Pharmacy 201 Drug Receptor Theory (2024-5) PDF

Drug Receptor Theory Prof. Paul F. Grassby Pharmacy 201 (2024-5) 1  Revision – Year 1 What is Pharmacology? Targets for drugs Receptors Ligands – endogenous and exogenous – specificity and selectivity Basic Drug receptor theory – the bindin...

Drug Receptor Theory Prof. Paul F. Grassby Pharmacy 201 (2024-5) 1  Revision – Year 1 What is Pharmacology? Targets for drugs Receptors Ligands – endogenous and exogenous – specificity and selectivity Basic Drug receptor theory – the binding reaction Agonists and Antagonists Pharmacy 201 (2024-5) 2  Antagonists and the pA2 Antagonist potency Determination of antagonist potency pA2 and its importance Inverse agonists Quiz and homework Pharmacy 201 (2024-5) 3  Principal pharmacological protein targets target + - receptors agonists antagonists ion channels stimulator blocker enzymes enhancer inhibitor carrier molecules accelerator inhibitor Pharmacy 201 (2024-5) 4 “Receptors” Pharmacy 201 (2024-5) 5 Ligands Pharmacy 201 (2024-5) 6  Endogenous and exogenous ligands for receptors Endogenous (within) – neurotransmitters chemical messengers – hormones – autocoids (Local Hormones) Exogenous (outside) – drugs – poisons – toxins Pharmacy 201 (2024-5) 7  Types of receptors Ionotropic receptors – Fast ion channels with a central pore e.g. Nicotinic receptors for Acetylcholine Metabotropic receptors – 7 trans-membrane receptors – Coupled to a G protein – Indirectly acting via a cascade Kinase linked receptors Intracellular receptors – Within cytoplasm – When activated enter the nucleus Pharmacy 201 (2024-5) 8 Receptor occupancy theory (2 state model) Pharmacy 201 (2024-5) 9 © 2005 Elsevier An isolated tissue experiment add drug response Pharmacy 201 (2024-5) 10 Trace of smooth muscle contraction Drug 1 Drug 1 Drug 2 single doses Drug 2 Time cumulative doses smooth muscle contraction Pharmacy 201 (2024-5) 11  EC50 The effective concentration of AGONIST that results in a 50% of maximum tissue RESPONSE Pharmacy 201 (2024-5) 12 Full agonist concentration-response curves Emax A B C EC50 Pharmacy 201 (2024-5) 13 Partial agonists Some drugs, despite 100% receptor occupancy do not produce 100% reponse. = PARTIAL AGONISTS Some drugs despite 100% receptor occupancy produce no response. = ANTAGONISTS Pharmacy 201 (2024-5) 14  Occupancy vs response response drug a drug b Spare Receptors occupancy If both drugs have the same affinity for the receptor (same KA) Full agonist A only needs to occupy 20% of receptors “SPARE” RECEPTORS Pharmacy 201 (2024-5) 15  Current drug-receptor theory f = transducer function (translated into a response) ε = efficacy (produce a stimulus) Ntot total number of receptors KA = agonst dissociation constant (affinity) xA = agonist concentration Pharmacy 201 (2024-5) 16  Drug specificity vs selectivity Specificity is reciprocal – drugs high binding site specificity – receptors high degree of ligand specificity Influenced by small chemical changes – eg L or D form, removal of an amino acid Side effects – lower potency, higher dose, less specificity NO DRUG IS totally SPECIFIC DRUGS ARE SELECTIVE Pharmacy 201 (2024-5) 17 Antagonists Pharmacy 201 (2024-5) 18  Antagonists Receptor antagonism (competitive) – reversible – Irreversible Chemical antagonism Pharmacokinetic antagonism Non competitive antagonism Physiological (functional) antagonism Pharmacy 201 (2024-5) 19 Reversible competitive antagonism Selective Competes with endogenous or exogenous ligands Zero or limited efficacy – ISA Antagonism can be overcome by increasing agonist concentration = SURMOUNTABLE Concentration-response curve is shifted to the right – no depression in slope or maximum response Degree of shift in the concentration-response curve is the DOSE RATIO Dose ratio can be expressed as the ratio of EC50’s Pharmacy 201 (2024-5) 20 Receptor occupation occupied receptors free drug molecules Unoccupied receptors RESPONSE Pharmacy 201 (2024-5) 21  Determination of the Potency of a competitive Antagonist The antagonist COMPETES for the receptor site with the agonist. In the presence of the antagonist you will need more agonist to get the same receptor occupation/response than without the antagonist. Unlike an agonist, the potency of an antagonist is just due to its affinity for the receptor (It has zero efficacy) Pharmacy 201 (2024-5) 22  How can we determine the potency (affinity) of an antagonist Construct a concentration-response curve for an agonist Add a concentration of antagonist and in the presence of the antagonist construct a second concentration response curve. What will happen??? Pharmacy 201 (2024-5) 23  rightwards shift Q: why is there a parallel rightwards shift with no depression of the maximum response? Pharmacy 201 (2024-5) 24  Antagonist Affinity (KB) Remember KA is the measure of AGONIST affinity – Concentration of drug needed to occupy 50% of the available receptors KB is the concentration of an ANTAGONIST needed to occupy 50% of the receptors. Pharmacy 201 (2024-5) 25  Antagonist KB What will happen to the EC50 of an agonist if you “block” 50% of the available receptors. For the same response (EC50) you will need TWICE the concentration of agonist. The curve will move to the right two fold This is expressed as the DOSE RATIO = 2 DOSE RATIO = EC50 with antagonist/ EC50 without antagonist Pharmacy 201 (2024-5) 26  rightwards shift Pharmacy 201 (2024-5) 27  pA2 The (negative) log (p) of the concentration of antagonist (A) that causes a 2 fold shift in the concentration response curve (2) i.e. the concentration that blocks 50% of the receptors i.e. the negative log of the KB i.e. a measure of the affinity (potency) of an antagonist Pharmacy 201 (2024-5) 28  Determination of the pA2 Can guess a concentration that will result is a two fold shift – highly unlikely Carry out a series of experiments with different concentrations of antagonist If the antagonism is competitive, the relationship between the antagonist concentration and the shift will be linear (proportionate) Pharmacy 201 (2024-5) 29  Determination of the pA2 If you plot a graph of concentration of antagonist vs the dose ratio (shift) it will be a straight line. If you plot a graph of log antagonist vs log dose ratio it will be a straight line If you plot a graph of the log dose ratio -1 vs antagonist, log of 2-1 = log 1 = 0, so you can read off the pA2 Pharmacy 201 (2024-5) 30  Schild plot Remember – both are Log Scales Pharmacy 201 (2024-5) 31  Schild plot For a competitive antagonist: slope = 1 straight line abscissal intercept = log KB Pharmacy 201 (2024-5) 32 This can be expressed as an equation (Schild equation) [B] concentration of antagonist KB dissociation constant of antagonist Pharmacy 201 (2024-5) 33  Importance of the pA2 — Measure of antagonist affinity (= potency) — Independent of agonist used As efficacy not important in the — Independent of tissue used determination of — Independent of receptor density pA2 — Single receptor types have an identical pA2 value to an antagonist irrespective of tissue or response characteristics. Pharmacy 201 (2024-5) 34 Histamine agonists - relative potency (EC50) in vitro Drug H1-receptors H2-receptors H3-receptors (ileum contraction) (right atrial rate) (histamine release from CNS) Histamine 100 100 100 Dimaprit 3 x 10 -4 -6 -5 Cimetidine 4.5 X 10 0.8 x 10 3.3 x 10 Thioperamide >10-4 >10 -5 4.3 x 10 -9 Pharmacy 201 (2024-5) 37  British Journal of Pharmacology (2000) 130, 692−698 Further evidence that 5-HT-induced relaxation of pig pulmonary artery is mediated by endothelial 5-HT2B receptors Pharmacy 201 (2024-5) 38 Constitutive Receptor Activation and Inverse Agonists Pharmacy 201 (2024-5) 39 Constitutive Receptor Activation and Inverse Agonists Pharmacy 201 (2024-5) 40 Some useful and interesting examples Pharmacy 201 (2024-5) 41 Why is this interesting???? Pharmacy 201 (2024-5) 42 Pharmacy 201 (2024-5) 43