1 Variations in Drug responsiveness By Dr.Abdul latif mahesar

2 When a drug is administered usually there is normal predicted response When a drug is administered usually there is normal predicted responseOR there may be there may be reduced response reduced response increased response OR increased response OR altered response altered 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 drug at different times. Even a single individual may respond differently to the same drug at different times.

3 Variations (changed response ) Tolerance Tachyphylaxis Drug resistance Hypersensitivity reactions (intolerance) Desensitization Anaphylactic reaction Idiosyncrasy

4 Tolerance It 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 to a) step down regulation of receptors b) exhaustion of the mediator c) increased metabolic degradation d) physiologic adaptation e) active extrusion of drug from cells

5 Tachyphylaxis Tachyphylaxis It is rapid decrease in response to a repeated administration of a drug Its onset is rapid Original effect cannot be obtained even with larger doses of drug e.g. Exhaustion of epinephrine by ephedrine.

6 Drug resistance Drug resistance It is a complete loss of effectiveness of a drug. e.g. antimicrobial drugs

7 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)

8 Anaphylaxis: Anaphylaxis: It is immediate hypersensitivity reaction on exposure to specific antigen or hapten leading to life threatening respiratory distress followed by vascular collapse. It is immediate hypersensitivity reaction on exposure to specific antigen or hapten leading to life threatening respiratory distress followed by vascular collapse. e.g. Penicillin e.g. Penicillin

9 Idiosyncratic reactions It is an inherent qualitative abnormal reaction It 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 change It is due to genetic change It is usually harmful. It is usually harmful. occurs in small proportion of populations occurs in small proportion of populations e.g. chlormaphenicol causes aplastic anemia e.g. chlormaphenicol causes aplastic anemia 1 in 50, 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 carbamzepine. hepatic porphyria ( abnormal haem synthesis) caused by carbamzepine. Malignant hyperthermia caused by suxamethonium and inhalational anesthetics. Malignant hyperthermia caused by suxamethonium and inhalational anesthetics.

10 Keeping this responsiveness of individual drug, there should be change of the drug or dose. Keeping this responsiveness of individual drug, there should be change of the drug or dose. These includes propensity( particular behavior ) of particular drug to produce tolerance or Tachyphylaxis as well as effects of age, sex, body size, diseases state and simultaneous administration of other drugs. These includes propensity( particular behavior ) of particular drug to produce tolerance or Tachyphylaxis as well as effects of age, sex, body size, diseases state and simultaneous administration of other drugs.

11 Mechanism: which may contribute to variations in drug responsiveness among patients or among individual patient at different times. Mechanism: which may contribute to variations in drug responsiveness among patients or among individual patient at different times. A) Alteration in concentration of drug that reaches receptor. B) Variation in concentration of an endogenous receptor ligand. B) Variation in concentration of an endogenous receptor ligand. C) Alteration in number and function of receptors C) Alteration in number and function of receptors D) Changes in components of response distal to receptor D) Changes in components of response distal to receptor

12 A) Alteration in drug concentration A)Patient may differ in rate of absorption, distribution, and elimination of drug. By alteration of concentration of drug that reaches relevant receptor may alter clinical response. A)Patient may differ in rate of absorption, distribution, and elimination of drug. By alteration of concentration of drug that reaches relevant receptor may alter clinical response. Some difference can be produced on the basis of age, weight,sex,diseases state liver and kidney function, drug metabolizing enzymes. Some difference can be produced on the basis of age, weight,sex,diseases state liver and kidney function, drug metabolizing enzymes.

13 variability in response to pharmacologic antagonist variability in response to pharmacologic antagonist e.g. Propranolol( β-blocker) will markedly slow the H.R of patient whose endogenous catecholamine are elevated (pheochromocytoma ), but will not affect the resting H.R of well trained marathon runner..

14 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. 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 hormones e.g. 1) Receptors for hormones Thyroid 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. ii) Agonist ligand induces a decrease in number( down regulation) or coupling efficiency of its receptors. e.g Albuterol

15 iii) Receptor specific desensitization mechanism act physiologically to allow cells to adopt to changes in rates of stimulation by hormones or neurotransmitters. iii) Receptor specific desensitization mechanism act physiologically to allow cells to adopt to changes in rates of stimulation by hormones or neurotransmitters. These mechanisms contribute to tacyphylaxis or tolerance and over shoot phenomena that follows with drawl of certain drugs. This may occur with agonist or antagonist Antagonists (up regulation) increase the number of receptors Antagonists (up regulation) increase the number of receptors e.g. Propranolol Agonists (Down regulation) decrease the number of receptors. This may be dangerous t o discontinue certain drugs. therefore drugs are to be with drawn slowly

16. Other factors which may cause variation in responsiveness.. age age 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 pathophysiologic mechanism responsible for disease. Drug therapy always be most successful when it is accurately directed at 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 sodium retention by kidneys. e.g. Vasodilator drug for hypertension leads to reflex tachycardia and sodium retention by kidneys.

17 Adverse Drug reactions By. Dr. Abdul Latif Mahesar Dept. of Medical Pharmacology King Saud University

18 The drugs prescribed for disease may themselves be the cause of diseases( adverse reactions) This may range from mere inconvenience to permanent disability to and death. The drugs prescribed for disease may themselves be the cause of diseases( adverse reactions) This may range from mere inconvenience to permanent disability to and death. such as such as Nausea and vomiting with any of the drug Nausea and vomiting with any of the drug Deafness with aminoglycosides Deafness with aminoglycosides Death with penicillin's Death with penicillin's

19 How much diseases they cause and why they cause ? How much diseases they cause and why they cause ? So that preventive measures can be taken. Which adverse effects are avoidable and which are not ? Which adverse effects are avoidable and which are not ? Some patients with history of allergy to drugs, are up to 4 times more likely to have another adverse reaction. Some patients with history of allergy to drugs, are up to 4 times more likely to have another adverse reaction. It is also useful to discover the cause of adverse reaction,so that,that can be avoided. It is also useful to discover the cause of adverse reaction,so that,that can be avoided.

20 Side effects: many unwanted effects, are medically minor and need not to stop the drug, called side effects. Side effects: many unwanted effects, are medically minor and need not to stop the drug, called side effects. Adverse reactions: harmful or seriously unpleasant effects occurring at therapeutic doses and which call for reduction of dose or withdrawal of the drug and /or forecast hazards from future administration. Adverse reactions: harmful or seriously unpleasant effects occurring at therapeutic doses and which call for reduction of dose or withdrawal of the drug and /or forecast hazards from future administration.

21 Toxicity: Direct action of the drug, often at high dose, damaging cell. Toxicity: Direct action of the drug, often at high dose, damaging cell. e.g. liver damage from paracetamol over dose, 8 th cranial nerve damage from gentamicin. 8 th cranial nerve damage from gentamicin. All the drugs are said to be toxic in over dose Some times drugs in ordinary dose may become toxic due to under lying abnormality in patient e.g. in renal impairments e.g. in renal impairments

22 Classification Type “A” OR Type “1” Type “A” OR Type “1” Generally these are excessive therapeutic effects Generally these are excessive therapeutic effects 75% of all adverse reactions. 75% of all adverse reactions. they can occur in every one they can occur in every one they are common they are common they are predictable they are predictable they are dose dependent they are dose dependent skill management can reduce their incidence skill 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 Insulin Hypotension Propranolol Hypotension Propranolol Bleeding warfarin

23 There may be adverse effects unrelated to main pharmacological actions of drugs belonging to this group but these are not serious and reversible. There may be adverse effects unrelated to main pharmacological actions of drugs belonging to this group but these are not serious and reversible. e.g Morphine ( an opioid analgesic) causes constipation during its use as analgesic. e.g Morphine ( an opioid analgesic) causes constipation during its use as analgesic.

24 These adverse effects may be These adverse effects may be irreversible irreversible like paracetamol hepatotoxicity like paracetamol hepatotoxicity aminoglyside 8 th cranial nerve damage Or Reversible Reversible like morphine poisoning reversed by administration of Naloxone. like morphine poisoning reversed by administration of Naloxone.

25 Type “B” ( Bizarre) like Type “B” ( Bizarre) like Hypersensitivity and Idiosyncrasy. Hypersensitivity and Idiosyncrasy. they are less than 25% of adverse effects they 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 drug not a part of normal pharmacology of drug can not be predicted. can not be predicted. non dose related non dose related

26 Adverse effects may be unrelated to normal pharmacology of the drug. Adverse effects may be unrelated to normal pharmacology of the drug. As paracetamol hepatotoxicity As paracetamol hepatotoxicity Aspirin induced tinitus Aspirin induced tinitus Thalidomide induced phaecomelia Thalidomide induced phaecomelia Primaquine induced haemolysis. Primaquine induced haemolysis.

27 These are due to unusual attributes of patient interacting with drug. These are due to unusual attributes of patient interacting with drug. These may be inherited abnormalities These may be inherited abnormalities ( idiosyncrasy ) and immunological process (drug allergy) ( idiosyncrasy ) and immunological process (drug allergy) These accounts for most drug fatalities. These accounts for most drug fatalities.

28 Type “C”( continuous) due to long term use of drugs Type “C”( continuous) due to long term use of drugs e.g. analgesic nephropathy Type”D” (delayed) Type”D” (delayed) e.g. teratogenesis, thalidomide causing phecomelia carcinogenesis,stilboestrol cause adenocarcinoma of vagina in female offspring. carcinogenesis,stilboestrol cause adenocarcinoma of vagina in female offspring.

29 Type “E”( ending of use) where discontinuous is too abrupt. Type “E”( ending of use) where discontinuous is too abrupt. e.g. Rebound adrenal insufficiency. over shoot of blood pressure due to propranolol withdrawal. over shoot of blood pressure due to propranolol withdrawal. Note : some authors include Type C,D&E as type “B”