FACTORS MODIFYING DRUG EFFECTS/DRUG VARIATIONS

BY Dr. Abdul Latif MahesarMedical pharmacologyKing Saud University

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On administration of a drug ,a predicted response is obtained but some times

Individuals may vary considerably in their responsiveness

Such as: respond differently to drugs both from time to time and from other individuals.

Some would show less than the usual response , and some may show more than usual response

Occasionally individuals exhibit unusual response IDIOSYNCRACY

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Physiological factors

AGE: Pregnancy Sex/gender Body weight Food Timings

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AGE

In new born there occurs

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

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There is increase in G.I.T absorption in newborns like ampicillin due to decreased acidity.

Tetracyclines produce teeth staining in children

Corticosteroids cause growth and developmental retardation

Antihistamines cause hyperactivity instead of hypoactivity.

These are all different responses than adults

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

Certain drugs may lead to serious consequences e.g. chloramphenicol causing gray baby syndrome.

sulphonamides causing kernicterus

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

e.g. Benzodiazepines, theophyllines 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 people so that drug produces greater and more prolonged effects at extremes of age .especially drugs which are excreted through kidneys as

there is decrease in G.F.R

Tubular function is also diminished. 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 hrs.

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

Gentamycin ,Digoxin ,Pencillins are contraindicated in old people.

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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.

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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 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

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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.

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Temperature Addition of mild to moderate hypothermia

decreases the systemic clearance of CY450 metabolizes drugs between 7-22% per degree Celsius below 37c during cooling. The addition of hypothermia decreases the potency and efficacy of certain drugs .

The therapeutic index of certain drugs is narrowed during hypothermia.

Therapeutic hypothermia has shown decrease in neurologic damage in patients experiencing cardiac arrest.

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Timings

It has been observed that endogenous body clock (circadian cycle) may affect the response of the drug.e.g.

In CHD(coronary heart dieseases) short acting calcium channel blockers seem to be less effective than beta blockers in reducing ischemic events during the night and early morning

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Food Presence of fatty food in stomach delays gastric

emptying,the plasma concentration of rifampicin and ampicillin may be much reduced if taken on full stomach

Calcium in milk interferes with absorption of tetracyclines and iron.

Substituting protein for fats and carbohydrates in diet ,increases drug oxidation rates.

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Charcoal grilled beef, cabbage, alcohol increases metabolism

Protein malnutrition affects pharmacokinetics of several drugs.

Citrus flavinoids in grape fruit (but not in orange juice) significantly increases absorption of cyclosporin calcium antagonists and probably other drugs

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PATHOLOGICAL FACTORS

DISEASES can cause individual variations in drug response.

Pharmacokinetic variations; Absorption: Gastric and intestinal stasis during an attack of

Migraine interferes absorption of drugs

Resection of gut may lead to malabsorption of iron,folic acid and fat soluble vitamins and of vit B12 after ileal resection

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Diarrhea increases the motility of the gut and decreases absorption.

Hypoalbuminaemia from any cause such as nephrotic syndrome, burn,malnutrition,sepsis allows higher proportion of albumin free drug in plasma which is readily available for metabolism and elimination but there can be risk with initial dose for drugs which are to be highly protein bound

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Metabolism:

Acute and chronic diseases of liver affects the blood flow and function of hepatocytes ,leading to decreased drug clearance, and prolong half life.

Drug metabolism is increased in hyperthyrodism and diminished in hypothyroidism

Excretion In acute and chronic renal impairment ,concentration of drugs

is altered..

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Pharmacodynamic variations:

Asthma can be precipitated by beta blocking drugs

Raised intracrainal pressure ,severe pulmonary insufficiency cuases patient to be inttolent to opioids precipitate respiratory failure

Change in receptors (Myasthenia gravis).person

becomes intolerant to quinine , quinidine and aminoglycoside

Increased sensitivity of adrenergic receptors in hyperthyroidism.

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Genetic factors:These are known as idiosyncratic responseThese are rare but very harmful. Acetylator status (important for metabolism) Slow acetylators:( isoniazid causing peripheral neuropathy on standard

dose and pyridoxine is added to T.B regime) Rapid acetylators: hepatotoxicity (hepatocellular necrosis)in fast acetylators

Defective carbon oxidation may cause poor oxidation of some drugs leading to some adverse effects

with standard doses of drugs like beta blockers.

Pseudocholine estrase deficiency Failure to rapid inactivation of Suxamethonium, leading to muscular block ,results paralysis.

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G-6-PD deficiency: ( haemolysis by primaquine) G6PD is necessary to maintain reduced glutathione in red cells and to prevent their hemolysis.

This occurs in small portion of people Such as chloramphenicol causes aplastic anemia 1 in

50,000.

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

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Envoirmental and diet:

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

Cigarette smokers metabolize some drugs more rapidly than non smokers.

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

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

Grapefruit juice induce CYP3A

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Other variations(quantitative )

More common More clinically important Patient may be

Hypo reactive: Hyper-reactive: to drug to a given dose

Hypersensitivity:allergic or other immunologic responsiveness to

drugse.g. Penicillins

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Tolerance with some drugs intensity of response to given

dose may change during course of therapy, usually decrease in response to continued administration of drug.e.g. Salbutamol (β-adrenergic agonist)

Opium ,barbiturates , Alcohol Tachyphylaxis:

when responsiveness diminishes rapidly after administration of druge.g. ephedrine

Amphetamine23

Idiosyncrasy: Is an abnormal genetic response and is usually

harmful

It occurs in small portion of population.

e.g. aplastic anaemia due to chlormaphenicol haemolysis by primaquine in G-6-PD defiency Hepatic porphyria by carbamazipine Malignant hyperthermia by suxamethonium

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Anaphylaxis

It is an immediate hypersensitivity reaction on exposure to specific antigen leading to life threatening respiratory distress followed by vascular collapse

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Change in response due to altered drug concentration

This may be due to change in rate of absorption ,distribution and elimination of drug. alteration in drug concentration that reaches relevant receptor may alter clinical response .

Variation in response may be due to variation in concentration of endogenous receptor ligand ,alteration in number of functional receptors, change in components distal to receptors.

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variability in response to pharmacologic antagonist as propranolol will markedly slow the heart rate of

patient whose endogenous catecholamine are elevated (in pheochromocytoma ) but will not affect the resting H.R of well trained marathon runner

A partial agonist SARALACIN at angiotensin II lowers blood pressure in pts with hypertension caused by increase in angiotensin II production and raises blood pressure in patients who produces low amount of angiotensin

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Alteration in number of receptors there occurs change in responsiveness caused by

increase or decrease in number of receptor sites or alteration in efficiency of coupling of receptor to distal effectors mechanism.

e.g. 1) Receptors for hormonesThyroid hormones cause increase in number of β-adrenergic receptors and hence increase in cardiac sensitivity to catecholamines

ii) Agonist ligand induces a decrease in number( down regulation) or coupling efficiency of its receptors.e.g salbutamol.

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Before starting a drug therapy clinician should be aware of

age general health specially severity and pathologic

mechanism of disease. Drug therapy always be most successful when it is

accurately directed at pathophysiologic mechanism responsible for disease.

even then there may be no benefit due to compensatory mechansim

e.g. Vasodilator drug for hypertension leads to reflex tachycardia and sodium retension by kidneys.

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Drug resistance

When drug looses the effectiveness. usually this happens with the improper use of

antibacterial drugs

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Synergism: when two drugs are administered at the same time , the

effect increases. Summation: the effect of two drugs having same action

are added have aditie effect.

e.g. beta blocker + diuretic have additive antihypertensive effect

Potenciation: when one drug increases the effect of other drug

e.g. levodopa +cabidopa

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DRUG – DRUG INTERACTION when one drug is administered, a response

occurs, if a second drug is given and response to 1st drug is altered ,a drug interaction is said to have occurred

This may be Desired or beneficial e.g. Multi drug treatment of T.B

Naloxone to treat Morphine overdose Undesired or hamful

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Clinically important drug interactions

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

e.g. Digoxin , Lithium

2. Drugs that are known enzyme inducers/inhibitors

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Distribution:

altered plasma protein binding ( binding of penytoin in chronic renal failure decreases

Impaired blood brain barrier ( infilitration of Penicillin in meningitis increases

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

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

e.g. oral contraceptive ,lithium, antiepileptic drugs

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

6. In patients with impaired kidney and liver function

7. In elderly who receive several drugs at the same time35

PHARMACODYNAMIC INTERACTIONS Both drugs act at same target site exerting synergism

or antagonism

Drugs may act at same or different receptors or process.

eg alcohal + benzpdiazepines (sedation)

Morphine + Naloxone ( to reverse opoid overdose)

Rifampicin + INH ( effective anti TB combination.)36

PHARMACOKINETIC INTERACTIONS

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

interaction may be synergistic or antagonistic.

Drug interaction can occur at

1. out side the body2. At site of absorption3. During drug distribution4. During drug metabolism5. During drug excretion.6. On receptor or body system.

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Interaction out side the body

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

Dilution in reservoir may also lead to loss of stability.

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

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AT THE SITE OF ABSORPTION

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

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

e.g anti cholinergics , antidepressants

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Other than gut : Local anesthetics and adrenaline.

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Purgatives reduce time spent in small intestine and reduce absorption.

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

Other than gut : Local anesthetics and adrenaline.

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DURING DISTRIBUTION

Displacement from plasma proteins binding

e.g. Sodium valproate displaces Phenytoin

Sulphonamides displaces bilirubin ( in neonates)

Displacement from tissue binding sites

e.g. Quinidine displaces Digoxin.

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Interaction during metabolism Enzme induction: liver micsrosomal enzymes are induced by a wide

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

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

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

chronic use of alcohal shows tolerance to general anesthetics.

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Enzyme inhibition

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

Eg. Cimetidine potenciates the effects of propranolol ,theophylline, warfarin and others

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Enzyme inducers.

Phenobarbital Rifampin Grisofulvin Phenytoin Ethanol Carbamazepine

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Enzyme inhibitors

Phenylbutazone Metronidazole Cimetidine Omperazole

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Interaction during excretion

this occurs in kidney by latering binding and hence filtration by inhibitin tubular secretion eg probenecid and pencillins by latering urine flow and or urine PH.

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Haemodynamic flow

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

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

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