Biomedis1)Factors Modifying Drug Effects (1)

8/11/2019 Biomedis1)Factors Modifying Drug Effects (1)

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(Biomedis1)FACTORS MODIFYING

DRUG EFFECTS

Dr. Zulkarnain R, MSi

Dept.Farmakologi & Therapeutik

Fak.Kedokteran USUM E D A N


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FACTORS MODIFYING DRUG ACTIONS

Individuals vary in drug effect from time to

time & from other individuals


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FACTORS MODIFYING DRUG ACTIONS

Nature of systemic effects of drugs depends onfollowing 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-druginteractions)


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I. Physiological factors

i) Age

Extreme of age show extreme drugsensitivity

Newborn babies & elderly= greater & more

prolonged effect of drugs b/c of less efficientdrug metabolism & renal functions


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GE

In new born there occurs

Decreases acid secretion

Decreased microsomal enzymes

Decreased plasma protein binding

Decreased G.F.R


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Infants

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

E.g.,

Chloramphenicol = Gray baby syndrome(inadequate metabolism)

Ampicillin & morphine = GIT absorption (lessacidity)

Tetrycycline= staining of teeth

Corticosteroids = retardation of growth inchildren


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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 degenerativechanges in kidney, liver, brain, heart

Cont.,


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E.g., Diazepam & benzodiazepines = t1/2

Benzodiazepines= more confusion & less sedation in

elderly

Hypotensive dugs= postural hypotension in elderly


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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


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Gender

Evidences show that men and women may respond

differently to same drugs

This may be due to body size, and amount of bodyfats.

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


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Gender

There appears to be difference in the activity of liverenzymes b/w men and women

Since the activity of enzymes vary that can result in

major difference in drug responseThis 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 teratogeniceffects

Reasons

Lipophilic drugs cross placental barrier

CO

GFR & renal elimination

Vd

Metabolism of some drugsE.g., pregnant uterus becomes more sensitive to

oxytocin


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Pregnancy

Causes several physiological changes that influence drugdisposition.

Volume of drug distribution is increased(total body water mayincrease by up to 8 liters) providing large space for water solubledrugs.Maternal plasma albumin concentration is reduced,more free drugswill be available

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

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

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


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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


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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


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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

PregnancyBody 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


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Pathological condition modify drug action

E.g., impaired renal function = decreasedrug excretion = drug accumulation

Liver disease= decrease metabolism of

drug=accumulation

Cont.

II. Pathological state


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Disease can cause pharmacokinetic orpharmacodynamic variation

a) PK variation

Variation in absorption

Gastric statisin migraine

Malbsorption ---ileal or pancreatic disease

Cont.


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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


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Pharmacodynamic alterations

Variation in receptors

In mysthania gravis, nephrogenic diabetes inspidus,

familial hypercholesterolemia


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III. Genetic factors

It affects drug action due to genetic differencesamong the races & certain persons in same

population

Genetic variation is an important source of PKvariability

Examples:

a) Genetic polymorphism= fast/slow acetylators

(hydralazine, procainamide, isoniazid)

Cont.


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Plasma choline estrase variant (suxamethonium)

Hydrooxylase polymorphism (extensive or poor

metabolism of debrisoquine)

Ethnic differences in drug metabolism =

propranolol, hemolytic anemia due to someoxidizing agents (primaquine, sulphonamides)


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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


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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


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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 multidrugtreatment of tuberculosis

Or undesirable or harmful


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Biomedis1)Factors Modifying Drug Effects (1)