INTRODUCTION TO

PHARMACOLOGY

Pharmacology for By:

medical laboratory DEJENE
technology HAILU
 INTRODUCTION TO
PHARMACOLOGY
What is Pharmacology?
Derived from Greek “pharmakon [drug], logos [Science ].

Pharmacology is the science of drugs dealing with

pharmacokinetics and pharmacodynamics of drugs.
Pharmacology studies the effects of drugs and

how they exert their effects.

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 What are drugs?
3

 A drug is any chemical or biological substance, synthetic or

non-synthetic, that when taken into the organism's body, will

in some way alter the functions of that organism.
 Drugs chemicals that are intended for treatment, diagnosis,

prevention and control of diseases

 Drugs are usually distinguished from endogenous
biochemicals by being introduced from outside the organism.

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 DRUG NOMENCLATURE
 Many names are given to drugs often confusing.

 It is therefore necessary to know drug nomenclature.

The following is the drug name system

1)Chemical/Molecular/Scientific name: It depicts

the chemical/molecular structure of the drug

e.g. paracetamol

N-acetyl-p-amino-phenol
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2) Generic/ Approved Name: It is the official medical

name of the drug. Removes confusion of giving several

names to the same drug regardless of who
manufactures them e.g: paracetamol (Britain English)
or Acetaminophen (American English)
3) Trade/Brand Name: These are names given to the

drug by the manufacturing and marketing company. In

most cases one drug could have so many trade/brand
names e.g paracetamol has many trade names. Like :
Pacimol, Tylenol, Paramol, Panadol, Capol etc.
5 5
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 Sources of Drugs
6

 Plants
 Microorganisms
 Animals
 Chemical synthesis
 Biotechnology
 Semi-synthetic: heroin, oxacilin,
Currently majority of the drugs used in therapeutics are
from synthetic source
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 Sources of drugs
1-Plant sources
various parts of plants may be used as sources of
drugs e.g. Leaves of belladonna for atropine, Bark of
cinchona for quinine and quinidine.

2-Animal sources
Insulin from pancreas of different animals e.g. cattle
or pig

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3-Mineral sources:
e.g. Magnesium sulphate and iodine
4-Microrganism:
Fungi and bacteria isolated from soil are important sources
of antibiotics e.g. penicillin
5-Synthetic drugs:
Many drugs are produced in the laboratory
e.g. sulphonamide, barbiturate, aspirin
6-Biotechnology:
Human insulin and growth hormone have successfully been
produced by genetic engineering
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 Branches of pharmacology
9

• Pharmacology is a vast science having major sub-

divisions:
Pharmacokinetics: deals with the action of body on the
drug [what the body do on the drug].
Pharmacodynamics: deals with action of drug on the
body [what the drug do on the body].

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 Pharmacokinetics
10

 Greek: Kinesis—movement

 What the body does to the drug.

 This refers to movement of the drug in and alteration of

the drug by the body; includes absorption, distribution,

binding/localization/storage, biotransformation and

excretion of the drug.

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 PHARMACOKINETICS…
11
PHARMACOKINETIC IMPORTANCE
1- To know the dose
2- To know the suitable route of administration
3- To know the dosage interval
4- To know the period of medication
 PHARMACOKINETIC comprises of: ADME

 Absorption
 Distribution
 Metabolism
 Excretion
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 Absorption
12

Absorption
Passage of a drug from its site of administration into
blood stream.
 is the transportation of the drug across the biological
membranes
There are different mechanisms for a drug to be
transported across a biological membrane:
 Passive (simple) diffusion
 Active transport
 Pinocytosis
 Facilitated diffusion
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 SIMPLE (PASSIVE) DIFFUSION
13

• The major role for the transportation of the drugs across

the cell membrane is simple (passive) diffusion.
• The substances move across a membrane according to a
concentration gradient.
• The concentration gradient is the factor that determines
the route and rate of the diffusion.
 No energy is required.
 There is no special transport (carrier) protein.
 No saturation.

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 ACTIVE TRANSPORT
14
 The transportation of the drug molecules across the cell
membrane against a concentration or an electrochemical
gradient.
 It requires energy (ATP) and a special transporter (carrier)
protein.
 There is «transport maximum» for the substances (the rate
of active transport depends on the drug concentration in
the enviroment).
e.g. levodopa and Methyl DOPA are actively absorbed from the
gut by the aromatic amino acid transporter.

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 FACILITATED DIFFUSION
15

 Occurs by the carrier proteins.

 Net flux of drug molecules is from the high concentration

to low concentration.
 No energy is required.

 Saturable.

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 Pinocytosis
16
It is the process of transport across the cell in particulate
form by formation of vesicles.
This is applicable to proteins and other big molecules, and
contributes little to transport of most drugs.
The drugs which have MW over 900 can be transported
by pinocytosis.
It requires energy.
The drug molecule holds on the cell membrane and then
surrounded with plasma membrane and inserted into the
cell within small vesicles.

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 FACTORS THAT AFFECT THE ABSORPTION OF THE
DRUGS
17

A)DRUG-RELATED FACTORS
 Molecular size
 Lipid solubility
 Degree of ionization
 Dosage form
 Chemical nature (Salt/organic forms, crystal forms, solvate
form etc.)
 Particle size
 Complex formation
 Concentration of the drug
B) SITE OF APPLICATION RELATED FACTORS
 Blood flow (at site of application)
 Area of absorption
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 SITE of APPLICATION RELATED FACTORS

18

Blood flow (at site of application):

 Ifthe blood flow is high at the site of application, it
causes an increase in absorption rate.
Area of absorption:
 If the surface area that allows the absorption of the
drug molecules is wide, then absorption rate from that
surface becomes high.

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 Route Of Administration

19

Affects drug absorption, because each route has its own

peculiarities.
Oral Route
Drug molecules are mostly absorbed from duodenum,
jejunum and upper ileum.
Disintegration and dissolution are the two main processes
for the oral administered drugs before the absorption
process.
The absorption rate and absorption ratio of the orally
administered drugs are closely related with the above two
parameters.
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 Oral application.
20

 Unionized lipid soluble drugs (e.g. ethanol) are readily absorbed

from GIT.
 Acid drugs (aspirin, barbiturates, etc.) are predominantly
unionized in the acid gastric juice and are absorbed from the
stomach.
 Acid drugs absorption from the stomach is slower, because the

mucosa is thick, covered with mucus and the surface is small.

 Basic drugs (e.g. atropine, morphine, etc.) are largely ioni-zed and

are absorbed only from the duodenum. 12/19/2023

Rout of
administration Advantage Disadvantage
oral route Safe Slow onset
 convenient not for irritant drugs
economical not for vomiting pt.
Polar drug poorly absorbed
Distraction by gastric acid &
GI enzymes
Not for unconscious

IV Fast onset of action Pain at the site of injection

Can be given for vomiting Relatively costly
patient expertise is needed
Can be given for Drug effect can’t be halted
unconscious patient

Anal route Can be given for Absorption is not reliable

unconscious patient Not preferred by adults

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 Bioavailability
22

Is the fraction of an administered dose of

unchanged drug reaching the systemic circulation
By definition, when a medication is administered
via IV its bioavailability is 100%, However other
routes (such as orally), its oral bioavailability
decreases (due to incomplete absorption and First
pass metabolism)

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 Bioavailability
23

Destroyed Not Destroyed Destroyed

in gut absorbed by gut wall by liver

to
Dose systemic
circulatio
n

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 II. Distribution
24

Distribution is the transport of drug from systemic

circulation into site of action. After absorption of a
drug, it is usually distributed through the different
tissues and the body fluid compartment including
A- The plasma
B- The extracellular fluid
C- The intracellular fluid

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 25

Distribution is a
Passive Process,
for which the • The Process occurs
driving force is
by the diffusion of
the Conc.
Free Drug until
gradient
equilibrium is
between the
established.
blood and
Extravascular
Tissues

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 DISTRIBUTION
26
Factors Affecting the Distribution of Drugs:
 Lipid solubility (diffusion rate)

 Ionization at physiological pH (dependent on pK)

 The Affinity of the drug to the tissue Proteins

 Blood Flow (Perfusion Rate)

 Binding to Plasma Proteins

 Disease like CHF, uremia, cirrhosis.

N.B Movement of a drug proceeds until an equilibration is established

between unbound drug in plasma and tissue fluids.
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 Factors Affecting the Distribution of Drugs

27

4. Plasma Proteins:
 The most important protein that binds the drugs in blood is
albumin for most of the drugs.
 Especially, the acidic drugs (salicylates, vitamin C,
sulfonamides, barbiturates, penicillin, tetracyclines,
warfarin, probencid etc.) are bound to albumin.
 Basic drugs (streptomycin, chloramphenicol, digitoxin,
coumarin etc.) are bound to alpha-1 and alpha-2 acid
glycoproteins, globulins, and alpha and beta lipoproteins.
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 Properties of plasma protein-drug binding

28
 Only the free (unbound) fraction of the drug circulating in

plasma can pass across the capillary membrane .

 Bound fraction serves as “drug storage”.

[DRUG]=1 mM [DRUG]=1 mM

[DRUG+PROTEIN]=9 mM

[TOTAL DRUG]=10 mM [TOTAL DRUG]=1 mM

INTERCELLULAR FLUID
PLASMA
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FACTORS AFFECTING DISTRIBUTION
29
5. Storage (Concentration-Sequestration) of
the Drugs in Tissues
◦ Stored drug molecules in tissues serve as drug
reservoir.
◦ The duration of the drug effect may get longer.
◦ May cause a late start in the therapeutic effect or
a decrease in the amount of the drug effect.

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 Tissue storage
30
 Heart and skeletal muscles – digoxin (to muscle proteins)
 Liver – chloroquine, tetracyclines, digoxin
 Kidney – digoxin, chloroquine
 Thyroid gland – iodine
 Brain – chlorpromazine, isoniazid, acetazolamide
 Retina – chloroquine (to nucleoproteins)
 Iris – ephedrine, atropine (to melanin)
 Bones and teeth – tetracyclines, heavy metals (to
mucopolysaccharide of connective tissue)
 Adipose tissues – thiopental, ether, minocycline, DDT

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 DISTRIBUTION

31

 Passage of the drugs to CNS:

 A BBB exists (except some areas in the brain) which limits the
passage of substances.
 Non-ionized, highly lipophilic, small molecules can pass into the
CNS and show their effects.
 Inflammation of the meninges of the brain increases
permeability of the BBB.
 Some antibiotics like penicillin can pass through the inflamed
BBB while it can’t pass through the healthy one.
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 Placental barrier
32
Placental membranes are lipid and allow free passage of
lipophilic drug, while restricting hydrophilic drugs.
The placental P-gp also serves to limit foetal exposure to
maternally administered drugs.
However restricted amounts of nonlipid soluble drugs,
when present in high concentration or for long periods in
maternal circulation, gain access to the foetus.
Thus, it is an incomplete barrier and many drugs, taken by
the mother, can affect the foetus or the newborn.
Penicillins, azithromycin, and erythromycin do not affect
the foetus and can be used during the pregnancy.
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 Placental barrier
33
 Passage of the drugs to fetus:
◦ Placenta doesn’t form a limiting barrier for the drugs to
pass to fetus.
◦ The factors that play role in simple passive diffusion,
effect the passage of drug molecules to the fetus.
 Placental blood flow
 Molecular size
 Drug solubility in lipids
 Fetal pH (ion trapping): fetal plasma pH: 7.0 to 7.2; pH
of maternal plasma: 7.4, so according to the ion
trapping rules, weak basic drugs tend to accumulate in
fetal plasma compared to maternal plasma. 12/19/2023
BIOTRANSFORMATION
 BIOTRANSFORMATION

35

The process of alterations in the drug structure by the

enzymes in the body is called “biotransformation (drug

metabolism)” and the products form after these reactions are
called “drug metabolites”.
Some drugs which don’t have any activity in vitro, may gain

activity after their biotransformation in the body.

These types of drugs are called “pro-drug” or “inactive

precursor”.
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 cont’d…
36

Drug examples that gain activity after

biotransformation (pro-drugs):
Pro-drug effective
metabolite
Enalapril enalaprilat
Lovastatin lovastatin acid
L-Dopa dopamine

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 Biotransformation
37
 Drug examples that is transformed to more active compounds
after biotransformation:

DRUG MORE ACTIVE

METABOLITE
Imipramine Desmethylimipramine
Codeine Morphine
Nitroglycerin Nitric oxide

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 Biotransformation
38
 Drug examples that is transformed to less active
compounds
DRUG after biotransformation:
LESS ACTIVE
METABOLITE
Aspirin Salicylic acid
Meperidine Normeperidine
Lidocaine De-ethyl lidocaine
(dealkylated)

 Drug examples that is transformed to inactive metabolites

afterDRUG
biotransformation INACTIVE
METABOLITE
Most of the drugs Conjugated compounds
Ester drugs Hydrolytic products
Barbiturates Oxidation products
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 Biotransformation

39
 The metabolites that are formed after biotransformation are
generally more polar, more easily ionized compounds compared
to the main (original) drug.
 So, these metabolites can be excreted from the body easily.
Organs in which biotransformation occurs:
 Liver** (the most important organ, the number and
variability of the biotransformation enzymes are the
highest)
 Lungs

 Kidney (tubular epithelium, sulphate conjugation)

 Gastrointestinal system (duodenal mucosa)

 Placenta

 Adrenal glands
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 Skin
 ENZYMATIC REACTIONS
40

The enzymatic reactions which the drugs are exposed to:

1. Oxidation
2. Reduction PHASE I
3. Hydrolysis
4. Conjugation PHASE II

DRUG X (inactive or less active**, same activity, higher activity) Y (generally inactive)

PHASE I PHASE II

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 CONJUGATION REACTIONS
41

1. Glucuronidation

2. Methylation
1. N- methylation
2. O-methylation

3. N-acetylation

4. Sulfate conjugation (sulfation)

5. Glutathione conjugation

6. Conjugation with amino acids

7. Conjugation with ribose or ribose phosphates 12/19/2023

 Glucuronidation

42

 These involve conjugation of the drug or its phase I meta-

bolite with an endogenous substrate to form a polar highly
ionized organic acid, which is easily excreted in urine or bile.
 Conjugation reactions have high energy requirements.
 Glucuronic acid is a highly hydrophilic compound, so it
decreases the lipid solubility of the drug after conjugation.
 Glucuronosyl transferases catalyze the reaction.

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 Characteristics of phase II products:
43

1) Product = conjugate

2) Usually are pharmacologically inactive.

3) Polar

4) More readily excreted in urine.

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Factors That Affect The Biotransformation of Drugs
44
1. Induction or inhibition of microsomal enzymes

2. Genetic differences

3. Age

4. Gender

5. Liver diseases

6. Environmental factors

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 Induction or inhibition of microsomal enzymes
45

 Various drugs or environmental factors lead to increases in the

activity of these enzymes by increasing the synthesis of

microsomal enzymes.
 The importance of the enzyme induction is the increasing

metabolism rate of the drugs and the reduction in their

activities.
 On the other hand, some drugs stimulate the enzymes that

inhibit themselves (biochemical tolerance).

 Unlike the enzyme induction, some drugs can inhibit the

microsomal enzymes. 12/19/2023

 INDUCERS
ENZYME DRUG or SUBSTANCE
46 THAT INDUCES THE ENZYME

Cigarette smoke, grilled meat (barbecue), aromatic

CYP1A2
polycyclic hydrocarbons, phenytoin

CYP2C9 Barbiturates, phenytoin, carbamazepine, rifampin

CYP2C19 NOT INDUCIBLE

CYP2D6 NOT INDUCIBLE

Barbiturates, phenytoin, rifampin, carbamazepine,

CYP3A4
glucocorticoids, griseofulvin, 12/19/2023
 Use of inducers result in

47
1. Increase the metabolism of the inducer.
2. Tolerance : Decreases the inducer’s pharmacological action.
3. Increase the metabolism of co-administrated drugs (drug
interaction)
E.g. Barbiturates and warfarin  thrombosis.
Phenytoin and oral contraceptive ( the woman gets pregnant )
4. Increase tissue toxicity by metabolite.
E.g. Paracetamol , phenacetin .
5. As therapy.
E.g. Phenobarbitone (given to babies with physiological
jaundice to induce liver microsomal enzymes) and
hyperbilirubinemia.
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 INHIBITORS
48
ENZYME DRUG or SUBSTANCE THAT INHIBITS THE
ENZYME

CYP1A2 Cimetidine, ethinyl estradiol, ciprofloxacin

Amiodarone, isoniazid, co-trimoxazole, cimetidine,
CYP2C9
ketoconazole
CYP2C1
Fluoxetine, omeprazole
9
Amiodarone, cimetidine, fluoxetine, paroxetine,
CYP2D6
haloperidol, diphenhydramine
Ketoconazole, erythromycin, , isoniazid, Ca
CYP3A4
channel blockers, red wine, grapefruit juice
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 Use of inhibitors result in:

49

 Impede the metabolism and excretion of the inhibitor and

Co-administered drugs, thus increasing t1/2.

 Prolong the action of the inhibitor and co- administrated

drugs  increased pharmacological activity

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 Liver Diseases
50

 Especially, the metabolism of drugs with a “high hepatic

clearance” decreases in liver diseases.

 This leads to accumulation of drugs in the body which are

metabolized in liver, and eventually causes an increase in

the effect and adverse effects as well.
 On the other hand, transformation of pro-drugs into their

active forms occurs less in liver diseases.

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 ENVIRONMENTAL FACTORS

51

 Especially pollutants can affect the microsomal enzymes.

 Induction of microsomal enzymes can occur with;

 DDT and some insecticides

 Benzopyrenes and other polycyclic aromatic hydrocarbons

(products of burned coal and petroleum products)

 Polycyclic hydrocarbons in the cigarette smoke can induce some enzymes like

CYP1A2 and CYP1A1 (For this reason, the metabolism rate of chlorpromazine,

theophylline and imipramine is significantly high in heavy smokers).

 Diet (Cabbage and cauliflower can induce CYP1A1 and CYP1A2)

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 ENVIRONMENTAL FACTORS
52

 Inhibition of microsomal enzymes can occur with;

 Carbon monoxide inhibits the microsomal enzymes.

 Grapefruit juice (some flavonoids in grapefruit juice can inhibit
CYP3A4)

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 53

EXCRETION

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 54
EXCRETION

Excretion is the passage out of systematically absorbed

drugs.

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RENAL EXCRETION
55

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 Drug elimination
56
Elimination of drug from body occurs by
excretion and metabolism
Drugs are eliminated from the body either
unchanged (parent compound), or as metabolites
Excretory organs, excluding the lung, eliminate
polar compounds more efficiently than
substances with high lipid solubility
Lipid soluble drugs are thus not readily
eliminated until they are metabolized to more
polar compounds
Occurs through a number of routes: the major
organ kidney being and include others: bile,
intestine, breast milk, and lung.
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 Excretion of Drugs (cont’d)
57
The kidney is the most important organ for
elimination of drugs and their metabolites

 Primary organ of removal for most

drugs, especially those that are water
soluble and nonvolatile
Three principle processes by which the kidney
eliminates drugs:
Glomerular filtration
Tubular secretion
Tubular reabsorption
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 Metabolism and
58
Elimination
Half-lives and Kinetics
 Half-life:
Plasma half-life: Time it takes for plasma
concentration of a drug to drop to 50% of initial level.
 Whole body half-life: Time it takes to eliminate half of
the body content of a drug.
 Factors affecting half-life
 Age
 Renal excretion
 Liver metabolism
 Protein binding

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PHARMACODYNAMICS
59

SET BY: DEJENE HAILU

12/19/2023
 PHARMACODYNAMICS
What the drug does when it gets there.
 It deals with the biochemical and physiological

effects of drugs and their mechanisms of action

 A thorough analysis of drug action can provide the

basis for rational therapeutic use of a drug

 Mechanisms of Action- the ways by which drugs

can produce therapeutic effects

60 60
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PHARMACODYNAMICS: Mechanism of action of a drug
61

 Once the drug is at the site of action, it can modify the rate

(increase or decrease) at which the cells or tissues function

by interacting with receptors.
 A drug cannot make a cell or tissue perform a function it

was not designed to perform

Mechanisms of Action :
• Receptor interaction

• Nonspecific interactions
61
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 What is Pharmacodynamics (PD)
62

• PD deals with

– Interaction of drugs with receptors and understanding the

molecular mechanisms by which a drug acts
– Relationship between drug concentration and magnitude of
the response

Why we study it ??

To understand how the drugs produce its therapeutic and toxic

effects.
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 Drug-receptor interaction
63
• Begins all the pharmacodynamic process.
• Receptors are biological macromolecules to which a ligand can bind and produce a
measurable response.

They include
 Regulatory proteins, which mediate the actions of endogenous
chemical signals such as neurotransmitters
 Enzymes, which may be inhibited by binding a drug (eg, dihydrofolate
reductase)
 Transport proteins (eg, Na+/K+ ATPase, the membrane receptor for
cardioactive digitalis glycosides)
 Structural proteins (eg, tubulin, the receptor for colchicine, and
anti-inflammatory agent).
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 Drug-receptor interaction
64
• Largely determine the quantitative relations between dose of

drug and pharmacologic effects.

• Responsible for selectivity of drug action.

• Mediate the actions of both pharmacologic agonists and

antagonist
• Many toxic chemicals produce their effect by interaction with

receptors.
• Drugs only modify an already existing biochemical
processes. 12/19/2023
 Drug-receptor interaction
65
• Involve formation of chemical bonds

- Hydrogen bonding other weak electrostatic interaction

- Usually interaction is reversible
- Few cases , strong covalent bonds are formed ( Toxic substances )
• Drug – receptor interaction initiates the action of the drug.

• Drug + Receptor D-R complex

biological response
 The formation of D-R complex depends on drug affinity for the receptors.

But the Pharmacological response depends on intrinsic activity

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 Dose-response relationship
66

The intensity and duration of a drug’s effects are a function

of drug concentration at the effect site

Two types of Dose-response relationship

A- Graded : Relates dose to intensity of effect e.g. blood

pressure. Reponses measured in usual units eg, B.P, Blood sugar
levels etc. It can take fraction.

B- Quantal :% of population responding to drug. Responses

are recorded as either positive or no response and can not take
fractions. 12/19/2023
 Affinity & intrinsic activity
67

Two factors that determine the effect of a drug on

physiologic processes are affinity and intrinsic activity.

A- Affinity is a measure of the tightness that a drug binds to
the receptor.
B- Intrinsic activity is a measure of the ability of a drug
once bound to the receptor to generate an effect activating
stimulus and producing a change in cellular activity.

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 Agonist & partial agonist
68

Agonist::A drug which binds to a receptor and

activates it, producing pharmacological response

(contraction, relaxation, secretion, enzyme
activation, etc.). Intrinsic activity =1
Partial agonist : A drug which binds to a
receptor and activates it, producing a
pharmacological response but less than full
agonist Intrinsic activity <1 but not zero
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 AGONIST and ANTAGONISTS
69

AGONIST: A drug is said to be an agonist when it

binds to a receptor and causes a response or effect. It
has intrinsic activity = 1

ANTAGONISTS: A drug is said to be an antagonist

when it binds to a receptor and prevents (blocks or
inhibits) a natural compound or a drug to have an
effect on the receptor. An antagonist has NO activity.
Its intrinsic activity is = 0

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 Partial agonist
70
% of maximal responses

Fuall agonis t vs partial agonis t

1.2
1 full agonis t

0.8
0.6
0.4
partial
0.2 agonis t

0
1.00 1000.00
log Conce ntration

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 PHARMACOLOGICAL ANTAGONISTS
71

A pharmacological antagonists can either be

Competitive and non-competitive
1. Competitive
They compete for the binding site
• Reversible

2. Non-competitve
Bind elsewhere in the receptor (Channel Blockers).

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 A-Pharmacological Antagonists

non competitive competitive

bind irreversibly to the receptors. bind reversibly to the receptors

Their effect Can’t be overcome Their effect Can be overcome by

by increasing the concentration of increasing the concentration of agonist
agonist

Calcium channel blockers Example atropine is a competitive agonist

for acetylcholine

72 12/19/2023
 Other Antagonists
FUNCTIONAL ANTAGONISTS
73

1. Physiologic Antagonists: A drug that binds to a non-

related receptor, producing an effect opposite to that
produced by the drug of interest.
• Its intrinsic activity is = 1, but on another receptor.

 Glucocorticoid Hormones  Blood Sugar

 Insulin  Blood Sugar
• Action of adrenaline counteracts that of histamine at

bronchioles.
12/19/2023
 2. Chemical74antagonists
• A chelator (sequester) of similar agent that interacts

directly with the drug being antagonized to remove

it or prevent it from binding its receptor.

• A chemical antagonist does not depend on

interaction with the agonist’s receptor (although

such interaction may occur).

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 Potency & Efficacy
75

Potency: is related to the amount of drug needed to produce

a given effect. In graded dose-response, potency of drugs
are compared using EC50 (The dose producing 50 % of
the maximum effect )
Efficacy: Is the maximum effect an agonist can produce
(Emax). Its More clinically important than potency .

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 Therapeutic Index
76
Is the ratio of the LD50 (Lethal dose that kills 50 %of
animals tested)to the ED50(is the amount of drug that
produces a therapeutic response in 50% of the people
taking it)
It represents measure of relative safety of the drug.

For example penicillin has a high therapeutic index as

compared to digoxin which have a low therapeutic index

Therapeutic index is clinically more important parameter
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Therapeutic Index

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 Desensitization , Tachyphylaxis &
Tolerance
78

 Some drug when given continuously or repeatedly their effects

gradually decreases
 If decrease of drug effect develops in very short time we call it

tachyphylaxis or desensitization
 If decrease of effect occurs during several days or weeks we call it

Tolerance
 Many different mechanisms can give rise to this type of phenomenon.

E.g. Change in receptors ; Loss of receptors; Exhaustion of mediators

Increased metabolic degradation ; Physiological adaptation
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 FACTORS MODIFYING THE DOSAGE AND
ACTION OF DRUGS
 Drugs effect varies from person to person
 Factors which influence the effect of drug:
Sex
Body Weight
Age
Disease status
Genetics/race
Drug interactions
Emotional state
Tolerance
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 DRUG INTERACTIONS
 A drug interaction may be beneficial or harmful
 A drug interaction may be either pharmacokinetic or
pharmacodynamic
A.PHARMACOKINETIC DRUG INTERACTIONS:
 Interaction during absorption e.g. chelation
 Interaction during distribution e.g plasma protein binding
 Interactions during biotransformation -two mechanisms:
 Enzyme induction –accelerated
biotransformation
 Enzyme inhibition-delayed metabolism
 Interactions during excretion
 Competition for secretion; probenced and penicillin

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B. PHARMACODYNAMIC INTERACTIONS
1. COMBINED EFFECT OF DRUGS
i. Synergism - the effect of two drugs are greater than the effect
of the summation of their individual actions (1 + 1> 2)
ii. Additive effect- action of two or more drugs is equivalent to
the summation of their individual actions (1 + 1= 2)
iii. Potentiation effect- net effect of one drug used together with
other non therapeutic substance is greater than the individual
effects of the drug (1+0 >1)

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 Pregnancy Considerations
 Drugs may cross the placenta
 Drugs may cross into breast milk
 Drugs may be teratogenic
 Teratogen - drugs or substances that blocks
normal growth of the fetus and causes one or
more developmental abnormalities

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 Pediatric and Geriatric Considerations:
83

Pediatric Considerations Geriatric Considerations

  Oral absorption   Oral absorption
  topical absorption -   Plasma protein
thinner skin concentration
  Plasma protein   Muscle mass,  body
concentration fat
  Free protein-bound drug   Liver/renal function
  Elimination/metabolism  Multiple diseases
 Multiple drugs

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DEVELOPMENT AND EVALUATION OF NEW DRUGS
Drug development comprises of two steps:
1. Preclinical development
 Experimentation ( invitro and invivo)
 Aims is to explore the drug’s efficacy and safety before it is
administrated to patients
 Varying drug doses are tested on animals (invivo and/or in
vitro systems
 Intact animals are essential for the acute, subacute, and
chronic toxicity tests
 Tests teratology and carcinogenicity
2. Clinical development
 Through four phases

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 B. Clinical development:
 Efficacy of drug is tested on humans in 4 phases
Phase - I: usually conducted in healthy volunteers to
test the tolerable dose and duration of action
Phase - II: comprises small scale trials on patients to
determine dose level and treatment offers
Phase - III: It involves randomized control trials on
moderately large number of patients and is done in
multiple centers
Phase – IV : Post marketing surveillance
 Reports about efficacy and toxicity received from different
medical centers

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