 4 to 6 weeks can become dependent and as
reduced as normal (refer to Chapter 5). Allopurinol, such if stopped abruptly can result in a withdrawal
answer A, is used in the prophylaxis of gout and syndrome, therefore patients should only be
of uric acid stones but is not known to cause prescribed short courses or benzodiazepines should
hyperglycaemia. Celecoxib (answer C) is an NSAID be withdrawn slowly (refer to pp. 118–119).
used in the management of inflammation associated 3. D. Propanolol is a beta-adrenoceptor blocker and
with severe osteoarthritis. It can cause several side can be very effective in alleviating the somatic
effects including bleeding, stomach ulcers and kidney manifestations of anxiety caused by marked

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 SBA answers

sympathetic arousal. Propranolol blocks excessive tests should be performed before starting treatment
catecholamine release. However, they also cause and every 6 to 12 months because lithium can cause
bronchoconstriction and should be avoided in patients hypothyroidism. Answer A is incorrect. Although a
with asthma (refer to p. 120). Answer A is incorrect. full blood count is useful to have before starting any
Buspirone is a serotonergic (5-HT1A) agonist medication, it is not essential to check, unlike urea
indicated for the short-term relief of generalized and electrolytes (U + Es) and thyroid function tests.
anxiety disorder. It is not particularly helpful in the Answer B is incorrect. Checking liver function tests
somatic manifestations of performance related anxiety is important when commencing any medication but
(refer to p. 120). Answer B is incorrect. Midazolam is a because lithium is renally excreted, checking U + Es
benzodiazepine. While short-acting benzodiazepines is more important. Answer C is incorrect. Lithium
(e.g., diazepam) are useful in short-courses for causes many drug interactions and side effects.
treating anxiety, midazolam has a slower onset and It is imperative that lithium levels are checked at
longer half-life and is typically used in the cessation of least every 3 months and during any intercurrent
status epilepticus or in anaesthesia (refer to p. 133). illness, that renal function and thyroid function are
Answer C is incorrect. Pheobarbital is a barbiturate checked at baseline and 6 to 12 monthly. Answer D
and acts to increase GABA-mediated inhibition on the is incorrect. Although checking parathyroid hormone
GABAA receptor. Barbiturates can be used to reduce and calcium is worth doing, it is not essential to do
anxiety but are not commonly prescribed because of before prescribing lithium. Note that before prescribing
the significant adverse effects associated with them lithium it is important to also do an EKG and check a
(e.g., respiratory failure) (refer to p. 133). Answer E is patient’s weight because lithium can cause cardiac
incorrect. Zolpidem is a newer-generation hypnotic arrhythmias and weight gain (refer to p. 124).
that is typically used to manage insomnia rather than 6. B. Lithium is a commonly used mood stabilizer and
anxiety. although its mechanism is unclear, it is useful in the
4. B. Citalopram is an example of an SSRI. SSRIs are treatment of mania and bipolar disorder. However,
usually first line for moderate to severe depression lithium has a long half-life and a narrow therapeutic
alongside psychological therapies. They block index. It is renally excreted and therefore should be
serotonin transporters, which inhibits serotonin used with caution in patients with renal impairment,
reuptake into nerve terminals from the synaptic cleft. and drugs that may affect kidney function should be
It would be important for the GP to warn the patient avoided. Answer A. Amlodipine, a calcium channel
of increased anxiety and agitation during the early antagonist, is an appropriate hypertensive because
stages of treatment (refer to p. 122). Answer A is it is not known to cause a rise in plasma lithium
incorrect. Amitriptyline is a TCA. TCAs are used as concentrations. Answers B and C are incorrect.
second-line or third-line treatment of depression (refer Bendroflumethiazide is a thiazide diuretic and
to p. 122). Answer C is incorrect. Mirtazapine is an furosemide is a loop diuretic. Diuretics promote
atypical antidepressant that has α2-adrenoceptor- renal sodium loss and affect reabsorption at renal
blocking activity, which results in an increase in the tubules. Their pharmacological action can result in
amount of noradrenaline in the synaptic cleft (refer an increase in plasma lithium resulting in toxicity;
to p. 124). Answer D is incorrect. Moclobemide vomiting, tremor, ataxia and drowsiness. Answers D
is an example of a reversible inhibitor of MAOA. and E are incorrect. Losartan, an angiotensin-receptor
MAO inhibitors block the action of enzymes that blocker, and ramipril, an angiotensin–converting
metabolize the monoamines and have antidepressant enzyme (ACE) inhibitor reduce the glomerular filtration
properties. They are particularly effective in patients rate and enhance tubular reabsorption of lithium,
with atypical or hysterical features. However, given thus increasing the risk of lithium toxicity. Therefore
their dietary and drug interactions, are reserved for diuretics and ACE inhibitors should be avoided in
refractory depression in most cases (refer to p. 124). patients taking lithium. If they have to be prescribed,
Answer E is incorrect. Venlafaxine is an SNRI and is careful monitoring of renal function and lithium levels
contraindicated in patients with hypertension. This should be undertaken. Note that NSAIDs also affect
is because SNRIs increase blood pressure. It is also kidney function and increase the risk of toxicity (refer
prescribed as a second-line treatment if two SSRIs to p. 124 and Chapter 5).
are unable to control the depressive symptoms (refer 7. D. Answer D is correct. Moclobemide is safe to
to p. 123). give in patients with cardiovascular disease. MAO
5. E. Before prescribing lithium, a patient must have inhibitors, such as moclobemide, are useful in the
their renal function checked. Lithium is renally treatment of depression or phobias with atypical or
excreted and should not be given to patients with hysterical features. However, TCAs should be avoided
renal impairment because there is a significant risk of in patients with cardiovascular disease given that they
lithium toxicity. Answer E is correct. Thyroid function can cause conduction abnormalities. Answer A is

235
 SBA answers

incorrect. Moclobemide should not be coprescribed Cannabis causes a tachycardia and dilated pupils.
with SSRIs (e.g., fluoxetine) because the combination Answer B is incorrect. Cannabis stimulates appetite
can cause a potentially fatal serotonergic syndrome and users often get the “munchies”. Answer D is
of hyperthermia, tremor, agitation, sweating and incorrect. Cannabis is used to treat spasticity in
dilated pupils, which can result in cardiovascular multiple sclerosis and as an antiemetic in certain
collapse (refer to p. 122). Answer B is incorrect. situations. Opioids are used clinically as analgesics.
TCAs (e.g., amitriptyline and imipramine) should be Cannabis is typically smoked or taken orally with
used cautiously in patients with epilepsy because food, it is not injected, and therefore answer E is
they lower the seizure threshold. Moclobemide is incorrect. Negative experiences include anxiety,
not known to cause significant problems in patients paranoid thoughts and self-consciousness. Long-
with epilepsy (refer to p. 129). Answer C is incorrect. term use of cannabis increases the risk of developing
Moclobemide blocks the action of MAOA and schizophrenia (refer to pp. 143–144).
MAOB enzyme, involved in the metabolism of the 2. E. Opioid withdrawal results in users feeling irritable,
monoamines. MAO in the gut wall and liver normally distressed and restless. Answer A is therefore
breaks down ingested tyramine but when MAO is incorrect. Answer B is incorrect as appetite is
inhibited, tyramine causes the release of noradrenaline unchanged acutely. Autonomic cold turkey symptoms
within the circulation, resulting in a potentially fatal include fever, sweating and piloerection; therefore
rise in blood pressure. Cough mixture contains answer C is incorrect. Answer D is incorrect. Patients
sympathomimetic amines and therefore should be have dilated pupils when they are withdrawing.
avoided because of the significant risk of severe Patients who have opioid toxicity may have
hypertension. Diets rich in cheese and game should constricted pupils (refer to p. 143).
be avoided for the same reasons (refer to p. 124). 3. E. Varenicline is a partial agonist at nicotinic
Answer E is incorrect. Moclobemide causes a dry acetylcholine receptors and reduces the craving
mouth, blurred vision and postural hypotension as a for nicotine. It is safe to give to patients with
result of the muscarinic and sympathetic blockade. epilepsy. It causes abnormal dreams, headaches
TCAs cause weight gain in addition to blurred vision and flatulence (refer to p. 142). Answer A
and dry mouth (refer to p. 124). is incorrect. Bupropion, although it reduces
8. D. Answer D is correct because sodium valproate is nicotine craving through selective inhibition of the
often used as first line in the treatment of tonic-clonic neuronal uptake of noradrenaline and dopamine,
seizures (as described in the question). It blocks use- is contraindicated in patients with epilepsy
dependent voltage-gated sodium channels while also because it can lower the seizure threshold (refer to
increasing the GABA content of the brain when given p. 142). Answer B is incorrect. Disulfiram is used
over a prolonged period. Sodium valproate should to help patients stay off drinking alcohol (refer
not be given to patients with hepatic dysfunction to p. 142). Answer C is incorrect. Flumazenil is
(refer to p. 132). Answer A is incorrect. Ethosuximide a benzodiazepine receptor antagonist. Answer
inhibits T-type calcium channels and dampens down D is incorrect. Ethanol is used as an antidote to
the thalamocortical oscillations that are critical in the methanol poisoning (refer to p. 142).
generation of absence seizures. Ethosuximide can
make tonic-clonic seizures worse (refer to p. 133).
Answer B is incorrect. Lamotrigine, one of the newer Chapter 10 Pain and anaesthesia
anticonvulsants, inhibits the release of glutamate (refer 1. C. This gentleman is currently on step 1 of the
to p. 133). Answer C is incorrect. Phenytoin does WHO analgesic ladder; he is taking a nonopioid
block use-dependent voltage-gated sodium channels (paracetamol) and an adjuvant (ibuprofen). Given that
but is no longer commonly used as first-line treatment his pain is persisting, his analgesia should involve step
of epilepsy given its poor side effect profile and narrow 2; a weak opioid (codeine), a nonopioid (paracetamol)
therapeutic window (refer to p. 132). Answer E is and an adjuvant if it is working and there are no
incorrect. Vigabatrin inhibits GABA degradation in the contraindications (ibuprofen), therefore answer C is
CNS through inhibition of GABA transaminase, the correct. Answer A is incorrect; aspirin is not a weak
enzyme normally responsible for the metabolism of opioid. Answer B is incorrect; morphine is a strong
GABA within the neurone (refer to p. 44). opioid that should be given when pain is increasing
despite the analgesia given at step 2 or when it is very
severe. Answer D is incorrect, given that the patient is
Chapter 9 Drug misuse at step 2 not step 3 on the WHO ladder. In addition,
1. C. Cannabis causes an altered state of the ibuprofen should continue, given that there are
consciousness and users feel “high”, euphoric no contraindications and it is an antiinflammatory
and socially uninhibited. Answer A is incorrect. that is useful for osteoarthritic pain. It is important for

236
 SBA answers

patients with pain to take regular paracetamol as a which is sometimes used in the prophylaxis of a
form of analgesia and thus just ibuprofen and codeine migraine, but again is not the mechanism of action of
is not enough (refer to Fig 10.1 on p. 145). sumatriptan (refer to p. 149).
2. B. Mr Jones requires opioid analgesia given the 5. B. Isoflurane is used in the maintenance of
severity of his pain and he requires it to act quickly. He anaesthesia but has fewer effects upon the
also requires medication that is not, predominantly, cardiorespiratory system (as compared with
excreted renally given his acute kidney injury as halothane) and therefore is an appropriate medication
evidenced by the raised creatinine. Fentanyl is a to use. However, isoflurane can be an irritant to the
selective μ receptor agonist that is mainly metabolized respiratory tract causing cough and laryngospasm.
by the liver. It has a rapid onset of action (5 minutes) It can also precipitate myocardial ischaemia in
when absorbed buccally. It has an extensive first- patients with coronary disease (refer to p. 156).
pass metabolism so is not especially effective when Answer A is incorrect. Although enflurane is an
given orally. Therefore, fentanyl lozenges are the best inhalational anaesthetic used in the maintenance
as required medication for Mr Jones’ breakthrough of anaesthesia, it is contraindicated in patients with
pain, given his renal impairment (refer to p. 147). The epilepsy and therefore should be avoided in this
other options listed are inappropriate because they patient. Answer C is incorrect. Halothane is used as
accumulate in renal impairment. If the renal function an inhalational maintenance anaesthetic; however, it
was normal, diamorphine (answer A) is a helpful has a narrow therapeutic window and there is a risk
medication to use for breakthrough pain, given its of cardiorespiratory depression in addition to severe
rapid onset. Morphine sulphate and oxycodone hepatic necrosis (refer to p. 155). It has therefore
(answer D and E) have a slightly longer onset of largely been replaced by isoflurane or sevoflurane.
action and are less useful for pain that comes on Answer D is incorrect. Etomidate, given intravenously,
quickly. Methadone (answer C) is used predominantly is not used in the maintenance of anaesthesia but is
to help misusers wean themselves off morphine or given for rapid induction of general anaesthesia (refer
diamorphine. to p. 154). Answer E is incorrect. Ketamine, given
3. E. Flushing (answer E) is caused by the histamine intravenously, can be used to maintain anaesthesia
release associated with opioid analgesia. Answer A but given the high incidence of dysphoria and
is incorrect; opioids suppress a cough. Answer B is hallucinations in adults, it is not commonly used (refer
incorrect; opioids cause constipation (not diarrhoea) to p. 154).
because of the stimulation of cholinergic activity
in the gut wall ganglia, resulting in smooth wall Chapter 11 Inflammation, allergic diseases
spasm. Answer C is incorrect; opioids stimulate the
parasympathetic third cranial nerve nucleus, which and immunosuppression
results in pupillary constriction. Patients with opioid 1. D. Ibuprofen is an example of a NSAID. It should
toxicity present with “pinpoint” pupils. Answer D is be avoided in patients with renal impairment and
incorrect; opioids cause a reduction in the sensitivity gastrointestinal ulceration because of its effects on
of the respiratory centre to carbon dioxide, leading platelets, gastric mucosa and renal vasculature (refer
to shallow and slow respiration. This can cause the to Box 11.5). Therefore answers A and C are incorrect.
serious adverse effect of respiratory depression. In some patients with asthma, taking NSAIDs can
Opioids also cause pancreatic stasis, drowsiness, induce bronchospasm and thus should be used with
sedation and vomiting (refer to pp. 147–148). caution in this patient population. Therefore answer B
4. A. Sumatriptan is a 5-HT1 receptor agonist and is is incorrect. NSAIDs can cause liver disorders, rarely
thought to constrict the dilated arteries associated and thus should be used cautiously in patients with
with migraines. Triptan medication can cause chest liver failure. Ibuprofen and other NSAIDs are used for
tightness and a tingling sensation. Answer B is the treatment of joint inflammation, so answer D is
incorrect. Pizotifen is a 5-HT1 receptor antagonist. correct (refer to Box 11.5).
However, it is used in the prophylaxis of a migraine 2. E. Hydroxychloroquine is a DMARD and one of
because it can reduce the vascular inflammation the antimalarial medications. The major adverse
associated with migraines (refer to p. 149). Answer C effect is retinal toxicity and thus patients should
is incorrect. β-Receptor antagonists are used in the have their vision monitored regularly while taking
prophylaxis of a migraine, but this is not the action hydroxychloroquine. Gold salts can cause diarrhoea,
of sumatriptan. Answer D is incorrect. Nonsteroidal ulceration and bone marrow suppression; therefore,
antiinflammatories (e.g., ibuprofen) are used as the answer A is incorrect (refer to p. 163). Answer B is
treatment for acute migrainous attacks. Answer E is incorrect. Sulfasalazine has been reported as causing
incorrect. Serotonin-noradrenaline reuptake inhibitor oligospermia (refer to p. 163). Answer C is incorrect.
(e.g., amitriptyline) is a tricyclic antidepressant, Steroids (e.g., prednisolone) cause thinning of the skin

237
 SBA answers

(refer to p. 167). Answer D is incorrect. Penicillamine negative bacteria. It irreversibly binds the 30S portion
causes a transient loss of taste in addition to bone of the bacterial ribosome, inhibiting the translation
marrow suppression. of mRNA to protein. Gentamicin is bactericidal and
3. E. Adalimumab is a monoclonal antibody that binds is used in the treatment of severe urine infections
TNF-α and suppresses the immune system. It can and bacterial endocarditis (refer to pp. 177–178).
therefore lead to reactivation of old tuberculosis and Tetracyclines (refer to p. 178), macrolides (refer to
thus a history of tuberculosis should be excluded p. 179) and clindamycin (refer to p. 179) are also
before starting therapy. Adalimumab is also protein synthesis inhibitors.
contraindicated in patients with heart failure and in Co-amoxiclav and meropenem (refer to p. 4) are
females who are pregnant or breastfeeding. Answers cell wall synthesis inhibitors so answers A & C are
A to D are not reasons to exclude the prescription of incorrect. Metronidazole inhibits nucleic acid and DNA
monoclonal antibodies. synthesis so answer D is incorrect (refer to p. 179).
4. E. Patients with psoriasis should be given emollients Metronidazole is used in the treatment of anaerobic
to use liberally and frequently to help hydrate the bacteria (e.g., in patients with aspiration pneumonia or
skin. First-line therapy for psoriasis includes topical intraabdominal sepsis). Trimethoprim is an antifolate
therapies (corticosteroids, vitamin D analogues and and affects the synthesis of purines and bacteria DNA,
dithranol with tar preparations). Second-line therapy thus answer E is incorrect (refer to p. 177).
includes phototherapy, psoralen and systemic agents 2. E. Vancomycin is a glycopeptide used in the treatment
such as cyclosporine and methotrexate (answer B of severe C. difficile pseudomembranous colitis. It
is therefore incorrect). Third-line treatment is with has been associated with ototoxicity, nephrotoxicity
TNF antagonists adalimumab and etanercept. and red man syndrome, particularly at high plasma
Answer E is correct. Coal tar modifies keratinisation doses. It is therefore essential to check the level of the
but adverse effects include skin irritation, acne-like vancomycin when treating patients (refer to
eruption and photosensitivity (refer to p. 167). Answer pp. 177–178). Gentamicin (an aminoglycoside) also
A is incorrect. Clobetasone butyrate is a moderately causes nephrotoxicity and ototoxicity (refer to
potent topical steroid, a very potent steroid is pp. 177–178). Levofloxacin (a quinolone) is known to
clobetasol propionate (refer to Box 11.11). Answer C cause gastrointestinal upset and tendon damage (refer
is incorrect. Dithranol and coal tar should not be used to p. 177), and so answer B is incorrect. Metronidazole
in patients with pustular psoriasis (refer to also causes gastrointestinal upset and alcohol should
p. 167). Answer D is incorrect. Calcipotriol is a vitamin not be consumed while taking it (refer to p. 179),
D analogue that inhibits epidermal proliferation and therefore answer C is incorrect. Erythromycin and
keratinocyte differentiation. Given its involvement trimethoprim are not known to cause ototoxicity and
in vitamin D metabolism, it should not be given to nephrotoxicity, therefore answers C, A, and D are
patients with disorders of calcium (refer to p. 167). incorrect. Erythromycin (a macrolide effective against
5. C. This scenario indicates an anaphylactic reaction to most gram-positive bacteria) may cause liver damage
penicillin. Treatment involves intramuscular adrenaline and jaundice if used long term (refer to p. 179) and
(therefore answer E is incorrect) that acts at α2- trimethoprim may cause a severe rash, but it is more
receptors to cause vasoconstriction and β2-receptors likely to be Stevens-Johnson syndrome. It can also
to cause bronchodilation (therefore answer C is cause a transient rise in creatinine and an acute kidney
correct). Intravenous adrenaline may cause a patient’s injury (refer to p. 177).
heart to stop because of a huge dose of adrenaline 3. A. This patient’s history suggests a sexually
reaching the heart, resulting in a fast arrhythmia and transmitted infection, such as chlamydia. Azithromycin
should be avoided. Bronchoconstriction is caused (a macrolide) can be given as a one-off dose for
by prostaglandins, not histamine, therefore answer uncomplicated chlamydial infections of the genital
A is incorrect (refer to Box 11.13). An anaphylactic tract. Macrolides reversibly bind to the 50S subunit of
reaction is mediated by IgE antibodies (not IgA) and is the bacterial ribosome and affect protein synthesis.
a type I hypersensitivity reaction (not type II). Therefore They are also used as an effective alternative
answer B is incorrect. Promethazine is an old, in penicillin-sensitive patients (refer to p. 179).
sedative H1-receptor antagonist and therefore answer Ciprofloxacin (a quinolone) is usually used in patients
D is incorrect (refer to p. 169). with pyelonephritis and they present more acutely
unwell with flank and suprapubic pain, pyrexia and
rigors. Answer B is therefore incorrect.
Chapter 12 Infectious diseases
Co-amoxiclav is usually prescribed in patients with
1. B. Gentamicin (an aminoglycoside) is a protein lower respiratory tract infections (refer to p. 174)
synthesis inhibitor, which is useful against gram- therefore answer C is incorrect. Meropenem (answer

238
 SBA answers

D) is used as a second-line or third-line antibiotic and and can be hepatotoxic, cause agranulocytosis
is not used in the treatment of chlamydia (refer to and a peripheral neuropathy. Therefore answer B
p. 177). Trimethoprim, although used in the treatment is incorrect. Pyridoxine (answer D) is also incorrect
of UTIs, is not typically used in the treatment of because it is given to help reduce the risk of peripheral
chlamydia (refer to p. 177). Therefore answer E is neuritis associated with isoniazid. Pyrazinamide is
incorrect. Doxycycline, however, is also used in the the final medication used to treat tuberculosis and
treatment of chlamydia (refer to p. 178). it causes hepatotoxicity and is contraindicated in
4. B. Clarithromycin is a macrolide antibiotic used in patients with gout because it is known to raise plasma
the treatment of respiratory infections, particularly in urate levels. Therefore pyrazinamide, answer C, is
patients allergic to penicillin. However, it is cytochrome incorrect (refer to p. 180).
p450 enzyme inhibitor and can, therefore reduce the 7. C. Nevirapine is a nonnucleoside reverse transcriptase
effectiveness of warfarin. Macrolides can also cause inhibitor, similar to efavirenz. Both these medications
cholestatic hepatitis. Monitoring of liver function are given orally and can cause a rash, dizziness and
tests and the INR should be considered in patients. headache. Nonnucleoside reverse transcriptase
Answers A and B are incorrect. Although amoxicillin inhibitor also induce the cytochrome p450 enzyme
and co-amoxiclav are used in the treatment of lower (refer to p. 185). Lamivudine, didanosine and
respiratory tract infections (LRTIs), it would not be zidovudine are nucleoside reverse transcriptase
sensible to give these antibiotics in a patient with an inhibitors and therefore answers A, B and E are
allergy to penicillin (refer to p. 174). Co-trimoxazole incorrect. Nucleoside reverse transcriptase inhibitors
(answer D) is used in the treatment of respiratory are given orally in the management of HIV infection
infections but is used predominantly for the treatment and can cause bone marrow suppression, resulting
of P. jiroveci pneumonia, most commonly seen in in anaemia and neutropenia in addition to nausea,
patients who are immunocompromized (refer to headaches and myalgia (refer to p. 184). Ritanovir is
p. 192). Answer E is incorrect. Although levofloxacin a protease inhibitor therefore answer D is incorrect.
is sometimes used in severe LRTIs, it is not known to Protease inhibitors prevent the virus-specific protease
affect the cytochrome p450 enzyme (refer to p. 177). of HIV cleaving the inert polyprotein product of
5. D. Answer A is incorrect because not treating the translation into various structural and functional
asymptomatic bacteriuria can result in cystitis or proteins and are used in the management of HIV
pyelonephritis for the mother or result in reduced infections in combinations with nucleoside reverse
intrauterine growth of the foetus and premature labour transcriptase inhibitor (refer to p. 184).
and neonatal delivery. Trimethoprim (answer B) is 8. E. Rubella, measles, mumps and oral polio are
contraindicated in the first and second trimester of vaccines containing live attenuated viruses. Diphtheria
pregnancy because it is teratogenic (refer to p. 177). vaccine contains inactivated bacterial toxins, so
Doxycycline (answer C) is also incorrect because it answer A is incorrect. Hepatitis A and parenteral
is not a typically used antibiotic in the treatment of polio are vaccines made up of inactivated viruses and
a urinary tract infection but importantly can cause therefore answers B and D are incorrect. Hepatitis B
impaired bone growth and dental hypoplasia, thus it is vaccine is genetically engineered thus answer C is
contraindicated in pregnant and breastfeeding women incorrect (refer to p. 194).
(refer to p. 178). Nitrofurantoin is the safest of the 9. C. Mebendazole is used in the treatment of
antibiotics listed for treatment of the asymptomatic pinworm. It is an example of the benzimidazole
bacteriuria (refer to pp. 179–180). However, it should family, which prevents the polymerisation of
be avoided in the third trimester because it can cause microtubules. They should not be given to pregnant
neonatal haemolysis. Ciprofloxacin (answer E) should women (refer to p. 193).
be avoided because there is a theoretic risk of causing Ivermectin is used in the treatment of tapeworm
neonatal joint problems if taken during pregnancy. by causing tonic paralysis of the worm’s peripheral
6. E. Rifampicin inhibits DNA-dependent RNA muscle system. It is also used in the treatment of
polymerase causing a bactericidal effect in the strongyloides infection, but not pinworm. Therefore
treatment of tuberculosis. However, it is known to answer A is incorrect (refer to p. 194). Levamisole is
cause an orange discolouration of bodily fluids. In used in the treatment of A. lumbricoides round worm
addition, patients taking rifampicin must be cautious infection, thus answer B is incorrect. It stimulates
when taking other medications because rifampicin is a nicotinic receptors at the neuromuscular junction
cytochrome p450 enzyme inhibitor (refer to and results in a spastic paralysis and expulsion of
p. 18). Ethambutol is bacteriostatic and given orally. It the worm (refer to p. 194). Niclosamide is also used
causes a reversible optic neuritis and therefore answer in the treatment of tapeworm (refer to p. 192) and
A is the incorrect answer. Isoniazid is bactericidal therefore answer D is incorrect. Praziquantel is the

239
 SBA answers

drug of choice for all schiztosome infections and answer D is incorrect (refer to p. 199). Methotrexate
not pinworms, therefore answer E is incorrect. is an antimetabolite, which competitively inhibits
10. A. Chloroquine is a schizonticide and is considered dihydrofolate reductase, inhibiting the synthesis
safe to use in pregnant women. It does not affect of DNA. It causes myelosuppression rather than
hypnozoites and in most areas P. falciparum is haemorrhagic cystitis, therefore answer E is incorrect
resistant to chloroquine, necessitating combination (refer to p. 199).
chemoprophylaxis with antifolates (refer to 3. C. Vincristine is a vinca alkaloid or mitotic inhibitor
p. 190). Mefloquine (answer C) is incorrect. It is and this class of chemotherapy is known to
not considered safe in pregnancy because it can cause neurological problems because tubulin
cause foetal abnormalities. Mefloquine is also a polymerisation is relatively indiscriminate (refer to
schizonticide but has no effect on gametocytes p. 9). Bleomycin is not known to cause neuropathy
of P. falciparum. Nevertheless, it is used as therefore answer A is incorrect. Bleomycin is
chemoprophylaxis (refer to p. 190). Quinine (the same used in the treatment of lymphoma but typically
family as mefloquine) is however safe in pregnancy causes pulmonary fibrosis (refer to pp. 199–200).
and is the treatment of choice for falciparum malaria Methotrexate is not known to cause neuropathy,
resistant to chloroquine. Dapsone and sulphonamide it more commonly causes myelosuppression,
are both antifolates and affect all growing stages of mucositis and pneumonitis thus answer B is
the malarial parasite. However, because they are incorrect (refer to p. 199). Mercaptopurine is
antifolates they should be avoided in pregnancy, converted into a fraudulent purine nucleotide that
therefore answers B and E are incorrect. Primaquine impairs DNA synthesis and is used as maintenance
is effective against hypnozoites and gametocytes. It therapy for acute leukaemia and does not
is useful in the radical cure of relapsing malarias and commonly cause neurotoxicity, therefore answer
prevention of transmission of P. falciparum. However, C is incorrect (refer to p. 199). Rituximab is used
it is contraindicated in pregnancy and thus answer D in the treatment of lymphoma, but it is not known
is incorrect (refer to p. 191). to cause neuropathies thus answer D is incorrect.
It commonly causes hypotension and fever during
Chapter 13 Cancer infusion and can worsen cardiovascular disease
(refer to p. 203).
1. C. Melphalan is an alkylating agent used to treat
haematological malignancies (refer to p. 199). 4. C. The BCR-ABL fusion gene is found in most
Cisplatin is a platinum compound that inhibits patients with chronic myeloid leukaemia (CML)
DNA synthesis; therefore answer A is incorrect. and in some patients with acute lymphoblastic
Dactinomycin is a cytotoxic antibiotic that interferes leukaemia, found on chromosome 22 and is known
with RNA polymerase and therefore answer B as the Philadelphia chromosome. Imatinib is a
is incorrect. Methotrexate is a folate antagonist, BCR-ABL tyrosine kinase inhibitor, which targets the
antimetabolite medication and therefore answer abnormal tyrosine kinase, created by the Philadelphia
D is incorrect (refer to p. 199). Vinblastine is a chromosome abnormality. Therefore imatinib is the
vinca alkaloid that inhibits the polymerisation of most appropriate treatment in this scenario (refer to
microtubules (refer to p. 200) and therefore answer E p. 201). Everolimus acts as an mTOR kinase inhibitor
is incorrect. and is not known to treat CML, therefore answer A is
incorrect (refer to p. 201). Hydroxyurea is used in the
2. B. Cyclophosphamide causes haemorrhagic cystitis
treatment of CML and polycythaemia rubra vera, but it
because a urinary metabolite of cyclophosphamide,
acts through the inhibition of ribonucleotide reductase
acrolein causes urothelial toxicity. This can be reduced
rather than on the BCR-ABL gene, therefore answer
by high fluid intake concomitantly. Cyclophosphamide
B is incorrect (refer to p. 201). Oxaliplatin is a platinum
can also cause interstitial pulmonary fibrosis, anorexia,
compound that inhibits DNA synthesis and is used in
pancreatitis and at high doses, cardiotoxicity (refer
the treatment of lung, cervical, bladder and testicular
to p. 199). Chlorambucil, used in the treatment of
cancers, therefore answer D is incorrect (refer to
haematological malignancies, can cause bone marrow
p. 200). Procarbazine is a methyl-hydrazine derivative
suppression and severe widespread rash but is not
with monoamine oxidase inhibitor actions and
known to cause haemorrhagic cystitis, therefore
cytotoxicity. It inhibits DNA and RNA synthesis and is
answer A is incorrect. Doxorubicin causes generalized
used in the treatment of Hodgkin lymphoma. It causes
toxicity and dose-dependent cardiotoxicity but
an adverse reaction with alcohol, therefore answer E
not haemorrhagic cystitis, therefore answer C is
is incorrect (refer to p. 201).
incorrect (refer to pp. 199–200). Melphalan is an
alkylating agent, similar to cyclophosphamide but is 5. D. Rituximab lyses B lymphocyte by its effect on the
not known to cause haemorrhagic cystitis, therefore CD20 protein expressed on the surface of white blood

240
 SBA answers

cells. It is given via an infusion for the treatment of Nivolumab is an anti-PDL1 antibody that has been
lymphoma. Cetuximab is licensed for the treatment approved for the treatment of advanced melanoma,
of metastatic colorectal cancers overexpressing therefore answer C is incorrect. Patients with HER2
epidermal growth factor receptors, therefore answer receptor-positive breast cancer are treated with
A is incorrect. Patients who have EGFR mutations trastuzumab, which targets the HER2 receptor and
overexpressed lung cancers are treated with erlotinib cells undergo arrest during the G1 phase of the
which inhibits the intracellular phosphorylation of cell cycle so there is a reduced proliferation of the
tyrosine kinase associated with the EGFR, therefore malignant cells, therefore answer E is incorrect.
answer B is incorrect.

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 EMQ Answers

increasing blood volume and blood pressure because

Chapter 1 Introduction to Pharmacology
of the pharmacokinetic property of the drug on
Receptor interactions and pharmacokinetics absorption, distribution, metabolism and excretion.
1. C. Activation of adenylyl cyclase. Continued 10. J. Drug excretion. Glomerular filtration, tubular
activation of adenylyl cyclase of the cholera toxin resorption and tubular secretion all determine the
results in secretion of large amounts of fluid. extent to which a drug will be excreted by the
2. A. Drug absorption. Drugs that are usually absorbed kidneys which can be reduced in the elderly and in
in the small intestine and enter the portal circulation patients with kidney diseases.
where they are extensively metabolized, which 11. D. Adherence. For some drugs to be effective,
results in less of the drug entering the systemic they must be taken at regular intervals to maintain
circulation. This is known as first pass metabolism. “steady-state” plasma levels. This is particularly
Lidocaine has a high degree of first past metabolism important for some antibiotics because the plasma
and therefore must be given via another route. levels need to be sufficient to kill bacteria.
3. G. Competitive antagonist. Naloxone acts as a
competitive antagonist at the opioid receptors and
thus reduces the ability of the agonist, heroin, to
Chapter 2 Peripheral nervous system
activate the receptor. Medications – their actions and side effects
4. Q. Phase 2 metabolic reaction. Paracetamol is 1. G. Lidocaine is a local anaesthetic that blocks
conjugated with glucuronic acid and sulphate. sodium channels and thus nerve conduction by
When high doses of paracetamol are ingested, binding to the sixth transmembrane region of the
these pathways become saturated and the drug fourth domain. Small nociceptive (painful) fibres are
is metabolized by the mixed function oxidases blocked preferentially because of the high surface
resulting in the formation of the toxic metabolite to volume ratio. Local anaesthetics are therefore
N-acetyl-benzoquinone which is inactivated by useful as movement and touch are not affected
glutathione. When glutathione is depleted, this toxic (refer to p. 20).
metabolite reacts with nucleophilic constituents in 2. C. Botulinum toxin A can be given via local injection.
the cell leading to necrosis in the liver and kidneys. It inhibits acetylcholine release by inactivating actin,
N-acetylcysteine can be administered because which is necessary for exocytosis. It can cause motor
these increase liver glutathione formation and the paralysis thus relieving symptoms (refer to p. 22).
conjugation reactions. 3. A. Atracurium is a nondepolarising neuromuscular
5. L. Continued inactivation of adenylyl cyclase. blocking agent, which acts as a competitive
6. I. Drug distribution. Highly lipid soluble drugs such antagonist by binding to the nicotinic acetylcholine
as thiopental will accumulate in fat and their half-life receptor. The main side effect is hypotension, but
will be much longer in obese patients than in thinner bronchospasm may be a problem in patients with
patients. asthma because of histamine release from mast
7. A. Drug absorption. Morphine is a weak base and cells (refer to p. 22).
is highly charged in the stomach, it is poorly and 4. D. Clonidine is an α2-adrenoreceptor agonist used
erratically absorbed from the stomach and therefore in the treatment of hypertensive migraine. It can
must be given as an injection or delayed release cause drowsiness and hypotension (refer to
capsules. Table 2.5).
8. P. Phase 1 metabolism. Phenytoin induces the 5. L. Phenylephrine is an α1-adrenoreceptor agonist
hepatic P450 system, therefore increasing the used in the treatment of nasal decongestion. It can
metabolism of several drugs. Therefore levels may cause hypertension and reflex bradycardia (refer to
be subtherapeutic rendering them ineffective. This Table 2.5).
highlights the importance of knowing how drugs are 6. I. Neostigmine is an anticholinesterase and can
metabolized. be used to reverse nondepolarising blockers (e.g.,
9. O. Pharmacokinetic interaction. NSAIDS bring about atracurium) but not depolarising blockers. It works
this effect by reducing prostaglandin synthesis in the by inhibiting acetylcholinesterase and thus increases
kidney, thus impairing blood flow and consequently the amount of acetylcholine in the synaptic cleft,
decreased excretion of waste and sodium. Thus enhancing cholinergic transmission.

243
 EMQ Answers

7. B. Atropine is a muscarinic antagonist which results 2. B. Amiodarone. Class III drugs are potassium-channel
in tachycardia and thus counteracts the bradycardic blockers. Amiodarone also blocks sodium and
effects of depolarising neuromuscular blocking agents, calcium channels (refer to p. 51).
which activate muscarinic receptors (refer to p. 12). 3. L. Verapamil. Class IV drugs that reduce the action
8. I & N. Pyridostigmine is used orally in the treatment potential duration through calcium antagonism (refer
of myasthenia gravis and has few parasympathetic to p. 51).
actions. The correct answer is physostigmine, 4. E. Digoxin. A cardiac glycoside with antiarrhythmic
which is an anticholinesterase drug that crosses properties. They are used in the treatment of atrial
the blood–brain barrier and has selectivity for the fibrillation and inhibit the membrane Na/K ATPase of
postganglionic parasympathetic junction. It can myocytes (refer to p. 47).
reduce intraocular pressure and thus is used in 5. J. Procainamide. A class Ia drug that is used in the
the treatment of glaucoma. However, side effects treatment of ventricular arrhythmias (refer to p. 50).
include bradycardia, hypotension, excessive
6. F. Flecainide. A class 1c drug that blocks sodium
secretions and bronchoconstriction (refer to p. 24).
channels similar to class Ia and Ib but shows no
9. J. Phentolamine binds reversibly. Note that
preference for refractory channels. It is used in
phenoxybenzamine is an irreversible antagonist
the treatment of atrial fibrillation in patients with
at α-adrenoreceptors. They cause a fall in blood
structurally normal hearts (refer to p. 50).
pressure caused by block of α-receptor–mediated
7. I. Metoprolol. A class II drug (a ß-adrenoceptor
vasoconstriction (refer to p. 26).
antagonist). They increase the refractory period
10. E. Carbidopa inhibits dopa decarboxylase and
of the AV node and prevent recurrent attacks of
increases dopamine levels but does not affect
supraventricular tachycardias (refer to pp. 50–51).
noradrenaline synthesis (refer to p. 26).
8. A. Adenosine. This antiarrhythmic is used to help
11. P. Reserpine is a drug used in the treatment
with the diagnosis of supraventricular tachycardia
of schizophrenia and reduces the stores of
(refer to p. 66).
noradrenaline presynaptically by preventing the
accumulation of noradrenaline in vesicles. The
displaced noradrenaline is immediately broken down Side effects and contraindications of
by monoamine oxidase and is, therefore, unable to cardiovascular medications
exert sympathetic effects (refer to p. 27). 1. A. Adenosine (refer to p. 66)
12. K. Phenelzine (monoxidase inhibitor). They prevent 2. M. Procainamide (refer to p. 50)
the breakdown of leaked catecholamines so that 3. B. Amiodarone (refer to p. 51)
noradrenaline that leaves the vesicle is protected 4. O. Verapamil (refer to p. 51)
and eventually leaks out from the nerve ending (refer 5. K. Losartan (refer to p. 56)
to p. 27). 6. I. Glyceryl trinitrate (refer to p. 52)
7. L. Metoprolol (refer to pp. 50–51)
Chapter 3 Respiratory system 8. E. Digoxin (refer to p. 47). The cardiac glycosides
Respiratory system drugs and their side effects have a very narrow therapeutic window, and toxicity
and contraindications is therefore relatively common. Effects of cardiac
glycosides are increased if plasma potassium
1. H. Salbutamol. An adverse effect of salbutamol is
decreases, because of reduced competition at
tremor (refer to p. 35).
the K+ binding side on the NA/K-ATPase. This is
2. D. Montelukast. These are common side effects of
clinically important because many diuretics, which
Montelukast (refer to p. 37).
are often used to treat heart failure, decrease plasma
3. C. Ipratropium. Benign prostatic hyperplasia and potassium thereby increasing the risk of glycoside-
glaucoma are contraindications (refer to p. 37). induced dysrhythmias.
4. E. Naloxone. It is used to reverse the effects of opiates 9. N. Spironolactone (refer to p. 48)
(refer to p. 41). 10. F. Enoxaparin (refer to p. 65)
5. A. Aminophylline. It has a narrow therapeutic range and
thus levels must be checked frequently (refer to p. 37). Appropriate management
1. A. Adrenaline 1.10,000 intravenously must be given
Chapter 4 Cardiovascular system in a cardiac arrest situation. Adrenaline 1.1000
Mechanism of action of antiarrhythmics intramuscularly is given in anaphylaxis (refer to p. 59).
1. H. Lidocaine. Class Ib drugs are given for ventricular 2. I. Fondaparinux. This low-molecular-weight heparin
arrhythmias following a myocardial infarction (refer to is used in the prevention of further clots following a
p. 50). myocardial infarction (refer to p. 65).

244
 EMQ Answers

3. F. Digoxin. This cardiac glycoside is used in the 4. K. Indapamide is a thiazide diuretic. It inhibits the
treatment of atrial fibrillation. For rate control, Na+/Cl– cotransporter. Similar to loop diuretics
ß-blockers are commonly prescribed but as this (answer H) it increases the secretion of K+ and H+
patient has asthma, these are contraindicated. into the collecting ducts but, in contrast, thiazide
Second-line rate control is then calcium-channel diuretics decrease Ca2+ excretion by a mechanism
blockers, but given her allergy, this is inappropriate. possibly involving the stimulation of a Na+/Ca2+
Digoxin can be used as a treatment for rate control exchange across the basolateral membrane (refer
(refer to p. 47). to p. 74).
4. K. Phenoxybenzamine. This is an α-adrenoceptor 5. R. Solifenacin is a muscarinic receptor antagonist
antagonist which is used in the treatment of used in the treatment of urge continence. Given
phaeochromocytoma-related hypertensive crises. its anticholinergical properties, it is contraindicated
Treatment with ß-blockers (e.g., bisoprolol) in patients with glaucoma (as is oxybutynin and
is dangerous because the tumour secreted tolterodine) (refer to p. 76).
sympathomimetics act unopposed on α- 6. M. Mannitol is an osmotic diuretic and causes a
adrenoceptors, increasing both peripheral vascular reduction in passive water reabsorption because
resistance and blood pressure (refer to p. 58). of its presence within the tubule lumen. Osmotic
5. E. Dipyridamole. This medication inhibits diuretics, unlike thiazide and loop diuretics, are not
phosphodiesterase enzymes involved in the inhibition used in the treatment of heart failure (refer to p. 75).
of platelet aggregation. It is used in conjunction with 7. J. Ibuprofen is a nonsteroidal antiinflammatory
aspirin in the prophylaxis of stroke in patients with (refer to the Clinical note on p. 70) that
transient ischaemic attacks (refer to p. 66). inhibits prostaglandin production by inhibiting
6. G. Ezetimibe. This lipid-lowering medication is cyclooxygenase. In patients in whom renal blood
indicated when cholesterol remains high despite flow is dependent on vasodilator prostaglandins,
intensive dietary changes and treatment with statins ibuprofen can precipitate renal failure. Paracetamol
at high doses. It inhibits the absorption of cholesterol (answer N) has little effect on the kidney and no
from the duodenum (refer to p. 61). Fish oils are used effect on salt and water retention.
in the treatment of severely raised triglycerides (refer 8. P. Sildenafil causes vasodilation because of
to p. 61). its inhibition of phosphodiesterase-mediated
degradation of cGMP and is used in the treatment
of erectile dysfunction but can affect other vascular
Chapter 5 Kidney and urinary system
beds resulting in these symptoms (refer to p. 76).
Mechanism of action and adverse effects of Although alprostadil (answer A) is used in the
medications treatment of erectile dysfunction its main side effects
1. P. Sildenafil is contraindicated in patients taking include penile pain and priapism.
nitrates because both medications cause 9. G. Eplerenone is a potassium-sparing diuretic that
vasodilation, which can result in severe hypotension acts through competitive aldosterone antagonism
(refer to pp. 76–77). whereas amiloride (answer B) works through
2. B. Amiloride blocks sodium reabsorption by sodium-channel blockade. The combination
the principal cells, thus reducing the potential of potassium-sparing diuretics and an ACE
difference across the cell, reducing K+ inhibitor increases the risk of hyperkalaemia. ACE
secretion. Whereas spironolactone (answer R) inhibitors cause hyperkalaemia because of their
is a potassium-sparing diuretic, it acts through inhibition of the renin-angiotensin aldosterone
competitive antagonism at aldosterone receptors, system (see Chapter 4) whereas potassium-
reducing Na reabsorption and therefore K+ and sparing diuretics reduce the secretion of
H+ secretion (refer to p. 75). potassium in the late distal tubule and collecting
3. L. Lithium is a mood stabilizer given to manage ducts (refer to p. 75).
bipolar disorder. However, it can inhibit the action 10. I. Furosemide is a loop diuretic that inhibits the
of ADH. ADH is released from the posterior pituitary Na+/K+/2Cl– cotransporter. This increases the
gland resulting in the increased expression of amount of sodium reaching the collecting duct and
aquaporins. This increases the amount of water thereby increases K+ and H+ secretion. Calcium
passively reabsorbed thus concentrating the urine. and magnesium reabsorption is also inhibited,
In the presence of lithium, ADH does not exert its owing to the decrease in potential difference across
effects and thus patients excrete large amounts of the cell normally generated from the recycling of
dilute urine. Desmopressin (answer D) is an analogue potassium. Indapamide is incorrect because it is a
of ADH and thus has the opposite effect to lithium thiazide diuretic. Similar to loop diuretics, thiazide
(refer to Clinical Note on p. 71). diuretics increase the secretion of K+ and H+ into

245
 EMQ Answers

the collecting ducts but, in contrast, they decrease salts cause diarrhoea and therefore is the incorrect
Ca2+ excretion by a mechanism possibly involving answer.
the stimulation of a Na+/Ca2+ exchange across the 7. P. Mebeverine is an antispasmodic that works
basolateral membrane. to directly relax smooth muscle. Answer W
11.H. Finasteride is a 5α-reductase inhibitor that propantheline is incorrect because, although it
converts testosterone to the more potent androgen is used as an antispasmodic in the treatment of
dihydrotestosterone. This inhibition leads to a irritable bowel syndrome, it is a muscarinic-receptor
reduction in prostate size, and improvement of urinary antagonist (refer to p. 85).
flow. Thus is used in the management of BPH. 8. Y. Terlipressin is often used in the treatment of
12. N. Mirabegron is a selective β agonist that has oesophageal varices to prevent catastrophic varial
been licensed recently for treatment of overactive haemorrhage (refer to p. 82).
bladder. Solifenacin, although used in patients 9. C. Biscodyl is a stimulant laxative that takes 15
with overactive bladder, is a muscarinic receptor to 30 minutes to take effect. It is important only
antagonist. Duloxetine is a serotonin noradrenaline to prescribe this medications for short courses to
reuptake inhibitor (see Chapter 8) used as second- prevent damage to the nerve plexuses within the gut
line treatment for stress incontinence. (refer to p. 86).
10. S. Orlistat is licensed in the treatment of obesity
Chapter 6 Gastrointestinal system but can cause flatulence and abdominal pain.
Methycellulose (answer R) works by promoting early
1. J. Enterochromaffin-like paracrine cells release
satiety to reduce food intake (refer to p. 88).
histamine. Histamine then acts locally on the
11. B. Azathioprine is an immunosuppressant used in
parietal cells where activation of the H2 receptor
the management of inflammatory bowel disease. It is
results in the stimulation of adenylyl cyclase and
metabolized to 6 mercaptopurine (refer to p. 88).
the subsequent secretion of acid. Answer T parietal
12. M. Lactulose is a semisynthetic disaccharide that
cells is incorrect because they directly secrete acid
produces an osmotic load, increasing the fluid
and answer U peptic cells is incorrect because they
content within the bowel, helping the passage
secrete digestive enzymes (refer to p. 79).
of stool. It can cause flatulence and abdominal
2. Z. Ursodeoxycholic acid is used in the treatment
discomfort as well as electrolyte disturbance (refer
of gallstones because it reduces cholesterol within
to p. 86).
bile (refer to p. 28). Cholestyramine (answer D) is
13. X. Sulfasalazine can cause infertility in males
incorrect because it acts as an anion exchange
secondary to oligospermia (refer to p. 88).
resin, binds acids in the gut and prevents their
reabsorption as used in treatment of pruritic
(refer to p. 89). Chapter 7 Endocrine and reproductive
3. L. Ispaghula husk is a bulk-forming laxative that
systems
stimulates peristaltic activity. It is contraindicated
if there is any intestinal obstruction (refer to p. 84). Adverse effects of endocrine drugs
Docusate sodium (answer H) is a faecal softener and 1. I. Octreotide is an analogue of somatostatin, which
is therefore incorrect. is used in the treatment of acromegaly as it ihibits
4. V. Pantoprazole is a PPI that irreversibly inhibits growth hormone release. Cholelithiasis (gallstones) is
H+/K+ ATPase. They are used in the treatment a well-recognized complication (refer to p. 105).
of GORD, peptic ulcers and in combination to 2. D. Clomifene is an antioestrogen used in the treatment
eradicate H. pylori. In some patients on multiple of infertility. Ovarian hyperstimulation is a rare
medications, PPIs can cause hyponatraemia complication (refer to p. 108). Tamoxifen (answer K)
(refer to p. 81). has antioestrogen effects but is not known to cause
5. Q. Metoclopramide. This can cause an oculogyric ovarian hyperstimulation.
crisis and torticollis secondary to its dopamine 3. A. Alendronate, a bisphosphonate, is used in the
receptor antagonism within the nigrostriatum of treatment of postmenopausal osteoporosis and can
the brain, which causes an excess of cholinergic cause oesophagitis, ulcers and erosions. Prescribers
output resulting in the extrapyramidal symptoms. must advise patients to swallow tablets with a full
Domperidone (answer I), although a dopamine glass of water and to remain sat upright for at least 30
antagonist, does not penetrate the blood–brain minutes afterwards. Denosumab (answer E) is used
barrier to the same extent as metoclopramide as second-line treatment of osteoporosis but is not
(refer to p. 83). known to cause this complication (refer to p. 110).
6. A. Aluminium hydroxide causes constipation and 4. F. Iodide is used in the treatment of a thyrotoxic crisis
is antacid (refer to p. 82). Answer O magnesium and inhibits the conversion of T4 to T3. It should

246
 EMQ Answers

not be given to pregnant or breastfeeding women Medications used in the treatment of mood
because it can cause a goitre in infants (refer to p. 8). disorders and insomnia
Carbimazole (answer C) is used in the treatment of 1. G. Mirtazapine is an atypical antidepressant that
hyperthyroidism but is not known to cause impotence, results in an increased amount of noradrenaline in
depression and insomnia. Levothyroxine (answer G) is the synaptic cleft. A dangerous but rare side effect
used in the treatment of hypothyroidism. of mirtazapine is agranulocytosis (where the white
blood cells become very low). If this occurs, then the
Chapter 8 Central nervous system medication must be stopped because of the risk of
Medications used in the treatment of Parkinson severe infection. Reboxetine (option I) is incorrect
disease, dementia and the eye because it acts as a selective inhibitor of noradrenaline
uptake (refer to p. 124).
1. G. Levodopa can cause cardiac arrhythmias arising
from increased catecholamine stimulation following 2. A. Buspirone is a 5-HT1A agonist that is prescribed
the excessive peripheral metabolism of L-dopa (refer orally and given for the short-term relief of generalized
to p. 114). anxiety disorder. Adverse effects include dizziness,
headache and light-headedness. Sertraline and
2. B. Cabergoline is a dopamine agonist effective in
fluoxetine (option E & K) are incorrect because they
treating the motor features of Parkinson disease.
are SSRIs (refer to p. 120).
Dopamine agonists are commonly prescribed in
younger patients because they cause fewer motor 3. J. Risperidone acts as an antagonist at both
fluctuations. However, patients should be warned dopamine and 5-HT receptors. Neuroleptic
about the risk of developing compulsive or disinhibited medications cause a variety of adverse effects as a
behaviours while taking cabergoline (refer to p. 116). result of the disruption of dopaminergic pathways
Selegiline (option L) selectively inhibits the MAOB (refer to p. 127). The effects are more pronounced
enzyme in the brain normally responsible for the with typical neuroleptics but can occur with newer,
degradation of dopamine and therefore is incorrect atypical neuroleptics. (Options C & H are also correct).
(refer to p. 116). 4. C. Clozapine acts at dopamine receptors and
3. K. Procyclidine is an example of an anticholinergic. is an effective medication for the treatment of
It acts as an antagonist at muscarinic receptors that schizophrenia but has several unpleasant side effects
mediate cholinergic excitation and is prescribed for including hypersalivation, sedation, tachycardia and
patients with Parkinson disease who have a severe significant weight gain. It is therefore used in severe,
tremor (refer to p. 116). longstanding schizophrenia (refer to p. 127).
4. H. Memantine selectively inhibits the excessive 5. B. Chlordiazepoxide is a benzodiazepine and
and pathological activation of NMDA receptors. potentiates the effect of GABA release and has
Memantine can cause a headache, dizziness and inhibitory effects on postsynaptic cells within the CNS.
constipation and is contraindicated in patients with Although zopiclone (option L), a newer-generation
a history of seizures. Donepezil (option D), although hypnotic, is thought to act on the GABAA receptor, it is
used in the management of mild to moderate not the same site as benzodiazepines, and zopiclone
Alzheimer dementia, is a cholinesterase inhibitor, are used in the short-term treatment of insomnia, not
which prevents the breakdown of ACh within the acute alcohol withdrawal (refer to p. 119).
synaptic cleft, and therefore is the incorrect answer 6. F. Melatonin acts at the MT1 receptor and improves
(refer to p. 117). sleep onset and quality in patients aged over 55 years
5. F. Latanoprost is prescribed in the treatment of and in children with autism (refer to p. 121). Zopiclone
open-angle glaucoma because it promotes outflow (option L) is used in the treatment of insomnia but
of aqueous fluid from the anterior chamber via an it acts on the GABAA receptor and therefore is the
alternative drainage route (refer to p. 136). Timolol incorrect answer.
(option M), a beta-adrenoceptor antagonist is also 7. H. Olanzapine has low affinity for the D2 receptor
used to reduce intraocular pressure within the eye but and high affinity for D1 and D4 receptors as does
is not known to cause brown pigmentation of the iris clozapine. However, olanzapine is usually first line
(refer to p. 134). whereas clozapine (option C) is used in refractory
6. J. Pilocarpine, a muscarinic antagonist, is used in cases of schizophrenia and therefore is incorrect
the management of acute closed angle glaucoma (refer to p. 127).
because it causes constriction of the pupil, allowing 8. D. Flumenazil is a benzodiazepine antagonist and
aqueous fluid to drain from the anterior chamber into can be given to patients suspected of taking a
the trabecular meshwork. It is also used to reverse benzodiazepine overdose. Patients with severe
mydriasis at the end of an ophthalmic examination social anxiety may be prescribed short-courses of
(refer to p. 136). benzodiazepines (refer to p. 127).

247
 EMQ Answers

Medications used in the treatment of epilepsy (refer to p. 17). Flumazenil (option F) is incorrect
1. A. Carbamazepine or G. Phenytoin. Both are because it is a benzodiazepine receptor antagonist.
commonly used anticonvulsants that induce Benzodiazepine toxicity causes hypotension and
the hepatic cytochrome P450 oxidase enzyme confusion (refer to p. 143).
resulting in the increased metabolism of warfarin. 5. D. Diazepam is a benzodiazepine that acts by
This also results in reduced amounts of warfarin, potentiating the inhibition of GABA transmission.
limiting its anticoagulant effects. Female patients on Benzodiazepines are widely abused drugs because
carbamazepine or phenytoin should be warned that they induce a dream-like effect. Withdrawal includes
oral contraception might be less effective rebound anxiety and insomnia (refer to p. 142).
(refer to p. 132). Ethanol (option E) also potentiates inhibitory GABA
2. C. Diazepam is a short-acting benzodiazepine that transmission but is not prescribed, therefore is
potentiates chloride currents through the GABAA incorrect.
channel complex and is commonly used in the 6. F. Ethanol can cause Wernicke encephalopathy which
management of status epilepticus. A potentially presents as a classic triad of confusion, ataxia and
harmful side effect is respiratory depression (refer to ophthalmoplegia. Long-term alcohol abuse can result
p. 133). Clonazepam (option B) is a longer-acting in thiamine deficiency and subsequently, Korsakoff
benzodiazepine and is not commonly used in the syndrome can develop. This causes amnesia and
management of status epilepticus. confabulation (refer to p. 142).
3. A. Carbamazepine is a commonly prescribed 7. E- Disulfiram, an aldehyde dehydrogenase inhibitor
anticonvulsant for generalized tonic-clonic seizures. given to patients trying to achieve alcohol cessation
Be aware that it is a hepatic enzyme inducer and (refer to p. 142).
interacts with many medications (e.g., warfarin) (refer 8. I. Ketamine causes thickening of the bladder
to p. 125). and urinary tract and can cause severe bladder
4. D. Ethosuximide is useful in treatment of absence dysfunction. Ketamine and MDMA (option K) are
seizures, which are caused by oscillatory neuronal taken because they cause feelings of relaxation and
activity between the thalamus and cerebral cortex pleasant out of body experiences. NMDA causes
(refer to p. 133). Vigabatrin (option I) should not be patients to overhydrate and have hyponatraemia,
given to patients with absence seizures and is typically therefore is not the correct answer (refer to p. 141).
only prescribed for patients with difficulty to control 9. B. Cocaine is usually snorted or smoked and causes
epilepsy by specialists only. euphoria. Adverse effects include paranoid psychosis
5. E. Lamotrigine inhibits glutamate release and is and tissue damage to the nostrils and at sites of
taken orally. Adverse effects include rash, fever, injection (refer to p. 4). Amphetamines also cause
hepatic impairment and malaise (refer to p. 133). the release of monoamines and inhibit monoamine
reuptake (refer to p. 140).

Chapter 9 Drug misuse

Drugs of misuse Chapter 10 Pain and anaesthesia
1. J. LSD, an example of a psychomimetic, can also Analgesia and anaesthesia
cause hallucinations and delusions, some are 1. J. Lidocaine is a local anaesthetic that is directly
pleasant, and others are frightening. bad trips. In injected into the skin and underlying tissue. This
chronic toxicity, flashbacks may occur long after the allows local surgery to be performed while the
trip (refer to p. 144). person is awake.
2. C. Delta-9-tetrahydrocannabinol (THC). Hashish 2. O. Nitric oxide diffuses into air containing
(option G) is the extracted resin of the cannabis plant closed spaces and accumulates in gaseous
(refer to p. 144). cavities. This increases the pressure within the
3. A. Clonidine is an α2-adrenoceptor agonist that lungs and will worsen a pneumothorax and will
reduces nausea, vomiting and diarrhoea associated significantly compromize breathing. It is useful in
with opioid withdrawal. Methadone (option K) the maintenance of anaesthesia or as analgesia
is incorrect because it is a long acting opiate. (e.g., labour). Although halothane (option N) is an
Methadone is used to help reduce the intensity of inhaled anaesthetic it is not as associated with this
opioid withdrawal, through substitution (refer to complication as nitric oxide.
p. 143). 3. C. μ-Receptors. These receptors are also
4. N. Naloxone is an opioid antagonist used in acute responsible for the major adverse effect of opioids,
toxicity of an opiate overdose. Bronchospasm respiratory depression. δ Receptors (option A) is
and flushing are caused by a histamine release incorrect. These do contribute to analgesia but are

248
 EMQ Answers

thought to be more important in the periphery (refer

to p. 145).
Chapter 11 Inflammation, allergic diseases
4. E. Amitriptyline. The pain described in this and immunosuppression
statement suggests neuralgic pain, discomfort in Medications used in the treatment of
the distribution of a particular nerve. Amitriptyline, a inflammation and immunosuppression
tricyclic antidepressant, is used in the management 1. R. Thromboxane A2 is involved in platelet
of neuralgic pain. Carbamazepine and gabapentin aggregation and vasoconstriction. Prostaglandin
are also useful for the treatment of neuropathic (option Q) is incorrect because they produce
pain (refer to p. 150). Morphine (option L), although increased vasodilation, vascular permeability and
a strong opioid, is not effective in the treatment of oedema in an inflammatory reaction. Prostacyclin
nerve-related pain. (option P) is incorrect because they inhibit platelet
5. B. κ Receptors. These receptors may also cause aggregation and cause vasodilation (refer to
sedation but do not contribute to physical box 11.2).
dependence. σ Receptors are not selective 2. N. Methotrexate has cytotoxic and
opioid receptors, but they may account for the immunosuppressant activity and acts as a
dysphoria produced by some opioids (refer to competitive inhibitor of dihydrofolate
p. 154). reductase, which is important for DNA
6. K. Midazolam, a benzodiazepine, reduces anxiety synthesis. Although it is a common first
and can also lessen the amount of general choice drug for the treatment of rheumatoid
anaesthetic required to achieve and to maintain arthritis, a full blood count and liver function test
unconsciousness. Atropine (option F) is incorrect should be checked regularly because it can cause
because it is a muscarinic antagonist given to help bone marrow suppression and liver cirrhosis.
reduce bronchial secretions and counteract the Patients should be coprescribed folic acid (refer to
bradycardia caused by some inhalation agents p. 8). Patients on methotrexate can also develop
(refer to p. 153). These two medications, alongside interstitial pulmonary fibrosis and may present with
analgesia and antiemetics, are given at the induction progressive shortness of breath. Penicillamine
of general anaesthesia. (option O) is a DMARD but it is not a folic acid
7. G. Etomidate can also cause pain on injection. antagonist. It chelates metal and is sometimes
Thiopental (option P) is incorrect, even though used in the treatment of Wilson disease that
it is an induction agent it typically causes causes excess copper deposition (refer to
bradycardia and respiratory depression (refer to p. 163).
p. 154). 3. G. COX-1 is expressed on platelets, gastric
8. N. Naltrexone has a half-life of 10 hours, whereas mucosa and renal vasculature. It is also involved
the shorter acting opioid receptor antagonist, in physiological cell signalling. Inhibition of COX-1
naloxone has a 2- to 4-hour half-life (refer to causes the majority of adverse effects associated
p. 149). with NSAIDs. COX-2 (option H) provides the
9. D. Adrenaline causes vasoconstriction of the blood analgesic and antiinflammatory effects of NSAIDs
vessels around the site of the LA injection preventing when inhibited (refer to p. 159).
the spread of the LA. Adrenaline should not be used 4. A. Aspirin irreversibly blocks the formation of
at extremities (e.g., end of digits) because of the risk thromboxane A2 and is therefore used in the primary
of ischaemia. and secondary prevention of cardiovascular disease.
10. I. Ketamine, a dissociative anaesthetic, is It also irreversibly inhibits cyclooxygenase. It can
commonly used as a general anaesthetic in children cause tinnitus in toxic doses. Celecoxib (option E)
but given the high incidence of dysphoria and is incorrect because it is a COX-2 specific inhibitor.
hallucinations in adults, it is less frequently used This drug is associated with an increased incidence
(refer to p. 154). of cardiovascular effects (e.g., myocardial infarction)
11. N. Halothane is an inhaled anaesthetic used as a (refer to p. 159).
maintenance agent. It has the potential to induce 5. J. Etanercept contains the ligand-binding
hepatotoxicity and hepatic necrosis and has been component of the human TNF receptor. It is
replaced largely by newer volatile anaesthetic (e.g., used to treat severe rheumatoid arthritis when
isoflurane). Nitric oxide (option O) is incorrect. DMARDs have not provided an adequate response.
This has low blood solubility and produces rapid Infliximab is a monoclonal antibody that binds
induction and recovery because relatively small TNF-α preventing its interaction with cell surface
amounts are required to saturate the blood. Nitric receptors. Neither infliximab or etanercept should
oxide must always be given with oxygen (refer to be given to patients with live vaccines (refer to
10.11 and p. 155). p. 164).

249
 EMQ Answers

6. K. Febuxostat reduces uric acid synthesis and 2. J. Flucloxacillin is used in the treatment of skin
is used in the prophylactic treatment of gout. infections (refer to p. 174). Benzylpenicillin (answer
Allopurinol works in the same way. These C) is incorrect because it is often inactivated by
medications can cause dyspepsia, headaches β-lactamase.
and a rash. They should not be given during an 3. D. Ceftriaxone. This antibiotic is part of the
acute attack (refer to p. 165). Colchicine (option F) cephalosporin family and is good against gram
is incorrect. It inhibits the migration of leucocytes negatives (refer to p. 176).
into the inflamed joint because colchicine inhibits 4. H. Doxycycline. This tetracycline antibiotic can
microtubular function and mitotic spindle formation. depress bone growth and cause permanent
It causes nausea, vomiting and diarrhoea but is discolouration of teeth. It also causes gastrointestinal
commonly used in the treatment of an acute gout reflux and photosensitivity. Doxycycline is typically
attack (refer to p. 165). used in the treatment of acne and atypical chest
7. I. Efudix (5 Fluorouracil) is used topically for the infections (refer to p. 178).
treatment of basal cell carcinomas and other areas 5. R. Trimethoprim. This antifolate antibiotic causes
of skin damage (e.g., actinic keratosis). Benzoyl bilirubin displacement and affects the synthesis
peroxide (option C) is incorrect because it is an of purine and bacterial DNA. Nitrofurantoin
antibacterial/keratolytic used in the treatment of (answer K) is incorrect. It can be given safely in
acne vulgaris (refer to Table 11.8). the treatment of UTIs up until the third trimester,
8. L. H1-receptor antagonists are used to counteract however, it should be avoided in the third
the actions of histamine that arise during an allergic trimester of pregnancy given the risk of neonatal
reaction. Histamine at H1-receptors causes capillary haemolysis.
and venous dilation, increased vascular permeability 6. E. Ciprofloxacin is a quinolone that inhibits
and contraction of smooth muscle. H2-receptor prokaryotic DNA gyrase and works effectively
(option M) is incorrect because they are involved in against gram-negative organisms. Ciprofloxacin
the regulation of gastric acid secretion (refer to Table is effective in the treatment of pyelonephritis and
11.11). levofloxacin is used for respiratory infections (refer
9. D. Cyclosporine reversibly suppresses both cell- to p. 177).
mediated and antibody-specific immune responses. 7. F. Clindamycin is a lincosamide used in the
It has a selective inhibitory effect on T cells and treatment of severe cellulitis (refer to p. 179).
is used for the prevention of graft and transplant 8. M. Metronidazole is a medication that is both an
rejection. Although it does not cause bone marrow antiprotozoal and has good anaerobic cover. It is
suppression, it is very nephrotoxic and can cause additionally used in the treatment of intraabdominal
kidney failure and hypertension (refer to pp. sepsis (refer to p. 179).
170–172). 9. S. Zanamivir is delivered via inhalation and is used
10. B. Azathioprine is a prodrug that has cytotoxic in the treatment of influenza A and B virus within
action on dividing cells, used to prevent graft 48 hours after onset of symptoms (refer to p. 182).
and transplant rejection as well as treatment for Amantadine (answer B) is incorrect. Amantadine
autoimmune conditions when corticosteroid therapy blocks a primitive ion channel in the viral membrane
is inadequate. Guidance in the United Kingdom (named M2) preventing fusion of a virion to host
is that patients commencing azathioprine have cell membranes and inhibits the release of newly
their thiopurine methyltransferase (TPMT) enzyme synthesized viruses from the host cell. It is not a
measured because if a patient has no or low TPMT neuraminidase inhibitor and is only used in the
activity, then they are at risk of developing the severe treatment of influenza A.
side effects associated with azathioprine (e.g., 10. A. Acyclovir is used in the treatment of HSV and VZV
bone marrow suppression, infections, alopecia and infections. Side effects include encephalopathy and
gastrointestinal disturbances) (refer to p. 172). renal impairment. Ganciclovir (answer K) is used in
the treatment of CMV infection because it is resistant
to acyclovir; the CMV genome does not encode
Chapter 12 Infectious diseases
thymidine kinase (refer to p. 183).
Medications used in the treatment of 11. T. Zidovudine is a nucleoside reverse transcriptase
inflammation and immunosuppression inhibitor used in the treatment of HIV. Enfuvirtide
1. Q. Tazocin is used in the treatment of neutropenic (answer I) works by preventing fusion of the HIV virus
sepsis (refer to p. 174). It is part of the penicillin with the host cell (refer to p. 184).
family and inhibits cell wall synthesis and is 12. L. Indinavir is a protease inhibitor. Answer N
bactericidal. (nevirapine) is a nonnucleoside reverse transcriptase

250
 EMQ Answers

inhibitor which inactivates reverse transcriptase and in acute lymphoblastic leukemia. It causes severe
is thus incorrect (refer to p. 185). toxicity to the liver and pancreas as well as CNS
13. P. Nystatin binds to ergosterol in the fungal cell depression (refer to p. 201).
membrane resulting in death and treatment of 5. M. Prednisolone is an adrenocortical steroid that
candida. inhibits the growth of some cancers but is also used
in the treatment of oedema associated with cancer
and can be used in palliative settings (refer to p. 201).
Chapter 13 Cancer
6. O. Tamoxifen acts as a competitive inhibitor at
Medications used in the treatment of cancer oestrogen receptors. Side effects include nausea,
1. I. Fluorouracil is converted into a fraudulent flushing and bone pain. Tamoxifen also increases the
pyrimidine nucleotide, fluorodeoxyuridine risk of endometrial cancer (refer to p. 202).
monophosphate, that inhibits thymidylate synthetase, 7. F. Degarelix is a GnRH antagonist that reversibly
impairing DNA synthesis. It is used in the treatment of binds to GnRH receptors in the pituitary gland,
superficial basal cell carcinoma and gastrointestinal blocking the release of LH and FSH, suppressing
tract cancers (refer to p. 199). Methotrexate the release of testosterone from the testes and
competitively antagonizes dihydrofolate reductase is used in the treatment of prostate cancer.
and prevents the regeneration of intermediates Bicalutamide is an androgen antagonist that acts at
(tetrahydrofolate) essential for the synthesis of purine androgen receptors thus suppressing testosterone
and thymidylate, therefore answer L is incorrect production, therefore answer B is incorrect (refer to
(refer to p. 199). p. 202).
2. G. Doxorubicin is used in the treatment of 8. J. Gardasil is one of the cervical cancer vaccines
acute leukaemia and lymphoma. It can be given given to girls aged 12 to 13 years (refer to p. 202).
intrathecally to treat bladder cancer. It produces Sipuleucel T is an example of autologous cellular
a dose-dependent cardiotoxicity because of immunotherapy and is used in the treatment of
irreversible free radical damage to the myocardium metastatic prostate cancer, therefore answer N is
(refer to p. 200). Bleomycin acts on DNA fragments incorrect (refer to p. 202).
and may cause pulmonary fibrosis, but has virtually 9. H. Filgastrin is an example of recombinant human
no myelosuppression, therefore answer C is granulocyte colony stimulating factor used to
incorrect. raise white blood cell counts after cytotoxic
3. D. Cisplatin is a platinum compound used in the chemotherapy (refer to p. 202). Aldesleukin is a
treatment of lung, cervical, bladder and testicular cytokine, specifically an IL-2 used in the treatment of
cancer. It acts by inhibiting DNA synthesis and metastatic renal cell carcinoma, therefore answer A
transcription. However, platinum compounds (e.g., is incorrect (refer to p. 202).
carboplatin and oxaliplatin) cause significant nausea 10. K. Gonadorelin stimulates the production of
and vomiting, often requiring concomitant 5-HT3 oestrogen and testosterone in a nonphysiological
antagonist antiemetics (e.g., ondansetron) and can manner, resulting in the disruption of endogenous
cause nephrotoxicity and ototoxicity (refer to p. 200). hormonal feedback systems, reducing the amount of
4. E. Crisantaspase breaks down circulating testosterone production. It is used in the treatment
asparagine and is used as a form of chemotherapy of prostate cancer (refer to p. 202).

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 Index

Note: Page numbers followed by f in- adrenaline, 28t, 59 aldosterone, 47, 54, 71, 73f, 100
dicate figures, t indicate tables and b anaphylactic shock, 169t antagonists, 75
indicate boxes. inactivation, 28–29 aldosterone-induced proteins
open-angle glaucoma, 136 (AIP), 73f
α-adrenoceptor, 25, 48 alemtuzumab, 203
A activation, 53f, 54 alendronate, 110, 111b
abacavir, 184 agonists, 48, 136–137 alfacalcidol, 112
abciximab, 66 antagonists alginates, 82
abnormal impulse conduction and for hypertension, 55t alkaline salts, 82
generation, 49 for phaeochromocytoma, 58 alkylating agents, 195, 196f, 199
absence seizures, 129t, 130, 132t for reversing mydriasis, 137 allergens, 33–34, 34f, 168
absorption, drug, 9 effects mediated by, 26 allergic disorders, 168–170, 168f
acarbose, 98 α1-adrenoceptor, 26 drug therapy of, 169–170, 169t
acetazolamide, 133, 136 antagonists, 56–57 allergic reactions to drugs, 16
acetic acids, 161t, 162 α2-adrenoceptor, 26 allergic rhinitis, 40–41, 169t
acetylcholine (ACh), 2, 20–21, 35, 79, 80f antagonists, 57–58 allopurinol, 12t
drugs inhibiting release of, 22 β-adrenoceptor, 25, 52 gout, 164t, 165
drugs inhibiting synthesis of, 22 agonists, 48 allylamines, 187–188
drugs inhibiting vesicular packaging antagonists (see beta-blockers) alpha-blockers, 75–76
of, 22 effects mediated by, 26 alprostadil, 77
parasympathetic nervous system, 29, 29f β1-adrenoceptor, 45 alteplase, 66
release of, 22 β2-adrenoceptor, 35 altretamine, 201
acetylcholinesterase (AChE), 20–21, 21f, activation, 53f, 54 aluminium hydroxide, 82
23 agonists, 35–37 alverine, 85
acetylsalicylic acid. See aspirin adrenoceptor agonists, 28 Alzheimer’s disease, 117
acid, 144 adrenoceptor antagonists, 28 amantadine, 115f, 116, 181–182
acid-related disease, 80–82. See also specific adrenocortical steroids, 201 amethocaine, 152t
disease adrenocorticotrophic hormone (ACTH), amide-linked local anaesthetic, 150, 150f
acne, 165, 166f, 168t 100–101, 102t, 104b amikacin, 177
acquired immune deficiency syndrome adsorbents, 85f, 87 amiloride, 73f, 75
(AIDS), 184–185, 192 affect, flattening of, 125 aminoglycosides
acquired resistance, 173 affective disorders, 121–125 acetylcholine (ACh), 22
acrolein, 199 bipolar, 124 antibiotics, 73
actin, 22 treatment of, 124 bacteria affected by, 175–176t
actinomycin D, 199 monoamine theory of depression, 121 loop diuretics, 73
action potential, 19 unipolar, 121 peptidoglycan cell walls, 174t
cardiac, 43, 44f site of action of drugs for, 122t, 123f protein synthesis, 177
nerve, 19, 20f, 20t treatment of, 122–124 sites of action, 174t, 178f
acyclovir, 183–184 afferent arterioles, 69–70, 70f aminopenicillin, 175–176t
adalimumab, 88, 164 affinity, 6 aminophylline, 37
adenoma, 92 African Caribbeans, hypertension in, 55b 4-aminoquinolines, 190
adenosine, 51 African trypanosomiasis, 192 8-aminoquinolones, 191
adenosine diphosphate (ADP), 62, 95 μ-agatoxins, 152t 5-aminosalicylate (5-ASA), 88, 163
inhibitors, 66 agonist drugs, 5–7, 6f aminosalicylates, 87–88
adenosine triphosphate (ATP), 73f, 95, 192 AIDS. See acquired immune deficiency amiodarone, 50t, 51, 94b
adenoviruses, 182t syndrome (AIDS) amitriptyline, 120, 122, 122t
adenylate cyclase, 147 albendazole, 193, 193t pain relief, 150
adenylyl cyclase, 4–5, 45, 54, 79 albumin, 9 amlodipine, 55b
adherence, patient, 14–15 alcohol, 13–14 amoebae, 189t
adjuvant chemotherapy, 195 misuse of, 140t, 142 amoebiasis, 191
administration, 8–9. See also specific route withdrawal, 142 amoebic dysentery, 191
adrenal medulla, 25 alcuronium, 23t amoxicillin, 82, 174, 175–176t

253
 Index

amphetamines, 27–28, 27f, 129 antibacterial drugs (Continued) anti-proliferatives, 170, 172
inactivation, 28 that inhibit bacterial nucleic acids, 177 antiprotozoal drugs, 188–192
misuse of, 139–140, 140t that inhibit cell wall synthesis, 174–177 antipseudomonal penicillin, 175–176t
amphotericin B, 186 that inhibit protein synthesis, 177–179 antipsychotics. See neuroleptic drugs
ampicillin, 87, 174, 175–176t antibiotics. See antibacterial drugs antipurines, 199
amprenavir, 185 antibody directed enzyme prodrug therapy antipyrimidines, 199
amsacrine, 201 (ADEPT), 203 antispasmodics, 84–85, 85f
amylase, 88–89 anticholinergics, 37 antithrombin III, 63, 65
anabolic steroids, 109, 140t parkinsonism, 115f, 116–117 α1-antitrypsin, 35
anaemia, 67–68 anticholinesterases, 23–24 antituberculosis therapy, 180
anaesthesia, 145f, 152t Alzheimer’s disease, 117 antitussives, 39–40
basic concepts, 145–147 intermediate-acting, 23 antiviral drugs, 181
general (see general anaesthesia) parasympathetic nervous system, 30 skin disorders, 168t
local (see local anaesthesia) short-acting, 23 anxiety, 117, 119t, 120
use of neuromuscular blockers in, 156 anticoagulants, 64–65 general anaesthesia, 153
anaesthetics, 153–156 direct oral, 65 anxiolytics, 117–121, 119t, 120b
dissociative, 140t anticonvulsants. See antiepileptics acting at serotonergic receptors,
anal disorders, 88 antidepressants, 120 120–121
anal fissures, 86, 88 major classes of, 122t apathy, 125
analeptic drugs, 41 pain relief, 150 apixaban, 65
analgesia sedative, 119t (see also specific class of apomorphine, 115f, 116
opioid analgesics (see opioids) antidepressant) aprotinin, 67
prior to general anaesthesia, 153 antidiarrhoeal drugs, 85f, 86–87 aquaporins, 70–71
analgesic ladder, 145, 145f antidiuretic hormone (ADH), 59, 71 aqueous humour, 134, 135f
anaphylactic shock, 16, 58–59, 169b, 169t antidopaminergic drugs, 82 drugs used to increase the drainage of,
androgen dihydrotestosterone, 109 antiemesis, postoperative, 153 135f, 136
androgenic steroids, 140t antiemetic drugs, 82–84, 144 drugs used to inhibit production of,
androgens, 109, 165 migraine, 149 134–136
agonists, 109 antiepileptics, 130–134, 131f, 132b open-angle glaucoma, 134–136
antagonists, 109, 202 mechanisms of action of, 130, 131f arachidonic acid, 159, 162
angel dust (PCP), 154 pain relief, 150 arachidonic acid metabolites, 159, 160f,
angina pectoris, 51–52 antifolates, 174t, 177, 190 160t, 162
drugs for, 52–54, 54t antifungal drugs, 186–188 arenaviruses, 181, 182t
stable, 51–52, 51b sites of action of, 186–188 aripiprazole, 127
unstable, 51–52 skin disorders, 168t aromatase inhibitors, 202
angiotensin II, 47, 54 antihistamines, 120–121 arrhythmias, 49
angiotensin-converting-enzyme (ACE) allergic disorders, 169–170, 170t antiarrhythmic drugs, 49–51, 50t, 54t
inhibitors, 48 histamine, 40–41, 129, 149, 159 general anaesthesia, 153
for hypertension, 55–56, 56f sedative, 119t levodopa induced, 114
renin–angiotensin system, 54, 56f antihormones, 201–202 artemisinin, 191
angiotensin-II receptor antagonists, 55–56, antihypertensive drugs, centrally acting, arterial occlusion, 63
55t 57–58 arterioles
anhedonia, 125 anti-inflammatory drugs, 38–39, 159–162 afferent, 69–70, 70f
anion inhibitors, 93–94, 94f glucocorticoids, 38–39, 101, 102–103t efferent, 69–70, 70f
antacids, 80f, 82 respiratory disorders, 38 aspirin, 9
antagonist drugs, 5–7 anti-leprosy therapy, 180–181 anti-inflammatory properties, 159–161,
anthelmintic drugs, 192–194 antimalarials, 162t, 163, 189–191 161t, 164
anti-androgens, 75–76, 109, 165, 201 antimetabolites, 197f, 199 for bleeding disorders, 65, 66f
anti-anginal drugs, 52–54, 54t antimicrobial agents gout, 164
antiarrhythmic drugs, 49–51, 50t, 54t diarrhoea, 86–87 asthma, 15, 33–35, 34f, 169t
antiasthmatic drugs, 35 intestinal motility, 85f and hypertension, 55t
antibacterial drugs, 173–186, 174t antimuscarinics, 122 management, 35, 36t
antimycobacterial drugs, 180–181 general anaesthetic, 153 NSAIDs and, 37b
chemotherapy, 173 intestinal motility, 84, 85f atenolol, 50, 52, 94
classification of, 173 antimycobacterial drugs, 180–181 atherosclerosis, 60–61
cytotoxic, 195, 196f anti-obesity drugs, 88 atopic disorders, 168
miscellaneous, 179–180 antioestrogens, 108 atorvastatin, 61
prescribing, 173–174 antiparasite preparations, 168t atracurium, 23t
resistance, 173 antiplatelet agents, 52, 54t, 63b, 65–66 atrial arrhythmias, 49
sites of action of, 174t antiporters, 1 atrial fibrillation, 43, 49b
skin disorders, 168t anti-progestogens, 108–109 atrial natriuretic peptide, 5, 71

254
 Index 

atrioventricular node (AVN), 43, 44f benzodiazepines, 118–120, 118f, 119t bromocriptine, 105, 115f, 116
atropine, 23–24, 30t epilepsy, 133 bronchial inflammatory mediators, 34–35
effects of, on the eye, 137t general anaesthesia, 153 bronchodilators, 35–38
intestinal motility, 84 half-lives of, 119t bronchospasm, 22
parasympathetic nervous system, 30t misuse of, 140t, 142–143 brown. See diamorphine (heroin)
attention deficit, 125 benzoyl peroxide, 168t buccal administration, 8
attention deficit hyperactivity disorder benzylpenicillin, 173 budesonide, 38–39, 87
(ADHD), 129 beta-blockers, 52, 57, 120 bulk-forming laxatives, 85–86
treatment of, 129 for hypertension, 55t bumetanide, 73
atypical antidepressants, 121, 122t, 124 hyperthyroidism, 94 β-bungarotoxin, 21f, 22
atypical neuroleptics, 127, 127t open-angle glaucoma, 134 bupivacaine, 151, 152t
Auerbach’s plexus, 84 betahistine dihydrochloride, 84 buprenorphine, 148, 148t
auranofin, 162t, 163 betamethasone, 102t, 104, 167, 167t bupropion, 142
automatic abnormal impulse generation, betaxolol, 134 buserelin, 109
49 bethanechol, 30t, 75 buspirone, 120
autonomic ganglia, 24, 25t bevacizumab, 203 butyrophenones, 127, 127t
autonomic nervous system, 24–32, 25f bezafibrate, 61
autonomic ganglia, 24, 25t bicarbonate
gastrointestinal disorders, 84 reabsorption, 70 C
parasympathetic nervous system (see secretion, 81 cabergoline, 105, 115f, 116
parasympathetic nervous system) biguanides, 97, 97t calcineurin, 170
sympathetic nervous system (see bile, 89 inhibitors, 170–172
sympathetic nervous system) bile acid binding resins, 62 calcipotriol, 167
axon terminal, 20–21 bile salts, 89 calcitonin, 91, 110–111
azapirones, 120 Billy. See amphetamines calcitriol, 111
azathioprine, 88, 172 bioavailability, 9 calcium, 45, 46f, 110–112
inflammatory bowel disease, 88 bipolar affective disorders, 124 antagonists, 56
organ transplant, 170 bisacodyl, 86 disorders of, 110
rheumatoid arthritis, 162t, 164 bismuth chelate, 81 drugs used in disorders of, 110–112
azithromycin, 175–176t, 179 bisoprolol, 52 physiology, 110
aztreonam, 177 bisphosphates, 110–111 calcium carbonate, 111
bladder, 69 calcium channels, 20–21, 147
outflow obstruction, 75 calcium gluconate, 111
B bleeding disorders, 66–67 calcium lactate, 111
bacille Calmette Guérin (BCG), 202 bleomycin, 199–200 calcium salts, 111
bacitracin, 179 blood glucose control, 95 calcium-channel blockers (CCBs), 52–53,
bacteria, 173, 174f blood pressure 53b, 55b, 55t
antibiotic resistance, 173 high (see hypertension) calcium-induced calcium release, 45
drugs of choice for selected, 175–176t normal, 55b calciviruses, 182t
bactericidal antibacterials, 173 blood replacement, 67–68 cAMP (cyclic adenosine
bacteriostatic antibacterials, 173 blood vessel constriction, 62 monophosphate), 5
Bacteroides fragilis, 175–176t Blow. See cannabis autonomic control of the heart, 45
bad trip, 144 bone, 110–112 β2-adrenoceptors, 35, 54
barbiturates, 118 disorders of, 110 opioid receptors, 147
anxiety, 133 drugs used in disorders of, 110–112 phosphodiesterase, 48
epilepsy, 133 physiology, 110 camphor, 166
misuse of, 140t Bordetella pertussis, 4, 175–176t cancer, 195
basal ganglia, 113, 114f botulinum toxin, 22 chemotherapy
Base. See amphetamines botulism, 22 concepts of, 195
basiliximab, 203 Bowman’s capsule, 69–70 cytotoxic, 195–201
basophils, 159 Bowman’s space, 69 diagnosis, 195
beclometasone, 102t, 104 bradycardia, 23–24, 153 endocrine therapy, 201–202
beclomethasone, 38 bradykinin, 54 immunotherapy, 202–203
bendroflumethiazide, 55b, 74 brain, 113, 114f therapies, 198t
benserazide, 115 brainstem, 113 Candida albicans, 186t
benzatropine, 116 bran, 85 cannabinoids, 140t, 143–144
benzimidazoles, 193 breast cancer, 109b cannabis, 140t, 143–144
benzixasoles, 127t breastfeeding, 16 capreomycin, 175–176t, 180
benznidazole, 192 bretylium, 27, 27f capsid, 181, 181f
benzocaine, 40 brimonidine, 136 captopril, 55
properties and uses of, 152t Broca’s area, 114f carbachol, 24, 30t

255
 Index

carbamazepine, 124–125, 130, 132 cerebrospinal fluid (CSF), 151 cinnarizine, 82–83
epilepsy, 132, 132t cerebrum, 113 ciprofibrate, 61
pain relief, 150 cestoda (tapeworms), 192, 193t ciprofloxacin, 87, 175–176t, 177, 180
carbapenems, 177 cetirizine, 169 circulation, 54–62
carbidopa, 15, 26–27, 27f cetrorelix, 110 atherosclerosis, 60–61
parkinsonism, 115, 115f cetuximab, 203 control of vascular tone, 54
carbimazole, 93, 93b cGMP (cyclic guanosine monophosphate), hypertension, 54–58
carbocisteine, 40 5, 52, 76 lipoprotein, 60–61
carbohydrate metabolism, corticosteroids, Chagas’ disease, 192 phaeochromocytoma, 58
102t chalk, 87 shock, 58–62
carbonic acid, 71f champix, 142 vasoconstrictors, 58–62
carbonic anhydrase inhibitors (CAIs), 136 charcoal, 87 circus movement re-entry, 49
carboplatin, 200 Charlie. See cocaine cisplatin, 200
carboprost, 110 cheese reaction, 124 citalopram, 122
carcinogenic drugs, 16 chelates, 81 clarithromycin, 82, 175–176t, 179
cardiac action potential, 43, 44f chemoreceptor trigger zone (CTZ), 82 clindamycin, 175–176t, 179
cardiac glycosides, 47–48, 73 chemotherapy, 181 clobazam, 133
cardiogenic shock, 58, 59b antibacterial, 173 clobetasol butyrate, 167, 167t
cardiovascular effects cancer, 195 clobetasol propionate, 167, 167t
of corticosteroids, 102t children, adherence in, 15 clofazimine, 175–176t, 181
of L-dopa, 114 Chlamydia trachomatis, 175–176t clomethiazole (chlormethiazole), 119t, 120
cardiovascular system, 43–68 chloral hydrate, 119t, 120 clomifene, 108
carrier molecules, 1 chlorambucil, 199 clonazepam, 132t, 133
carvedilol, 74 chloramphenicol clonidine, 27, 27f, 57
catecholamines, 15 bacteria affected by, 175–176t opioid withdrawal, 143
metabolism of by COMT, 29 protein synthesis, 174t, 177–179 clopidogrel, 52, 66
metabolism of by MAO, 29 site of action of, 174t, 178f closed-angle glaucoma, 114, 134, 136
catechol-O-methyltransferase (COMT) chlordiazepoxide, 119–120, 142 Clostridium botulinum, 22
inhibitors, 27, 29, 115–116, 115f chloride, absorption of, 74f Clostridium difficile, 87, 175–176t, 177
metabolism of catecholamines by, 29 chlormethiazole (clomethiazole), 120 clot formation, 63
cefadroxil, 176 chloroquine, 162t, 163, 190 clotrimazole, 187
cefamandole, 176 chlorphenamine, 169 clotting factors, 67. See also specific factor
cefixime, 175–176t, 176 chlorpromazine, 83, 126, 127t clozapine, 127, 127t, 129
cefotaxime, 176 chlorpropramide, 98 coagulation, 63–67
cefradine, 176 chlortalidone, 74 coagulation cascade, 63, 64f
ceftazidime, 175–176t cholecystectomy, 89 coal tar, 167
cefuroxime, 175–176t, 176, 176b cholecystitis, 89 co-beneldopa, 115, 117b
celecoxib, 159, 162 cholelithiasis, 89 cocaine, 27f, 28, 121, 140, 140t, 152t
cell membranes, 9, 174f cholera, 4 properties and uses of, 152t
cell wall synthesis, 174–177, 174f cholesterol, 60–61, 186 co-careldopa, 115
central depressants, 119, 140t, 142–143 absorption inhibitor, 61 co-codamol, 147b
central nervous system, 113–134 gallstones, 89 codeine, 40, 87, 148t, 149
affective disorders, 121–125, 123f cholestyramine, 89 cognitive behavioural therapies (CBT),
anxiety and sleep disorders, 117 choline, 21 123b
basic concepts, 113 choline acetyl transferase (ChAT), 21 coke. See cocaine
corticosteroids, 102t cholinergic activity, drugs that inhibit colchicine, 164t, 165
dementia, 117 striatal, 116–117 cold turkey, 143
depressants, 119, 153 cholinesterase inhibitors, 24 colestipol, 62
epilepsy, 129–134 Alzheimer’s disease, 117 colestyramine, 62
eye, 134–137 parasympathetic nervous system, 30 colistin, 180
Parkinson’s disease and parkinsonism, chromogranin A, 27 colitis, ulcerative, 87–88
113–117, 114–115f chronic obstructive pulmonary disease collecting duct, 70–72, 73f, 75
psychotic disorders, 125–129 (COPD), 35, 36f colloids, 94f
central stimulants, 139–142, 140t chylomicrons, 60 combined oral contraceptive pill (COCP),
centrally acting antihypertensive drugs, chyme, 79 107, 107b
57–58 chymotrypsin, 88 comedones, 165
cephalosporins, 174–176t cigarette smoke, 35 competitive antagonists, 6–7, 7f
first-generation, 175–176t, 176 cilastatin, 177 competitive inhibition, 159
second-generation, 176 ciliary muscle, 136 congestive cardiac failure (CCF), 46–47,
third-generation, 175–176t, 176 ciliates, 189t 46–47t
cerebellum, 113, 114f cimetidine, 81 conjugation, 12

256
 Index 

μ-conotoxins, 152t cyclosporine, 88, 170 dexamethasone, 102t, 104

constipation, 85–86 organ transplant, 170 dexamphetamine, 129
constrictor pupillae, 136 rheumatoid arthritis, 162t, 163 dextropropoxyphene, 148t, 149
contraceptives, oral, 107 skin disorders, 168t dextrose monohydrate (glucose), 99–100
controlled drugs, 139, 140t cyproterone, 109, 165 diabetes mellitus, 95–100
coronaviruses, 182t cytarabine, 196f, 199 characteristics, 96
corticosteroid receptors (CR), 100 cytochrome P448, 12 control of plasma glucose, 95
corticosteroid-responsive genes (CRGs), cytochrome P450, 11, 81 and hypertension, 55t
100 cytokines, 171, 202 hypoglycaemia, 99–100
corticosteroids, 12t, 27f, 28, 162 inhibitors, 164 insulin, 95–96
adrenal, 100–105 cytomegalovirus (CMV), 181 management of, 96–99
anal disorder, 88 cytomegalovirus immunoglobulin secondary, 96
exogenous, 100–104 (CMVIg), 182 type 1, 96
major effects of, 102t cytoplasmic membrane, 174t type 2, 96
mechanism of action of, 100 cytotoxic drugs, 68 diacylglycerol (DAG), 5
for respiratory disorders, 38 adverse effects of, 197t, 199 diamorphine (heroin)
rheumatoid arthritis, 164 antibiotics, 196–197f, 199–200 action of, 7
for septic shock, 59 cancer chemotherapy, 195–201 misuse of, 140t, 143
skin disorders and, 167 inflammatory bowel disease, 88 opioid analgesics, 148, 148t
synthesis and release, 100, 101f mechanisms of genetic resistance to, diarrhoea, 85–86, 85f
therapeutic notes on specific, 104–105 197–198 diazepam, 119, 119t, 131f, 132t, 133–134,
therapeutic use of, 100–105, 102t resistance to, 197 153
topical, 167, 167t rheumatoid arthritis, 162t dibenzazepine, 132
corticotrophin-releasing factor (CRF), site of action of, 195, 196f dibenzodiazepines, 127, 127t
100, 101f dicyclomine, 84
cortisol. See hydrocortisone didanosine (ddI), 184
cortisone, 100, 162
D diencephalon, 113
co-trimoxazole, 177, 192 dabigatran, 65 dietary control of diabetes, 99
coughs, 39–40 dacarbazine, 201 diethylcarbamazine, 193t, 194
countercurrent multiplier system, 70 daclizumab, 203 diethylstilbestrol, 201
COX. See cyclooxygenase dactinomycin, 199–200 diffuse toxic goitre, 92, 93b
Crack. See cocaine danazol, 109 digestive enzymes, 79
crescendo angina, 51 danthron, 86 digoxin, 47, 48–49b
crisantaspase, 196f, 201 dapsone, 175–176t, 180, 190 dihydrocodeine, 148t, 149
Crohn’s disease, 87 decongestants, 40 dihydrofolate reductase, 177
Cryptococcus neoformans, 186t deflazacort, 104 dihydrofolate synthetase, 177
crystalloids, 68 degarelix, 202 dihydropteroate synthetase, 190
Cushing’s syndrome, 96, 102, 103f delayed after-depolarizations dihydropyridine CCBs, 52–53
and corticosteroids, 104b (DADs), 49 dihydrotestosterone, 75
management of, 105 delirium tremens, 142 dihydroxyphenylalanine (dopa), 26–27
cyanobalamin, 68 delta-9-tetrahydrocannabinol diiodotyrosine (DIT), 94f
cycle-specific drugs, 195 (THC), 144 diloxanide, 191
cyclic adenosine monophosphate (cAMP). delusional disorders, 125 diltiazem, 51, 53, 53b, 56
See cAMP (cyclic adenosine dementia, 117 dinoprostone, 110
monophosphate) denosumab, 111–112 dipeptidylpeptidase-4 (DPP-4) inhibitors,
cyclic guanosine monophosphate (cGMP). deoxycortone, 102t 97t, 98
See cGMP (cyclic guanosine dependence, drug, 139, 148 diphenhydramine, 120–121
monophosphate) depolarization, 44–45 diphenylbutylpiperidines, 127, 127t
cyclizine, 82–83 depolarizing (non-competitive) blockers, dipivefrine, 136
cyclooxygenase 23 dipropionate, 38
arachidonic acid, 159 depot-progesterone drugs, 107–108 dipyridamole, 66
aspirin, 65, 66f depressants disease-modifying antirheumatic drugs
COX 1, 159–160 central, 119, 140t, 142–143, 153 (see also (DMARDs), 159, 162–163, 162t
COX 2, 159–160 tricyclic antidepressants) disodium etidronate, 110
NSAIDs, 159–160 depression, 121 disopyramide, 50
cyclopentolate, 30t, 137t dermatitis (eczema), 165, 165f disordered thought, 125
cyclophilin, 171 dermatophytes, 186t dissociative anaesthetics, 140t
cyclophosphamide, 199 desflurane, 154 distal convoluted tubule, 70–72, 73f, 75
cycloplegia, 136, 137t desirudin, 65 distribution, drug, 9–10
cycloplegic drugs, 136, 137t desmopressin, 59, 67, 76 disulfiram, 142
cycloserine, 175–176t, 180 detrusor muscle, 76 dithranol, 166f, 167

257
 Index

diuretics, 15, 48 drug-receptor interactions, 5–7 epilepsy, 129–134

causes of oedema, 74 duloxetine, 76 causes of, 130
for hypertension, 55t, 57 duodenal ulcers, 79, 82 treatment of, 130 (see also
types of, 73–75 (see also loop diuretics; dydrogesterone, 108 antiepileptics)
osmotic diuretics; potassium- dynorphins, 147, 147t epileptic syndromes, 129–130, 129t
sparing diuretics) dysentery, 191 epinephrine. See adrenaline
DNA dyskinesia epoetin, 68
linked receptors, 2t, 5 levodopa induced, 114–115 eptifibatide, 66
replication, 174f tardive, 128, 128b erectile dysfunction, 76–77
synthesis, 195 dyslipidaemia and hypertension, 55t ergocalciferol, 111–112
viruses, 182t ergometrine, 110
DNA-dependent RNA polymerase, 174f
dobutamine, 28t, 48, 59
E ergosterol, 187
ertapenem, 177
docusate sodium, 86 early after-depolarizations (EADs), 49 erythromycin, 87, 175–176t, 179
domperidone, 115, 115f ecstasy (MDMA), 81, 140–141, 140t erythropoietin, 68
intestinal motility, 83–84 eczema. See dermatitis essential hypertension, 54
nausea and vomiting, 83 edrophonium, 23 ester-linked local anaesthetics, 150, 150f
prior to general anaesthesia, 154b efavirenz, 185 estradiol, 108
donepezil, 117 efferent arterioles, 69–70, 70f estriol, 108
dopa decarboxylase, 26–27, 114 eicosanoids, 159, 160f, 160t, 162 etamsylate, 67
dopamine, 48, 59, 113 elderly patients etanercept, 164
agonists, 115f, 116 adherence in, 14–15 ethambutol, 175–176t, 180
antagonists, 83–84, 127–128, 127t adverse effects of drugs on, 16 ethanol, 12t, 142
drugs stimulating release of, 116 electrolytes, diarrhoea, 86 ethosuximide, 130, 132t, 133
drugs that increase activity of, 114–116 emergency contraception, 108 etomidate, 154
precursors, 114–116, 115f emetic drugs, 82 etonogestrel-releasing implant, 107
dopamine receptors, 125, 128f emollients, 166–167 etoposide, 200
agonists, 48, 105 emphysema, 35 eukaryotic cells, 174t
classes of, 126t enalapril, 55, 74 everolimus, 201
D1 receptors, 126t endocrine secretions, 84 excretion, drug, 13
D2 receptors, 114, 115f, 125, 126t endocrine system, 91–112 gastrointestinal, 13
D3 receptors, 126t endocrine therapy, 195, 201–202 renal, 13
D4 receptors, 126t endogenous depression, 121 exemestane, 202
dopaminergic neurons, 113 endogenous opioids, 147, 147t exogenous corticosteroids, 100–104
dopaminergic pathways, adverse effects of endogenous pathway, 60, 60f exogenous pathway, 60, 60f
neuroleptics on, 128–129, 128f endorphins, 147, 147t extrinsic cardiac compensation, 46–47
dope. See cannabis endothelial cells, 62 extrinsic pathway, 63
dorsal horn, 145 endothelium, injury, 62 eye, 134–137, 135f
dorzolamide, 136 endothelium-derived relaxing factor examining the, 136–137
dose ratio, 7 (EDRF), 30, 54 glaucoma, 134
dosulepin (dothiepin), 122 end-plate potential (EPP), 21 M4 receptors, 30
doxapram, 41 energy-dependent carriers, 1 ezetimibe, 61
doxazosin, 56, 75 energy-independent carriers, 1
enflurane, 154, 156
doxorubicin, 199–200
doxycycline, 178 enkephalins, 147, 147t
F
dronedarone, 51 enoximone, 48 factor V, 63
drug(s) entacapone, 27f, 29, 115–116, 115f factor VII, 63
adverse effects of, 1 Entamoeba histolytica, 189t, 191 factor VIIa, 63
classification of, 1 enteral administration, 8 factor VIII, 63
controlled, 139, 140t enterobacteria, 175–176t factor IX, 63
dependence, 139 enterochromaffin-like cells, factor X, 63
development, 17, 17t 79, 80f factor XI, 63
interactions, 15–16, 107b enterococci, 175–176t, 177 faecal softeners, 86. See also stool modifiers
metabolism (see metabolism, drug) enterohepatic circulation, 13 famciclovir, 183
names of, 1, 8f enzyme induction, 15 fat metabolism, corticosteroids, 102t
overdose, 12–13 enzyme-inducing agents, 12, 12t febuxostat, 165
patient history of, 16–17 enzyme-inhibiting agents, 12, 12t felodipine, 52
tolerance, 139, 140t enzymes, 1 female reproductive tract, 105
withdrawal, 139 eosinophils, 34–35, 159 fenemates, 161t, 162
drug misuse, 139–144, 140t ephedrine, 15, 27–28, 27f, 40, 59 fentanyl, 147, 151b, 152t, 153, 154b
definitions, 139 epidermal growth factor, 5 ferriprotoporphyrin IX, 190
drugs used, 139–144, 140t epidural anaesthesia, 151 fibrates, 61–62

258
 Index 

fibrin, 63 G glucocorticoids (Continued)

fibrinogen, 63 side effects of, 102, 103f
fibrinolysis, 63 gabapentin, 130, 132t, 133 synthesis and release, 100
fibrinolytic agents, 66 galantamine, 117 therapeutic notes on specific, 104
for bleeding disorders, 66 gall bladder, 88–89 used therapeutically, 102t
effect on coagulation cascade, 64f gallamine, 23t, 25t glucocorticosteroids
fibroblasts, 162 gallstones, 89 in asthma, 34f, 35
fight-or-flight response, 19 gametocytes, 188 endogenous/exogenous, 105
filgrastim, 203 gamma-aminobutyric acid (GABA) inflammatory bowel disease, 88
finasteride, 75, 109 receptor, 118, 130 topical, 41
first pass metabolism, 8 gamma-aminobutyric acid (GABA)A glucose
first-order kinetics, 13f, 14 receptor, 3, 118, 118f diabetes mellitus, 95, 99–100
fish oils, 62 ganciclovir, 184 hypoglycaemia, 99–100
flagellates, 189t ganglion-blocking drugs, 24 glucose receptors, 95
flashbacks, 144 ganglion-stimulating drugs, 24 α-glucosidase inhibitors, 98
flattening of affect, 125 ganirelix, 110 glutathione, 12–13
flecainide, 50, 50t Ganja. See cannabis glycerol, 136–137
flucloxacillin, 174, 176b gastric parietal cells, 79, 80f glyceryl trinitrate (GTN), 52
fluconazole, 187 gastric stasis, 84 glycine receptor, 3
flucytosine, 188 gastric ulcers, 79 glycopeptides, 174t, 176–177
fludrocortisone, 102t, 104–105 gastrin, 79, 80f glycoprotein IIb/IIIa inhibitors, 66
fluid maintenance, diarrhoea, 86 gastrin receptors, 79 glycosides, cardiac, 47–48, 73
fluid replacement, 67–68 gastrinoma, 79 glycosuria, 96
diabetes, 99 gastrointestinal excretion, 13 goitre, 93, 93b
flukes, 192, 193t gastrointestinal system, 79–89 gold salts, 162t, 163
flumazenil, 41, 119 gastro-oesophageal reflux disease gonadotrophin-releasing hormone
fluorodeoxyuridine (GORD), 79–80, 81f, 84 (GnRH), 105, 105f, 202
monophosphate, 199 gate-control mechanism, 145 agonists, 109
fluoroquinolones, 175–176t gating, 1 antagonists, 109–110
fluorouracil, 199 Gear (cannabis). See cannabis gonadotrophins, 105
5-fluorouracil, 188, 196f, Gear (heroin). See diamorphine (heroin) gonadotrophin-surge-attenuating factor,
199–200 gemeprost, 110 105
fluoxetine, 122, 122t gemfibrozil, 61 gonads
flupentixol, 127, 127t general anaesthesia, 151–156, 152t female, 105
fluphenazine, 126, 127t anaesthetic agents, 153–156 male, 106
flutamide, 202 basic concepts, 151–152 goserelin, 109
fluticasone furoate, 38 induction, 153 gout, 55t, 159, 164–165, 164t
fluticasone propionate, 38 maintenance, 153 G-protein, 1
fluvoxamine, 122 premedication, 152–153 receptors linked to, 3–5
focal seizures, 129–130, 129t generalized seizures, 129–130, 129t, 132t second-messenger systems, 4–5, 4f
folate, 68, 177 genetic resistance to cytotoxic drugs, 197 targets for, 4–5
folic acid, 68 genomes, 174t grand-mal epilepsy, 129, 129t
antagonists, 199 gentamicin, 73, 175–176t, 177 granulocyte-macrophage colony-
folinic acid, 200 gestrinone, 109 stimulating factor (GM-CSF), 203
follicle-stimulating hormone (FSH), 105, Giardia lamblia, 191 grass. See cannabis
105–106f giardiasis, 191 Graves’ disease, 92, 93b
food allergy, 169t glaucoma, 134 grey baby syndrome, 179
formoterol, 39 glibenclamide, 98 griseofulvin, 188
fosphenytoin, 134 gliclazide, 98 guanethidine, 27, 27f
Frank–Starling curve, 47, 47f gliptins, 98 guanosine diphosphate (GDP), 3–4, 3f
free fatty acids (FFAs), 60 glomerular capillaries, 13 guanosine triphosphate (GTP), 3–4, 3f
frontal lobe, 114f glomerular filtration, 13, 69 guanylyl cyclase, 5, 32, 54, 76
fuel homeostasis, 96t glomerulus, 69
GLP-1 agonist, 97t, 98–99
full agonists, 6, 6f
fungal infection, 186, 186t. See also glucagon, 95, 100
H
antifungal drugs glucocorticoids, 100, 162 H. See diamorphine (heroin)
furosemide, 73 allergic disorders, 169t haematoma, 62
fusidic acid, 179 anti-inflammatory, 38–39, 101, haemophilia, 65–67
protein synthesis, 174f, 177 102–103t Haemophilus influenzae, 175–176t, 179
resistance to, 173 as immunosuppressant agent, 170 haemorrhoids, 86, 88
site of action of, 174f, 177 inflammatory bowel disease, 87–88 haemostasis, 62–64
fusion inhibitors, 185 major effects of, 102t management of disorders of, 64–67

259
 Index

half-life (t1/2), 9 human immunodeficiency virus. See HIV imipenem, 175–176t, 177
hallucinations, 125 (human immunodeficiency virus) imipramine, 27f, 122, 122t
hallucinogens, 140t, 144 human normal immunoglobulin (HNIg/ immediate-phase response, 35
haloperidol, 83, 126–127b, 127, 127t gamma globulin), 182 immunoglobulin E (IgE), 168
halothane, 154–155 human papilloma virus (HPV), 202 immunoglobulins, 182–183
hangover, 119, 121, 142 hydralazine, 48, 48b, 57 immunomodulators, 185
Hashimoto’s thyroiditis, 92 hydrochloric acid (HCl), 79 immunostimulation, 202
hashish, 143 hydrocortisone, 100, 102t immunosuppressants, 170–172
hay fever, 169t anaphylactic shock, 104 corticosteroids, 101, 102–103t
headache, 149–150 inflammatory bowel disease, 87 gout, 164t
heart, 43–54 skin disorders, 167, 167t inflammatory bowel disease, 88
autonomic control of the, 45 therapeutic notes on, 104 rheumatoid arthritis, 162t, 163–164
basic concepts, 43–46 hydrolysis, 12 immunotherapy, 195, 202–203
blood flow through, 43, 43f hydroperoxidases, 159 impotence, 76–77
contractility, 45–46 hydrophilic route of block, 150–151, 150f inactivation, 28–29
dysfunction, 46–54, 46–47t hydrophobic route of block, 150–151, 150f incontinence, urinary, 76
treatment of, 47–48 hydroxocobalamin, 68 indapamide, 74
rate and rhythm, 43–45 3-hydroxy-3-methylglutaryl co-enzyme A indinavir, 185
heart block, 49 reductase inhibitors, 61 indometacin, 162, 164t
heart failure hydroxyprogesterone, 108 induction, general anaesthesia, 152t, 153
drugs for, 47–48, 54t hydroxyquinine, 162t, 163 infectious diseases, 173–194
and hypertension, 55t 5-hydroxytryptamine (5-HT), 119t, 122t, anthelmintic drugs, 192–194
Helicobacter pylori, 79b, 80–82, 179 123f, 127t antibacterial drugs, 173–186
helminthic infection, 192, 193t blockers, 127, 127t antifungal drugs, 186–188
hemicholinium, 22 5-hydroxytryptamine1A (5-HT1A), 120 antiprotozoal drugs, 188–192
Henderson–Hasselbalch equation, 9, 150 5-hydroxytryptamine3 (5-HT3) receptor, antiviral drugs, 181
hepadnaviruses, 182t 84, 119t infiltration anaesthesia, 151
heparin, 64f, 65 antagonists, 84 inflammation, 159–162
hepatic necrosis, 156 hydroxyurea, 196f, 201 anti-inflammatory drugs (see
heroin. See diamorphine (heroin) hyoscine, 30t, 84, 154b ­anti-inflammatory drugs)
herpes viruses, 181, 182t hypercalcaemia, 110, 110b arachidonic acid metabolites, 159, 160f,
hexamethonium, 25t hyperlipidaemias, 61–62 160t, 162
h-gates, 19, 20f hypersensitivity reactions, 168, 168f gout, 159, 164–165, 164t
high-density lipoproteins (HDL), 57, 60 hypertension, 54–58, 55t rheumatoid arthritis, 162–164
highly active antiretroviral therapy hyperthyroidism, 92–93 skin disorders, 165–168
(HAART), 185, 186b causes of, 93b inflammatory bowel disease, 87–88
hirudins, 65 management, 93–95 inflammatory mediators, 159
histamine, 22, 23t, 26, 79 hypnotics, 117–121, 119t, 121b infliximab, 88, 164
allergic disorders, 168 sleep disorders and, 117–121 influenza viruses, 181
migraine, 149 hypnozoites, 188 inhalation anaesthetic agents, 152t,
histamine receptors, 79, 80f hypoglycaemia, 99–100 153–156, 155f
H1-receptor antagonists (see hypoglycaemics, oral, 97–99 inhaled therapy algorithm, 36f
antihistamines) hypotension, 47t, 53, 155–156 inhalers, 39
H2-receptor antagonists, 81, 81f, 89, 153 levodopa induced, 114 inhibin, 106–107
H1-receptors, 170t hypothalamic–pituitary axis, 106 innate resistance, 173
H2-receptors, 170t hypothalamic–pituitary–adrenal axis, 100, inositol phosphate, 5
H3-receptors, 170t 101f inositol (1,4,5) triphosphate (IP3), 5, 54
HIV (human immunodeficiency virus), hypothalamic–pituitary–ovarian axis, 105, insomnia, 117, 119b
184, 184f, 192 105f insulin, 8, 95–96, 95f
drugs used in, 185–186 hypothalamus, 71, 91, 105 administration of, 8–9
HIV-1, 181, 185 corticosteroids, 102t management of diabetes mellitus,
HMG CoA reductase inhibitors, 61 hypothyroidism, 92 96–97, 97t
homeostasis, fuel, 96t causes of, 92t metabolic effects, 96t
hormonal control of intestinal motility, 84 management, 92 insulin receptor, 2t
hormone replacement therapy (HRT), 108 hypovolemic shock, 58, 59b insulin zinc suspension, 96, 97t
hormones, 2, 201–202. See also specific intercalated cells, 70
hormone
H-receptors. See histamine receptors
I interferons (IFNs), 185, 202
interleukin (IL)-1, 163–164
5-HT3 antagonist, 200 ibuprofen, 159, 162, 163b interleukin (IL)-2, 171, 202
human chorionic gonadotrophin, 140t ibutilide, 51 interleukin 5 monoclonal
human epidermal growth factor 2 (HER2) imatinib, 201 antibody, 39
receptor, 203 imidazole antifungals, 186 intermediate-acting insulin, 96–97

260
 Index 

intestines, 84–88 kernicterus, 177 liquid paraffin, 86

anal disorders, 88 ketamine, 140t, 141 lisinopril, 55
basic concepts, 84–87 ketoconazole, 105, 187 lispro, 96–97
drugs that affect motility of, 84–85, 85f kidneys Listeria monocytogenes, 175–176t
inflammatory bowel disease, 87–88 basic concepts, 69 lisuride, 115f, 116
obesity, 88 effect of corticosteroids on, 102t lithium, 71, 124
intraocular pressure (IOP), 134, 136 functions of, 69 liver
intravenous anaesthetic agents, 152t, nephron, 69–72, 70–73f coagulation, 63
153–154 structure of, 70f damage, 156
intravenous fluids, 68 kinetic order, 13–14 lobeline, 24
intravenous injection of drugs, 8 local anaesthesia, 150–151, 150f, 152t
intravenous regional anaesthesia (IVRA), L basic concepts, 150
152t mechanism of block, 150
intrinsic cardiac compensation, 47 labetalol, 28t properties and uses, 152t
intrinsic pathway, 63 β-lactam antibiotics. See cephalosporins routes of administration, 151
iodide, 91, 93, 94f lactulose, 86 unwanted effects, 151
iodine, 91, 93 Lambeth Conventions, 49 local anaesthetics
ion channels, 1 lamivudine (3TC), 184, 186b anal disorders, 88
G-protein, 3–5, 3f lamotrigine, 130 ester-linked, 150, 150f
inhibition of, 130, 131f epilepsy, 132t, 133 topical, 40
receptors directly linked to, 2–3, 3f pain relief, 150 lofepramine, 122, 122t
ionization, local anaesthetics, 150 lansoprazole, 81 long-acting insulin, 96
iosine monophosphate dehydrogenase, L-arginine, 32 long-acting muscarinic receptor
172 latanoprost, 136 antagonists (LAMA), 39
ipecacuanha, 82 late-phase response, 35 long-term oxygen therapy, 35, 38b
ipratropium, 30t laxatives, 85–86, 85f loop diuretics, 48, 73–75, 74f
ipratropium bromide, 37, 38b L-dopa (levodopa), 15, 27f, 114–116, 115f for hypertension, 57
iridectomy, 136 lecithin cholesterol acyltransferase loop of Henle, 69–73, 70f, 72f
irinotecan, 203 (LCAT), 61 loperamide, 87
iris, 136 left ventricular failure, 46, 47t loratadine, 169
iron, 67–68 Legionella species, 175–176t lorazepam, 119, 119t, 132t, 133–134
irreversible antagonists, 7 Leishmania species, 192 lormetazepam, 119t
irreversible inhibition, 159 leishmaniasis, 192 losartan, 56
irreversible inhibitors of MAO, 124 lepirudin, 65 low-density lipoproteins (LDL), 57, 60–61
irritable bowel syndrome, 84–85 lepromatous leprosy, 180 lower oesophageal sphincter (LOS),
ischaemic heart disease and hypertension, leprosy, 180 79–80, 84
55t leptin, 88 low-molecular-weight heparins
islets of Langerhans, 95 leucocytes, 159 (LMWHs), 65
isocarboxazid, 124 leukotriene receptor antagonists, 37–38 L-triiodothyronine sodium, 92
isoflurane, 154, 156 leukotrienes, 37, 37b, 159, 160f, 162 L-tyrosine, 26
isoniazid, 175–176t, 180 allergic disorders, 168 lumefantrine, 191
isophane insulin, 97, 97t leuprolide, 109 lumiracoxib, 162
isoprenaline, 25, 28t levamisole, 194, 202 luteinizing hormone (LH), 105, 105–106f
isosorbide dinitrate (ISDN), 52 levodopa (L-dopa), 15, 27f, 114–116, 115f lymphocytes, 159
isosorbide mononitrate (ISMN), 52 levofloxacin, 177 lysergic acid diethylamide class B (LSD),
ispaghula husk, 62, 85–86 levomepromazine, 83 140t, 144
itraconazole, 187 levonorgestrel, 108 lysis, 174f, 180
ivabradine, 54 levothyroxine, 92
ivermectin, 193t, 194 levothyroxine sodium, 92
Leydig cells, 106, 106f
ixabepilone, 200
lidocaine, 50, 50t, 122, 151
M
properties and uses of, 152t macrolides, 174–176t, 177, 179
J unwanted effects, 151 polyene, 186–187
lincosamides, 177, 179 site of action of, 174f, 178f
jack. See diamorphine (heroin)
liothyronine, 92 macrophages, 159, 162
junk. See diamorphine (heroin)
lipase, 88–89 macula densa, 70
juxtaglomerular apparatus, 70
lipid transport, 60, 60f magic mushrooms, 144
lipid-lowering drugs, 61–62 magic-bullet approach, 203
K lipocortin, 162
lipoprotein circulation, 60–61
magnesium carbonate, 82
magnesium sulphate, 38
kaolin, 87 lipoprotein lipase (LPL), 60 maintenance, general anaesthesia, 153,
keratolytics, 167 lipoxygenase, 159 155f

261
 Index

malaria, 162t, 163, 188–191, 189f methylphenidate, 129 MOPP (mechlorethamine, vincristine,
male reproductive tract, 106–107 1-methyl-4-phenyl-1,2,3,6- procarbazine and prednisone), 201
mania, 121–122, 124, 127 tetrahydropyridine (MPTP), 113 morning-after pill, 108
manic-depressive disorder. See bipolar metoclopramide, 83 morphine, 9, 147, 147b, 148t
affective disorders intestinal motility, 84 misuse of, 140t
mannitol, 40, 75, 136 postoperative antiemesis, 153 therapeutic notes, 148–149
MAO inhibitors. See monoamine oxidase metolazone, 74 motility, intestinal, 84, 85f
inhibitors (MAOIs) metoprolol, 50, 52 stimulants, 84, 85f
Maraviroc, 185 metronidazole, 79, 82, 175–176t, 179, 193t motor end-plate, 20–21, 23
marijuana, 143 amoebic dysentery, 191 motor neurons, 20–21
mast-cell stabilizers, 38, 169t giardiasis, 191 moulds, 186t
MDMA (ecstasy), 81 trichomonas vaginitis, 191 movement disorders, 128, 128f
mebendazole, 193, 193t metyrapone, 105 moxisylyte, 137
mebeverine, 85 metyrosine, 26–27 moxonidine, 57
mechlorethamine (chlormethine), 201 mexiletine, 50 M-receptors. See muscarinic receptors
mecysteine hydrochloride, 40 m-gate, 19, 20f MRSA (methicillin-resistant
medroxyprogesterone, 108 miconazole, 187 Staphylococcus aureus), 173, 176b
medroxyprogesterone acetate, 107–108 midazolam, 119, 119t, 133, 153, 154b mTOR (mammalian target of rapamycin),
medulla oblongata, 114f mifepristone, 108 201
mefenamic acid, 162 migraine, 149 mTOR kinase inhibitors, 201
mefloquine, 190 mild depression, 123b mucolytics, 40
Meissner’s plexus, 84 milrinone, 48 mucosal strengtheners, 80f, 81
melarsoprol, 192 mineralocorticoid receptors, 71, 73f mucous barrier, 79
melatonin, 121 mineralocorticoids, 162 mucus, 79
melphalan, 199 major effects of, 102t multikinase inhibitors, 201
menopause, 108 synthesis and release, 100 muscarine, 30t
menstrual cycle, 105–106, 106f therapeutic notes on, 104–105 muscarinic receptor agonists, 137
menthol, 166 used therapeutically, 102t for reversing mydriasis, 137
menthol vapour, 40 mini-pill, 107 muscarinic receptor antagonism, 129
mepilumozab, 39 minocycline, 178 muscarinic receptor antagonists, 76, 80f,
mercaptopurine, 172, 196f, 199 minoxidil, 57 136
meropenem, 177 miotics. See muscarinic receptor agonists action of, 37
merozoites, 188 mirabegron, 76 effects of, 136–137, 137t
mesalazine, 88 mirtazapine, 122t, 124 general anaesthesia, 153
mescaline, 140t, 144 misoprostol, 81 intestinal motility, 84, 85f
mesocortical dopamine pathways, 128 mitotane, 201 parkinsonism, 116–117
mesolimbic dopamine pathways, 128 mitotic inhibitors, 196–197f, 200 site of action, 115f
mesterolone, 109 moclobemide, 122t, 124 type of, 137
metabolic acidosis, 99 model-independent approach, 14, 15f muscarinic receptors, 79, 80f
metabolism, drug, 10–13 molecule size effect on absorption, 9 activation, 23
factors affecting, 12 mometasone, 38 agonists, 30, 30t
paracetamol poisoning, 12 monoamine oxidase (MAO), 27, 29 antagonists, 30–32, 30t
phase 1 metabolic reactions, 11–12 monoamine oxidase inhibitors (MAOIs), M1 receptors, 30, 79
phase 2 metabolic reactions, 12 124 M2 receptors, 30, 45
sites of, 11 breakdown of noradrenaline stores, 27 M3 receptors, 30, 37, 54, 79
metformin, 95b, 97–98, 97t dopaminergic activity, 116 M4 receptors, 30
methacholine, 30t drug interactions, 15–16 myasthenia gravis, 22t, 23, 23b
methadone, 140t, 143 mechanism of action, 122t mycobacteria, 180
methanol poisoning, 142 monoamine theory of depression, 121 Mycobacterium avium cellulare, 179
methicillin-resistant Staphylococcus aureus parkinsonism, 115f, 116 Mycobacterium leprae, 175–176t, 180
(MRSA), 173, 176b site of action, 123f Mycobacterium tuberculosis, 173, 175–176t,
methionine, 13 monoamine oxidaseA (MAOA), 124 178, 180
methotrexate, 88, 162t, 163, 168t, 196f, 199 monoamine oxidaseB (MAOB), 115–116, mycolic acid, 180
methylcellulose, 85, 87–88 115f, 124 mycophenolate mofetil, 172
methyldopa, 57 monoamine theory of depression, 121 Mycoplasma pneumoniae, 175–176t
α-methyldopa, 26–27, 27f monobactam, 177 mycoses, 186–187, 186t
methylenedioxymethamfetamine. See monoclonal antibodies, 39, 88, 164, 203 mydriasis, 136
MDMA monoiodotyrosine (MIT), 94f mydriatic drugs, 136, 137t
methylenedioxymethamphetamine monosodium urate, 164 myeloproliferative disorders, 68
(MDMA) (ecstasy), 140–141, 140t montelukast, 37 myenteric plexus, 84
α-methylnoradrenaline, 26–27 mood stabilizers, 124 myocardial ischaemia, 49

262
 Index 

myosin light chain kinase (MLCK), 54 nicotinic acetylcholine receptor norethisterone, 108
myxoedema, 92 (nicAChR), 2, 22, 22t nuclear factor of activated T cells (NF-
distinguishing features of, 25t ATc), 171
nicotinic acid, 62 nucleic acids, 174t
N nicotinic agonists, 24 antibacterial drugs that inhibit, 177
nabilone, 84 nifedipine, 52–53, 53b, 56 inhibition of replication of, 183–185
N-acetylcysteine, 13, 40 nifurtimox, 192 nucleoside analogue reverse transcriptase
N-acetyl-p-benzoquinone, 12–13 nigrostriatal dopamine pathways, 128 inhibitors, 184–185
Na+/K+ ATPase pump, 19, 47, 69–71 nitrates, 48 nucleoside reverse transcriptase inhibitors,
nalbuphine, 148t organic, 52 185
naloxone, 7, 41, 149 nitrazepam, 119, 119t nucleotide metabolism, 174f
naltrexone, 149 nitrergic nervous system, 32 nystatin, 88, 187
nandrolone, 109 nitric oxide (NO), 32, 52, 54
nausea, 82–84, 114 erection, 76
after general anaesthesia, 153 pain pathways, 145
O
causes of, 83f nitric oxide synthase (NOS), 32 obesity, 88
levodopa induced, 114 nitrofurantoin, 175–176t, 179–180 obstructive airways disease, 35
nebulizers, 39 nitrous oxide, 155, 156b management of, 35–39
nedocromil sodium, 38 N-methyl-D-aspartate (NMDA) occipital lobe, 114f
Neisseria gonorrhoeae, 175–176t antagonists, 117, 130 octreotide, 105
Neisseria meningitidis, 175–176t N-methyl-D-aspartate (NMDA)-type oedema, underlying causes of, 74
nelfinavir, 185 glutamate receptors, 154 oestrogen, 105–106, 106f, 108
nematoda (roundworms), 192, 193t nociceptors, activation of, 145, 146f agonists, 108
neostigmine, 23–24 nocturia, 76 antagonists, 108
nephron, 69–72, 70–73f nodal cells, 44–45 oestrogen antagonists, 202
nerve block, 151 (see also local nonadrenergic noncholinergic (NANC) oestrogens, 201
anaesthesia) nerves, 35 ofatumumab, 203
nerve conduction, 19–20 nonadrenergic, noncholinergic olanzapine, 127, 127b, 127t
nerve fibre size, 20 neurotransmission (NANC), 76 olsalazine, 88
neuralgic pain, 150 nonbenzodiazepine hypnotics, 118, 119t, omeprazole, 81–82
neuraminidase inhibitors, 182 120 ondansetron, 84, 200
neurocardiac M2 receptors, 30 noncompetitive antagonists, 7, 7f one-compartment model, 14, 14f
neuroendocrine disorders, 128, 128f non-depolarizing blockers, 22–23, 23t open-angle glaucoma, 134
neuroleptic drugs, 125–127 non-depolarizing ganglion blockers, 24 treatment of, 134–136
adverse effects of, 127–129, 128b nonmedical options, 117 κ-opiate receptors, 146, 146f, 149
atypical, 127 non-nodal cells, 43–44 μ-opiate receptors, 87, 145, 146t, 149
classes of, 127t nonnucleoside reverse transcriptase σ-opiate receptors, 146, 146t
immune reactions to, 129 inhibitors, 185 opiate-like antimotility drugs, 85f, 87
malignant syndrome, 129 nonselective receptor blockade, 129 opioid analgesics, 143
side effects, 129b nonsteroidal anti-inflammatory drugs opioid antagonists, 149
typical, 126–127 (NSAIDs), 15, 37, 70, 159–160, 161t opioid peptides, 145, 146f
neuroleptic malignant syndrome, 128b -associated ulcers, 81 opioid receptors, 145–147, 146t. See also
neuromuscular blockers, 156 and asthma, 37b specific receptor
neuromuscular junction (NMJ), 20–22, general adverse effects of, 161t opioids, 140t, 148t
21f, 22t gout, 164 endogenous, 147, 147t
drugs affecting the, 22–24, 23t major clinical effects of, 161t for inappropriate coughs, 40
neuronal control of intestinal motility, 84 migraine, 149 misuse of, 140t, 143
neuronal excitability, 130 neuralgic pain, 150 side-effects of, 147
neuroparietal M1 receptors, 30 pain relief, 146t oral administration, 9
neuropeptide Y, 88 prior to general anaesthesia, 153 oral contraceptives, 107
neurotransmitters, 2 therapeutic notes on, 161–162 oral hypoglycaemics, 97–99
neutrophils, 34–35, 159, 162, 166 noradrenaline, 25, 27f, 28t, 35, 59 oral rehydration therapy (ORT), 86
nevirapine, 185, 186b drugs decreasing synthesis of, 26–27 organ transplant, 170
niclosamide, 192, 193t drugs increasing synthesis of, 27 organic nitrates, 52
nicorandil, 53 drugs inhibiting release of, 27 organophosphorus compounds, 24
nicotinamide adenine dinucleotide drugs inhibiting storage of, 27 orlistat, 88
phosphate (reduced) drugs inhibiting the breakdown of orphenadrine, 116
(NADPH), 11 leaked stores of, 27 orthomyxoviruses, 182t
nicotine, 24 drugs promoting release of, 27–28 oseltamivir, 182
misuse of, 140t, 141 inactivation, 28–29 osmotic diuretics, 75
replacement products, 141–142 synthesis, 26 osmotic laxatives, 86

263
 Index

osteoclasts, 110 Parkinson’s disease phenazocine, 148–149, 148t

osteodystrophy, 110 aetiology of, 113 phencyclidine (PCP), 140t, 146
osteomalacia, 110 basal ganglia systems involved in, 114f phenelzine, 27f, 29, 122t, 124
osteoporosis, 102, 103f, 104b, 110, 111b pathogenesis, 113 phenindione, 64
ovarian hormones, 105 treatment of, 113–117 phenobarbital, 132t, 133
ovaries, 105 paroxetine, 122, 122t phenol, 88, 166
oxaliplatin, 200 partial agonists, 6, 6f phenothiazines, 83, 126, 127t
oxcarbazepine, 132 partial repolarisation, 44 phenoxybenzamine, 26, 58
oxicams, 161t, 162 partial seizures, 129t, 130, 132t, 133 phenoxymethylpenicillin, 174–176
oxidation, 11–12 parvoviruses, 182t phentolamine, 26, 28t, 58
oxybuprocaine, 152t pazopanib, 201 phenylephrine, 28t, 59, 137
oxybutynin, 76 PCP (angel dust), 154 phenytoin, 50, 81, 130
oxygen therapy, 39 penicillamine, 162t, 163 epilepsy, 132, 132t, 134
long-term, 35, 38b penicillin, 174–176, 174–176t pain relief, 150
oxymetazoline, 28t pentazocine, 148–149, 148t pholcodine, 40
oxytocic drugs, 110 pentostatin, 201 phosphatidylinositol (4,5) bisphosphate, 5
oxytocin, 110 peppermint oil, 85 phosphodiesterase (PDE), 37, 76
pepsin, 81–82 inhibitors, 48, 76–77
P peptic ulceration, 79–82, 79b, 80f phosphodiesterase 4 inhibitors, 39
peptide bonds, 178–179, 178f phospholipase A2, 159, 162
pacemaker potential, 44–45 peptidoglycan cell walls, 174t phospholipase C (PLC), 5, 54, 59, 65
pain, 145–156 peptidoglycan synthesis, 176, 180 physostigmine, 23–24
basic concepts, 145–147 pergolide, 116 phytomenadione, 67
headache, 149–150 perianal thrush, 88 picornaviruses, 182t
neuralgic, 149–150 peripheral dopa decarboxylase inhibitors, pilocarpine, 30t
perception, 145 115f closed-angle glaucoma, 136
pamidronate, 110 peripheral dopamine receptor antagonists, open-angle glaucoma, 136
pancreas, 88–89, 95–100 115f for reversing mydriasis, 137
pancreatic supplements, 88–89 peripheral nervous system, 19–32 pilosebaceous unit, 165
pancreatin, 89 autonomic nervous system, 24–32 pimozide, 127, 127t, 129
pancuronium, 23t nerve conduction, 19–20 pioglitazone, 98
papaverine, 77 nitrergic nervous system, 32 piperazine, 193
papovaviruses, 182t somatic nervous system, 20–24 piperazine side chains, 126
para-aminobenzoic acid, 174f, peripheral vascular disease, 55t piperidine side chains, 126
177, 190 peritubular capillaries, 69 piracetam, 133
para-aminophenols, 161t, 162 pertussis, 4 pirenzepine, 30t
paracetamol, 159, 162 pethidine, 148, 148t piroxicam, 162
poisoning, 12–13 petit-mal seizures, 130 pituitary gland, 102t, 105
paracrine secretions, 84 pH pizotifen, 149
paraffinomas, 86 effect on absorption, 9 pKa values, 9
paramyxoviruses, 182t importance of, in local anaesthetics, 150 plasma glucose control, 95
parasites, 168t, 192, 193t phaeochromocytoma, 58 plasmin, 63
parasympathetic nerves, 29f, 31t, 35 pharmacodynamics, 15 plasminogen, 63
parasympathetic nervous system, 29–32, pharmacokinetics, 8–15, 150 Plasmodium falciparum, 188
29f administration, 8–9 Plasmodium malariae, 188–189
drugs acting on, 29f, 30–32, 30t definition of, 8 Plasmodium ovale, 188–189
effect on the heart, 45, 45t drug absorption, 9 Plasmodium vivax, 188
parasympathetic receptors, 30 drug distribution, 9–10 plateau phase, 44
parasympatholytics. See muscarinic drug excretion, 13 platelets, 62, 65–66
receptor antagonists general anaesthesia, 155 aggregation, 160
parasympathomimetics. See muscarinic mathematical aspects of, 13–14 plug formation, 62
receptor agonists pharmacological sanctuaries, 198 platinum compounds, 198t, 199–201
parathion, 24 pharmacology Pneumocystis jiroveci, 192
parathyroid hormone (PTH), 110 definition, 1 pneumonia, pneumocystis, 192
parenteral administration, 8–9 drug names and classification, 1 polydipsia, 96
parietal cells, gastric, 79, 80f how they work, 1 polyene macrolides, 186–187
parietal lobe, 114f molecular basis, 1–5 polymyxins, 174t, 179
parkinsonism transport systems, 1 polyuria, 96
aetiology of, 113 phase 1 metabolic reactions, 11–12 pons, 114f
pathogenesis, 113, 114f phase 2 metabolic reactions, 12 postganglionic fibres, 24, 29
treatment of, 113–117, 115f phase-specific drugs, 195, 197f postoperative antiemesis, 153

264
 Index 

postsynaptic agents, 22–23, 23t propranolol quetiapine fumarate, 127

parasympathetic nervous system, 30–32 anxiety, 120 quinidine, 50
sympathetic nervous system, 28 clinical uses, 28t quinine, 190
pot. See cannabis drug interactions, 15 quinoline-methanols, 190
potassium, 69–70, 96, 99 effects of, 50, 50t, 52 quinolones, 174t, 177, 180
potassium channels, 19, 20t, 147 hypertension, 26 QX222, 152t
activators, 53–54 hyperthyroidism, 93b, 94 QX314, 152t
blockers, 51 propylamine side chains, 126
potassium equilibrium potential, 19
potassium perchlorate, 93, 94f
propylthiouracil (PTU), 93, 94f
prostacyclin, 62, 65, 66f, 159
R
potassium-sparing diuretics, 48, 75 prostaglandin analogues, 134, 136 radioiodine, 94–95
potency, 7, 7t prostaglandin E, 110 raloxifene, 111
potentiation, 15 prostaglandin E2, 81, 110 Raltegravir, 185
poverty of speech, 125 prostaglandin F, 110 ramipril, 55
poxviruses, 182t prostaglandin I2, 81 ranitidine, 81
practolol, 28t prostaglandins ranolazine, 54
pramipexole, 115f, 116 allergic disorders, 168 rapid-acting insulin, 96, 97t
prasugrel, 66 inflammation, 159, 160t, 162 rasagiline, 115f
pravastatin, 61 prostanoids, 159, 160t rate limiting CCBs, 52
praziquantel, 192, 193t prostate cancer, 109b rate-limiting step (RLS), 22, 26–27
prazosin, 28t, 56, 75 protamine, 67 RATS mnemonic, 113b
prednisolone, 38, 102t, 201 protamine zinc insulin, 96 reabsorption, 69–71
inflammatory bowel disease, 87 protease inhibitors, 185 reabsorption, drug, 13
therapeutic notes on, 104 protein C, 63 reactive depression, 121
prednisone, 12, 201 protein kinase A, 5, 54 reboxetine, 122t, 124
preganglionic fibres, 24–25 protein kinase C, 5 receptor reserve, 7
pregnancy, 55t protein kinase G, 52 receptors, 2–5
premedication, 152t, 153 protein metabolism, corticosteroids, 102t DNA linked, 2t, 5
presynaptic agents, 22 protein synthesis, 174f G-protein linked, 3–5
parasympathetic nervous system, 30 antibacterial drugs that inhibit, interactions with drugs, 5–7
sympathetic nervous system, 26–28 177–179, 178f ion channel linked, 2–3
presynaptic release, 22 proton pump inhibitors (PPI), 81, 153 tyrosine kinase linked, 2t, 5 (see also
primaquine, 191 protozoal infection, 188, 189t specific receptor)
primary hyperlipidaemias, 61 proximal tubules, 69–70, 71f α-receptors, 25
primary hypertension, 54 Prozac, 122, 122t agonists, 27f
primidone, 133 pruritus, 89 antagonists, 27f
principal cells, 70 Pseudomonas aeruginosa, 173, 175–176t β-receptors agonists, 136
Prinzmetal’s angina, 51 psilocybin, 140t, 144 β1-receptors, 26
probenecid, 164t, 165 psoralen, 168t β2-receptors, 26
procainamide, 50, 50t psoriasis, 166, 166f, 168t recombinant human granulocyte colony-
procaine, 152t psychiatric side-effects, levodopa induced, stimulating factor (rh-GCSF), 203
unwanted effects, 151 114 rectal administration, 8
procarbazine, 196f, 201 psychological effects of dopaminergic 5α-reductase, 109
prochlorperazine, 83, 152t antagonism, 128 reduction, 12
procyclidine, 116 psychomotor epilepsy, 129t, 130 re-entry, 49
prodynorphin, 147t psychotic disorders, 125–129 reflection re-entry, 49
proenkephalin, 147t psychotomimetic drugs, 144 rehydration therapy
progesterone, 105–106, 105–106f, 108 pulmonary surfactants, 41 diabetes, 99
progesterone-only pill (minipill), 107, 107b pumps, 1 diarrhoea, 86
progesterones, 201 purines, 165 hypercalcaemia, 110b
progestogen, 107 Purkinje fibres, 43 renal artery, 55t, 69
agonists, 108 pyrazinamide, 175–176t, 180 renal corpuscle, 69
antagonists, 108–109 pyrazinoic acid, 180 renal excretion of drugs, 13
proguanil, 190 pyrazolones, 161t renal pelvis, 70
prokaryotic cells, 174t pyridostigmine, 24 renal prostaglandins, 70
promethazine, 169 pyrimethamine, 190 renal tubule, 73
pro-opiomelanocortin (POMC), 100, 147t renin, 47, 70
renin-angiotensin system (RAS), 47, 54,
propantheline, 84
prophylactic drugs, 38–39
Q 56f, 70, 72, 100
propionic acids, 161t, 162 quaternary ammonium compounds, 9, reoviruses, 182t
propofol, 154, 154–155b 22–23, 150 reperfusion, 49

265
 Index

repolarisation, 44 schizophrenia (Continued) sodium equilibrium potential, 19

reproductive system, 105–110 symptoms and signs, 125 sodium glucose cotransporter (SGLT2) 2
drugs that affect, 107–110 theories of, 125–126 inhibitor, 99
female, 105 treatment of, 126 sodium nitroprusside, 57
hormonal control of, 105–107 secondary diabetes mellitus, 96 sodium picosulphate, 86
male, 106–107 secondary hyperlipidaemias, 61 sodium retention, 102t, 109
reserpine, 27, 27f secondary hypertension, 54 sodium valproate, 127b, 132, 132t, 134b
resistance, drug, 173, 180, 197 second-messenger systems, 4–5, 4f, 147 soluble TNF-α blocker, 164
respiration, 33 secretions during general anaesthesia, 153 somatic nervous system, 20–24, 25f
respiratory distress syndrome, 41 sedative antihistamines, 119t somatostatin analogues, 105
respiratory stimulants, 41 sedative H1-receptor antagonists, 120–121 sorafenib, 201
respiratory syncytial virus, 182t seizures, 129, 129t sotalol, 51
respiratory system, 33f selective oestrogen receptor modulator, South American trypanosomiasis, 192
resting membrane potential, 19 111 spacer devices, 39
resting potentials, 43–44 selective serotonin reuptake inhibitors speech, poverty of, 125
reteplase, 66 (SSRIs), 120, 122–123, 122t, 123f speed. See amphetamines
retinoic acid, 5 selegiline, 115–116, 115f spermatogenesis, 106
retinoids, 168t senna, 86 spinal anaesthesia, 151
retroviruses, 182t septic shock, 58, 59b spinal cord, 113, 114f
reversible inhibitors of MAOA (RIMAs), serotonergic agonists, 120 spinal shock, 58, 59b
122t, 124 serotonergic receptors, 120–121 spinothalamic tract, 145
reversible, non-competitive serotonin, 62 spironolactone, 48, 48b, 73f, 75
inhibition, 159 agonists, 149 sporozoans, 189t
rhabdoviruses, 182t antagonists, 149–150 sporozoites, 188
rheumatoid arthritis, 162–164 serotonin-noradrenaline reuptake squalene oxidase, 188
rhinitis, allergic, 40–41, 169t inhibitors (SNRIs), 122t, 123–124, stable angina, 51–52, 51b
ribavirin, 184 123f stanozolol, 109
ribosomes, 174f, 178, 178f serotonin-receptor antagonists, 84 staphylococci, 174–177, 175–176t
rickets, 110 Sertoli cells, 106, 106f statins, 61
rickettsiae, 175–176t sertraline, 122, 122t status epilepticus, 119, 130, 132t, 134
rifampicin, 174–176t, 180 sevoflurane, 156 stavudine (d4T), 184
right ventricular failure, 46, 47t shock steroidal anti-inflammatory drugs. See
risperidone, 127, 127b, 127t causes of, 58 glucocorticoids
ritonavir, 185 management of, 58–60 steroids. See anabolic steroids; androgenic
rituximab, 203 signs of, 58 steroids; corticosteroids
rivaroxaban, 65 types of, 58 stibogluconate, 192
rivastigmine, 117 short-acting β2 agonist (SABA), 38b stimulant laxatives, 86
rizatriptan, 149 short-acting insulin, 96–97, 97t stimulants, central, 139–142, 140t
RNA viruses, 182t sibutramine, 88 stomach
rocuronium, 24, 154b sildenafil, 76–77 basic concepts, 79
roflumilast, 39 simvastatin, 61 gastro-oesophageal reflux, 79–80, 81f
ropinirole, 115f, 116 sinoatrial node (SAN), 43, 44f peptic ulceration, 79–82, 80f
rosiglitazone, 98 sipuleucel-T, 202 prevention and treatment of acid-related
roundworms, 192, 193t size of molecules, effect on absorption, 9 disease, 80–82
skeletal muscle innervation, 20–21 stool modifiers, 85f, 87
skin disorders, 159, 165–168, 165–166f, streptococci, 175–176t
S 167–168t streptokinase, 66
salbutamol, 15, 28t, 35, 38 Skunk. See cannabis streptomycin, 175–176t, 178
salicylic acid, 159, 160f, 161, 161t sleep disorders, 117–121, 119t stress incontinence, 76
gout, 164 sleeping sickness, 192 striatal cholinergic activity, drugs that
skin disorders, 167 smack. See diamorphine (heroin) inhibit, 116–117
saline purgatives, 86 smoking cessation, 142 strong opioids, 147–148, 147t
salmeterol, 35, 37, 39 smooth muscle, drugs acting directly on, strontium ranelate, 112
saquinavir, 185 85, 85f sublingual administration, 8
sarin, 24 smooth muscle-glandular M3 receptors, 30 submucous plexus, 84
saxitoxin, 152t snow. See cocaine substituted benzamides, 127t
schizoaffective disorder, 125 sodium, 69–70 succimer, 1
schizonticides, 189, 189f absorption of, 74f sucralfate, 81
schizonts, 188 sodium aurothiomalate, 162t, 163 sulfadiazine, 177
schizophrenia, 125–129, 127b sodium channels, 19–20f, 20, 20t sulfamethoxazole, 175–176t, 177
epidemiology, 125 sodium cromoglycate, 38 sulfapyridine, 88, 163

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 Index 

sulfasalazine, 88, 162t, 163 theophylline, 37, 37b, 77, 81 topoisomerase II inhibitors, 200
sulfinpyrazone, 164t thiabendazole, 193, 193t toremifene, 108
sulfonylurea, 97t, 98b thiamazole, 93, 94f toxic nodular goitre, 92
sulphonamides, 177, 190 thiazide and related diuretics, 74–75 β-toxins, 152t
sulphonylureas, 98 thiazides, 48, 57, 72f, 74–75 tranexamic acid, 67
sulpiride, 127, 127t thiazolidine ring, 174 transduction, physiology of, 20–22, 21f
sumatriptan, 149 thiazolidinediones, 97t, 98 transmitter peptides, 145
sunitinib, 201 thiocyanate, 57 transplantation
suramin, 192 thiopental, 153–154, 155b nonmedical options, 117
surface anaesthesia, 151 general anaesthesia, 153–154 organ, 170
suxamethonium, 23 status epilepticus, 134 transport systems, 1
sympathetic nerve stimulation, 31t thioridazine, 126, 127t tranylcypromine, 29, 122t, 124
sympathetic nervous system, 25–29 thioureylenes, 93, 94f trastuzumab, 203
drugs acting on the, 26–28, 27f thioxanthines, 127, 127t travoprost, 136
effect on the heart, 45, 45t thought alienation, 125 trematoda (flukes), 192, 193t
sympatholytics. See α-adrenoceptor, thrombin, 63 tretinoin, 201
antagonists; beta-blockers thrombosis, 63–64 triamcinolone, 102t, 104
sympathomimetic amines, 59 thromboxane, 159–160 triamterene, 73f, 75
sympathomimetic vasoconstrictors, 169t thromboxane A2, 49, 62, 65, 66f, 159 triazole antifungals, 186–187
sympathomimetics1. See α-adrenoceptor, thrombus, 63 tribavirin, 184
agonists; β-adrenoceptors, agonists arterial, 63b trichloroethanol, 120
symporters, 1 atrial, 63b Trichomonas vaginalis, 191
symptomatic bronchodilators, 35 venous, 63, 63b trichomonas vaginitis, 191
synaptic transmitter substances, 5 thrush, perianal, 88 tricyclic antidepressants (TCAs), 27,
thymidylate synthetase, 199 120–122, 122t
thyroglobulin. See colloids inactivation, 28
T thyroid gland, 91–95 migraine, 149
T cells, 170–172 basic concepts, 91–92 site of action of, 123f
proliferation, 167 thyroid dysfunction, 92–95 unipolar depressive disorders, 122–124,
suppression, 171f thyroid hormones, 5, 91f, 94f 122t
tabun, 24 control of secretion of, 91–92 triggered abnormal impulse generation, 49
tacalcitol, 167 production of, 91 triglyceride (TGA), 60
tachycardia, 46t thyroid peroxidase, 91, 94f trihexyphenidyl, 30t
tachypnoea, 47t, 59b thyroid-stimulating hormone (TSH), 91, triiodothyronine (T3), 91, 91f, 94f
tamoxifen, 108, 202 91f, 94f trimethoprim, 175–176t, 177, 192
tamsulosin, 76 thyrotrophin-dependent pump, 91 trimipramine, 122
tapeworms, 192, 193t thyrotrophin-releasing hormone (TRH), trips, 144
tar preparations, 167 91, 91f tropicamide, 30t, 137t
tardive dyskinesia, 128, 128b thyroxine (T4), 91–92, 91f, 94f true incontinence, 76
taxanes, 201 thyroxine binding globulin, 91–92, 91b true yeasts, 186t
teicoplanin, 176 tiagabine, 133 trypanosomiasis, 192
temazepam, 119, 119t ticagrelor, 66 trypsin, 88
temporal lobe, 114f timolol, 134 tryptophan, 124
epilepsy, 129t, 130 tinidazole, 179, 191 tuberculoid leprosy, 180
temsirolimus, 201 tiotropium, 37, 39 tuberculosis, 180
tension-type headache, 149 tiotropium bromide, 39 tuberoinfundibular neurons, 128
terbinafine, 187 tirofiban, 66 tubocurarine, 25t
terfenadine, 170 tissue factor, 63 tubular function, 69–70
teriparatide, 112 tissue factor pathway inhibitor, 63 tubular reabsorption, 13
terlipressin, 82 tissue-type plasminogen activator (tPA), tubular secretion, 13
testes, 106 63, 66 tubules, 69–70
testosterone, 75, 106–107, 109 titanium-based emollients, 166 tubulin, 165
tetanic fade, 22–23 togaviruses, 182t tumour necrosis factor (TNF), 202
tetracaine, 152t tolbutamide, 98 tumour necrosis factor (TNF)-α, 164
tetracycline, 81, 87, 174f, 174–176t, tolcapone, 115f, 116 type 1 diabetes (absolute insulin
177–178 tolerance, drug, 139, 140t, 148 deficiency), 96, 99b
site of action of, 178f tonic-clonic epilepsy, 129, 129t, 134b dietary control, 99
tetrahydrocannabinoids (THCs), 140t topical administration, 8 type 2 diabetes (insulin resistance), 96
tetrahydrofolate, 199 topical local anaesthetics, 40 dietary control, 99
tetrodotoxin, 152t topiramate, 133 typical neuroleptics, 126–127, 127t
thalidomide, 16, 175–176t, 201 topoisomerase I inhibitors, 201 tyramine, 27f, 29, 124

267
 Index

tyrosine, 26–27 vecuronium, 23t, 24 weak opioids, 147, 148t

tyrosine hydroxylase, 26–27 venlafaxine, 122t, 123 weed. See cannabis
tyrosine kinase linked receptors, 2t, 5 venous occlusion, 63 Wernicke’s area, 114f
ventricular arrhythmias, 49 wheal and flare, 169t
verapamil, 50t, 51–53, 51b, 56 whizz. See amphetamines
U very low-density lipoproteins (VLDL), whooping cough, 4
ulcerative colitis, 87–88 57, 60 withdrawal, acute alcohol, 119–120
ulcers, peptic. See peptic ulceration vesamicol, 21f, 22 withdrawal, drug, 139, 140t
unfractionated heparin, 65 vigabatrin, 132t, 133 worms, 192, 193t
unipolar affective disorders, 121 vinblastine, 200
site of action of drugs, 122t, 123f vinca alkaloids, 200
treatment of, 122–124 vincristine, 200 X
unstable angina, 51–52 vinorelbine, 200 xanthine oxidase inhibitors, 165
uptake 1 and 2, 28–29 virions, 181, 181f xanthines, 37
ureters, 69–70 viruses, 181, 181f
urethra, 69 classification of medically important,
urge incontinence, 76 182t Y
uric acid, 164 infection of host’s cell and replication, YAG (yttrium-aluminium-garnet) laser
uricosurics, 165 183f surgery, 136
urinary incontinence, 76 replication of, 183f yeast-like fungi, 186t
urinary system, 75–77 vitamin A derivatives, 168t yeasts, 186t
basic concepts, 69 vitamin B12, 68 yellow card scheme, 17
structure of, 70f (see also kidneys) vitamin D, 5, 111 yohimbine, 27–28, 27f
urine, 69 preparations, 112
ursodeoxycholic acid, 89 vitamin D analogues, 167
uterine contractions, 110 vitamin K Z
antagonists, 64–65
zafirlukast, 37
for bleeding disorders, 64f, 67
V effect on coagulation cascade, 64f
zalcitabine (ddC), 184
zaleplon, 120
vaccines, 202 vitamin K epoxide, 64, 64f
zanamivir, 182
vaginitis, trichomonas, 191 vitreous humour, 134, 135f
zero-order kinetics, 13–14, 13f
valaciclovir, 183 volume of distribution (Vd), 9
zidovudine (AZT), 184, 186b
valproate, 130 vomiting, 82–84
zinc-based emollients, 166
valsartan, 56 after general anaesthesia, 153
Zollinger–Ellison syndrome, 79
vancomycin, 173, 175–176t, 176, 176b causes of, 83f
zolpidem, 120
varenicline, 142 levodopa induced, 114
zopiclone, 118, 119t, 120
variant angina, 51 von Willebrand’s disease, 66–67
zotepine, 127
varicella zoster virus (VZV), 181 von Willebrand’s factor, 62
zyban, 142
vascular tone, control of, 54
vasoconstrictors, 58–62, 151
vasodilators, 54–57
W
vasopressin. See antidiuretic hormone warfarin, 64–65, 64f, 65b, 81
(ADH) water reabsorption, 69–70, 75

268