(Biomedis1)FACTORS MODIFYING

DRUG EFFECTS
Dr. Zulkarnain R, MSi
Dept.Farmakologi & Therapeutik
Fak.Kedokteran USU
M E D A N
FACTORS MODIFYING DRUG ACTIONS
Individuals vary in drug effect from time to
time & from other individuals

FACTORS MODIFYING DRUG ACTIONS
Nature of systemic effects of drugs depends on
following factors:
Physiological factors (age, sex, pregnancy,
lactation, body wt., food)
Pathological state (kidney or liver disease)
Environmental factors
Psychological /emotional state

Interaction with other drugs (drug-drug
interactions)


I. Physiological factors

i) Age
Extreme of age show extreme drug
sensitivity
Newborn babies & elderly= greater & more
prolonged effect of drugs b/c of less efficient
drug metabolism & renal functions
AGE


In new born there occurs

Decreases acid secretion
Decreased microsomal enzymes
Decreased plasma protein binding
Decreased G.F.R






Infants
Premature infants= poor renal & hepatic functions
------- more sensitive to various drugs

E.g.,
Chloramphenicol = Gray baby syndrome
(inadequate metabolism)
Ampicillin & morphine = GIT absorption (less
acidity)
Tetrycycline = staining of teeth
Corticosteroids = retardation of growth in
children
Elderly
Renal & hepatic function decline slowly after
middle age
Activity of hepatic microsomal enzymes
decline with age
Vd of lipid soluble drugs increases
Elderly require less due to degenerative
changes in kidney, liver, brain, heart
Cont.,
E.g., Diazepam & benzodiazepines = t1/2


Benzodiazepines= more confusion & less sedation in
elderly
Hypotensive dugs= postural hypotension in elderly

ii) Sex/Gender
Response & dose= d/f in men & women
Metabolism of some drugs= less in women
(more adipose tissues)
E.g., alcohol, diazepam
Women require lesser dose than male
Gender
Evidences show that men and women may respond
differently to same drugs

This may be due to body size, and amount of body
fats.
But there are also some less easily explained
differences in gender specific drug response

Aspirin shows greater benefit in men than women
in cardiovascular diseases


Gender
There appears to be difference in the activity of liver
enzymes b/w men and women
Since the activity of enzymes vary that can result in
major difference in drug response
This difference in liver activity may explain why
women routinely wakes up from general anesthesia
several minutes before a man given an equal dose.
It has been observed that women with red hair and fair
skin are particularly responsive to effects of the
analgesic Pentazosine than man of same character.

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iii) Pregnancy
Avoid drugs during pregnancy due to teratogenic
effects
Reasons
Lipophilic drugs cross placental barrier
CO
GFR & renal elimination
Vd
Metabolism of some drugs
E.g., pregnant uterus becomes more sensitive to
oxytocin
Pregnancy

Causes several physiological changes that influence drug
disposition.

Volume of drug distribution is increased(total body water may
increase by up to 8 liters) providing large space for water soluble
drugs.
Maternal plasma albumin concentration is reduced,more free drugs
will be available

Metabolic rate is increased, so the free drugs will be available for
elimination.

Cardiac out put is increased, leading to increased renal blood flow
and glomerular filtration and increased renal elimination of drugs.

Lipophilic molecules readily traverse placental barrier. Drugs that
are transferred to fetus are slowly eliminated.

iv) Lactation
Avoid drugs during lactation due to harm to
baby
Drugs easily appear in milk but < therapeutic
dose


E.g., tetracycline, sedatives, hypnotics, opoids


V) Body wt./surface area & size
Conc. Of drug at site of action=ratio b/w body
wt. & amount of drug

D/f quantity of drug for light & heavier
persons
D/f quantity of drug for smaller & larger
persons
Low amount of drug for smaller perosns
vi) food
Some drugs have interaction with food and
they alter the response of drug

E.g., toxic symptoms appear after eating of
cheese, red wine & chicken liver if patient is
taking MAOI (more release of NA=fatal
cerebral hemorrhage)
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PHYSIOLOGICAL FACTORS:
Age
Sex
Pregnancy
Body weight

PATHOLOGICAL FACTORS
Diseases of liver and kidney
Malnutrition

GENETIC FACTORS
Slow acetylators
Fast acetylators
G-6-phosphate dehydrogenase deficiency
Deficiency of pseudocholinestrase
Malignant hyperthermia

ENVIRONMENTAL FACTORS
Smoking
Alcohol


Pathological condition modify drug action

E.g., impaired renal function = decrease
drug excretion = drug accumulation
Liver disease= decrease metabolism of
drug=accumulation

Cont.
II. Pathological state
Disease can cause pharmacokinetic or
pharmacodynamic variation

a) PK variation
Variation in absorption
Gastric statis in migraine
Malbsorption ---ileal or pancreatic disease

Cont.

Variation in distribution
Alterd PPB of phenytoin in chronic renal failure
(binding of phenytoin to PPB
Variation in metabolism
Hepatic cirrhosis & portal HTN

Variation in excretion
Acute and /or chronic renal failure
Pharmacodynamic alterations
Variation in receptors
In mysthania gravis, nephrogenic diabetes inspidus,
familial hypercholesterolemia
III. Genetic factors
It affects drug action due to genetic differences
among the races & certain persons in same
population
Genetic variation is an important source of PK
variability
Examples:
a) Genetic polymorphism= fast/slow acetylators
(hydralazine, procainamide, isoniazid)
Cont.
Plasma choline estrase variant (suxamethonium)

Hydrooxylase polymorphism (extensive or poor
metabolism of debrisoquine)

Ethnic differences in drug metabolism =
propranolol, hemolytic anemia due to some
oxidizing agents (primaquine, sulphonamides)
IV. Environmental factors
Microsomal enzyme inducers

e.g., Hydrocarbons in tobacco smoke, charcoal broiled
meat induce CYP1A

Smokers metabolize drugs more rapidly than non
smokers
V) Psychological state
General anesthetics required in dose for nervous
& anxious patients
Higher doses of chlorpromazine needed in
schizophrenics
Placebos (inert dosage form) produce therapeutic
benefits in psychomotor angina pectoris &
bronchitis in asthma
VI) Interaction with other drugs
Administration of one drug (A) can alter action of
another drug (B) by PK or PD mechanisms
This is c/d drug-drug interaction
May be desired or beneficial like multidrug
treatment of tuberculosis
Or undesirable or harmful
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