FFP1-67 Antagonists STS 2023 (2).pptx

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-67 Drug Receptor Interactions: Antagonists Prof Steve Safrany 341 [email protected] Dr. Roger Preston Learning outcomes • Define 'Antagonists’ • Explain the difference between reversible, irreversible, competit...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-67 Drug Receptor Interactions: Antagonists Prof Steve Safrany 341 [email protected] Dr. Roger Preston Learning outcomes • Define 'Antagonists’ • Explain the difference between reversible, irreversible, competitive, non–competitive antagonists • Describe how each type of antagonist affects the dose-response curve • Explain population studies for 'all-or-none’ responses What is an ‘antagonist’? antagoni st agonis t recept or respon se Agonist - a ligand which binds to a receptor and causes a biological recept or No response Antagonist - binds to a receptor but… (i) has no effect (ii) prevents the effects of an Intrinsic activity/efficacy • Intrinsic activity (α) is the ability to produce a response • Also called Efficacy α =1: Full agonist 1> α >0: Partial agonist α =0: antagonist α < 0: inverse agonist What is a ‘competitive’ antagonist? • Binds to the same site as the agonist and the two compete with each other – Orthosteric • If binding is reversible, the effect is surmountable by excess agonist • How does a competitive antagonist affect a log dose response curve? Reversible Irreversible What is a ‘non-competitive’ antagonist? • Antagonist binds to a different site from agonist • Called an ‘allosteric’ antagonist or inhibitor • Consequences appear the same as irreversible How does a non-competitive antagonist affect a log dose response curve? Not this simple – if spare receptors are present we will see a change in EC50 first Example of functional antagonism Target enzyme – Adenylyl cyclase, converts ATP into cyclic AMP Ri – muscarinic Rs – adrenergic m2, m4 β1, β2, β3 β- Antagonists Classifications Physiologic Pharmacokineti c al Chemical Competitive Non-competitive Antagonists - overview • Classified by how and where they bind • Binding strength ‐ Reversible ‐ Irreversible (truly or effectively) • Binding site ‐ Competitive ‐ Non-competitive Antagonists - examples • Competitive – Reversible e.g., beta blockers, antihistamines – Irreversible e.g., clopidogrel, phenoxybenzamine • Non-competitive – Allosteric site e.g., channel blockers – diltiazem, verapamil Antagonists - examples • Chemical – Binding endogenous ligand e.g., etanercept, TNF-α and TNF-β • Pharmacokinetic – Increasing metabolism e.g., St John’s wort, oestrogen • Physiological – Actions oppose each other e.g., salbutamol in asthma What is an inverse agonist? • An inverse agonist induces an opposite signalling outcome to • Results with antagonists are predictable The two-state model The two-state model Inv Ag Agonist R R* IR AR* Agonists have higher affinity for R* Inverse agonists have higher affinity for R The two-state model Antagonist R AnR R* AnR* Antagonists have equal affinity for R and R* No change in the equilibrium Range of agonist and antagonist N drugs O ! Benzodiazepine and GABA receptor Loss of drug response or desensitisation • Desensitisation / tachyphylaxis: the effect of a drug diminishes when it is given repeatedly or continuously • Tolerance: similar, but develops more slowly – Refractoriness can due to: • change or loss of receptors (most agonists) • Exhaustion of mediators (amphetamine) • Increased metabolic degradation (alcohol) • Physiological adaption (diuretics-> RAS) • What might happen with long-term Just one more concept and then something different • A receptor can switch on more than one signalling pathway – Conventional agonism • A biased agonist will selectively trigger one of these signalling cascades What if drug response is not linear or easily measurable? • A graded dose-response curve can be constructed for responses that are measured on a continuous scale, e.g., heart rate • Sometimes effects are ‘all-or-nothing’ i.e., quantal rather than graded – e.g., sleep, death, infection, pregnancy, presence or absence of epileptic seizures • So how can we measure potency, and safety in these drugs? Frequency distribution curve • A frequency distribution or quantal doseresponse curve can be constructed for drugs that elicit an ‘all-or-none’ response • Thus the response (y) axis is % people who respond to a What is the median effective dose 50% (ED50)? • Helps identify drug dose required to elicit therapeutic benefit • The median ED50 is the dose required to produce a therapeutic effect in 50% of the What is the median effective dose 50% (ED50)? • Dose required to produce a specified response in 50% of a population • But which response? The difference between therapeutic index and therapeutic window Summary (1) Five types of antagonism (others exist) ‐ Competitive ‐ Non-competitive ‐ Chemical ‐ Pharmacokinetic ‐ Physiological They bind the orthosteric or an allosteric site Their effects on dose-response curves of agonists Summary (2) ugs can be agonists, antagonists or inverse ago Selective affinity for R or R* ased agonism occurs sponses can be graded or quantal Both can be handled the same mathematically Quantal – ED50 states 50% of the population… erapeutic index erapeutic window What we have learned… • Define 'Antagonists’ • Explain the difference between reversible, irreversible, competitive, non–competitive antagonists • Describe how each type of antagonist affects the dose-response curve • Explain population studies for 'all-or-none’ responses