PD-Dose Response Curve & Drug Combined Effects

DOSE-RESPONSE
RELATIONSHIP
Dose-response Relationship
 Drug potency and efficacy
 Therapeutic efficacy
 Drug selectivity
 Drug specificity
 Therapeutic index/window
Combined Effect of Drugs
 Synergism- (a) Additive (b) Supra-additive (potentiation)
 Antagonism- (a) Physical antagonism (b) Chemical antagonism
(c) Physiological/functional antagonism
(d) Receptor antagonism- Competitive antagonism (equilibrium & Non-equilibrium type ) &
Non-competitive antagonism.
Dose-Response Curve (DRC)-
- is a graph b/w the dose of a given drug (on x-axis) &
response produced by the drug (on y-axis).
• Dose-response relationship has two components:
1. Dose-plasma concentration relationship- P.K &
2. Plasma concentration-response relationship - is the actual DRC/relationship.
• The clinical response to the increasing dose of a drug is defined by the shape of DRC.
• Initially the extent of the response increases with increase in dose till the maximum response is
reached.
• The shape of DRC is rectangular hyperbola- bcz D+R interaction obeys law of mass action.\
• After the maximum effect has been obtained, further increase in doses doesn’t increase the
response.
Graded dose response curve by increasing the
Ach concentrations- Hyperbola curve
Contraction phase Relaxation Phase
Base line for 30 sec for 90 sec

each dose/ conc.
90 sec
W W W W W W W
0.1μg/ml 0.2 μg 0.4 μg 0.8 μg 1.6 μg 3.2 μg 6.4 μg/ml
Graded dose-response curve
If the dose is plotted on a logarithmic scale-
DRC curve becomes sigmoid & a linear relationship b/w log of dose & the
response is seen in the middle/intermediate zone.
Characteristics of A Log Dose-Response Curve
Maximum response /
Ceiling response
Y-axis
50 %
Sigmoid shape
ED 50
Maximum Dose/
LDRC E.g- Histamine- guinea pig ileum contractions, X- axis Ceiling dose
Ach- frog rectus muscle contractions
• Slope (middle portion- which is therapeutic importance/ clinical significance) is
straight line in the log DRC.
• Potency (lower portion)- it’s the measure of the amount of drug requires to
produce response. Or dose of a drug required to produce the standard effect.
• Efficacy (upper potion)- It’s the maximum effect/response produced by a drug.
Or denotes the maximum response reflected by the height of the LDRC
• Potency & efficacy are the key determinants of drug activity.
Slope-
1. If a the DRC is steeper- means that a small increase in dose produces a large response.
 Ex- Narrow T.index drugs (like barbiturates)
 Loop diuretics & Hydralazine -likely to cause toxicity & individualisation of dose is
required.
2. If a the DRC is flat/less steeper – means that with an increase in dose, there is little
increase in response.
 Ex- Hydrochlorothiazide - standard dose can be given to most patients.
 BZD’s having less toxicity & safer.
Advantages of DRC-
I. To know whether a drug is competitive or non-competitive inhibitor & for easier
comparison.
II. A wide range of drug doses can be easily displayed on a graph.

 Drug Potency-
• The position of DRC on the dose axis is the index of drug potency.
• Def- Amount of drug needed to produce a certain response.
• A DRC positioned rightward indicates lower potency
Ex- 10 mg of morphine = 100 mg of pethidine as analgesic,
• Morphine is 10 times more potent than pethidine.
• However, a higher potency, in itself, does not confer clinical superiority unless the
potency for therapeutic effect is selectively increased over potency for adverse
effect.
• Helps in choosing the dose of a drug.
Drug Efficacy-
• The upper limit of DRC is the index of drug efficacy.
• Refers to the maximal response that can be elicited by the drug.
E.g. Morphine produces a degree of analgesia not obtainable with any dose of aspirin.
Morphine is more efficacious than aspirin.
• Helps in selecting the choice of a drug.
Both refers to different characteristics of the drug.
• The two can vary independently:
(a) Aspirin is less potent as well as less efficacious analgesic than morphine.
(b) Pethidine is less potent but equally efficacious analgesic as morphine.
(c) Furosemide is less potent but more efficacious diuretic than metolazone.
(d) Diazepam is more potent but less efficacious CNS depressant than
pentobarbitone.
Therapeutic efficacy/clinical effectiveness-
• Its expressed in terms of
(a) degree of benefit/relief afforded by the drug (in the recommended dose range) or
(b) the success rate in achieving a defined therapeutic end point.
Ex- The degree of relief in parkinsonian symptoms afforded by levodopa-carbidopa
is much greater than that possible with trihexyphenidyl: the former has higher
therapeutic efficacy than the latter.
• A drug which makes a higher percentage of epileptic pt’s totally seizure free than
another drug, is the more therapeutically effective antiepileptic.
Drug selectivity
• Drugs seldom produce just one action: the DRCs for different effects of a drug
may be different.
• The extent of separation of DRCs of a drug for different effects is a measure of its
selectivity.
e.g. the DRCs for br.dilatation & cardiac stimulation are quite similar in case of
isoprenaline, but far apart in case of salbutamol - the latter is a more selective
br.dilator drug.
Therapeutic index (TI)-
• The DRC for different actions of a drug could be different.
• The gap b/w the therapeutic effect DRC & the adverse effect DRC defines the
safety margin or the TI of a drug.
• TI (in exp. studies):-
Significance-
• TI gives an idea about safety of the drug.
• The higher the TI, the safer is the drug.
• TI varies from species to species.
• For a drug to be consider reasonably safe, its TI is must be >1.
• Pn’s has high TI while Li & digoxin has low TI.
• TI may be different for each action of a drug.
• Ex- TI of aspirin used for headache is different from its TI for inflammation.
Limitation of TI-
• TI doesn’t consider the idiosyncratic responses that result in toxicity.
• Moreover, the data are based on animal studies which may be difficult to apply on
human beings & considers only 50% of a given set of animals.
• For the better safety, drug should be effective in 99% & lethal to 1% of the test
population.
Such index called as safety factor- LD1/ED99.
Therapeutic Window (T.W) or Range (T.R)-
• T.W is the range of plasma conc. below which drug is ineffective & above which
toxicity appears.
• The dose which produces minimal therapeutic effect & the dose which produces
maximal acceptable adverse effect.
• Hence, it’s a desirable to have drugs plasma conc. within the range.
• Individual variability, the effective dose for some subjects may be toxic for
others; defining the therapeutic range for many drugs is a task.
• A drug may be capable of inducing a higher therapeutic response (have higher
efficacy) but develops intolerable adverse effects may stop the use of higher doses.
• e.g. prednisolone in bronchial asthma.
• A drug should be prescribed only when the benefits outweigh the risks.
Drugs with low TI have a narrow T.W.
Drug Ideal plasma conc./range

digoxin 0.8-2ng/ml.
Carbamazepine 3-10mcg/ml
Li 0.5-1.3mEq/L
Imipramine 50-200ng/ml.
Clonidine 0.2-2ng/ml.
So, drugs with narrow T.I should be titrated carefully & pt’ should be continuously monitored.
Drug specificity
• Specificity of a drug refers to the range of actions produced by it.
• Drugs can produce one or limited or widespread effects/actions on many organs of the
body.
• Specificity is governed by:
(a) whether a drug acts on a single receptor/ target or on many targets, &
(b) how widely the target is distributed in the body.
 Omeprazole (highly selective)  bcz it acts only on one target molecule H+K ATPase
(proton pump) which is localized to the gastric parietal cells.
 Chlorpromazine (multiple targets)  D2, α, M, H1 & 5HT antagonist & Na+ channel
blocker  produces a wide range of actions.
 Dexamethasone- GR agonist produces effects involving many organs & tissues, 
bcz GR is expressed in every cell of the body.
Combined Effect of Drugs-
• When two or more drugs are given simultaneously or in quick succession, they
may be either indifferent to each other or exhibit synergism orantagonism. The
interaction may take place at P.K or at P.D level.
1. Synergism
• When the action of one drug is facilitated or increased by the other, they are said
to be synergistic.
(a) Additive- The effect of the two drugs is in the same direction & simply adds up.
effect of drugs A + B = effect of drug A + effect of drug B.
• S/e’s of the drugs of an additive pair may be different – don’t add up.
• Thus, the combination is better tolerated than higher dose of one drug.
(b) Supra-additive (potentiation)
• The effect of combination is greater than the individual effects of the
components:
effect of drug A + B > effect of drug A + effect of drug B.
• Here, one drug produces no effect alone, but enhances the effect of the other
(potentiation).
2. Antagonism
• When one drug decreases or abolishes the action of another, they are said to be
antagonistic:
effect of drugs A + B < effect of drug A + effect of drug B
• Usually in an antagonistic pair one drug is inactive as such but decreases the effect
of the other.
• Depending on the mechanism involved, antagonism may be:
(a) Physical antagonism
(b) Chemical antagonism
(d) Receptor antagonism.
(a) Physical antagonism
• Based on the physical property of the drugs, e.g. charcoal adsorbs alkaloids & can
prevent their absorption - used in alkaloidal poisonings.
(b) Chemical antagonism
• The two drugs react chemically & form an inactive product, e.g.
KMnO4 oxidizes alkaloids- used for gastric lavage in poisoning.
Tannins + alkaloids—insoluble alkaloidal
• Drugs may react when mixed in the same syringe or infusion bottle:
Thiopentone sod. + succinylcholine chloride
• The two drugs act on different receptors or by different mechanisms, but have
opposite overt effects on the same physiological function, i.e. have
pharmacological effects in opposite direction, e.g.
Histamine & adrenaline on bronchial muscles & BP.
Glucagon & insulin on blood sugar level.

(d) Receptor antagonism
• One drug (antagonist) blocks the receptor action of the other (agonist).
• Important mechanism of drug action.
• Receptor antagonism can be competitive or non-competitive.
Competitive antagonism (equilibrium type)
• Antagonist is chemically similar to the agonist, competes &
binds to the same site.
• In presence of antagonist (has affinity but no IA- no
response is produced) the agonist LDRC is shifted to the
right.
• Since antagonist binding is reversible & depends on the
relative conc. of the agonist & antagonist molecules.
• Higher agonist conc. progressively overcomes the block - a
parallel shift of the agonist DRC with no suppression of
maximal response.
• The extent of shift is dependent on the affinity & conc. of
the antagonist.
• A partial agonist, having affinity for the same receptor, also
competes with & antagonizes a full agonist, while producing DRC competitive antagonism-
a submaximal response of its own. A—agonist, B—competitive antagonist,
Non-equilibrium antagonism
• Certain antagonists bind to the receptor with covalently (irreversible) or dissociate slowly
(due to very high affinity).
• Agonist can't reduce receptor occupancy of the antagonist molecules.
• The agonist DRC is shifted to the right & the maximal response is lowered.
• Since, agonist are unable to compete with the antagonist there is a flattening of agonist DRC.
• Ex. Phenoxybenzamine is a non-equilibrium antagonist of adrenaline at the a adrenergic
receptors.
Non-competitive antagonism
• The antagonist is chemically unrelated to the
agonist, binds to a allosteric site & alters the
receptor in such a way that it is unable to combine
with the agonist, or is unable to transduce the
response, so that the downstream chain of events
are uncoupled.
• Also called allosteric antagonism.
• Because the agonist & antagonist are combining
with different sites, there is no competition b/w
them - even high agonist conc. is unable to
reverse the block completely.
• Increasing antagonist conc.’s progressively flatten
the agonist DRC.
• Non-competitive antagonists have been produced
DRC competitive antagonism-
experimentally, but are not in clinical use. A—agonist, C—Non-competitive
antagonist
• Thank U

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DOSE-RESPONSE

Contraction phase Relaxation Phase

Base line for 30 sec for 90 sec

II. A wide range of drug doses can be easily displayed on a graph.

Drug Ideal plasma conc./range

Histamine & adrenaline on bronchial muscles & BP.

Glucagon & insulin on blood sugar level.

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