FACTORS MODIFYING

DRUG ACTION
Dr Krishna Badal
FACTORS MODIFYING DRUG ACTION
 Variation in response to the same dose of
a drug between different patient and
even in the same patient on different
occasion is a rule rather than exception.

 There are a number of factors which can

influence drug response. Individuals may
often show quantitative variations in
drug response but rarely show
qualitative variations.
 FACTORS MODIFYING DRUG
ACTION
 Patient related  Drug related
factors: factors:
1. Personal factors: 1. Dose of drug
 Age 2. Time of
 Sex administration of
 Race drug
 Nutritional status 3. Route of
2. Genetic factors administration of
3. Environmental Factors drug
4. Pathological conditions 4. Cumulation
5. Psychological factors 5. Drug
6. Drug tolerance biotransformation
7. Drug dependence and excretion.
 PERSONAL FACTORS --- AGE
 Extreme of age (too young or too old ) alters
drug activity because
 Children are immature
 Organ functions , blood brain barrier, Enzyme
machinery.
 Old age there is degenerative changes in organs.
 So drug are given very cautiously to children
and old age.
 PERSONAL FACTORS --- AGE
(INFANT AND CHILDREN)
 If Chloramphenicol is given to infant, it may lead
to gray baby syndrome.
 If Sulphonamide is given to infants for typhoid
fever , it may lead to kernicterus.
 Children are growing and are susceptible to
special adverse effect of drug
 Tetracycline Retardation of bone and teeth
growth
 Steroids Early fusion of epiphysis with
diaphysis, leading to short stature
 Sepsis ( infant) sepsis( infant)

Chloramphenicol given
Sulphonamide given

Failure of
Highly lipid Have more affinity for
metabolism
soluble drug plasma protein than bilirubin
due to absence
So can’t be
or deficiency
excreted
of enzyme
through kidney So bilirubin is displaced
glucuronyl
transferase
Cross blood brain barrier
Accumulation in body

Cross blood brain barrier Deposition in basal ganglia

Deposition to
cardio-respiratory center Kernicterus

Gray baby syndrome

 PERSONAL FACTORS --- AGE
(OLD AGE)
 In old age renal function is progressively
decreased hence drug dose have to be adjusted.
 Eg;
 Streptomycin in treating TB
 Young adult = 1 g/ day
 Old age ( above 50 yrs ) = 0.75 g / day
 Old age ( above 70 yrs ) = 0.5 g/ day
 High dose of streptomycin in old age group may
cause Vestibulocochlear nerve ( VIII ) damage
leading to deafness.
 PERSONAL FACTOR --- SEX
Male:
 Some drug shows its adverse effects in male
only
 Eg;
 Gynaecomastia (Ketoconazole ,Chlorpromazine,
digitalis)
 Lossof libido by ketoconazole
 Oestrogen in male increase feminine character.
 PERSONAL FACTOR --- SEX
Female:
 In case of female the following factors
modify drug action
 Menstruation
 Pregnancy
 Lactation

1.Menstruation:
 Intakeof aspirin for analgesia during menstruation
may cause heavy menstrual Bleeding

Aspirin Antiplatelet Increase blood loss

 PERSONAL FACTOR --- SEX
2. Pregnancy:
A. Relative safe period
 Drugs during pregnancy may cause
 1st trimester = Abortion and congenital malformation
 3rd trimester and 2nd trimester = Functional disturbances to
fetus
B. Physiological changes in pregnancy may alter
drug action ( esp; 3rd trimester )
 GI motility is reduced so delayed in oral drug absorption
 Renal blood flow increase markedly hence lipid soluble
drug excretion increase
 Hepatic microsomal enzyme undergoes induction hence
many drug metabolism increases.
 PERSONAL FACTOR --- SEX
(PREGNANCY)
1.Abortion:
 Aspirin, H1 blocker (antihistamine)
 Misoprostol
2.Structural malformation:
 Aspirin = Cleft lip and palate
 Steroid = Talipes
 Thalidomide (hypnotic) = Phocomelia (total absence
of limb)
3.Functional disturbances:
 Steroid = Premature closure of metaphysis leading to
short stature.
 Diabetic mother on oral hypoglycemic agent =
hypoglycemia in future baby
 Aspirin = premature closure of ductus arteriosus
leading to CVS disorder
 PERSONAL FACTOR --- SEX
3. Lactation:
A nursing mother should take caution while
taking drug, as it can pass through milk and
cause effect in baby
Eg;
 Ifnursing mother is taking sleeping pills
(benzodiazepines ), it can pass to baby and cause
CNS depression
 Mother taking tetracycline may hamper the
growth of baby
PERSONAL FACTORS --- RACE
 Human being have some racial difference
regarding drug activity
 Eg:
 Thiacetazone ( Anti TB) well tolerated by
Africans and Asians than European and Chinese
population
 Chloramphenicol has shown few cases of aplastic
anaemia in India and Hong Kong than west.
 PERSONAL FACTORS ---
NUTRITIONAL STATUS
1. In malnourished people:
 Lessprotein less enzymes less drug metabolism
prolonged drug action normal dose may lead to
adverse effect
2. In obese :
 Body surface area is more so normal dose may be
less effective
3.People with special food habit
 Instrict vegetarian urine is alkaline hence If alkaline
drug is given then there will be less excretion so
more action of drug. Hence drug dose should be
adjusted
 Consumption of food with preservatives ( contains
hydrocarbon) increases the microsomal enzyme
activity hence decrease drug activity by increasing
metabolism
 GENETIC FACTOR
 Pharmacogenetics is concerned with the
genetic variability of drug effects.
 Genetic variation may either influence
the
(A) Pharmacokinetics of a drug or
(B) Occur in the target genes that mediate the
therapeutic effect of drugs. (Pharmacodynamic
level)
 GENETIC FACTOR
Genetic variants of pharmacokinetics.
 Subjects who break down a drug more slowly owing to a
genetic defect are classified as “slow metabolizers” or
poor metabolizers” in contrast to “normal
metabolizers.”
 When delayed biotransformation causes an excessive rise
in plasma levels, the incidence of toxic effects increases
 Eg;
 Immunosuppressants like azathioprine and
mercaptopurine can cause bone marrow damage in slow
metabolizers.
 Atypical Pseudocholinesterases causes prolonged
succinylcholine apnoea
 Gluccose-6-P dehydrogenase deficiency causes
Hemolytic anaemia with oxidizing drug like Primaquine,
sulfonamides, dapsone , quinine , Chloroquine etc.
 Acetylator Polymorphism = Isoniazid , Hydralazine ,
Procainamide causes SLE in slow acetylators
GENETIC
FACTOR
 Genetic variants of
pharmacodynamics.
 Genetic polymorphisms
can also involve genes
that directly or indirectly
mediate the effects of
drugs and, hence, alter
pharmacodynamics.
 In these cases, the
biological effects of a
drug are changed, rather
than its plasma levels.
 Eg;
 The genetic variants of β-
adrenoceptors.
 If we give antihypertensive
drug to such patients then
less effect is seen.
 ENVIRONMENTAL FACTORS
 Several environmental factors may affect the
drug response
 Eg:
 In urban area environment is polluted with
hydrocarbon which is a microsomal enzyme
inducer leading to decrease effect of drug.
 People working in insecticide factory have
increased microsomal enzyme activity.
 PATHOLOGICAL CONDITIONS
1. Drugs
are given only when there is
pathological state such that they can
work.
 Antipyretics (Paracetamol) acts only when
there is fever.
 Antiemetic acts only when patient vomits.
 Antibiotics only when there is infection.
 PATHOLOGICAL CONDITIONS
2. Several disease can also alter the drug
disposition and drug action
 GI disease can alter the drug absorption
 Liver disease :
 Metabolism of drug is decreased and may produce toxic effects
hence dose should be decreased. eg; Morphine, Phenobarbitone
 Serum albumin is reduced hence plasma protein binding is reduced.
So more drugs is present in plasma.
 Kidney disease:
 Excretion of drug is reduced leading to accumulation and adverse
effect
 Eg; Aminoglycosides, Ethambutol etc need dose reduction in renal
failure
 Thyroid disease:
 Hypothyroid patient are more sensitive to morphine, and other CNS
depressants
 Hyperthyroid patient can tolerate high doses of morphine
 PSYCHOLOGICAL FACTORS
 Personality of the doctor as well as patient
doctor relationship can also affect response
to a drug. Some patients respond to inert
dosage forms(placebo) in conditions like
pain, anxiety, bronchial asthma.
 PLACEBO EFFECT
 “Placebo” is a dummy medicine having no
pharmacological activity.
 The effect produced by it is called
placebo effect. Sugar tablets and distilled
water injection are used as placebos.
 Uses:
 placebos are used for the relief of subjective
symptoms like anxiety, headache, tremors,
pain, insomnia, also used in clinical trials in
order to minimize bias.
FACTORS AFFECTING PLACEBO EFFECT
1. Patient factors:
 Patients with neurotic symptoms often respond to
placebos.
2. Drug factors:
 The placebo response can be affected by the physical
presentation or route of administration of the drug.
E.g., colourful tablets, such as red, blue, green and
injectable preparations give better placebo effect.
3. Doctor factors:
 personality of the doctor, motivation, way of
instruction, doctor patient relationship are important
factors that also affect response to placebo.
 TOLERANCE
 It means “need for larger doses of a drug to
produce a given response”.
 Tolerance develops to nasal decongestant effect
of ephedrine on repeated use. Patients on
organic nitrates for angina develop tolerance on
long-term therapy. Tolerance is commonly seen
with drugs like morphine, alcohol, amphetamine,
etc.
 TYPES OF
TOLERANCE
Tolerance

Natural tolerance Acquired

tolerance
 NATURAL
TOLERANCE
 It is genetically determined reduced/ lack of
response to a drug.

 Species tolerance:
 Some species are tolerant to certain drugs, e.g.,
rabbits can tolerate large doses of atropine.
 Racial tolerance:
 Some races show tolerance to certain drugs.
Black people need higher concentration of
atropine to dilate pupil than Mongolians.
 ACQUIRED
TOLERANCE
 It develops on repeated exposure to a drug.
Sometimes, tolerance develops only to
certain effects, E.g., on repeated use of
morphine, tolerance develops to its
euphoriant and analgesic effects but not to
its miotic and constipating effects.
MECHANISM OF DEVELOPMENT
OF TOLERANCE
 It could be pharmacokinetic or
pharmacodynamic tolerance.
1. Pharmacokinetic tolerance (Dispositional
tolerance):
 It is due to reduced concentration of the drug at
the site of action- may be as a result of decreased
absorption, increased metabolism and excretion.
For E.g., rifampicin induces the metabolism of OC
pills by inducing metabolic enzymes.
2. Pharmacodynamic tolerance (functional
tolerance):
 The drug effect is reduced, which may be due to
down-regulation of receptors or decrease in
receptor-coupled signal transduction. Repeated use
of opioids, barbiturates results in development of
tolerance due to decrease in number of receptors.
 TACHYPHYLAXIS
 Tachyphylaxis (tachy= rapid, phylaxis=
protection; acute tolerance):
 Repeated use of certain drugs at short intervals
may result in rapid decrease in
pharmacological response. This is know as
tachyphylaxis or acute tolerance.

 E.g.,
tyramine, ephedrine and amphetamine.
These drugs, they act by releasing
noradrenaline from adrenergic nerve endings.
Repeated administration of drug causes gradual
depletion of neurotransmitter and hence
reduces response.
 DRUG DEPENDENCE
 Drug dependence:
 WHO defines it as ‘ a state, psychic, and
sometimes also physical, resulting from the
interaction between living organism and drug
characterized by behavioral response that always
include a compulsion to take the drug on a
continuous or periodic basis in order to
experience its psychic effects and sometimes to
avoid the discomfort of its absence, e.g.,
opioids, alcohol, barbiturates, amphetamine,
e.t.c.
 DRUG DEPENDENCE
 The dependence could be physical or
psychological.
 Psychological dependence: There is an intense
desire to continue taking the drug as the patient
feels that their well-being depends upon the drug.
 Physical dependence:
 Repeated drug use produces physiological changes in the body,
which makes continuous presence of the drug in the body
necessary to maintain normal function.
 Abrupt stoppage of the drug results in an imbalance wherein
the body has to readjust to the absence of the drug resulting
in the development of signs and symptoms known as
withdrawal syndrome. The withdrawal signs and symptoms are
generally opposite to the effects produced by the drug.
 DOSE OF DRUG
Barbiturates
 Adequate dose of Coma
drug is required for
Medullary
optimum action. depression
Benzodiazepines

 Less amount of drug CNS

Anesthesia
may not show efficacy effects

where as increasing
dose may produce Hypnosis
adverse effects
Sedation ,anxiolytic

Increasing Dose

CNS effects of sedatives and hypnotics

With increasing dose of drug
TIME OF ADMINISTRATION OF DRUG
 Sedatives and hypnotics are used at bed time
for their maximum effects
 Drug for motion sickness better act at empty
stomach
 Analgesic taken after meal to decrease
chance of peptic ulcer.
 Steroid are taken usually at morning time as
it cause less pituitary- adrenal suppression.
 ROUTE OF ADMINISTRATION OF
DRUG
1.Different route of administration may increase or decrease the
activity of drug.
 Insulin
 Subcutaneously = Diabetics
 Intravenously = In diabetic emergency
 Oral= No action
2. A drug may have entirely different uses through different route
a) Magnesium sulphate
 Oral= Purgatives
 Applied locally in inflamed area= decrease swelling.
 Intravenous = Decrease intracranial pressure

= Used as anticonvulsant in eclampsia

b) Diazepam/ Benzodiazepines:
 Oral = Anxiolytic and sedatives
 Intravenous = Anesthetic agent

= Used in seizure disorder

 CUMULATION
 When the rate of administration of drug is
greater than its excretion the drug will
accumulate in body.
 Drug having high plasma half life
accumulates in body.
 Eg;
 Digitalis, Sulphonamide , Phenobarbitone
 Cumulative effect is generally undesirable
but may be useful in treatment of CCF by
digitalis