Drug Receptor Interactions: Antagonists PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-67 Drug Receptor Interactions: Antagonists Prof Will Ford 337 [email protected] Dr. Roger Pre...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-67 Drug Receptor Interactions: Antagonists Prof Will Ford 337 [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 agonis st t recept recept or or respon No se response Agonist - a Antagonist - binds ligand which to a receptor but… binds to a receptor and (i) has no effect causes a (ii) prevents the biological 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 If binding is  How does a competitive antagonist affect a log concentration response curve? EC50 values With increasing antagonist concentration:  Parallel right-ward shifts of the concentration-response curve  EC50 increases with increasing antagonist concentration  Degree of shift is directly proportional to the concentration of antagonist  Maximal response stays the same  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 competitive Differences between competitive and non-competitive antagonism on log dose response curve EC50 EC50 values values EC50 increases with EC50 decreases with competitive antagonist competitive antagonist concentration concentration Log concentration curve Emax reduces with shifts to the right but Emax noncompetitive antagonist unaffected concentration  How does a non-competitive antagonist affect a log dose response curve? No spare receptors Spare receptors present EC50 values EC50 values Max response falls with increasing Max response only falls with increasing antagonist concentration antagonist concentration when receptor reserve is used up EC50 increases with increasing antagonist concentration EC50 increases with increasing antagonist concentration  Antagonism that does not affect agonist binding 1) Affinity for the receptor is unchanged – EC50 unchanged 2) Size of response ↓ as 2nd messenger ↓ Example of functional antagonism Target enzyme – Adenylyl cyclase, converts ATP into cyclic AMP Ri – muscarinic Rs – β- adrenergic m2, m4 β 1, β 2, β 3 Antagonists - Classifications Physiologic Pharmacokineti al c 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 Results with induces an opposite antagonists are signalling outcome to 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 R* AnR AnR* Antagonists have equal affinity for R and R* No change in the equilibrium  Range of agonist and antagonist FYI drugs 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 antagonist treatment?  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 dose- response 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 windowNOAEL no observed adverse effect = level NOAEL  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