• Learning Objectives:

• To:
• Calculate the antagonist pA2 value using Schild
plot
• Know types of dose response curves and their
applications
• Know the mechanisms underlying variation in drug
responsiveness
 Quantitative Aspects of Drug-Receptor Interaction

Binding reactions for one drug:

The reversible drug-receptor reaction can be
represented by:
A + R k+1 AR
Drug free receptor K-1 complex
(xA) ( Ntot – NA) (N A)
The relationship between drug concentration &
occupancy (PA= NA/Ntot ) is theoretically
described by:
PA = X A (Hill-langmuir equation)
XA + KA
XA = drug conc.
KA= equilibrium constant
 KA : The conc. of the drug required to occupy
50% of the receptor at equilibrium.
↓KA →↑ affinity of the drug to the receptor.
 Binding reaction when more than one drug is present
(agonist & antagonist):
• In the presence of ↑ conc. of agonist, increasing the
antagonist conc. → parallel rightward shift of the
agonist dose-response curve.
• The magnitude of the rightward shift of the curve
depends on the concentration of the antagonist and
its affinity for the receptor.
• DR = 1 + B/KB (Schild equation)
• DR: dose ratio.
• It is the conc. of agonist required to produce a
defined response in the presence of antagonist
divided by the concentration of agonist required to
produce the same response in the absence of the
antagonist.
• B: antagonist conc., KB: antagonist equilibrium
constant.
• Reversible competitive antagonist potency can
be expressed as PA2 value (is the negative
logarithm of the molar concentration of
antagonist, which reduces the response of
double dose (2X) of agonist to that of a single
dose (X).
• Determination of PA2 using Schild plot:
• DR-1 = B/KB………………..Schild equation
• Schild eq. can be presented logarithmically:
• Log(DR-1)= logB-logKB
• PA2 is calculated from Schild plot (log DR-1 vs. log B).

• The slope of the plot gives information about the

nature of the antagonist (the slope equal 1 for
reversible competitive antagonist).
 Dose Response-Curves
• The relation between the drug concentration
(dose) & the clinical effect (response) of the
drug is described by:
• E = Emax X C
C + EC50

•
 2 types:
1. Graded dose response-curve
2. Quantal dose response-curve
1. Graded dose response-curve:
• It is a graph of increasing responses to
increasing doses of a drug (log scale)
• It is used to measure potency & efficacy of
drugs
Potency:
is the conc. or the dose of a drug required to
produce 50% of the maximal effect (median
effective dose or conc.”ED50 or EC50” )
• ED50 is used to compare potencies of drugs
• The lower EC50 the more potent drug.
Relative potency = EC50 (standard)/EC50 (tested drug)

Drug x Drug y

2 4
• Maximal efficacy (Emax):
Is the maximum effect that produced by the drug
at very high conc.

Efficacy is more important

for clinical effectiveness
than potency if the dose
of the drug is convenient
but potency is important if
large doses are
inconvenient.
 Limitations:
• Graded dose response curves are applied
for a single individual, patient, or isolated
tissues (limited in application to other
patients, owing to the great potential
variability among patients in severity of
disease and responsiveness to drugs)
• Not applied if the response is quantal (all or
none)
2. Quantal dose-response curve:
It is a plot of cumulative proportion or % of
individuals that exhibit (therapeutic or lethal)
effect at each dose against log dose (as the
dose increases the number or proportion of
patients responding increases).
No. of Cumulative % of
Dose No. of Subjects Responders % Responders responders
1 10 0 0 0

2 10 1 10 10

3 10 3 30 40

4 10 5 50 90

5 10 7 70 160

6 10 8 80 240

7 10 9 90 330

8 10 10 100 430
ED50 LD50
 It determines:
1. Median effective dose (ED50→potency)
2. Median toxic dose (TD50)
3. Lethal dose (LD50)
4. Therapeutic index (T.I.) =
TD50 or LD50
ED50 ED50
• The therapeutic index of a drug is usually defined
as the ratio of LD50 or TD50 to ED50 OR the ratio
of a dose that produced undesired effect to a
dose produced desired effect.
• Values of LD50 and TD50 are derived from
quantal dose-response curves generated in
animal studies. THERAPEUTIC INDEX – AN INDEX OF SAFETY

Hypnosis Death
• ↑T.I indicates the safety of the drug e.g.
amoxicillin
• ↓T.I e.g. digoxin, theophyline & warfarin
 N.B:
• Both curves provide information about Potency
But
• Graded dose-response curve indicates Emax
• Quantal dose-response curve indicates the
potential variability of responsiveness among
individuals
 Variation in Drug Response

• Quantitative or qualitative
• Quantitative variation in drug response:
• Hyporeactivity or hyperreactivity
- Tolerance:
Gradual decrease in drug response as a result of
continuous or repeated drug administration. It
takes days or weeks e.g. barbiturates and nitrates
tolerance
- Tachyphylaxis or desensitization:
- The response of the drug is diminished rapidly
(min.-hr) after repeated administration of the
drug. e.g. amphetamine tachyphylaxis
• Drug resistance:
loss of effectiveness of antimicrobial or
anticancer drugs.
• Qualitative variation in drug response:
• Idiosyncratic drug response: It is genetically
determined abnormal & harmful drug response
occurs, rarely & unrelated to the dose of the
drug.
• Examples:
1. Primaquine, sulfonamides & dapsone cause
hemolytic anemia in individuals with G-6-PD
deficiency.
2. Genetic polymorphism
• oxidation rate (↓ oxidation rate →TCA toxicity)
• acetylation rate (slow acetylators → INH
peripheral neuropathy).
(fast acetylators → INH hepatotoxicity).
3. Chloramphenicol → aplastic anemia.
4. Suxamethonium → suxamethonium apnea due
to the presence of abnormal type of
cholinesterase that fails to inactivate
suxamethonium rapidly → prolongs the duration
of action of suxamethonium.
• The mechanisms for variation in drug response
1. Alteration in the receptors numbers:
• Down regulation: gradual decrease in the
numbers of the receptors (internalization) due to
prolong exposure of the receptor to the agonist.
e.g. β-agonists.
• Up-regulation: ↑ the numbers of the receptors
e.g. thyroid hormones → up regulation of β1
receptors in the heart.
2. Change in receptors:
Conformational change in the ion channel
linked receptor (nAch ) → desensitization
• Phosphorylation of G-protein coupled receptor
→ desensitization
• Alteration in receptors numbers and change in
receptors contribute to two phenomena:
a. Tolerance or tachyphylaxis
b. Overshoot phenomena which follow withdrawal
of certain drugs.
• Propranolol (β-antagonist) →(upregulation)
↑response to endogenous catecholamines →
ˣ
hypertensive crisis.
• Clonidine (α2-agonist) →(down regulation) →
less inhibition of sympathetic discharge by
ˣ
endogenous catecholamines →hypertensive
crisis.
3. Exhaustion of mediators:
Amphetamine desensitization occurs due to
depletion of the stored noradrenaline
4. Increased metabolic degradation:
Tolerance to some drugs (barbiturates &
phenytoin) occurs due to auto-induction.
(pharmacokinetic tolerance).
5. Physiological adaptation:
The development of homestatic response that
decreases drug response. Antihypertensive
effect of thiazide diuretics is limited due to
activation of renin-angiotensin system.
• Antihypertensive effect of vasodilator drug
(hydralazine) is decreased due to compensatory
increases in sympathetic nervous tone and fluid
retention (additional drugs, β-blocker and
diuretic, may be required to achieve a useful
therapeutic result).
• Physiological adaptation decreases many side
effects during drug administration.
6. Active extrusion of the drug from the bacterial or
parasitic cell (efflux):
Results in antimicrobial and anticancer
resistance e.g. tetracycline resistance