FACTORS MODIFYING DRUG EFFECTSDr.Datten Bangun,MSc,SpFKDr.Yunita Sari Pane,MSiDept.Farmakologi & TherapeutikFak.Kedokteran USUM E D A N

FACTORS MODIFYING DRUG ACTIONSIndividuals vary in drug effect from time to time & from other individuals

FACTORS MODIFYING DRUG ACTIONSNature 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 factorsGenetic factorsPsychological /emotional state

Interaction with other drugs (drug-drug interactions)

*PHYSIOLOGICAL FACTORS:Age SexPregnancyBody weight

PATHOLOGICAL FACTORSDiseases of liver and kidneyMalnutrition

GENETIC FACTORSSlow acetylatorsFast acetylatorsG-6-phosphate dehydrogenase deficiencyDeficiency of pseudocholinestrase Malignant hyperthermia

ENVIRONMENTAL FACTORS Smoking Alcohol

GENETIC FACTORSSlow acetylatorsFast acetylatorsG-6-phosphate dehydrogenase deficiencyDeficiency of pseudocholinestrase Malignant hyperthermia

ENVIRONMENTAL FACTORSSmoking Alcohol

I. Physiological factors

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

In new born there occurs

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

i) Age

InfantsPremature 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 teethCorticosteroids = retardation of growth in children

ElderlyRenal & hepatic function decline slowly after middle ageActivity of hepatic microsomal enzymes decline with ageVd of lipid soluble drugs increasesElderly require less due to degenerative changes in kidney, liver, brain, heartCont.,

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

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

ii) Sex/GenderResponse & dose= d/f in men & womenMetabolism of some drugs= less in women (more adipose tissues)E.g., alcohol, diazepam Women require lesser dose than male

GenderEvidences 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

GenderThere appears to be difference in the activity of liver enzymes b/w men and womenSince 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.

*

iii) PregnancyAvoid drugs during pregnancy due to teratogenic effectsReasonsLipophilic drugs cross placental barrier CO GFR & renal elimination VdMetabolism 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) LactationAvoid drugs during lactation due to harm to babyDrugs easily appear in milk but < therapeutic dose

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

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

D/f quantity of drug for light & heavier personsD/f quantity of drug for smaller & larger personsLow amount of drug for smaller perosns

vi) foodSome 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 intervalnyapanjang

Pathological condition modify drug action

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

Cont.II. Pathological state

Disease can cause pharmacokinetic or pharmacodynamic variation

a) PK variation Variation in absorptionGastric statis in migraineMalbsorption ---ileal or pancreatic disease

Cont.

Variation in distributionAlterd PPB of phenytoin in chronic renal failure (binding of phenytoin to PPB Variation in metabolismHepatic cirrhosis & portal HTN

Variation in excretionAcute and /or chronic renal failure

PPB = Plasma Protein Binding)

Pharmacodynamic alterationsVariation in receptorsIn mysthania gravis, nephrogenic diabetes inspidus, familial hypercholesterolemia

III. Genetic factorsIt affects drug action due to genetic differences among the races & certain persons in same populationGenetic variation is an important source of PK variabilityExamples:Genetic polymorphism= fast/slow acetylators (hydralazine, procainamide, isoniazid)-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 DeficiencyHas the highest prevalence in the Middle East, tropical Africa and Asia, and parts of the Mediterranean. X-linkedLife 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 treated with an oxidant drugingest fava beans == Favismcontact a severe infection

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 factorsMicrosomal enzyme inducers

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

Smokers metabolize drugs more rapidly than non smokers

V) Psychological stateGeneral anesthetics required in dose for nervous & anxious patientsHigher doses of chlorpromazine needed in schizophrenicsPlacebos (inert dosage form) produce therapeutic benefits in psychomotor angina pectoris & bronchitis in asthma

VI) Interaction with other drugsAdministration of one drug (A) can alter action of another drug (B) by PK or PD mechanismsThis is drug-drug interactionMay be desired or beneficial like multidrug treatment of tuberculosisOr undesirable or harmful

Thank you for your attention