FACTORS MODIFYING

DRUG RESPONSE
 LEARNING OBJECTIVES
At the end of this session student should be
able to:
Describe how different dosages alter the
absorbtion,distribution,onset & duration of action of
drugs.
 DRUG RESPONSE AND ITS IMPORTANCE

variations in response to same dose of a drug

between different patients
in the same patient on different occasions
The dose of drug is generally expressed in the range,
which gives therapeutic effect in majority of patients.
The dose range is usually based on the average
requirements of an adult and is not strictly applicable
under all circumstances.
IMPORTANT FACTORS MODIFYING DRUG
ACTION ARE:
BODY WEIGHT
AGE
SEX
ROUTE OF DRUG ADMINISTRATION
TIME OF DRUG ADMINISTRATION
GENETIC FACTORS
METABOLIC DISTURBANCES
PATHOLOGICAL CONDITIONS
TOLERANCE
TACHYPHYLAXIS
CUMMULATION
DRUG INTERACTIONS
IMPORTANT FACTORS MODIFYING DRUG :
BODY WEIGHT :
average dose of a drug is mentioned in
terms of mg/Kg body weight. However, the
dose mentioned may not be applicable to
all cases.
in cases of edema weight of patient
increases due to the accumulation of ECF
in malnutrition metabolizing capacity of
drug is reduced
these factors should be kept in mind while
calculating the dose of drug.
IMPORTANT FACTORS MODIFYING DRUG :
AGE:
Pharmacokinetics of many drugs change with
age.
Newborn: liver and renal function less developed
Elderly: hepatic and renal functions decline
Glomerular filtration rate: low in infants
Blood brain barrier: more permeable in infants &
may cause accumulation
 IMPORTANT FACTORS MODIFYING DRUG :
SEX:
Females: smaller body size, require doses that are on lower
side of the range.
Consideration given to menstruation, pregnancy and lactation.
Drugs given during pregnancy may affect the fetus.
Physiological changes during pregnancy alter drug disposition
drugs like methyldopa and blockers interfere with sexual
function in males but not in females.
Gynecomastia produced by drugs like Digitalis, Cimetidine,
and Metoclopramide occurs in males not in females.
 ROUTE OF DRUG ADMINISTRATION:
governs the speed and intensity of drug response.
In general, intravenous dose of drug is usually
smaller than oral, and time of onset of action is quick
with intravenous route.
A drug may have entirely different uses through
different routes. For example Magnesium sulfate
given orally produce purgation, applied locally on
inflamed area decreases the swelling while
intravenously it produces CNS depression and
hypotension.
 TIME OF ADMINISTRATION:
There is delayed drug absorption when drug is given orally
after meals, which slows down the effects of drug.Under
certain circumstances drugs must be given before meals.
To prevent mixing of drug with food
Anthelminthics.

To get immediate effect:

Drugs used for prevention of
motion sickness.

To prevent formation of insoluble complexes:

Tetracyclines.

To prevent specific side effects,for example to prevent

hypoglycemia insulin and sulfonylureas are given before
meals.
 GENETIC FACTORS:
The dose of a drug to produce same effects may vary 4
6 folds among different individuals. This is mainly due to
the differing rates of drug metabolism as the amount of
microsomal enzymes is genetically controlled.
There are some specific genetic defects that lead to
variation in drug response.
Example;
Hemolysis by Primaquine and Sulfonamides in persons
with G.6.P.D. deficiency.
Slow metabolism of Isoniazid in slow acetylators.
 METABOLIC DISTURBANCES:
Changes in water and electrolyte balance body
temperature and acid base balance may modify
the effects of drug.
For example aspirin reduces body temperature
only in presence of fever and have no effect on
body temperature when it is normal.
Iron is well absorbed in states of iron deficiency .
 PATHOLOGICAL CONDITIONS:

several diseases influence drug disposition and

action.
Hepatic, renal and cardiovascular diseases
have important influence on drug clearance and
drug actions.
Drugs must be carefully used in presence of
diseases of these organs.
 DRUG INTERACTIONS:
Drugs may modify the response to each other
by pharmacokinetic or pharmacodynamics
interaction between them.
Drug interaction does not necessarily mean
that their concurrent use is contraindicated;
many drugs can be used beneficially and
some with dose adjustment.
Drug combinations can produce:
Additive effect.
Synergism.
Potentiation.
Antagonism.
ADDITIVE EFFECT OR SUMMATION
When total pharmacological effect produced by concomitant use of
two or more drugs is equal to the sum of their individual effects, it is
called Additive effect.
1 + 1 = 2.
Example: Combination of ephedrine and Theophylline in the
treatment of asthma. The individual side effects of an additive pair
may be different, and may not add up. The combination is better
tolerated than higher dose of one component.
 SYNERGISM
When total pharmacological effect
produced by concomitant use of two or
more drugs is higher than the sum of
their individual effects, it is called
Synergism.
1 + 1 = 2.
Example:
Codeine + Aspirin > Analgesia.
Sulfonamide + Trimethoprim > Antibacterial effect.
 POTENTIATION

Enhancement of effect of one agent by another; so that the

combined effect is more than the sum of their individual
effects is called Potentiation.
In case of potentiation one agent has no effect when given
alone but increases the effects of other co-administered
drug.
0 + 1 = 2.
Example:
Levodopa + Carbidopa => Parkinsonism.
Ampicillin + Clavulanic acid = > Antibacterial effect.
Biological Effect
POTENTIATION

A+B
A
ANTAGONISM
The phenomenon of opposing effects
when two or more drugs are given
together is called Antagonism.

There are three types of antagonism

Chemical antagonism.
Physiological antagonism.
Pharmacological antagonism.
 CHEMICAL ANTAGONISM
In this type of antagonism two or more drugs react chemically to form
inactive product, it occurs without involvement of drug receptors.

Examples:
Acids react with Alkalis,
Heparin and Protamine sulfate.

PHYSIOLOGICAL ANTAGONISM
When two drugs produce opposite effects on same physiological function
by acting on different receptors it is called Physiological or Functional
antagonism.

Example:
Histamine and epinephrine on bronchial smooth muscles.
Acetylcholine and epinephrine on conducting system of the heart.
 PHARMACOLOGICAL ANTAGONISM

When two drugs produce opposite effects

on same physiological function by acting on
same receptors it is called Pharmacological
antagonism.
PHARMACOLOGICAL ANTAGONISM

Competitive antagonist Non competitive antagonism

Equilibrium (reversible). Non equilibrium (irreversible).

 COMPETITIVE EQUILIBRIUM ANTAGONISM
agonist and antagonist compete for same receptor site.
Drug receptor binding is weak & non-covalent.
The extent to which the antagonist opposes the action of
agonist is dependent upon the number of receptors occupied by
agonist and antagonist.
The antagonism is surmountable i.e. the antagonism can be
reversed by increasing the concentration of agonist at receptor
site, for example atropine and acetylcholine on muscarinic
receptors.
Maximal response of agonist is achieved by increasing the
concentration of agonist at receptor site.
 COMPETITIVE NON-EQUILIBRIUM
ANTAGONISM
agonist and antagonist compete with one another for same receptor site.

Antagonist binds with receptor by covalent bond.

Example: Epinephrine and Phenoxybenzamine on receptors.

NON COMPETITIVE ANTAGONISM

Agonist and antagonist bind at different sites on the same receptors.

The antagonist inactivates the receptor so that effective complex with

agonist cannot be formed irrespective of the concentration of agonist.
Example: Acetylcholine and Decamethonium on nicotinic receptors
TOLERANCE
Reduction in the response due to

continued use or repeated administration

of drug is called TOLERANCE.

 CROSS TOLERANCE:
It is the development of tolerance to pharmacologically
related drugs, e.g. alcoholic need relatively large
doses of barbiturates, as they are tolerant to this class
of drugs.
Closer the drugs are, more complete is the cross-
tolerance between them; e.g. there is partial tolerance
between morphine and barbiturates but complete
cross-tolerance betw,,lk;leen morphine and pethidine.
 MECHANISM OF TOLERANCE:
Reduction in response may be due to the changes
in absorption, distribution, metabolism and
excretion leading to the decreased effective
concentration of drug at the site of action, e.g.
barbiturates on repeated administration enhance
their own metabolism due to enzyme induction,
this is called DISPOSITIONAL OR
PHARMACOKINETIC TOLERANCE.
Reduction in response may be due to the reduced
responsiveness of target tissues due to down
regulation of receptors; this called FUNCTIONAL
OR PHARMACODYNAMIC TOLERANCE.
TACHYPHYLAXIS
Rapid reduction in responsiveness due to
repeated administration of drug at frequent
intervals is called TACHYPHYLAXIS.
It is also known as ACUTE TOLERANCE.
This is usually seen with indirectly acting drugs,
e.g. ephedrine, tyramine, and amphetamine act by
releasing catecholamines in the body, synthesis of
which does not match release and stores deplete
rapidly.
Slow dissociation of drug from receptors is another
mechanism responsible for the development of
Tachyphylaxis.