FACTORS MODIFYING DRUG

EFFECTS

Dr.Datten Bangun,MSc,SpFK
Dr.Yunita Sari Pane,MSi
Dept.Farmakologi & Therapeutik
Fak.Kedokteran USU
MEDAN
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
Genetic factors
Psychological /emotional state

Interaction with other drugs (drug-drug interactions)

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 4
 GENETIC FACTORS
Slow acetylators
Fast acetylators
G-6-phosphate dehydrogenase deficiency
Deficiency of pseudocholinestrase
Malignant hyperthermia

ENVIRONMENTAL FACTORS
Smoking
Alcohol
 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
 i) 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.
13
 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)
Grape fruit;inhibit metabolism terfenadine--
Torsade de pointes pd org yg Q-T intervalnya
panjang
 II. Pathological state
Pathological condition modify drug action

E.g., impaired renal function = decrease

drug excretion = drug accumulation
Liver disease= decrease metabolism of
drug=accumulation

Cont.
 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

PPB = Plasma Protein Binding)

 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)
b) -isoniazid;obat tbc :fast n slow acetylators
 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)
 Glucose-6-phosphate
Dehydrogenase Deficiency

G6PD Deficiency: an inherited disease

characterized by hemolytic anemia
caused by the inability to detoxify
oxidizing agents.
Most common disease-producing
enzyme abnormality in humans.
Over 200 million people.
 G6PD Deficiency
Has the highest prevalence in the
Middle East, tropical Africa and Asia,
and parts of the Mediterranean.
X-linked
Life span of individuals is shortened
as a result of complications arising
from chronic hemolysis.
Increased resistance to malaria
shown by female carriers.
There are many variations of G6PD
Deficiency - most individuals never
show any clinical manifestations.
Some patients, however, develop
hemolytic anemia if they are
1) treated with an oxidant drug
2) ingest fava beans == Favism
3) contact a severe infection
1) Oxidant drugs: commonly used drugs
that produce hemolytic anemia in
patients with G6PD deficiency are
best remembered from the mnemonic
AAA:
Antibiotics (e.g. sulfamethoxazole)
Antimalarials (e.g. primaquine)
Antipyretics (e.g. acetanilid)
 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 drug-drug interaction
May be desired or beneficial like multidrug
treatment of tuberculosis
Or undesirable or harmful
Thank you for your attention