Lec 5. Kinetics & Elimination II (Pharmacology) PDF

Fundamentals of Pharmacology-COM5082 Lecture 5: Pharmacokinetics-Drug Metabolism and Elimination Hoang Nguyen, M.D., Ph.D., RPh., FACHE Assistant Professor of Foundational Sciences Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine (KCPCOM) Contact for questions or app...

Fundamentals of Pharmacology-COM5082 Lecture 5: Pharmacokinetics-Drug Metabolism and Elimination Hoang Nguyen, M.D., Ph.D., RPh., FACHE Assistant Professor of Foundational Sciences Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine (KCPCOM) Contact for questions or appointment: [email protected] Learning Objectives After Completion of this section of Pharmacokinetic 2, first year M1 students will be able to: 1. List major pathways of drug metabolism and name the various factors that alter metabolizing pathway: e.g, age, genetic, disease states 2. Describe the major sites and mechanisms of drug elimination 3. Describe the disease states that alter elimination kinetics 4. Demonstrate graphically the differences between zero order and first order kinetics 5. Calculate the rate of drug elimination using simple kinetic equations and graphical techniques 6. Calculate dosing regimens using known pharmacokinetic parameters 7. Concept of half-life Overview of Drug Metabolism and Elimination Drug Metabolism    Liver is the main organ involved in drug metabolism. Within the cells of the liver are a group of enzymes that specifically function to metabolize for drug. Drug Metabolism will go through 2 phases: Phase I and Phase II These enzymes are referred as the drug microsomal metabolizing system (DMMS). The DMMS utilizes cytochrome P450 enzymes that are important in oxidation and reduction reactions that convert drugs into their metabolites   By stimulating this system, the drugs actually increase the amount of enzymes (cytochrome P450s) in the system; this process is referred to as enzyme induction. Consequently, the duration of drug action is decreased. Other drugs can inhibit the drug microsomal metabolizing enzymes to cause enzyme inhibition, hence, it will increase the duration and intensity of the drugs inhibited. (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Drug Metabolism: Phase I  Reduction, Oxidation, Hydrolysis (R-OH)with cytochrome P450 usually yield slightly polar, water-soluble metabolites (often still active).  Phase I metabolism may increase, decrease, or have no effect on pharmacological activity.  Geriatric patients lose phase I first. Drug Metabolism: Phase II     Conjugation (Methylation:add methyl group, Glucuronidation:add glutathione to drug, Acetylation:add acetyl group to drug, Sulfation) (Geriatric has too Much GAS) usually yields very polar, inactive metabolites (renally excreted).Glucuronidation is the most common and the most important conjugation reaction. Enzymes involved:  For the Methylation process: S Adenosylmethionine (SAM),  For the Glucuronidation process: Glucotathione-transferases;  For the Acetylation: N acetyltransferases Co-factor required:  For the Methylation process: transmethylases;  For the Glucuronidation proces: glutathione;  For the Acetylation process: acetylcoA Examples are: Acetaminophen, Diazepam and Morphine Cytochrome P-450 Enzymes 3A4 Liver Gut Lumen Enterocyte Systemic Circulation Cytochrome P-450 Enzymes 3A4 Liver Gut Lumen Enterocyte Systemic Circulation Cytochrome P-450 Enzymes Systemic Circulation 3A4 Gut Lumen Enterocyte Liver (Adapted, First Aid USMLE Review 2021) Drug Metabolism on Neonates/Infants vs. Aging Alcohol vs. Smoking  Neonates/Infants: There is a reduced capacity for drug metabolism. Consequently, drug elimination occurs more slowly and drug duration of action is prolonged. After the first year, drug metabolism gradually become proportional to those of the adult. Aging: The rate of drug metabolism decreases with age. The age-related decreases in liver blood flow – Diminished cardiac output: • Decrease cardiac output = Decrease hepatic perfusion = Decrease delivery of drug to the liver for metabolism. – Increased body fat: • Increase Vd = prolong clearance time.  Remember: Smoking and Alcohol consumption will cause microsomal enzyme induction, thus will increase the rate of drug metabolism. Renal Elimination  Involves three physiological processes:    Glomerular filtration Proximal Tubular Secretion Distal Tubular Reabsorption (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Drug Elimination Eliminated Renally as Metabolized Drug Systemic Circulation Liver Gut Lumen Enterocyte Renal Elimination Elimination Kinetics-Zero order kinetics  [drug] decreases linearly with time  Rate of elimination is constant, independent of [drug]  Clearance is greater at low [drug], and less at high [drug] Cl = Rate of elimination of drug Plasma drug [ ]  PEA (pea is round, shape like “O” in zero order): Phenytoin, EtoH, Aspirin  No true t1/2 Elimination Kinetics-1st order kinetic With 1st order elimination, a constant percentage of the drug is lost per unit time.  Onset of action=describe the time from drug administration to the first observable drug effect.  [drug] decreases exponentially with time  An elimination rate is proportional to [drug].  Clearance is constant  T1/2 is constant regardless of [drug]  Flow-depend elimination Cl = Rate of elimination of drug Plasma drug [ ]  (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Half-life (t1/2)  Time required for the blood or plasma concentration of the drug to fall to half of its original level.  Important in determining the frequency of drug administration  In order to maintain a continuous drug effect, the drug must be given at intervals that keep the plasma concentration above the minimal effective concentration.  The rate of drug metabolism and excretion are the major factors that determine half-life  When liver or kidney disease is present, half-life is prolonged, thus dose or frequency of administration can be reduced.  T1/2=0.7xVd  CL  The higher of Vd, the longer the half-life  The higher of CL, the shorter of half-life.  Increase hepatic blood flow will shorter of half-life  Increase of metabolism will shorter of half-life Practice Question on calculate half-life  A 22-year-old male ingests an overdose of an opioid analgesic. The plasma drug concentration is found to be 24mg/L. How long will it take for the drug to reach a plasma concentration of 3 mg/L, if the drug’s half-life is 5 hours? A. 12 hours B. 15 hours C. 48 hours D. 72 hours E. 1 week Resources  1. Basic and clinical pharmacology by Katzung, 15th edition.  2. Videos: https://sketchy.com/