Kwame Nkrumah University of

Science & Technology, Kumasi,

Ghana

PRINCIPLES OF DRUG ACTION

Part 4: Quantitative Drug Receptor Interactions

George Ainooson, PhD

Dept. of Pharmacology
CHS, KNUST
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Learning outcomes:
At the end of the module, students will be able to:
• Demonstrate knowledge of modern pharmacology, from
the molecular basis of receptors and cell signaling, to the
effect of drugs on whole body systems

• Identify the major classes of drug receptors and sites of

drug action within the body; Pharmacological mechanisms
by which drugs of various classes may alter biochemical
physiological or pathophysiological parameters to produce
therapeutic or unwanted effects.

• Demonstrate knowledge of dose response curves and

how they are used to determine drug potency,
efficacy and toxicity. www.knust.edu.
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 Assignment
Define the following
• KA
• pD2
• ED50

• EC50 • pA2

• Kd • LD50

• IC50 • LC50
• 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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Receptor Occupancy

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 Drug characteristics

Spare receptors
• Are receptors which exist in excess of those
required to produce a full effect.

• There is nothing different about spare

receptors. They are not hidden or in any way
different from other receptors.

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 Dose-Response Relationships
• Drug effect is generally proportional to the number of
occupied receptors.
• 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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Dose-response curves

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Dose-response curves

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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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 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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 Drug characteristics

Diff. 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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Constitutive Receptor Activity (CRA) and
Inverse Agonist Effects
Receptor proteins can spontaneously adopt an
“active” conformation

• capable of regulating cellular signaling

systems in the absence of an agonist.

• e.g delta opioid receptors NG108-15

neuroblastoma cells, constitutively activates
Gi proteins in the absence of agonist

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 Constitutive Receptor Activity (CRA) and
Inverse Agonist Effects
The two-state model

• For constitutively active receptors, an appreciable

proportion of receptors adopt the R* conformation in the
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absence of any ligand.
Characterization of Drug effects

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 Combined Drug Effect
Additivity /Additive effect
are when the sum of the effect equals the two individual chemical effects
combined. In this case, 2 + 2 = 4.

Synergism
when the sum of the effect is more than the two individual chemical effects
combined. For this effect, 2 + 2 = 10.

Potentiation
This effect results when one substance that does not normally have an effect
is added to another chemical, making the second chemical much more active

0 + 2 > 2, not just 2

Antagonism/Antagonist effect
- Antagonism is the opposite of synergism. It is the situation where the
combined effect of two or more compounds is less toxic than the individual
effects;
for example: 4 + 6 < 10
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Antagonism

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 Drug characteristics

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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 RECEPTOR ANTAGONISM
• Mechanism of Receptor Antagonism
 Types of antagonism
Antagonis
t

Receptor Non-receptor
Antagonis Antagonist
t

Active binding Allosteric

site binding site

Pharmacoki
netic
Reversible Irreversible Reversible Irreversible antagonism

Functional/
Competitive Competitive Physiological Chemical
Reversible Irreversible Noncompetitive
antagonism antagonism
Antagonism

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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? www.knust.edu.
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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
coumadin.

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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
Receptor Antagonism

Competitive antagonism Noncompetitive antagonism

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Measuring Drug Action

Competitive antagonism Noncompetitive antagonism

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Characterization of Drug effects

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 Drug Characteristics
Drug Selectivity
• Is the degree to which a drug acts on a given subset of
receptors relative to other receptors in the family.

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
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

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 Decreased responsiveness to drugs
Desensitization
• The decreased ability of a receptor to respond to
stimulation by a drug or a ligand
Inactivation
• Loss of ability of a receptor to respond to
stimulation
Tachyphylaxis
• Rapid loss of drug effect (minutes). Repeated
administration of the same dose of a drug results in
a reduced effect of the drug.

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Decreased responsiveness to drugs
Refractoriness
• After a receptor is stimulated a period of time is
required before the next receptor-drug interaction
can produce effect.
Tolerance
• is conventionally used to describe a more gradual
decrease in responsiveness to a drug, taking
hours, days or weeks to develop, at which point
increased amounts are necessary to obtain the
desired effects.

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Decreased responsiveness to drugs

Drug resistance
• is a term used to describe the loss of
effectiveness of antimicrobial or antitumor
drugs.

Down regulation
• Repeated or persistent drug interaction results in
the removal of the receptor from sites where
subsequent drug-receptor interactions could take
place.

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Mechanisms of loss of Drug Effect

• Change in receptors • Physiological adaptation

– Changes (structural and
• Translocation of functional) that can
receptors affect drug response.

• Exhaustion of
mediators • Active extrusion of
drug from cells
– mainly relevant in
• Increased metabolic
cancer
degradation of the
chemotherapy)
drug
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 REFERENCES AND FURTHER READING

• Rang & Dale's Pharmacology - 9TH Edition(2018)

• Goodman and Gilman's The Pharmacological Basis

of Therapeutics, 13th Edition – 2017.

• Medical Pharmacology at a Glance, Michael J.

Neal 9th Edition – 2020

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