Pharmacodynamics 2: Receptor Theory PDF

Pharmacodynamics 2: Receptor Theory Robert Sims HA209 [email protected]  Lecture Structure Receptor theory Concentration-effect / Dose-response curves; affinity, efficacy Agonists, antagonists, allosteric modulators Therapeutic range and therapeutic index ...

Pharmacodynamics 2: Receptor Theory Robert Sims HA209 [email protected]  Lecture Structure Receptor theory Concentration-effect / Dose-response curves; affinity, efficacy Agonists, antagonists, allosteric modulators Therapeutic range and therapeutic index  The concept of receptors Receptor theory probably the main scientific theory of pharmacology Term “receptor” from Ehrlich; “side chain” chemical binding theory from immunology Langley (1878, 1905): chemical binding theory for all drugs Developed later by others, e.g. Clark & Gaddum (1920s-1930s); models of receptor actions predated discovery of receptors Firmly established by Sir James Black (1965; propranolol)  “Target” / “Receptor” “Drug receptor” is sometimes used to describe anything a drug interacts with to cause an effect… …these days, the term “drug target” is preferable instead. Better to use “receptor” only to mean proteins that recognise and respond to endogenous signalling mediators However, drug-receptor interactions key to understanding pharmacology  Binding sites Receptors have an active (“orthosteric”) binding site for their endogenous, activating ligand (agonist) Binding sites have high specificity to endogenous agonists Ligand binding induces conformational changes to activate receptor May also contain secondary (“allosteric”) binding sites for other ligands Binding site of the muscarinic acetylcholine receptor  Affinity & efficacy Ligand-receptor Ligand Receptor complex A + R A R AFFINITY: EFFICACY: The ability of a ligand to The ability of a ligand to bind to a target generate an effect Together, affinity and efficacy determine potency; i.e. the ability of a ligand to generate a response  Dose – response relationships Effect / Response (%) 100 100 Effect / Response (%) 50 50 x-axis in logarithmic scale 0 0 [Ligand] Log10 [Ligand] Concentration-effect curve when measuring effect of drug at target site Dose-response curve when measuring the physiological response to a systemically administered drug  D-R curves – affinity and efficacy 100 A B Ligand B has the same Effect / Response (%) efficacy as ligand A, but a lower affinity 50 C Ligand C has the same affinity as ligand A, but a lower efficacy 0 log10[Ligand]  EC50 & Potency Emax Emax maximal effect 100 EC50: the concentration at which Effect / Response (%) the effect is half maximal 50 Potency is the concentration of drug required to cause an effect; measured by EC50. EC50 (IC50 when measuring potency in 0 log10[Ligand] terms of response reduction.)  Full & partial agonists Full agonists: induce a maximal response (100% of the endogenous agonist) Agonist A + R A R Partial agonists: induce a submaximal response (