Drug-Receptor Concepts 3 (2024-2025) PDF

WEEK 13 MPharm Programme Drug-Receptor Concepts 3 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA115 Drug Receptor Concepts WEEK 13 Drug-Drug...

WEEK 13 MPharm Programme Drug-Receptor Concepts 3 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA115 Drug Receptor Concepts WEEK 13 Drug-Drug Interactions Slide 44 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Drug-Drug Interactions Drug Antagonism Summation / Additivity Synergism / Potentiation Slide 45 of 76 MPharm PHA115 Drug Receptor Concepts  Drug-Drug Interactions WEEK 13 Drug Antagonism ‘interaction between two drugs such that the effect of one is diminished or completely abolished in the presence of the other’ Types of drug antagonism Competitive antagonism (pharmacological / receptor) Non-competitive antagonism Chemical antagonism Pharmacokinetic antagonism Physiological or Functional antagonism Slide 46 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Drug Antagonism Competitive Antagonism the agonist & antagonist drugs compete for same receptor binding site antagonist drug binding reduces chances of agonist binding   agonist effect 2 subtypes, depending on nature of antagonist- receptor interaction Reversible or surmountable Irreversible or insurmountable Slide 47 of 76 MPharm PHA115 Drug Receptor Concepts  Competitive Antagonism WEEK 13 Reversible Competitive Antagonism both the agonist & antagonist drugs bind reversibly to the receptor the fraction of receptors occupied depends on 2 drugs’ relative receptor affinities & concentrations antagonism can be overcome by increasing concentration of agonist drug this leads to two effects on the agonist log D-R curve (in the presence of an effective dose of the antagonist drug) a parallel shift to the right no reduction in the maximal response Slide 48 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Competitive Antagonism 100 50 E Emax 0 Agonist Concentration Slide 49 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Competitive Antagonism Irreversible Competitive Antagonism the antagonist drug binds irreversibly to the receptor (due to high affinity or covalent bonding) a fraction of receptors rendered permanently unavailable for agonist drug binding the antagonism cannot be overcome by increasing the concentration of the agonist drug this leads to two effects on the agonist log D-R curve (in the presence of an effective dose of the antagonist drug) a reduction in the slope of the curve a reduction in the maximal response Slide 50 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Irreversible Competitive Antagonism System Without Spare Receptors 100 E 50 Emax 0 Log Agonist Concentration Slide 51 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Irreversible Competitive Antagonism System with Spare Receptors 100 Irreversible Antagonist Log Agonist Concentration Slide 52 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Drug Antagonism Non-competitive Antagonism the antagonist drug does not compete with agonist drug for same receptor binding site the antagonist drug may bind to a different site on the receptor or interfere with response coupling the antagonism cannot be overcome by increasing concentration of agonist drug this leads to two effects on the agonist log D-R curve (in the presence of an effective dose of the antagonist drug) a reduction in the slope of the curve a reduction in maximal response Slide 53 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Non-competitive Antagonism 100 E 50 Emax 0 Log Agonist Concentration Slide 54 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Drug Antagonism Chemical Antagonism results from direct interaction between the antagonist & agonist drugs the ‘antagonist’ drug binds to / combines with the active drug (‘agonist’) in solution the active drug is rendered inactive or unavailable to interact with its target receptors typical examples protamine vs heparin dimercaprol vs heavy metals (Hg, Cu, Pb) Slide 55 of 76 MPharm PHA115 Drug Receptor Concepts  Drug Antagonism WEEK 13 Pharmacokinetic Antagonism the ‘antagonist’ drug acts to reduce the effective concentration of the active drug (‘agonist’) at its site of action possible mechanisms reduced absorption from the GIT ferrous salts vs tetracycline antibiotics increased metabolic degradation phenobarbital vs warfarin increased renal excretion NaHCO3 vs aspirin Slide 56 of 76 MPharm PHA115 Drug Receptor Concepts  Drug Antagonism WEEK 13 Physiological / Functional Antagonism interaction of two opposing agonist effects in a single biological system  cancelling out of each other’s effect the two drugs elicit opposing responses by acting on different receptors typical examples acetylcholine vs noradrenaline (heart rate) glucocorticoids vs insulin (blood sugar levels) Slide 57 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Summation / Additivity Summation When the combined effect of two drugs which elicit the same overt response, regardless of their mechanism of action, is equal to the algebraic sum of their individual effects Additivity When the combined effect of two drugs, which act by the same mechanism, is equal to that expected by simple addition of their individual effects Slide 58 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Synergism / Potentiation Synergism or Potentiation When the conjoint effect of two drugs is greater than the algebraic sum of their individual effects the synergist may act to increase the concentration of the other drug at its receptor sites tyramine & MAO inhibitors increase the responsiveness of the other drug’s receptor-effector protein benzodiazepines & GABA (GABAA receptor) Slide 59 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Synergism / Potentiation GABAA Receptor Ion channel Slide 60 of 76 MPharm PHA115 Drug Receptor Concepts  Synergism / Potentiation WEEK 13 Potentiation By Benzodiazepines Slide 61 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 MPharm Programme Drug-Receptor Concepts 4 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA115 Drug Receptor Concepts WEEK 13 Variation in Drug Responsiveness Slide 63 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Variation in Drug Responsiveness Definitions, Types & Mechanisms Drug Tolerance Definitions Mechanisms Slide 64 of 76 MPharm PHA115 Drug Receptor Concepts  Variation in Drug Responsiveness WEEK 13 Scope inter-patient variation intra-patient variation Possible consequences lack of efficacy unexpected side effects Possible mechanisms pharmacokinetic pharmacodynamic Slide 65 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 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 PHA115 Drug Receptor Concepts  Acquired Tolerance WEEK 13 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 PHA115 Drug Receptor Concepts WEEK 13 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 PHA115 Drug Receptor Concepts WEEK 13 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 PHA115 Drug Receptor Concepts WEEK 13 Clinical Selectivity Slide 70 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 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 PHA115 Drug Receptor Concepts WEEK 13 Clinical Selectivity 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 PHA115 Drug Receptor Concepts WEEK 13 Clinical Selectivity 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 PHA115 Drug Receptor Concepts WEEK 13 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 PHA115 Drug Receptor Concepts WEEK 13 Concept of Therapeutic Index Slide 75 of 76 MPharm PHA115 Drug Receptor Concepts WEEK 13 Recommended Reading Katzung BG, Vanderah TW. Basic & Clinical Pharmacology, 16th Edition. New York: McGraw-Hill, 2024. ISBN: 978-1260463309. Ritter JM et al. Rang & Dale’s Pharmacology, 10th Edition. London: Elsevier, 2023. ISBN: 978-0323873956. Slide 76 of 76 MPharm PHA115 Drug Receptor Concepts