Foundations of Pharmacology PHAR2210 Introduction to Drug Action PDF

Foundations of Pharmacology PHAR2210 Introduction to Drug Action A/Prof Lynette Fernandes These lecture slides and associated unit materials are the intellectual property of A/Prof Lynette Fernandes and should not be shared without her permission. S...

Foundations of Pharmacology PHAR2210 Introduction to Drug Action A/Prof Lynette Fernandes These lecture slides and associated unit materials are the intellectual property of A/Prof Lynette Fernandes and should not be shared without her permission. Sharing course materials without permission breaches UWA’s student conduct regulations and may constitute a breach of the Copyright Act 1968.  Learning outcomes Describe a receptor Describe the relationship between agonist concentration and receptor occupancy Describe the relationship between agonist concentration and response Explain drug selectivity Explain agonism, partial agonism and antagonism in terms of drug affinity and efficacy Explain the differences between surmountable and insurmountable receptor antagonism Analyse concentration-response curves  Resources Pharmacology Education Project https://www.pharmacologyeducation.org/pharmacology/pharmacodynamics Interactive Clinical Pharmacology https://www.icp.org.nz/pharmacodynamics/linear-vs-log-graphs Selected figures on the LMS from Goodman and Gilman’s The Pharmacological Basis of Therapeutics 13th edition 2017 McGraw-Hill Education. Pharmacodynamics: Molecular Mechanisms of Drug Action. Chapter 3 Rang and Dale’s Pharmacology, 10th edition 2024, London Elsevier. How drugs act: General principles.  What is pharmacology? “the study of the effects of drugs on the function of living systems” (Rang and Dale’s Pharmacology, 2024) – chemical substances of known structure e.g., paracetamol, caffeine, morphine therapeutics desirable Pharmacodynamics drugs living systems Pharmacokinetics adverse effects undesirable  Pharmacokinetics - Pharmacodynamics Drug effects result from interaction between drug and (components of) the organism Pharmacokinetics describes the fate of a drug – absorption, distribution, metabolism, excretion – what the body does to a drug Pharmacodynamics is the study and measurement of drug effects – what a drug does to the body How do drugs produce their effects? – fundamental concepts in drug action indicated in “ ”  “A drug will not work unless it is bound” Paul Ehrlich (1854-1915), 1908 Nobel Prize Nobelprize.org Most drugs exert their effects by binding to protein targets 1. receptors 2. ion channels allows ion movement across cell membranes 3. enzymes catalyse biochemical reactions 4. transporters or carrier molecules ions and small organic molecules across cell membranes  “Most drugs cause their effects via receptors” Receptors are proteins that allow a chemical agent (drugs, hormones, neurotransmitters) to initiate a change in cell function Receptors are the cell’s ‘sensing elements’ Receptors provide molecular communication between chemical agent and transduction process “Most drugs cause their effects via receptors” cell signal chemical transduction change in receptor agent cell function (e.g., drug, hormone, neurotransmitter) cardiac cell: adrenaline b-adrenoceptor increased contractility “Different cell types have different receptor profiles” cardiac cell vascular smooth noradrenaline muscle cell acetylcholine High densities of muscarinic acetylcholine receptors High densities of a-adrenoceptors respond to substances that act on respond to substances that act on muscarinic acetylcholine receptors a-adrenoceptors e.g., noradrenaline e.g., acetylcholine Different cell types express different types and densities of receptor. This determines the hormones and neurotransmitters to which the cell responds  “Drugs can mimic or block the actions of endogenous substances” Agonists and antagonists are ligands and bind to the receptor Agonists mimic the actions of endogenous ligands Antagonists block the actions of endogenous ligands Agonist Antagonist endogenous receptor change in ligand/agonist cell function e.g., noradrenaline a-adrenoceptor vascular smooth muscle cell contracts  “Receptors show ligand selectivity” Each receptor type is activated by a small number of substances Receptor activation requires a good 3-D “fit” between agonist and receptor a-adrenoceptors vascular smooth phenylephrine muscle cell paracetamol  “Useful drugs show selectivity” Selectivity is reciprocal – each drug only binds to certain receptors – each receptor recognises only certain drugs Phenylephrine – binds to a-adrenoceptors in vascular smooth muscle cells – relieves nasal congestion – binds only weakly to other receptor types fewer adverse effects phenylephrine vascular smooth vascular smooth muscle cell muscle cell vasoconstriction  “Selectivity is not absolute” Most drugs act on more than one receptor Increasing dose activates other receptors – adverse effects muscarinic acetylcholine histamine receptors receptors salivary vascular smooth diphenhydramine gland cell muscle cell dry mouth  decongestant   Drug-induced responses Drugs act by binding to specific drug targets Agonists bind to and activate receptors A + R A R A R + T A = agonist R = receptor T = transducer A R T response  “Agonists bind to and activate receptors” Agonist binding requires intermolecular forces between agonist and receptor – van der Waals forces, hydrogen bonding Agonist binding is usually reversible forward rate constant, k+1 A + R A R backward rate constant, k-1 If forces of attraction are strong (k+1 >> k-1), agonist has high affinity for the receptor If forces of attraction are weak (k +1