Drug-receptor interactions

Pharma
428

Drug-receptor interactions
Overview
Most drugs produce their actions by interacting with
receptors.
Drug +receptor  drug-receptor complex  response
So, a receptor has the ability to bind a drug and then
couple this binding to a response. This ability of a
receptor makes us expect a response for each drug-
receptor complex formed, but in fact, this efficiency of
receptors varies and depends on the factors that will
be discussed in this chapter.
(in the diagram)  K1 = association constant
K2 = dissociation constant
K3 = efficacy
K1 and K2 depend on affinity and occupancy
 Affinity: ability of a drug to bind to a receptor
 Occupancy: fraction of receptors occupied to the total number
of receptors
- Efficacy: (intrinsic activity): ability of a drug to change the receptor
conformation to produce a response.
So, a pharmacological response depends on the affinity and efficacy.

Drug-receptor binding
Drug + receptor  drug-receptor complex
 This equation should follow the law of mass action, which means
that as the concentration of a drug increases, the number of
drug-receptor complex (receptor occupancy) increases.
 If the affinity increases, then a lower amount of drug will be
needed to produce a given occupancy

This curve
depends on the
affinity only

This is a hyperbolic curve

1
 Drug-receptor interactions
Pharma
428
Agonist concentration curves (Dose-response curves)
We usually use the log of a drug’s concentration (instead of using the
concentration value itself). This will help us to
plot the curve even in extremely low
concentrations of drugs.
 It makes a sigmoid (s-shaped) curve
(instead of hyperbolic)
 It is called a log-dose response curve
(LDR)
By raising the dose (((above the “threshold dose
level” ))), there will be a gradual increase in the
response of that drug.
Thus, LDR of similarly active drugs produce
parallel LDR curves, enabling us to compare
between the potencies of qualitatively similar
drugs.
Potency (EC50 or ED50): the concentration or dose
needed to produce a 50% maximal response.
Efficacy (Emax) is the max response the drug can produce
Efficacy of an agonist depends on both affinity (binding) & intrinsic
activity.
Concentration-response curves cannot be used for direct estimation of
the affinity of the agonist to the receptor because:
 The concentration of the drug at the receptors usually differs
from the known concentration
 Many factors interact produce pharmacologic response or
efficacy called “intrinsic activity”
 A concentration-occupancy curve is used instead (see above).

2
 Drug-receptor interactions
Pharma
428
Agonist/Antagonist & Affinity/Efficacy

Difinitions
Affinity is the tendency of a drug to bind to its
receptor.
Intrinsic activity (Efficacy) is the ability of the
drug to activate the receptor.
Full agonist drugs have both high affinity and
high efficacy .
Partial agonist drugs possess weak efficacy
even at 100% occupancy, producing only
submaximal tissue response
 When a partial agonist competes with a
full agonist to the receptor, the partial
agonist will act as a competiive
antagonist, because it will decrease the
efficacy of the agonist alone.
Antagonist drugs have appreciable receptor
affinity but zero efficacies. (see curve above)
Inverse agonist
 Some receptors are stable more in active
state in absence of endogenous or
exogenous agonists
 Inverse agonist decreases that constitutive
(inherent) activity, keeping the receptor
more in the inactive conformation

3
 Drug-receptor interactions
Pharma
428
Spare Receptors:
 Max drug response can occur at <100% occupancy, i.e., a
number of receptors remain unoccupied at 100% effect
 In D-R interactions, Kd value is higher than EC50 , except in the
case of presence of spare receptors, where EC50 will be higher.

Quantal Dose-Response Curves

Quantal responses include effects that are either present or NOT
Examples include vomiting, death, sleeping,
toxic effect (bleeding vs no bleeding)
Most biological responses are graded like
blood pressure, plasma cholesterol, body
weight,…etc.

Therapeutic Index
The therapeutic index is the ratio of the toxic or
lethal dose of a drug to produce a toxic/lethal
effect to the ED50 to produce a therapeutic
effect
TI = LD50 / ED50
LD50 = lethal dose: the concentration of drug
that gives lethal effect in 50% of the cases.
ED50 = the concentration of drug that gives a
therapeutic effect in 50% of the cases
!!!!! not the same as ED50 in potency !!!!!
Drugs with high therapeutic index have wide
safety margin
Drugs with low therapeutic index have narrow
safety margin

Drug Antagonism
Chemical antagonism, chemicals that disable
the drug’s effect. e.g. heparin (negatively charged) is neutralised by
positive ionic compounds in the blood.
Pharmacokinetic antagonism, by enhancing hepatic metabolism of
the drug by another (warfarin and barbiturates), or gastrointestinal
absorption inhibition.

4
 Drug-receptor interactions
Pharma
428
Physiologic antagonism: counteracting the action of a drug
functionally
Receptor blockade antagonism

Reversible (Surmountable) Competitive Antagonism

An antagonist drug binds selectively & prevents the agonist binding
Increasing agonist concentration can restore the agonist occupancy
(surmountable))
They increase the ED50 of the agonist, but not Emax or the slope
Most antagonistic drugs are competitive

Irreversible Competitive Antagonism

Antagonist molecule dissociates very slowly or not at all from the
receptor-antagonist complex.
Increasing the agonist does not effect antagonist occupancy or the
receptor blockade (non-surmountable
blockade).

Non competitive antagonism

Antagonist bind to other site than the

active site (doesn’t effect the binding
between the receptor and the agonist).
They may block any point in the
transduction cascade.
They cause ↓in the slope and ↓of the Emax
No effect on EC50

5
 Drug-receptor interactions
Pharma
428
Desensitization and Tachyphylaxis
Tachyphylaxis the rapid diminishing response of a drug after a drug’s
administration.
Receptors are said to be desensitized
Desensitization and tachyphylaxis are used when it is developing in
the course of few minutes.
Tolerance describes a more gradual loss of drug-induced clinical
effects that develop in the course of days or weeks.
Refractoriness is sometimes used to indicate the loss of therapeutic
response.
Drug resistance describes the loss of the effect of anti-tumour and
antimicrobial drugs.

Mechanisms of Desensitization
1. Conformational change in receptors or
receptor phosphorylation
2. Down-regulation of receptors
3. Depletion of mediators
4. Pharmacokinetic desensitization
5. Pumping of drugs out from intracellular site
(chemotherapy)

1- Receptor Changes
Conformational change in the receptor that
the agonist-receptor binding occurs but the
transduction (activation) does not take place,
Phosphorylation of the intracellular
regions of the receptor protein interferes
with its ability to activate target channels or
enzymes producing second messengers

2- Receptor down-regulation
This process usually takes place with prolonged
exposure to agonist drugs leading to a gradual
decrease in the number of receptors expressed on cell membrane
Receptor down-regulation is a slower process than receptor-second
messenger uncoupling

3- Depletion of Mediators
Drugs acting indirectly via transmitter release can cause depletion of that
transmitter and hence loss of action

6
 Drug-receptor interactions
Pharma
428
4- Pharmacokinetic Desensitization
Drugs which stimulate hepatic metabolism may enhance their own
metabolism and hence a lower plasma concentration with repeated
administration of the same dose

Self-Assessment Questions

 What are the main molecular targets for Drugs? Can you consider plasma
membrane and cell organelles as molecular targets?
 Describe the structure of each of the four main classes of receptors.
 Mention the changes that occurs upon binding of an agonist to each of the
four main classes of receptors.
 Mention different mechanisms of receptor desensitization.
 Define full agonist, partial agonist, antagonist as regards: affinity (binding,
occupancy), efficacy & intrinsic activity
 Describe the effects of competitive, non-competitive antagonists on
agonist D-R curve
 Drug A has almost equal Kd values for receptor X1 & X2 subclasses,
whereas drug B Kd value for X1 is much lower than that for X2 receptor
subtype. Make a conclusion about the specificity of the given drugs for the
receptor subtypes. Are A & B agonists or antagonists or can be either?