Pharmacodynamics PDF

‫بسم هللا الرحمن الرحيم‬ ‫‪Pharmacodynamics‬‬  Pharmacodynamics  Pharmacodynamics: the study of effects of chemicals and drugs on living system and the study of mechanisms of these effects.  This describes the action of the drug on the body, including receptor interac...

‫بسم هللا الرحمن الرحيم‬ ‫‪Pharmacodynamics‬‬  Pharmacodynamics  Pharmacodynamics: the study of effects of chemicals and drugs on living system and the study of mechanisms of these effects.  This describes the action of the drug on the body, including receptor interactions, dose response phenomena, and mechanisms of therapeutic and toxic action.  (it is about what the drug does to the body) 2  Binding of drug molecules to cells  Most drugs produce their effects by binding to protein molecules (enzymes e.g. Ach E, carrier molecules e.g. choline carrier, ion channels e.g. voltage sensitive K+, Ca++, Na+ channels and receptors e.g. α & β adrenoceptors). 3  Binding of drug molecules to cells  There is some exceptions such as osmotic diuretics, neutralizing antacids.  Bisphosphonates used to treat osteoporosis bind to calcium salts in the bone matrix, rendering it toxic to osteoclasts. 4  Nonreceptor-mediated Mechanisms 1-Physical action a. Osmosis: some drugs act by exerting an osmotic effect b. Adsorption: activated charcoal adsorbs toxins c. Demulcent: cough syrup produces a soothing effect in pharyngitis by coating the inflamed mucosa d. Radioactivity: radioactive isotopes emit rays & destroy tissues 2-Chemical action a. Acid neutralization , antacids are weak bases; hence they neutralize acid in the stomach in peptic ulcer b. Chelation heavy metals are eliminated from the body by chelating agents  Protein targets for drug binding 1. Enzymes e.g. Ach E, xanthine oxidase, carbonic anhydrase, dopa decarboxylase, MAO and COMT. 2. Carrier molecules e.g. choline carrier (blocked by hemicholinium), SSR , NA uptake. 6  Protein targets for drug binding 3. Ion channels: (pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of all living cells) e.g. voltage sensitive K+, Ca++, Na+ channels. 4. Receptors e.g. α & β adrenoceptors, acetylcholine muscarinic and nicotinic 7 receptors.  Types (families) of receptors Type 1: Ion channel linked receptors: They are membrane (transmembrane) receptors e.g. acetylcholine nicotinic receptor, GABAA and glutamate receptors. They are coupled directly to ion channel, They are receptors on which fast neurotransmitters act (response within milliseconds). 8 9  Types of receptors Type 2: G-protein coupled receptors:  They are membrane (transmembrane) receptors which are coupled to intracellular effectors system via a G- protein e.g. Ach muscarinic receptors, adrenergic receptors (both α and β) and receptors of many hormones.  (Response occur within seconds). 10 11  Types of receptors Type 3: Kinase linked receptors:  They are membrane (transmembrane) receptors which incorporate an intracellular protein Kinase domain (usually tyrosine Kinase) within their structure e.g. receptors for insulin, growth hormone and various cytokines.  (Response occur within hours). 12 13  Types of receptors Type 4: Receptors that regulate gene transcription:  known as nuclear receptors they are cytosolic or intranuclear proteins. Ligand must be highly lipophilic; targets are usually transcription factors.  They include receptors for steroids hormones, thyroid hormones, and other agents such as retinoic acid and Vitamin D.  (Response occur within hours). 14  1) Lipophilic ligand (e.g. testosterone) diffuses through 1 the plasma membrane. 2) Testosterone binds to its 2 intracellular receptor to form a hormone receptor complex. 3) Hormone-receptor complex 3 enters the nucleus binds to the target transcription factor on DNA. 4 4) Target mRNA is transcribed, and target protein is synthesized (biological effect).  Types of receptors 16  Drugs & receptors  Drug acting on a receptor may be agonist, partial agonist, inverse agonist or antagonist.  Agonist: is the drug which it when bind to its receptor it initiate changes in the cell function producing effects of various types.  Antagonist: is a drug that binds to the receptor without initiating such changes.  Inverse agonists can be regarded as drugs with negative efficacy. 17  Agonists Full Agonist Produce maximal effect  Agonist mimic the (large), causes the receptor endogenous ligand response to work at its maximal to a receptor. activity.  They bind to a receptor to produce a biologic response. Partial Agonist Produce a partial effect (small), not to the same extent of Emax produced by a full agonist.  Types of Agonists: A. Full Agonists B. Partial Agonists  Drugs & receptors  Agonist potency depend on affinity (tendency to bind to receptor) and efficacy (ability once bound to initiate changes that lead to effect).  Full agonist produces maximal effect, so it has high efficacy.  Partial agonist produces sub maximal effect, so it has intermediate efficacy.  Antagonist has affinity but zero efficacy. 19 Potency & efficacy  Drug Antagonism  Drug antagonism can be defined as a decrease or complete abolition of the effect of one drug in the presence of another.  Types of drug antagonism: 1. Chemical (pharmaceutical) antagonism:  Occur when two substances combine in solution, so that the effect of the active drug is lost e.g. dimercaprol (chelating agent) and lead. 21  Drug Antagonism 2. Pharmacokinetic antagonism:  The antagonist effectively reduces the concentration of the active drug at its site of action e.g. warfarin and phenobarbitone (the last is enzyme inducer that increase the metabolism of the other). 22  Drug Antagonism 3. Antagonism by receptor block (Competitive antagonism): i. Reversible antagonism (Reversible Competitive antagonism): e.g. atropine + Ach, it is surmountable antagonism characterize by parallel shift of the log dose – response curve; there is no reduction on the maximal 23 response.  Drug Antagonism ii. Irreversible competitive antagonism:  The antagonist dissociate very slowly, or not at all from the receptors (occur with drugs that posses reactive group that form covalent bond with receptors) e.g. (noradrenaline with phenoxybenzamine ) (5HT & methysergide), this type of drug antagonism is characterize by non surmountable, reduced maximal response and non parallel shift in the 24 log-dose response curve.  Drug Antagonism 4. Physiological antagonism:  Interaction of two drugs whose opposing action in the body tend to cancel each other e.g. NA and Ach on the vascular smooth muscles, NA and histamine on bronchioles , histamine and omeprazole on the gastric parietal cells. 25  Desensitization and Tachyphylaxis  Desensitization and tachyphylaxis:  Gradual decrease of the response of a drug when given continuously or repeatedly that develops in few minutes.  Tolerance: is more gradual decrease in response of a drug when given continuously or repeatedly (days or weeks).  Refractoriness: loss of therapeutic efficacy.  Resistance: loss of effectiveness of 26 antimicrobial.  Pharmacology – terminology  Idiosyncratic reaction: is abnormal and usually harmful drug effect that occurs in small proportion of individuals e.g. chloramphenicol causes aplastic anemia in approximately 1 in 50,000 patients.  Teratogenesis: production of developmental malformations of the fetus e.g. the absence of limbs after thalidomide, Teratogenesis usually occurs during the first trimester. 27  Thalidomide phocomelia 28  Pharmacology – terminology  Therapeutic index: the therapeutic index also known as therapeutic ratio or range is comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic affects.  A commonly used measure of therapeutic index is the toxic dose of a drug for 50% of the population (TD50) divided by the minimum effective dose for 50 % of the 29 population (ED50).  Therapeutic index  Therapeutic index = TD50 ED50  Drugs with lower therapeutic index (ratio, range) such as digoxin, dimercaprol, theophylline, lithium and warfarin require drug monitoring. 30 Therapeutic index (TI) (Small vs. large) With smaller TI, you need to consider benefits over risks of giving a drug. Larger TI are safer for use. Small therapeutic Large therapeutic Index Index (ex. Warfarin) (ex. Penicillin)