biomedis1)factors modifying drug effects (1)
TRANSCRIPT
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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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