Introduction to Pharmacodynamics 2 PDF

Pharmacodynamics II Differentiate between agonists and antagonists and their action on receptors Compare the full agonists and the partial agonists Describe other mechanisms of action of drugs Explain the nature of competitive and noncompetitive inhibitors of enzymes (SDL) Drugs Acting on Receptors...

Pharmacodynamics II Differentiate between agonists and antagonists and their action on receptors Compare the full agonists and the partial agonists Describe other mechanisms of action of drugs Explain the nature of competitive and noncompetitive inhibitors of enzymes (SDL) Drugs Acting on Receptors Agonists – Compounds that bind and activate receptors  agonists – Drug agonists mimic the action of endogenous agonists (mediators) – Both agonists and antagonists posses affinity but only agonists have intrinsic efficacy (intrinsic efficacy = 1 in full agonists; =0 in pure antagonists, somewhere in the middle for partial agonists) Full Agonists and Partial Agonists Full agonists are compounds that can produce the largest response (maximal response) Partial agonists are compounds that can only produce a submaximal response The difference between full agonists and partial agonists lies in the relationship between occupancy and response (efficacy) – Full agonists have high efficacy – Partial agonists have median efficacy Rang et al. 1999. Pharmacology (4th ed.). Fig 1.5, P 10. Explanation for partial agonists: Two-state Model for Drug-receptor Interactions Partial agonists can not shift all receptors to an activated state Rang et al. 1999. Pharmacology (4th ed.). Fig 1.6, P 11. Antagonists Compounds that bind but do NOT activate receptors  antagonists (often called blockers) – Drug antagonists reduce or block the action of endogenous agonists by preventing their attachment to receptors Antagonism and its Mechanisms Antagonism is defined as the effect of one drug (or the natural ligand) is diminished or completely abolished in the presence of another drug Possible mechanisms – Reversible competitive antagonism – Irreversible competitive antagonism – Non-competitive antagonism (agonist binds to different site from ligand binding site) Binding sites at the metabotropic (G-protein coupled) glutamate receptor Reversible and Irreversible Antagonism Reversible antagonism Irreversible antagonism A certain number of receptors is rendered inactive (protein can only be reactivated by re-synthesis) Raffa et al. 2005. Netter’s Illustrated Pharmacology. Fig 1-23, Pg 24 Drugs acting on Channels Passive transport is the movement of a substance across a cell membrane along its concentration gradient (from high to low concentration). The process requires no chemical energy Examples for drugs that act on (passive) Channels Voltage-gated and ligand-gated ion channels can also serve as direct targets for drug action The most common type of interaction involves a physical blocking of the channel by the drug molecule Such effect prevents the transfer of ions across the cell membrane Examples: – calcium channel blocking drugs that block calcium channels in the heart and smooth muscle reducing their contractility – local anaesthetics block sodium channels and thus generation and transmission of sensory impulses Drugs acting on Transporters Active transport is the movement of a substance across a cell membrane against its concentration gradient (from low to high concentration). The process often uses chemical energy such as from adenosine triphosphate (ATP) Examples for drugs that act on (activeenergy consuming) Transporters Ions and other larger molecules require active (energy-consuming) carriers (pumps) to move across the cell membrane against their concentration gradient Drug may interfere and inhibit activity of such systems Examples:  Antidepressants inhibit reuptake of noradrenaline or serotonin into the nerve terminals after synaptic transmission   their effect on postsynaptic receptors Enzymes: the biological catalysts Drugs that Act on Enzymes Drugs may act on enzymes in form of competitive and noncompetitive inhibition – competitive inhibition - a drug acts as a substrate analogue to reversibly block enzyme’s active site and thus inhibit the biochemical process – non-competitive inhibition - a drug binds to a site different from the enzyme indirectly blocking its function Competitive vs non-competitive Inhibition (in most cases reversible) Enzyme Inhibition (Mechanism) I Competitive I I Uncompetitive (very rare) Non-competitive E Equation and Description Cartoon Guide Substrate E S S E S I I I I Compete for Inhibitor active site S Different site E + S← → ES → E + P + I ↓↑ EI E + S← → ES → E + P + + I I ↓↑ ↓↑ EI + S →EIS [I] binds to free [E] only, and competes with [S]; increasing [S] overcomes Inhibition by [I]. [I] binds to free [E] or [ES] complex; Increasing [S] can not overcome [I] inhibition. S I E + S← → ES → E + P + I ↓↑ EIS [I] binds to [ES] complex only, increasing [S] favors the inhibition by [I]. Juang RH (2004) BCbasics Irreversible inhibition (can be competitive and non-competitive Irreversible inhibition occurs by covalent adduct formation - this examples shows organic phosphates (can be competitive or non-competitive) Irreversible inhibition – another example Penicillin – inhibitor of glycoprotein peptidase – bacterial cell wall synthesis Irreversible enzyme inhibitors Examples of drugs that work on enzymes Drugs that Work by Simple Chemical Action A few drugs act on simple chemical processes These drugs are often basic inorganic compounds or none-complex organic compounds Examples: magnesium hydroxide (antacid) in the treatment of peptic ulcer Mg(0H)2+2HCl  MgCl2+2H2O Drugs that Work by Physical Action Few drugs act by a purely physical mechanism Example: drugs that act on osmosis – Osmotic laxatives – Osmotic diuretics Loss of drug efficacy over time - Tachyphylaxis and Tolerance Definition: A gradual decrease in responsiveness to a drug (such as an opiate, benzodiazepine or other drug), so that larger and larger doses are required to achieve the same effect Desensitisation and tachyphylaxis are synonymous terms used to describe this phenomenon, which often develops in the course of a few minutes. The term tolerance is conventionally used to describe a more gradual decrease in responsiveness to a drug, taking days or weeks to develop Molecular mechanism is often a decrease in receptor expression Raffa et al. 2005. Netter’s Illustrated Pharmacology. Fig 1-18, Pg 20 Many different mechanisms can give rise to loss of drug efficacy over time including changes (e.g. conformational - phosphorylation) in the receptor loss of receptors exhaustion of mediators increased metabolic degradation of the drug physiological adaptation active extrusion of drug from cells References Rang, H.P., Dale, M.M., Ritter, J.M. and Moore, P.K. (Ed). (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. Bullock, S., Manias, E. & Galbraith, A. (Ed). (2007). Fundamentals of Pharmacology (5th ed.). Sydney: Pearson Education Raffa, R.B., Rawls, S.M. & Beyzarov, E.P. (Ed.). (2005). Netter’s Illustrated Pharmacology. Icon Learning Systems