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Variations in Drug responsiveness

By

Dr.Abdul latif mahesar 200811

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When a drug is administered usually there is normal When a drug is administered usually there is normal predicted response predicted response

OR OR there may bethere may be

reduced responsereduced response increased response ORincreased response OR altered responsealtered response

Individuals may vary considerably in their responsiveness.Individuals may vary considerably in their responsiveness.

Even a single individual may respond differently to the same Even a single individual may respond differently to the same drug at different times.drug at different times.

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Variations Variations (changed response )(changed response )

Tolerance

Tachyphylaxis

Drug resistance

Hypersensitivity reactions (intolerance)

Desensitization

Anaphylactic reaction

Idiosyncrasy

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ToleranceIt is a gradual decrease in responsiveness to repeated administration of a drug.

It is slow in onset( takes days or weeks to develop)e.g. Salbutamol ( beta 2 –agonist ) Diazepam ( anxiolytic ) Morphine ( opioid analgesic )

Original effect can be obtained by increasing the dose. Which may lead to dependence and later addiction with some drugs.

This reduced effect of drug may be due toa) step down regulation of receptorsb) exhaustion of the mediatorc) increased metabolic degradationd) physiologic adaptatione) active extrusion of drug from cells

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TachyphylaxisTachyphylaxis

It is rapid decrease in response to a repeated administration of a It is rapid decrease in response to a repeated administration of a drugdrug

Its onset is rapidIts onset is rapid

Original effect cannot be obtained even with larger doses of drugOriginal effect cannot be obtained even with larger doses of drug

e.g. Exhaustion of epinephrine by ephedrine.e.g. Exhaustion of epinephrine by ephedrine.

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Drug resistanceDrug resistance

It is a complete loss of effectiveness of a drug.It is a complete loss of effectiveness of a drug.

e.g. antimicrobial drugse.g. antimicrobial drugs

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Hypersensitivity ( more than normal response of the body to a drug)

This can be corrected by

Desensitization( if a person is allergic to a drug ,he can be administered

a small amount of drug to which he is allergic and then it is to be gradually increased until the normal dose is tolerated)

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Anaphylaxis:Anaphylaxis: It is immediate hypersensitivity reaction on exposure to specific It is immediate hypersensitivity reaction on exposure to specific

antigen or hapten leading to life threatening respiratory antigen or hapten leading to life threatening respiratory distress followed by vascular collapse.distress followed by vascular collapse.

e.g. Penicilline.g. Penicillin

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Idiosyncratic reactionsIdiosyncratic reactions It is an inherent qualitative abnormal reactionIt is an inherent qualitative abnormal reaction It is an increase in response with a therapeutic dose.It is an increase in response with a therapeutic dose. It is due to genetic changeIt is due to genetic change It is usually harmful .It is usually harmful . occurs in small proportion of populationsoccurs in small proportion of populations e.g. chlormaphenicol causes aplastic anemiae.g. chlormaphenicol causes aplastic anemia 1 in 50,000.1 in 50,000. G6PD deficiency leads to hemolysis caused by primaquaine.G6PD deficiency leads to hemolysis caused by primaquaine. hepatic porphyria ( abnormal haem synthesis) caused by hepatic porphyria ( abnormal haem synthesis) caused by

carbamzepine.carbamzepine. Malignant hyperthermia caused by suxamethonium and Malignant hyperthermia caused by suxamethonium and

inhalational anesthetics.inhalational anesthetics.

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Keeping this responsiveness of individual drug, Keeping this responsiveness of individual drug, there should be change of the drug or dose. there should be change of the drug or dose.

These includes propensity( particular behavior ) These includes propensity( particular behavior ) of particular drug to produce tolerance or of particular drug to produce tolerance or Tachyphylaxis as well as effects of age, sex , Tachyphylaxis as well as effects of age, sex , body size , diseases state and simultaneous body size , diseases state and simultaneous administration of other drugs.administration of other drugs.

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MechanismMechanism: which may contribute to variations in : which may contribute to variations in drug responsiveness among patients or among drug responsiveness among patients or among individual patient at different times.individual patient at different times.

A)A) Alteration in concentration of drug that reaches Alteration in concentration of drug that reaches receptor.receptor.

B)B) Variation in concentration of an endogenous Variation in concentration of an endogenous receptor ligand.receptor ligand.

C)C) Alteration in number and function of receptors Alteration in number and function of receptors

D)D) Changes in components of response distal to Changes in components of response distal to receptorreceptor

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A) Alteration in drug concentrationA) Alteration in drug concentration

A)A) Patient may differ in rate of absorption, Patient may differ in rate of absorption, distribution, and elimination of drug. By distribution, and elimination of drug. By alteration of concentration of drug that alteration of concentration of drug that reaches reaches relevant receptor may alter clinical relevant receptor may alter clinical response.response.

Some difference can be produced on the Some difference can be produced on the basis of basis of age, weight ,sex ,diseases state liver and kidney age, weight ,sex ,diseases state liver and kidney function, drug function, drug metabolizing enzymes.metabolizing enzymes.

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variability in response to pharmacologic variability in response to pharmacologic antagonistantagonist

e.g. Propranolol( e.g. Propranolol( ββ-blocker) will markedly slow the H.R of -blocker) will markedly slow the H.R of patient whose endogenous catecholamine are elevated patient whose endogenous catecholamine are elevated (pheochromocytoma ), but will not affect the resting H.R of (pheochromocytoma ), but will not affect the resting H.R of well trained marathon runner.well trained marathon runner.

..

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Alteration in number of receptorsAlteration in number of receptors

There occurs change in responsiveness caused by increase or There occurs change in responsiveness caused by increase or decrease in number of receptor sites or alteration in efficiency decrease in number of receptor sites or alteration in efficiency of coupling of receptor to distal effectors mechanism.of coupling of receptor to distal effectors mechanism.

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

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

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iii)iii) Receptor specific desensitization mechanism act Receptor specific desensitization mechanism act physiologically physiologically to allow cells to adopt to changes in rates of stimulation to allow cells to adopt to changes in rates of stimulation by hormones by hormones or neurotransmitters .or neurotransmitters .

These mechanisms contribute to tacyphylaxis or tolerance and These mechanisms contribute to tacyphylaxis or tolerance and over over shoot phenomena that follows with drawl of certain drugs .shoot phenomena that follows with drawl of certain drugs .

This may occur with agonist or antagonist This may occur with agonist or antagonist

Antagonists (up regulation) increase the number of receptorsAntagonists (up regulation) increase the number of receptorse.g. Propranolol e.g. Propranolol

Agonists (Down regulation) decrease the number of receptors.Agonists (Down regulation) decrease the number of receptors.This may be dangerous t o discontinue certain drugs. therefore This may be dangerous t o discontinue certain drugs. therefore

drugs drugs are to be with drawn slowlyare to be with drawn slowly

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..

Other factors which may cause variation Other factors which may cause variation in in responsiveness.responsiveness.

..

ageage

general health specially severity and pathologic mechanism of disease.general health specially severity and pathologic mechanism of disease.

Drug therapy always be most successful when it is accurately directed at Drug therapy always be most successful when it is accurately directed at pathophysiologic mechanism responsible for disease.pathophysiologic mechanism responsible for disease.

There may be no benefit due to compensatory mechansim There may be no benefit due to compensatory mechansim

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

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Adverse Drug reactionsAdverse Drug reactions

By. Dr. Abdul Latif MahesarBy. Dr. Abdul Latif Mahesar

Dept. of Medical PharmacologyDept. of Medical Pharmacology

King Saud UniversityKing Saud University

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The drugs prescribed for disease may The drugs prescribed for disease may themselves be the cause of diseases( adverse themselves be the cause of diseases( adverse reactions) This may range from mere reactions) This may range from mere inconvenience to permanent disability to and inconvenience to permanent disability to and death.death.

such as such as NauseaNausea and vomiting with any of the drug and vomiting with any of the drug DeafnessDeafness with aminoglycosides with aminoglycosides DeathDeath with penicillin's with penicillin's

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How much diseases they cause and why they cause ? How much diseases they cause and why they cause ? So that preventive measures can be So that preventive measures can be taken.taken.

Which adverse effects are avoidable and which are Which adverse effects are avoidable and which are not ?not ?

Some patients with history of allergy to drugs, are up Some patients with history of allergy to drugs, are up to 4 times more likely to have another adverse to 4 times more likely to have another adverse reaction.reaction.

It is also useful to discover the cause of adverse It is also useful to discover the cause of adverse

reaction ,so that ,that can be avoided.reaction ,so that ,that can be avoided.

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Side effects:Side effects: many unwanted effects , are many unwanted effects , are medically minor and need not to stop the drug, medically minor and need not to stop the drug, called side effects.called side effects.

Adverse reactions:Adverse reactions: harmful or seriously harmful or seriously unpleasant effects occurring at therapeutic unpleasant effects occurring at therapeutic doses and which call for reduction of dose or doses and which call for reduction of dose or withdrawal of the drug and /or forecast withdrawal of the drug and /or forecast hazards from future administration. hazards from future administration.

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Toxicity:Toxicity: Direct action of the drug, often at high dose Direct action of the drug, often at high dose , damaging cell., damaging cell.e.g.e.g. liver damage from paracetamol over dose, liver damage from paracetamol over dose,

88thth cranial nerve damage from gentamicin . cranial nerve damage from gentamicin .

All the drugs are said to be toxic in over doseAll the drugs are said to be toxic in over dose

Some times drugs in ordinary dose may become Some times drugs in ordinary dose may become toxic due to under lying abnormality in patient toxic due to under lying abnormality in patient

e.g.e.g. in renal impairments in renal impairments

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Classification Classification Type “A”Type “A” OR Type “1” OR Type “1” Generally these are excessive therapeutic effectsGenerally these are excessive therapeutic effects 75% of all adverse reactions.75% of all adverse reactions. they can occur in every onethey can occur in every one they are commonthey are common they are predictablethey are predictable they are dose dependentthey are dose dependent skill management can reduce their incidenceskill management can reduce their incidence they are mostly part of normal pharmacology of drug.they are mostly part of normal pharmacology of drug.

e.g. Hypoglycemia Insuline.g. Hypoglycemia Insulin Hypotension PropranololHypotension Propranolol

Bleeding warfarinBleeding warfarin

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There may be adverse effects unrelated to There may be adverse effects unrelated to main pharmacological actions of drugs main pharmacological actions of drugs belonging to this group but these are not belonging to this group but these are not serious and reversible.serious and reversible.

e.g Morphine ( an opioid analgesic) causes constipation e.g Morphine ( an opioid analgesic) causes constipation during its use as analgesic.during its use as analgesic.

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These adverse effects may beThese adverse effects may be irreversibleirreversible like paracetamol hepatotoxicity like paracetamol hepatotoxicity

aminoglyside 8aminoglyside 8thth cranial nerve damage cranial nerve damage

Or Or ReversibleReversible like morphine poisoning reversed by administration like morphine poisoning reversed by administration

of Naloxone.of Naloxone.

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Type “B”Type “B” ( Bizarre) like ( Bizarre) like Hypersensitivity and Idiosyncrasy.Hypersensitivity and Idiosyncrasy.

they are less than 25% of adverse effectsthey are less than 25% of adverse effects

only occur in some people ( only in minority of patients)only occur in some people ( only in minority of patients)

not a part of normal pharmacology of drugnot a part of normal pharmacology of drug

can not be predicted.can not be predicted.

non dose relatednon dose related

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Adverse effects may be Adverse effects may be unrelated to normalunrelated to normal pharmacologypharmacology of the drug. of the drug.

As paracetamol hepatotoxicityAs paracetamol hepatotoxicity Aspirin induced tinitusAspirin induced tinitus Thalidomide induced phaecomeliaThalidomide induced phaecomelia Primaquine induced haemolysis. Primaquine induced haemolysis.

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These are due to unusual attributes of patient These are due to unusual attributes of patient interacting with drug.interacting with drug.

These may be inherited abnormalities These may be inherited abnormalities

( idiosyncrasy ) and immunological process ( idiosyncrasy ) and immunological process (drug allergy) (drug allergy)

These accounts for most drug fatalities.These accounts for most drug fatalities.

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Type “C”(Type “C”( continuous) due to long term continuous) due to long term use use of drugsof drugs

e.g. analgesic nephropathye.g. analgesic nephropathy

Type”DType”D” (delayed) ” (delayed) e.g. teratogenesis , thalidomide causing e.g. teratogenesis , thalidomide causing

phecomelia phecomelia carcinogenesis ,stilboestrol cause carcinogenesis ,stilboestrol cause

adenocarcinoma of vagina in female offspring.adenocarcinoma of vagina in female offspring.

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Type “EType “E”( ending of use) where discontinuous ”( ending of use) where discontinuous is too abrupt.is too abrupt.

e.g. Rebound adrenal insufficiency.e.g. Rebound adrenal insufficiency.

over shoot of blood pressure due to propranolol over shoot of blood pressure due to propranolol withdrawal. withdrawal.

Note :Note : some authors include Type C,D&E as some authors include Type C,D&E as type “B”type “B”