FACTORS MODIFYING FACTORS MODIFYING DRUG EFFECTSDRUG EFFECTS

BY BY Dr. Abdul Latif MahesarDr. Abdul Latif MahesarMedical pharmacologyMedical pharmacology

King Saud University 2008King Saud University 2008

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Individuals respond differently to drugs both from time to time and from Individuals respond differently to drugs both from time to time and from other individuals.other individuals.

Some would show less than the usual response , most would show the Some would show less than the usual response , most would show the unusual responseunusual response

and some would show more than usual responseand some would show more than usual response

FACTORSFACTORSPhysiological Physiological PathologicalPathologicalGeneticGeneticEnvironmentalEnvironmental

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PHYSIOLOGICAL FACTORS:PHYSIOLOGICAL FACTORS:Age Age SexSexPregnancyPregnancyBody weightBody weight

PATHOLOGICAL FACTORSPATHOLOGICAL FACTORSDiseases of liver and kidneyDiseases of liver and kidneyMalnutritionMalnutrition

GENETIC FACTORSGENETIC FACTORSSlow acetylatorsSlow acetylatorsFast acetylatorsFast acetylatorsG-6-phosphate dehydrogenase deficiencyG-6-phosphate dehydrogenase deficiencyDeficiency of pseudocholinestrase Deficiency of pseudocholinestrase Malignant hyperthermiaMalignant hyperthermia

ENVOIRNMENTAL FACTORSENVOIRNMENTAL FACTORS Smoking Smoking AlcoholAlcohol

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AGEAGEIn new born there isIn new born there is

Decreases acid secretion (gastric secretion )Decreases acid secretion (gastric secretion )

Decreased microsomal enzymes (glucuronyltransferase)Decreased microsomal enzymes (glucuronyltransferase)

Decreased plasma protein bindingDecreased plasma protein binding

Decreased G.F.R and tubular secretionsDecreased G.F.R and tubular secretions

Immature blood brain barrier.Immature blood brain barrier.

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Due decreased gastric acidity absorption of ampicillin and Due decreased gastric acidity absorption of ampicillin and amoxicillin is greater in neonates.amoxicillin is greater in neonates.

Tetracyclines produce teeth staining in childrenTetracyclines produce teeth staining in children

Corticosteroids cause growth and developmental Corticosteroids cause growth and developmental retardationretardation

Antihistamines cause hyperactivity instead of hypoactivityAntihistamines cause hyperactivity instead of hypoactivity ..

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Several enzymes are important for drug metabolism , ( hepatic Several enzymes are important for drug metabolism , ( hepatic microsomal oxidase, glucuronyl and acetyl transferase) have microsomal oxidase, glucuronyl and acetyl transferase) have low activity in neonates low activity in neonates

Certain drugs may lead to serious consequences Certain drugs may lead to serious consequences chloramphenicol causing gray baby syndrome. chloramphenicol causing gray baby syndrome. sulphonamides causing kernicterussulphonamides causing kernicterus

Activity of hepatic microsomal enzyme also Activity of hepatic microsomal enzyme also decreases with age leading prolonged half life of decreases with age leading prolonged half life of some drugs.some drugs.

Benzodiazepines, theophyllinesBenzodiazepines, theophyllines This may lead to accumulation of drug on repeated doses.This may lead to accumulation of drug on repeated doses.

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Drug elimination is less efficient in new born babies , and in old Drug elimination is less efficient in new born babies , and in old people so that drug produces greater and more prolonged people so that drug produces greater and more prolonged effects at extremes of age , especially drugs which are effects at extremes of age , especially drugs which are excreted through kidneys as GFR is reduced.excreted through kidneys as GFR is reduced.

Tubular function is also diminished.Tubular function is also diminished. e.g. Normal plasma half life of gentamicin is 1-4 hrs, in e.g. Normal plasma half life of gentamicin is 1-4 hrs, in

babies it is 10 hrs and in premature babies it may be up to 18 babies it is 10 hrs and in premature babies it may be up to 18 hrs.hrs.

G.F.R declines to 25% ,in person of 50 years of age and 50% G.F.R declines to 25% ,in person of 50 years of age and 50% in person 75 years of age.in person 75 years of age.

gentamycin ,Digoxin ,pencillin are contraindicated in old people.gentamycin ,Digoxin ,pencillin are contraindicated in old people.

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PREGNANCYPREGNANCY::causes several physiological changes that influence drug causes several physiological changes that influence drug

disposition.disposition.

Volume of distribution is increasedVolume of distribution is increased

Metabolic rate is increased due to placenta.Metabolic rate is increased due to placenta.

Maternal plasma albumin concentration is reducedMaternal plasma albumin concentration is reduced

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

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

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SexSex Testosterone increases the rate of metabolism in malesTestosterone increases the rate of metabolism in males

benzodiazepines decrease metabolism of some drugs in benzodiazepines decrease metabolism of some drugs in femalesfemales

females are more susceptible to autonomic drugs drugs females are more susceptible to autonomic drugs drugs ( estrogen inhibits choline estrase)( estrogen inhibits choline estrase)

Body weightBody weight

People with more weight and larger body surface require People with more weight and larger body surface require larger dose of the drug to produce required therapeutic larger dose of the drug to produce required therapeutic effect.effect.

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PATHOLOGICAL FACTORSPATHOLOGICAL FACTORS

Certain diseases of kidneys ,liver and other systems Certain diseases of kidneys ,liver and other systems can cause individual variations in drug response.can cause individual variations in drug response.

Pharmacokinetic variations;Pharmacokinetic variations;

Changes in Changes in Absorption:Absorption: Gastric stasis (Migraine)Gastric stasis (Migraine)

Malabsorption (Pancreatic insufficiency) Malabsorption (Pancreatic insufficiency)

Drug absorption is incomplete in pts with malabsorption, edema Drug absorption is incomplete in pts with malabsorption, edema of ileal mucosa due to heart failure or nephrotic syndrome.of ileal mucosa due to heart failure or nephrotic syndrome.

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In nephrotic syndrome plasma albumin is reduced, this In nephrotic syndrome plasma albumin is reduced, this alters disposition and protein binding alters disposition and protein binding

Diarrhea increases the motility of the gut and decreases Diarrhea increases the motility of the gut and decreases absorption.absorption.

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Distribution:Distribution:altered plasma protein binding ( binding of penytoin in altered plasma protein binding ( binding of penytoin in

chronic renal failure decreases chronic renal failure decreases

Impaired blood brain barrier ( infiltration of Penicillin Impaired blood brain barrier ( infiltration of Penicillin in to meningitis increasesin to meningitis increases

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Metabolism:Metabolism: of drugs is decreased in Chronic liver disease ,altering of drugs is decreased in Chronic liver disease ,altering the drug effectsthe drug effects

ExcretionExcretion:: Acute and chronic renal failure ,concentration of drugs is Acute and chronic renal failure ,concentration of drugs is

altered.altered.

Hypothermia reduces clearance of many drugs in elderlyHypothermia reduces clearance of many drugs in elderly . .

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Pharmacodynamics variations:Pharmacodynamics variations:

Change in receptors (Myasthenia gravis)Change in receptors (Myasthenia gravis)

Increased sensitivity of adrenergic Increased sensitivity of adrenergic

receptors in hyperthyroidism.receptors in hyperthyroidism.

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Genetic factors:Genetic factors: Acetylator statusAcetylator status ( to isoniazid causing peripheral neuropathy) ( to isoniazid causing peripheral neuropathy)

hepatotoxicity in fast acetylatorshepatotoxicity in fast acetylators

Defective carbon oxidationDefective carbon oxidation

Pseudocholine estrase defeciency Pseudocholine estrase defeciency FailureFailure to rapid to rapid inactivation of Suxamethonim, leading to muscular inactivation of Suxamethonim, leading to muscular block ,results paralysis.block ,results paralysis.

G6PD deficiency:G6PD deficiency: ( haemolysis by primaquine) G6PD is ( haemolysis by primaquine) G6PD is necessary to maintain reduced glutathione in red cells and to necessary to maintain reduced glutathione in red cells and to prevent their hemolysis.prevent their hemolysis.

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Hepatic porphyriaHepatic porphyria

PolymorphismPolymorphism

Malignant hyperthermiaMalignant hyperthermia: (by suxamethonium due to : (by suxamethonium due to inherited abnormality in Ca inherited abnormality in Ca 2+2+ release from release from sarcoplamic reticulum in striated muscles.)sarcoplamic reticulum in striated muscles.)

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Envoirmental and diet:Envoirmental and diet:Pollutants are capable of inducing P450 enzymes, such as Pollutants are capable of inducing P450 enzymes, such as hydrocarbons present in tobacco smoke, charcoal broiled meat hydrocarbons present in tobacco smoke, charcoal broiled meat induce CYP 1A. induce CYP 1A.

Polychlorinated biphenyls used in industry, cuciferous Polychlorinated biphenyls used in industry, cuciferous vegetables also induce CYP 1Avegetables also induce CYP 1A

grapefruit juice induceCYP3Agrapefruit juice induceCYP3A

Cigrate smokers metabolise some drugs more rapidly than non Cigrate smokers metabolise some drugs more rapidly than non smokers.smokers.

Industrial workers exposed to some pesticides metabolisze Industrial workers exposed to some pesticides metabolisze certain drugs more rapidly than who are non exposed.certain drugs more rapidly than who are non exposed.

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DRUG – DRUG INTERACTIONDRUG – DRUG INTERACTION

when one drug is administered, a response occurs, if a when one drug is administered, a response occurs, if a second drug is given and response to 1second drug is given and response to 1stst drug is drug is altered ,a drug interaction is said to have occurredaltered ,a drug interaction is said to have occurred

This may be This may be

Desired or beneficialDesired or beneficial

e.g.e.g. Multi drug treatment of T.B Multi drug treatment of T.B

Naloxone to treat Morphine overdoseNaloxone to treat Morphine overdose

Undesired or harmfulUndesired or harmful

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Clinically important drug interactionsClinically important drug interactions

1. Drugs that have steep dose response curve and small 1. Drugs that have steep dose response curve and small therapeutic index, small change in concentration at site therapeutic index, small change in concentration at site will lead to substantial changes in effect.will lead to substantial changes in effect.

e.g. Digoxin , Lithiume.g. Digoxin , Lithium

2. Drugs that are known enzyme inducers/inhibitors2. Drugs that are known enzyme inducers/inhibitors

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3. Drugs that exibit saturable metabolism 3. Drugs that exibit saturable metabolism e.g. Phenytoin , Theophyllinee.g. Phenytoin , Theophylline

4. Drugs used for prolong period and precise plasma concentration are 4. Drugs used for prolong period and precise plasma concentration are requiredrequired

e.g. oral contraceptive ,lithium, antiepileptic drugse.g. oral contraceptive ,lithium, antiepileptic drugs

5.5. Different durgs used to treat same disease Different durgs used to treat same disease e.g. Theophylline, Salbutamole.g. Theophylline, Salbutamol

6. In patients with impaired kidney and liver function6. In patients with impaired kidney and liver function

7. In elderly who receive several drugs at the same time7. In elderly who receive several drugs at the same time

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PHARMACODYNAMIC INTERACTIONSPHARMACODYNAMIC INTERACTIONS

Both drugs act at same target site exerting synergism or Both drugs act at same target site exerting synergism or antagonismantagonism

Drugs may act at same or different receptors or process.Drugs may act at same or different receptors or process.

eg alcohal + benzpdiazepines (sedation)eg alcohal + benzpdiazepines (sedation)

Morphine + Naloxone ( to reverse Morphine + Naloxone ( to reverse opoid overdose)opoid overdose)

Rifampicin + INH ( effective anti TB combination.)Rifampicin + INH ( effective anti TB combination.)

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PHARMACOKINETIC INTERACTIONSPHARMACOKINETIC INTERACTIONS

Drug act remotely from target site to alter plasma concentrationDrug act remotely from target site to alter plasma concentratione.g. enzyme induction /inhibitione.g. enzyme induction /inhibition

interaction may be synergistic or antagonistic.interaction may be synergistic or antagonistic.

Drug interaction can occur atDrug interaction can occur at

Out side the bodyOut side the bodyAt site of absorptionAt site of absorptionDuring drug distributionDuring drug distributionDuring drug metabolismDuring drug metabolismDuring drug excretion.During drug excretion. On receptor or body system.On receptor or body system.

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Interaction out side the bodyInteraction out side the body

Drugs are added to reservoir or syringes to make drugs Drugs are added to reservoir or syringes to make drugs soluble they are prepared in salt forms, mixing these soluble they are prepared in salt forms, mixing these drugs may lead to precipitation (incompatibility)drugs may lead to precipitation (incompatibility)

Dilution in reservoir may also lead to loss of stability.Dilution in reservoir may also lead to loss of stability.

Protamine in zinc may bind with soluble insulin and Protamine in zinc may bind with soluble insulin and delay its effectsdelay its effects..

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AT THE SITE OF ABSORPTIONAT THE SITE OF ABSORPTION

Direct chemical interactionDirect chemical interactione.g. Antacids + Tetracycline's ,Iron form insoluble e.g. Antacids + Tetracycline's ,Iron form insoluble complexes ,this can be prevented if drugs are administered at complexes ,this can be prevented if drugs are administered at 2hrs apart.2hrs apart.

Gut motility: drugs which reduce gastric emtying delay Gut motility: drugs which reduce gastric emtying delay absorption of other drugsabsorption of other drugs

e.g anti cholinergics , antidepressantse.g anti cholinergics , antidepressants

.Other than gut : Local anesthetics and adrenaline..Other than gut : Local anesthetics and adrenaline.

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Purgatives reduce time spent in small intestine and reduce Purgatives reduce time spent in small intestine and reduce absorption.absorption.

Alteration in gut flora: antimicrobials potentiates ant coagulants Alteration in gut flora: antimicrobials potentiates ant coagulants by reducing bacterial synthesis of vit.Kby reducing bacterial synthesis of vit.K

Other than gut : Local anesthetics and adrenaline.Other than gut : Local anesthetics and adrenaline.

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DURING DISTRIBUTIONDURING DISTRIBUTION

Displacement from plasma proteins bindingDisplacement from plasma proteins binding

e.g. Sodium valproate displaces Phenytoine.g. Sodium valproate displaces Phenytoin

Sulphonamides displaces bilirubin ( in Sulphonamides displaces bilirubin ( in neonates)neonates)

Displacement from tissue binding sitesDisplacement from tissue binding sites

e.g. Quinidine displaces Digoxin.e.g. Quinidine displaces Digoxin.

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Interaction during metabolismInteraction during metabolism

Enzme induction:Enzme induction: liver micsrosomal enzymes are induced by a wide variety of liver micsrosomal enzymes are induced by a wide variety of

drugs and these affect the metabolism of other drugs reducing drugs and these affect the metabolism of other drugs reducing their concentration and hence effect.their concentration and hence effect.

e.g oral contraceptive metabolism is enhanced if Phenytoin is e.g oral contraceptive metabolism is enhanced if Phenytoin is co-administered ,leading to unplanned pregnancyco-administered ,leading to unplanned pregnancy

eg loss of anticougulant effect of Warfarin leading to danger of eg loss of anticougulant effect of Warfarin leading to danger of thrombosis if barbiturates are administered.thrombosis if barbiturates are administered.

chronic use of alcohal shows tolerance to general anesthetics.chronic use of alcohal shows tolerance to general anesthetics.

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Enzyme inhibitionEnzyme inhibition

Certain drugs inhibit the liver microsomal Certain drugs inhibit the liver microsomal enzymes ,hence increase the activity of drugs enzymes ,hence increase the activity of drugs which are to be metabolized by these enzymes.which are to be metabolized by these enzymes.

e.g. Cimetidine potenciates the effects of e.g. Cimetidine potenciates the effects of propranolol ,theophylline, warfarin and otherspropranolol ,theophylline, warfarin and others

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Enzyme inducers.Enzyme inducers.

PhenobarbitalPhenobarbital

RifampinRifampin

GrisofulvinGrisofulvin

PhenytoinPhenytoin

Ethanol Ethanol

CarbamazepineCarbamazepine

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Enzyme inhibitorsEnzyme inhibitors

PhenylbutazonePhenylbutazone

MetronidazoleMetronidazole

CimetidineCimetidine

OmperazoleOmperazole

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Interaction during excretionInteraction during excretion

this occurs in kidney this occurs in kidney by binding at glomeruli and hence by pass filtrationby binding at glomeruli and hence by pass filtration by inhibitin tubular secretion by inhibitin tubular secretion eg probenecid and pencillinseg probenecid and pencillins by changing urine PH.by changing urine PH.

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Haemodynamic flowHaemodynamic flow

variation in hepatic blood flow may influence the rate variation in hepatic blood flow may influence the rate of inactivation of drugs as in reduced cardiac out put.of inactivation of drugs as in reduced cardiac out put.

drugs which reduce cardiac out put like Propranolol drugs which reduce cardiac out put like Propranolol may reduce the metabolism of other drugs.may reduce the metabolism of other drugs.