Consequences of drug receptor interactions

2. Introduction
At molecular level drug must be
bound to particular constituents of
cells and tissue in order to produce
an effect.
P. Ehrlich (German physician,
biologist, chemist) summed it “a
drug will not work unless it is
bound”.
The critical binding sites are often
referred to as drug targets. Receptor
is one of the common drug target.
Receptor
Drug

3. Receptors
Macromolecular structure
protein in nature, situated
usually on the cell surface
which has specific
“chemorecognition”
property which when
combine with appropriate
chemical substance
results in a series of
biochemical events that
may lead to a response.

4. Receptor Functions : Two essential functions
1. Recognization of specific ligand molecule (Ligand binding
domain) (exogenous: drug and endogenous: hormone,
neurotransmitter, autacoids)
2. Transduction of signal into response (Effector domain)
(Initiation of a biochemical event that leads to characteristic
change in the physiological function of the cell i.e. the
response.)
Ligand binding
domain
Transduction of signal
into response

5. Terms
Affinity: The tendency of a drug to
bind to receptor is governed by its
affinity.
Affinity: A > B
Efficacy: It is the capacity of a drug
receptor complex to dissociate and
elicit response.
Efficacy: A > B
Potency: The quantity of a drug
requires to produce desired
response.
Potency: A > B

6. Formula
[ D ] + [ R ] [ D ][ R ] Response + D
+ R
Affinity = K1 and K2
Efficacy = K3
This reaction can be explained in terms of Law of Mass
action.
(The rate of chemical reaction is directly proportional
to concentration of reacting molecule.)
K1
K2
K3

7. Agonism
It describes the process of binding of
a drug to its specific receptor, activate
it and produce some molecular and
cellular response.
Agonist are the chemical substances
or drugs that can interact (combine)
with a receptor (affinity) and thereby
initiate a cellular reaction or response
(efficacy) are termed by agonist.
It must have affinity and efficacy.
Efficacy maximum = 1
e.g. Adrenaline in cardiac arrest
stimulate β1 receptor – increase force
of contraction and heart rate.

8. Partial Agonist
Process of binding of a drug
with its receptor and
produce relatively
insufficient response.
Partial agonist have
some antagonistic effect.
Efficacy = 0 – 1
e.g.
 Nalorphine
 Pantazosine
 Pindplol

9. Inverse Agonist
Binding of a drug with a receptor
and produce opposite effect.
Affinity present
Efficacy = -1
e.g Benzodiazepines produces
CNS depression.
β Carbolines produce excitation,
anxiety and convulsion.

10. D-D combination
Summation :-Two drugs eliciting same response,
but with different mechanism and their combined
effect is equal to their summation. (1+1=2)
Aspirin Codiene
PG - Opiods receptor +
Analgesic+ Analgesic+
++

11. D-D combination
Additive: combined effect of two drugs acting by
same mechanism
Aspirin glucocorticoids
PG PG
Analgesic+ Analgesic+
+ +

12. Synergism (Supra additive):- (1+1=3)
The combined effect of two drug effect is higher
than either individual effect.
Ex:-
1.Sulfamethaxazole+ Trimethoprim
2. Levodopa + Carbidopa.

13. Antagonism
It is a phenomenon which
describes binding of a drug to
its receptor but cannot
activate it and will prevent
action of an agonist.
Affinity more than agonist.
Efficacy = 0;
e.g:
 Atenolol –Block b1 receptor of
heart
 Naloxane – Block Opioid receptor

14. Types of Antagonism
Chemical
Physiological
Pharmacological

15. Physiological antagonism
Two antagonists, acting at different sites,
counter balance each other by producing
opposite effect on same physiological system.
Histamine –acts on H1 R- Vasoconstriction
Nor epinephrine –acts on beta 2R -Vasodilatation

16. Chemical antagonism –
 When a drug antagonizes the effect of another drug by
simple chemical reaction without action on the receptor.
Chelating agents – e.g. desferioxamine in iron
overload, EDTA in increased Ca++
level.
Charge neutralization – e.g. Heparin strongly
electronegative  neutralizes protamine sulfate.
Acid neutralization – e.g. HCL + Antacid.

17. Pharmacological Antagonism
Competitive
Reversible antagonism
where agonist & antagonist
compete for same receptor
Antagonism can be
overcome by increased
concentration of agonist.
Parallel shifting of dose –
response curve
Non-Competitive
Irreversible binding of
receptor
Agonist cannot compete
with antagonist
There will be resynthesis of
R and action will be regain.

18. Therapeutic index:
Is the ratio of median toxic dose
to median effective dose.
If a drug having TD50 is 100mg
& ED 5mg,then TI is
100/5=20 .
TI should be more than one
50
50
ED
TD
indexcTherapeuti =

19.  MARGIN OF SAFETY = LD1 / ED99
 The ratio of the dosage required to kill 1% of population,
compared to the dosage that is effective in 99% of population.
 The higher the margin of safety, the better.
Drugs with high therapeutic index –
Paracetamol, thiazide, diazepam, clonazepam.
Drugs with low therapeutic index –
Digitalis, anticoagulant, hypoglycemic agents, antiepilaetics,
antiarrhythmic.

20. :
Therapeutic window:
Optimal therapeutic range of plasma concentrations
at which most o the patients experience the desired
effect.
Therapeutic range Therapeutic window
Sub
optimal
optimal

21. Dose response relationship /curve
The pharmacological effect of a drug depends on its
concentration at the site of action, which in turn is
determined by the dose of the drug administered. such a
relation is called the D-R relation ship.
The extent to which the desired response alters as the dose
is change.
Dose is plotted on the horizontal axis
Response on the vertical axis.

22. Graded Dose response curve:
In this relationship as the dose of drug increased the
effect or the response of the drug is also increase.
Hyperbolic curve Sigmoid curve
→ Dose → log Dose
→Response%
→Response%
→Dose- Response curve → Log Dose Response curve

23. Quantal Dose Response curve:
It determines the dose of a drug
required to produce specific]
magnitude of effect in a large
 number of individual patients or
experimental animals (e.g. releif of
headache), or for preservation of safety
of experimental subjects (eg, using low
doses of a cardiac stimulant and
specifying an increase in heart rate of
20 beats/min as the quantal effect), or
it may be an inherently quantal event
(eg, death of an experimental animal).

24. Quantal dose-effect plots. Shaded boxes (and the accompanying black curves) indicate
the frequency distribution of doses of drug required to produce a specified effect; that
is, the percentage of animals that required a particular dose to exhibit the effect. The
open boxes (and the corresponding colored curves) indicate the cumulative frequency
distribution of responses, which are lognormally distributed.

25. Clinical importance:
Both curves provides information regarding the
potency & selectivity of drugs.
Graded dose response curve indicates the maximal
efficacy of drug.
The quantal dose response curve indicates the
potential variability of responsiveness among
individuals & TI.

27. Dose-response curves for two hypothetical drugs. Drug
X: the dose that brings about the maximum wanted effect is less
than the lowest dose that produces the unwanted effect. The ratio
ED50 (unwanted effect)/ED50 (wanted effect) indicates that drug
X has a large therapeutic index: it is thus highly selective in its
wanted action. Drug Y causes unwanted effects at doses well
below those which produce its maximum benefit.The ratio ED50
(unwanted effect)/ED50 (wanted effect) indicates that the drug has
a small therapeutic index: it is thus nonselective

28. Q. write down the therapeutic implication of
pharmacological antagonism?

29. Questions?
Questions?
Questions?
Questions??
Questions?
Thank you for your attention