Pharmacology Lecture: Pharmaco-dynamics PDF

Pharmacology Pharmacogenetics LECTURE (4) Pharmaco-dynamics (4) DR. El-Sawy 1  Pharmacology...

Pharmacology Pharmacogenetics LECTURE (4) Pharmaco-dynamics (4) DR. El-Sawy 1  Pharmacology Pharmacogenetics  Study of variation in response to single drug due to genetic Pharmaco- genetics variation of single (or few) gene(s).  Broader term, which studies how ALL of genes (genome) can Pharmaco- influence the responses to drugs. genomics  Currently, variations in around 20 genes provide useful predictions of reactions to 80-100 drugs. Genes of particular relevance to pharmacogenetics :  Variation in drug metabolism  one of the best studied areas of pharmacogenetics.  Most drugs undergo metabolism, but there are some exceptions.  Cytochromes P450 : Most important gene family that contribute to oxidative metabolism. This metabolism called Phase I metabolism. Four different cytochromes P450 → CYP2D6, CYP2C9, CYP2C19 & CYP3A4 are the most important. CYP2D6 and CYP2C19:  Significant percentages of population) → completely lack one of these enzymes due genetic polymorphisms in both copies of the gene.  Effect of Genetic polymorphism : 1. Alter drug targets: Enzymes, ion channels or transporters. 2. Cause adverse drug reactions which may involve : a. Exaggerated drug response. b. Inappropriate immune response. DR. El-Sawy 2  Pharmacology Pharmacogenetics  Management : 1. Fresh plasma transfusion 2. Mechanical ventilation until drugs are cleared Pseudo- from body. cholinesterase  Testing: (PChE) deficiency Use of a biochemical test. Done when patients show exaggerated sensitivity to succinylcholine and testing of other family members may also be performed G PD deficiency Thiopurine methyltransferase (TPMT) Acetylator phenotypes  Management: Use of direct-acting oral anticoagulants Resistance to (DOACs) such as rivaroxaban and warfarin dabigatran. The cost of DOACs is high at present and more studies are needed to confirm superiority of these drugs over warfarin. DR. El-Sawy 3  Pharmacology Pharmacogenetics  An antiplatelet drug used to prevent thrombosis in high risk patients.  The drug itself is inactive and must be catalyzed by the hepatic enzyme CYP2C19 to exert its antiplatelet effect.  Some people (14%) have genetic deficiency of this enzyme (called CYP2C19 poor metabolizers), thus their livers can not activate clopidogrel and so they are at risk of therapeutic failure.  The FDA added a boxed warning to clopidogrel label stating that CYP2C19 poor metabolizers may not Resistance benefit from treatment with this drug and that a to genetic test to determine CYP2C19 status is available. clopidogrel  Prescription of alternative antiplatelet drugs to clopidogrel for all patients needing this treatment is now increasing.  Codeine requires activation (demethylation) to morphine by CYP2D6 for effective analgesia.  It also converted to other metabolites but these lack Codeine analgesic activity.  CYP2D6 poor metabolizers are unlikely to benefit from codeine as an analgesic. DR. El-Sawy 4  Pharmacology Pharmacogenetics Drug interactions in vitro: e.g. anti-pseudomonal penicillins and aminoglycosides form complexes in the infusion fluid. Drug interactions in vivo: A. Absorption: Formation of Tetracycline + Ca2+, Mg2+ and Al3+ Complexes Cholestyramine +digitalis and thyroxin. Absorption can Adrenaline ↓ absorption of local anesthetics due to VC. be blocked Colchicine ↓ absorption pf vitamin B12 Anticholinergic drugs : ↓ intestinal motility → ↑ Change in absorption of some drugs. intestinal Prokinetic drugs : ↑ intestinal motility → ↓ absorption of motility some drugs. Antacids ↓ absorption of salicylates. Changes in Ketoconazole is poorly absorbed in absence of gastric gastric pH acidity. B. Distribution: Sulfonamides displace bilirubin from plasma protein in premature infants → kernicterus. Phenylbutazone displaces warfarin → excessive bleeding. DR. El-Sawy 5  Pharmacology Pharmacogenetics C. Metabolism: Inhibition or induction of microsomal metabolism. Inhibition of non-microsomal enzymes:  ↓ metabolism of some drugs e.g. benzodiazepines, MAO inhibitors serotonin and norepinephrine.  Inhibits acetaldehyde dehydrogenase enzyme → ↓ metabolism of acetaldehyde →accumulation of Disulfiram acetaldehyde causes flushing, nausea, vomiting & tachycardia. D. Excretion: Reduction in urinary elimination: 1. robenecid →↓renal excretion of enicillin. 2. Quinidine →↓renal excretion of digoxin. Changes in urinary pH : Alkalinization of urine Acidification of urine e.g. : Sodium bicarbonate Ammonium chloride Effect : ↑ excretion of weak acids ↑ excretion of weak bases Changes in urinary volume:  Diuretics can increase toxicity of some drugs by reducing plasma volume e.g. thiazide can increase lithium toxicity. Stimulation of biliary excretion:  Phenobarbital ↑ biliary excretion of many drugs by increasing both bile flow and the synthesis of conjugating proteins. DR. El-Sawy 6  Pharmacology Pharmacogenetics  Competitive  Non-competitive Antagonism  Chemical  Physical  MAO inhibitors Synergism can cause toxic synergism with TCA (tricyclic anti- depressant drugs).  Ethanol Potentiation can enhance CNS depression caused by opioids. Changes in intracellular or  Diuretic- induced hypokalemia extracellular can ↑ digitalis toxicity. environment DR. El-Sawy 7