MBS Pharmacology 5.pdf

Metabolism and Excretion Dr. Kiran C. Patel College of Allopathic Medicine Department of Medical Education Metabolism  Drug Metabolism Administration Oral IV IM SC Rectal Transdermal Absorption-Gastrointestinal tract Dist...

Metabolism and Excretion Dr. Kiran C. Patel College of Allopathic Medicine Department of Medical Education Metabolism  Drug Metabolism Administration Oral IV IM SC Rectal Transdermal Absorption-Gastrointestinal tract Distribution-systemic circulation Metabolism-Liver Excretion -Kidneys  Drug metabolism: Active → inactive → facilitate excretion ↓toxicity Prodrug → active drug https://ars.els-cdn.com/content/image/3-s2.0-B9780323885416000247-f35-06-9780323885416.jpg  Phase 1 Reaction Hepatic enzymes Hepatocyte smooth endoplasmic reticulum mitochondria Hemeproteins CYP450 system CYP3A4 (50%) CYP2D6 These metabolize most of our drugs Phase 1 Involve intramolecular modifications that convert lipophilic molecules into more polar molecules. Biotransformation : Oxidation Reduction Hydrolysis ↑ polarity, ↑water solubility, ↑excretion  Factors Genetic polymorphism-genetic variation of drug metabolism Fast or slow CYP450- CYP2D6 most common polymorphism Rapid metabolizer Active → inactive quickly ↓ active drug concentration → ↓ therapeutic effect https://therunningchannel.com Slow metabolizer ↑ active form of the drug ↑ undesired/toxic side effects  CYP450 Inducers vs Inhibitors CYP450 inducers ↑CYP450 enzyme activity Coadministration Drug X - Captopril Drug Y can be a CYP450 inducer Metabolism of Drug X ↑ Therapeutic effect ↓ CYP450 inhibitors – decrease CYP450 enzyme activity Drug X -Captopril Drug Y can be a CYP450 inhibitor Metabolism of Drug X ↓ ↑ undesired/toxic side effects  Main site of drug metabolism - Liver Liver disease Cirrhosis ↓ amount and efficacy of CYP450 ↓ active → inactive ↑ active drug concentration and side effects. Toxicity ↓ CYP450 system efficacy Age  Phase 2 Reaction Conjugation Active → inactive Polarity, water solubility Phase 2 → ↑↑ polarity and water solubility Transferase enzymes Methyltransferase - methyl, methylation Acetyltransferase - acetyl, - acetylation Sulfotransferase - sulfa groups, sulfation Glutathione transferase - glutathione molecules Glucuronosyltransferases – Glucuronidation (most common)  Excretion Main way drugs are excreted from the body - kidneys Bile Exhalation Feces Osmosis.org  Factors Filtration Afferent arteriole → glomerulus where → bowman’s capsule → proximal convoluted tubule Hydrostatic pressure - driving force GFR Renal disease (AKI, CKD, diabetes, HTN) ↑ serum drug concentration Dose adjustments  ↑ drug – protein binding ↓ decrease filtration Main determinants of protein binding are: # of available binding sites (i.e. protein concentration) # of drug molecules (i.e. drug concentration) Lipophilicity and pKa of the drug ↑lipid solubility , ↑protein binding ↑ drug – protein binding , ↑ serum drug concentration Liver cirrhosis, ↓ albumin leading to less protein binding, ↑ excretion  Secretion 20% of the plasma flow → filtered, → efferent arteriole → peritubular capillaries. Peritubular capillaries → tubular lumen Solubility and concentration gradient. Drug X polar, water soluble and large molecules Organic ion transporters -actively peritubular capillaries → tubular lumen against a concentration gradient (low to high) Drug Y nonpolar, lipid soluble, small high in plasma vs low in tubular fluid This drug easily permeates through the cell membrane reaching the filtrate Passive, high to low  Reabsorption Nonpolar, lipid soluble, small are easily reabsorbed from the renal tubule Distal convoluted tubule. Passive diffusion Phase 1 Phase 2 Liver to facilitate its excretion. Clearance  Factors affecting drug elimination/clearance Intrinsic drug properties polarity size pKa Genetic variation Disease - first-pass metabolism. Hepatic clearance: blood flow to the liver, intrinsic clearance, the fraction of drug bound to protein. Renal clearance GFR tubular secretion reabsorption. Half-life (t½)  First Order Kinetics Most common Elimination rate varies Fraction, % of drug elimination is constant t½ constant Drug concentration and rate of elimination are directly proportional 4-5 half-life’s 95% elimination Steady state  Zero Order Kinetics Very few drugs display zero order kinetics Aspirin Elimination constant Fraction, % of drug elimination varies t½ variable Drug concentration and rate of elimination are independent of each other Increase in drug concentration we will not increase the rate of elimination