Pharmacodynamics 2: Receptor Theory PDF

Pharmacodynamics 2: Receptor Theory Robert Sims HA209 [email protected] Lecture Objectives Receptor theory Concentration-effect / Dose-response curves Affinity, efficacy, potency Different types of receptor activity: agonists, antagonists, allosteric modula...

Pharmacodynamics 2: Receptor Theory Robert Sims HA209 [email protected] Lecture Objectives Receptor theory Concentration-effect / Dose-response curves Affinity, efficacy, potency Different types of receptor activity: 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 the receptor May also contain secondary (“allosteric”) binding sites Binding site of the muscarinic for other ligands acetylcholine receptor Dose-response relationships Key concept of pharmacology to measure the effect of a drug More drug = more effect “Concentration-effect” if measuring effect of drug at target site “Dose-response curve” when measuring the response to a systemically administered drug Can measure many different types of response: Cellular (e.g. intracellular calcium concentration) Physiological (e.g. blood pressure) Subjective (e.g. pain) Population (e.g. fatality rate) Units Square brackets around a name indicates concentration of that substance: e.g. [aspirin] = the concentration of aspirin Scientific concentration is usually measured in molarity (M, or moles/litre) In medicine, often don’t know drug concentration at site of action: Units of drug (e.g. milligrams) per kilogram of body weight (mg/kg) Doses will just be in units such as milligrams (mg), millilitres (ml), etc.  Constructing D-R curves Dose 100 0 1 Response (%) 3 10 50 30 100 300 Example of organ bath 1000 0 experimental setup; drug causes muscle tissue to Dose constrict; measure force via  Sigmoidal representations 10 10 0 0 Response (%) Response (%) 50 50 x-axis in logarithmic scale 0 0 Dose Log10 dose Dose 0 1 3 10 30 100 300 100 log[dose] 0 0.5 1 1.5 2 2.5 0 3 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  D-R curves – affinity & efficacy 100 Ligand B has the A B same efficacy as ligand A, but a lower Effect / Response affinity 50 C Ligand C has the same affinity as ligand A, but a lower (%) efficacy 0 log10[Ligand ]  EC50 & potency Emax: maximal effect Emax 100 EC50: the concentration at which the effect is half Effect / Response maximal Potency is the 50 concentration of drug required to cause an effect; (%) measured by EC50 EC50 0 Note that lower EC50 means log10[Ligan more potent d] Full & partial agonists Full agonists: induce a maximal response (100% of the endogenous agonist) when receptors saturated Agonist A + R A R Partial agonists: induce a submaximal response (