PRINCIPLES OF DRUG ACTION

Part II
• Quantitative Drug Receptor Interactions

Kofi Oduro Yeboah, MPhil, MPSGh, PharmD

Dept. of Pharmacology
CHS, KNUST
Objectives
To discuss quantitative aspects of drug –receptor interactions and their
associated dose response curves pertaining to;
• Agonist effect
• ED50 & EC50
• Inverse agonism
• Antagonist effect
• Competitive & Non-competitive
• Reversible & Irreversible

• Drug toxicity/inhibitory effects

• LD50, LC50, IC50, TI

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Drug-Receptor Interactions

• Occupation of a receptor by a drug molecule may or may not result in

activation of the receptor.

• Activation means that the receptor is affected by the bound molecule

in such a way as to alter the receptor’s behaviour towards the cell and
elicit a tissue response.

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Drug-Receptor Interactions; Binding and activation

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 Concentration-Response Relationship

• Drug effect is proportional to the number of occupied receptors.

• Drug (D) + Receptor (R)  DR → Effect

• Drugs that bind to these receptors may behave as an agonist,

antagonists, partial agonist/ partial antagonist or inverse agonist

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 Dose-Response Relationships

• The concentration of drug at the site of action

controls the effect
• Regardless of how the drug effect occurs.

• Dose-response data are normally represented on a

graph with
• Dose or dose fxn (log dose) on x-axis
• Measured effect on y-axis

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 Hypothetical dose-response curve
Features
• Potency (displacement of the curve along the x-
axis) - EC50, pD2, pA2

• Maximal efficacy (greatest attainable response)

• Slope (Δ response / unit dose)

• The DRC is hyperbola or sigmoidal

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Dose-response curve

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 Drug characteristics

• Spare receptors the maximum response of a tissue

may be produced by agonists when they are bound to
less than 100% of the receptors. Under these
circumstances the tissue is said to possess spare
receptors

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 Drug characteristics
• Agonists: Are drugs capable of binding to and activating a
receptor.

• Antagonists: are drugs that combine with receptor, but do not

activate them. Antagonists reduce the probability of the
transmitter substance (or another agonist) combining with the
receptor and so reduce or block its action.

• Affinity: The tendency of a drug to bind to the receptors is

governed by its affinity,

• Efficacy: whereas the tendency for it, once bound, to activate

the receptor. Agonists also possess significant efficacy,
whereas antagonists, in the simplest case, have zero efficacy.

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 Types of agonists
• Agonists are drugs capable of binding to and
activating a receptor.
• Full Agonists : give maximal response.
efficacy = 1
• Partial Agonists : can occupy a receptor but do not give
maximal response
0 < efficacy <1
• Inverse Agonist : Cause intrinsic/constitutively active
targets to become inactive
negative efficacy
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Drug characteristics

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Characterization of Drug effects

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 Characterization of Drug effects
• Antagonism

• An antagonist is a molecule that inhibits the action

of an agonist but has no effect in the absence of
the agonist

• ~ zero efficacy

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 Types of antagonism

Antagonist

Receptor Non-receptor
Antagonist Antagonist

Active binding Allosteric

site binding site

Pharmacoki
netic
Reversible Irreversible Reversible Irreversible antagonism

Functional/Physi
Competitive Competitive ological Chemical
Reversible Irreversible Noncompetitive
antagonism antagonism
Antagonism

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RECEPTOR ANTAGONISM
• Mechanism of Receptor Antagonism

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 Characterization of Drug effects
• Antagonism

• An antagonist is a molecule that inhibits the action

of an agonist but has no effect in the absence of
the agonist

• ~ zero efficacy

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 Antagonism
Functional/Physiological Antagonism
• Drugs produce opposing effects on the same physiological
system

• β2- adrenoceptor agonist (eg Salbutamol) induces

bronchodilation while Cholinergic agonist such as
(methacholine) produce bronchoconstriction

• What about Adrenaline versus Acetylcholine on the heart?

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 Antagonism
Pharmacokinetic Antagonism

• Is the result of one drug suppressing the effect of a

second drug by reducing its absorption, altering its
distribution, or increasing its rate of elimination.

• e.g. phenobarbital-induced enzyme induction increases the

metabolism of the anticoagulant warfarin

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 Antagonism
Chemical Antagonism
Chemical antagonism refers to the uncommon situation where
the two substances combine in solution to cancel an effect.

Examples
• the use of chelating agents (e.g. dimercaprol) that bind
to heavy metals and thus reduce their toxicity

• The neutralising antibody (infliximab) which has an anti-

inflammatory action due to its ability to sequester the
inflammatory cytokine tumour necrosis factor (TNF)
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MEASURING DRUG ACTION
-Antagonism

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Receptor Antagonism

Competitive antagonism Noncompetitive antagonism

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MEASURING DRUG ACTION

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 Drug characteristics

Drug Selectivity
• Is the degree to which a drug acts on a given
receptor relative to other receptors.

Eg 1. Adrenomimetic agents
• a1, a2, b1, b2 — Epinephrine
• a1, a2, b1- Norepinephrine
• a1 - Phenylephrine; methoxamine
• a2 - Clonidine
• b1, b2 - Isoprenaline (isoproterenol)
• b1 - Dobutamine
• b2 - Terbutaline; salbutamol, metaproterenol
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Drug characteristics

DRUG SPECIFICITY
• Is the degree to which a drug acts on a given
organ/system relative to other organs/systems
.
Eg Histamine H1 receptor antagonist
• immune system - Antiinflammatory
• CNS - sedation

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 MEASURING DRUG ACTION
• ED50 is the drug dose that causes a therapeutic response in
50% of the population.
• EC50 is the drug concentration that causes a 50% of the
maximal response.
• IC50 is the drug concentration of an inhibitor that causes
50% inhibition.
• TD50 is the drug dose that causes toxicity in half of the
study population

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Drug Safety

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Drug Safety

TD50

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 Drug Safety
Therapeutic Window
• The range of doses of a drug that elicits a therapeutic response,
without unacceptable adverse effects (toxicity) in a population.
Therapeutic Index/Ratio (TI)
• Is one method of estimating a drug’s margin of safety

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Drug Safety

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Drug Safety

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 DECREASED RESPONSIVENESS TO DRUGS

Desensitization/ Tachyphylaxis
• Rapid loss of drug effect (minutes)
Tolerance
• is conventionally used to describe a more gradual decrease
in responsiveness to a drug, taking hours, days or weeks to
develop
Refractoriness
• used mainly in relation to a loss of therapeutic efficacy
Drug resistance
• is a term used to describe the loss of effectiveness of
antimicrobial or antitumor drugs.

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 Mechanisms that give rise to loss of Drug effect

• change in receptors • physiological adaptation

• translocation of • active extrusion of

receptors drug from cells
✓(mainly relevant in
• exhaustion of cancer chemotherapy)
mediators

• increased metabolic
degradation of the
drug
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 Sample Questions
1. The effect that a drug exerts is proportional to the number of receptors occupied by the drug
BECAUSE the effect of a drug always follows first-order kinetics.
2. pA2 is a measure of the potency of an antagonist BECAUSE pA2 is the negative logarithm of the
molar concentration of an antagonist that reduces the EC50 of an agonist by two-fold.
3. Phospholipase C is a second messenger in signal transduction pathways BECAUSE phospholipase
C is one of the targets through which G protein-coupled receptors control different aspects of cell
function
4. The drug dose that causes a therapeutic response in 50% of the population is termed as?
A. TD50
B. LD50
C. ED50
D. EC50
5. Occupation of a receptor by a given agonist is governed by
i. Intrinsic activity
ii. Affinity
iii. ka of the agonist
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 Sample Questions
Matching: The Main G protein subtypes and their functions
A. Inhibits adenylyl cyclase and decreases cAMP
B. Inhibits adenylyl cyclase and increases cAMP
C. Effects mainly due to βγ subunits
D. Activates phospholipase C and increases inositol trisphosphate
E. Stimulates adenylyl cyclase and increases cAMP
1. Gi – coupled receptors
2. G0 – coupled receptors
3. GS – coupled receptors
4. Gq – coupled receptors

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 Sample Questions

Classification: Types of receptor and non-receptor antagonism

A. Structural protein
B. Kinase-linked receptor
C. Ligand-gated ion channel
D. Metabotropic receptor
E. Nuclear receptor
1. Adrenoceptors
2. Cytokine receptors
3. Actin
4. Peroxisome proliferator-activated receptor gamma
5. Glutamate receptors
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