Drug-Receptor Concepts 4 (2023-24) PDF

WEEK 12 MPharm Programme Drug-Receptor Concepts 4 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Drug Receptor Concepts WEEK 12 Slide 63 of 76 Variation in Drug Responsiveness MPharm PHA112 Drug Receptor Concepts WEEK 12 Variation in Drug R...

WEEK 12 MPharm Programme Drug-Receptor Concepts 4 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Drug Receptor Concepts WEEK 12 Slide 63 of 76 Variation in Drug Responsiveness MPharm PHA112 Drug Receptor Concepts WEEK 12 Variation in Drug Responsiveness Definitions, Types & Mechanisms Drug Tolerance Definitions Mechanisms Slide 64 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Variation in Drug Responsiveness Scope inter-patient variation intra-patient variation Possible consequences lack of efficacy unexpected side effects Possible mechanisms pharmacokinetic pharmacodynamic Slide 65 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Variation in Drug Responsiveness Possible types of variation qualitative variations quantitative variations Quantitative variations Hyper-responsiveness Hypo-responsiveness or tolerance Tolerance Innate vs acquired tolerance Tolerance vs Tachyphylaxis Slide 66 of 76 MPharm PHA112 Drug Receptor Concepts Acquired Tolerance WEEK 12 Definitions ‘An acquired state of progressively decreasing responsiveness to a drug as a result of prior or repeated exposure to the drug or another drug with a similar action’ Mechanisms Pharmacodynamic Metabolic Exhaustion / Depletion of mediators Physiological adaptation Slide 67 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Mechanisms of Acquired Tolerance Pharmacodynamic Receptor ‘down-regulation’ reduction in receptor density e.g. 1-adrenergic receptor Receptor ‘uncoupling’ uncoupling of receptors from their effector systems e.g. 2-adrenergic receptor Metabolic enhanced metabolism of the drug due to induction of metabolising enzymes e.g. alcohol, barbiturates, etc Slide 68 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Mechanisms of Acquired Tolerance Exhaustion / Depletion of mediators common with indirectly-acting drugs due to depletion of endogenous stores of mediators of the drug’s action Amphetamine, nitrates Physiological adaptation evoked compensatory or homeostatic mechanisms blunts or cancels the drug’s effects Diuretics, nitrates Slide 69 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Clinical Selectivity Slide 70 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Clinical Selectivity Absolute vs Relative Selectivity Therapeutic or Desirable effects vs Adverse or Undesirable or Side effects Concept of Therapeutic Index Slide 71 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Clinical Selectivity 12 Absolute vs Relative Selectivity no drug has only one single, specific effect drugs produce a spectrum of effects hence ‘relative’, not ‘absolute’, selectivity of drug action relative selectivity ‘the degree to which a drug acts upon a given site relative to all possible sites of interaction’ Slide 72 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Clinical Selectivity 12 Therapeutic vs Undesirable / Side effects drug effects split into therapeutic & undesirable undesirable effects may be minor or serious how do undesirable effects come about? both effects may be mediated via same receptor-effector mechanism – e.g. nitrates, insulin, warfarin both effects may be mediated via identical receptors located in different tissues – e.g. haloperidol, verapamil both effects may be mediated via different types of receptors – e.g. salbutamol, propranolol Slide 73 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Concept of Therapeutic Index Therapeutic Index Determined by the ratio of toxic to therapeutic dose median toxic dose (TD50) Therapeutic Index = median effective dose (ED50) Provides a useful measure of the margin of safety of the drug the benefit to risk ratio of the drug e.g. penicillin vs warfarin Slide 74 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 12 Slide 75 of 76 Concept of Therapeutic Index MPharm PHA112 Drug Receptor Concepts WEEK Recommended Reading 12 Katzung BG, Trevor AJ. Basic & Clinical Pharmacology, 15th Edition. New York: McGraw-Hill Education, 2021. ISBN: 978-1260452310. Ritter JM et al. Rang & Dale’s Pharmacology, 10th Edition. London: Elsevier, 2023. ISBN: 978-0323873956. Slide 76 of 76 MPharm PHA112 Drug Receptor Concepts