Drug-Receptor Concepts 2 (2023-24) PDF

WEEK 11 MPharm Programme Drug-Receptor Concepts 2 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug-Receptor Interactions What happens when a drug binds to its receptor? Slide 24 of 76 MPharm PHA112 Drug Recept...

WEEK 11 MPharm Programme Drug-Receptor Concepts 2 Dr G Boachie-Ansah [email protected] Dale 113 ext. 2617 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug-Receptor Interactions What happens when a drug binds to its receptor? Slide 24 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Consequences of Drug-Receptor Interaction One of four possible things can happen The drug may mimic a natural, endogenous chemical messenger  produce the same effect as the natural chemical messenger (called an ‘Agonist’ drug) The drug may ‘block’ the receptor, i.e. prevent the natural chemical messenger from binding  produce no effect (called an ‘Antagonist’ drug) Slide 25 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Consequences of Drug-Receptor Interaction One of four possible things can happen (cont’d) The drug may bind to a site near the binding site for a natural, endogenous chemical messenger & influence its binding   or  the effect of the natural chemical messenger (called an ‘Allosteric modulator’) The drug may bind to the site normally occupied by a natural, endogenous chemical messenger  produce an opposite effect to the natural chemical messenger (called an ‘Inverse Agonist’ drug) Slide 26 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Types of Drug-receptor Interaction Agonist Antagonist Positive Allosteric Modulator Negative Allosteric Modulator Slide 27 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug Agonism & Antagonism What is the basic distinction between ‘Agonist’ & ‘Antagonist’ drugs? Both have ‘affinity’ for their receptors ‘a measure of the ease with which a drug binds to its receptor’ ‘a measure of the probability that a drug molecule will interact with a receptor to form a drug-receptor complex’ ‘Affinity’ expresses the chances of the drug binding to its receptor (By analogy, a key fitting into a lock) affinity is measured by the KD of the drug Affinity = 1/KD Slide 28 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug Agonism & Antagonism What is the basic distinction between ‘Agonist’ & ‘Antagonist’ drugs? Agonist drugs have ‘efficacy’, whereas antagonist drugs have no ‘efficacy’ ‘a measure of the ability of the drug-receptor complex to couple or transduce the drug binding into a biological response’ ‘Efficacy’ expresses the ability of the drug to ‘activate’ or cause a conformational change in the receptor that will lead to a biological response. (By analogy, the key turning the lock) ‘efficacy’ (e) may be 0, low or very high Slide 29 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Agonist Drug Action 11 Agonist ‘a drug that binds to its receptor, activates the receptor, and elicits a biological response’ Two types of Agonist Full agonist Partial agonist Slide 30 of 76 MPharm PHA112 Drug Receptor Concepts Agonist Drug Action WEEK 11 Full Agonist binds to its receptor, activates the receptor & is capable of eliciting the maximum possible response has high efficacy (e) e.g. dobutamine, salbutamol Partial Agonist binds to its receptor and activates the receptor, but can only elicit less than the maximum possible response intermediate efficacy (e) reduces the response elicited by the full agonist e.g. buprenorphine, oxymetazoline Slide 31 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Slide 32 of 76 Full vs Partial Agonist MPharm PHA112 Drug Receptor Concepts Antagonist Drug Action WEEK 11 Antagonist (pharmacological) ‘a drug that binds to its receptor but fails to activate the receptor, and so fails to elicit a response’ it has an efficacy (e) of 0 it competes with the agonist drug (or natural chemical messenger) for binding to the receptor its biological ‘effect’ results from preventing the agonist drug (or natural chemical messenger) from binding to its receptor e.g. atenolol, chlorphenamine, naloxone Slide 33 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Drug-Receptor Interactions 11 The 'Spare Receptor' / 'Receptor Reserve' concept exceptions to the ‘receptor occupancy theory’ full agonists may elicit maximum response without full receptor occupancy system is said to have ‘spare receptors’ or a ‘receptor reserve’ enables economy of hormone / transmitter secretion allows low affinity drugs to elicit maximum possible response Slide 34 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Drug-Receptor Interactions Characteristics of the Graded Dose-Response Curve Slide 35 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Intensity of Effect 11 Log Drug Concentration Slide 36 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Characteristics of the Graded Dose-Response Curve 11 Potency A measure of amount of drug needed to elicit a specified response reflected in the location of D-R curve along dose axis experimentally expressed as ED50 or EC50 clinically expressed as absolute or relative potency not a critical characteristic of the drug e.g. morphine vs diamorphine (heroin) Slide 37 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Potency 11 Slide 38 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Characteristics of the Graded Dose-Response Curve 11 Maximal efficacy maximal response / effect produced by the drug reflected as a plateau in the log D-R curve the most important characteristic of drug e.g. paracetamol vs morphine maximal efficacy may be determined or limited in clinical practice by the onset of adverse side effects! Slide 39 of 76 MPharm PHA112 Drug Receptor Concepts WEEK 11 Slide 40 of 76 Maximal Efficacy MPharm PHA112 Drug Receptor Concepts WEEK Characteristics of the Graded Dose-Response Curve 11 Slope slope of curve varies from drug to drug reflects the magnitude of change in response per unit change in dose the slope may be an important consideration in clinical practice under certain circumstances! Slide 41 of 76 MPharm PHA112 Drug Receptor Concepts WEEK Characteristics of the Graded Dose-Response Curve 11 Biological variability different responses to same dose of drug in different individuals different responses to same dose of drug in same individual possible sources of variation in drug response Age Gender Genetic factors Polypharmacy Pathological state Slide 42 of 76 MPharm PHA112 Drug Receptor Concepts