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Basic Principles of Drug Metabolism

Basic Principles of Drug Metabolism. 2. NAPLEX. Pg. 51. Phase I (functionalization) Oxidation (most important), reduction, and hydrolysis Function: introduce a polar group to make molecules more hydrophilic Method: catalyzed by hepatic CYP450 system enzymes.

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Basic Principles of Drug Metabolism

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  1. Basic Principles of Drug Metabolism 2 NAPLEX Pg. 51

  2. Phase I (functionalization) Oxidation (most important), reduction, and hydrolysis Function: introduce a polar group to make molecules more hydrophilic Method: catalyzed by hepatic CYP450 system enzymes General Pathways of Drug Metabolism

  3. - Function is to attach small, polar, and ionizable components. • Form water soluble conjugated products. • Conjugated metabolites are easily excreted in the urine and generally have little or no pharmacologic activity or toxicity. Phase II (conjugation)

  4. phenytoin p-hydroxyphenytoin glucuronide hydroxylation glucuronidation conjugate of phenytoin cefuroxime axetil cefuroxime hydrolysis aspirin salicylic acid glucuronide hydrolysis + glucuronidation acetic acid acetaminophen glucuronide and sulfate conjugates conjugation Examples of Drug Metabolism

  5. Introduction to drug interactions • Types of drug interaction • Reasons for occurrence • Clinical significance Drug Interactions Go to Chapter 17, pg. 445

  6. Absorption Interactions • Tetracycline-divalent and trivalent cations • Ciprofloxacin antacids • Digoxin-cholestyramine • Thyroid-cholestyramine • Digoxin-metoclopramide • Ciprofloxacin-sucralfate Distribution Interactions • Warfarin-aspirin • Warfarin-chloral hydrate • Warfarin-clofibrate • Warfarin-ciprofloxacin • Methotrexate-aspirin Pg. 451

  7. Enzyme Induction Interactions: Enzyme inducers: • Barbiturates • Rifampin • Cigarette smoking - also charred meats / foods • Phenytoin • Phenylbutazone • Griseofulvin • Carbamazepine • Alcohol (chronic ingestion) Metabolic or Biotransformation Interactions

  8. Enzyme inhibitors: • Alcohol (acute ingestion) • Amiodarone • Cimetidine • Co-trimoxazole • Cyclosporine • Erythromycin • Metronidazole – also other “azole” antifungals • Reverse transcriptase inhibitors • Fluvoxamine / Fluoxetine • Ritonavir

  9. Excretion Interactions Probenecid-penicillins - naproxen - cephalosporins Lithium-diuretics - ACE inhibitors - Fluoxetine - NSAIDs Potassium-amiloride - triamterene - spironolactone Review list of interactions on pg. 452469.

  10. phenytoin p-hydroxyphenytoin glucuronide hydroxylation glucuronidation conjugate of phenytoin cefuroxime axetil cefuroxime hydrolysis aspirin salicylic acid glucuronide hydrolysis + glucuronidation acetic acid acetaminophen glucuronide and sulfate conjugates conjugation Examples of Drug Metabolism

  11. Patient Laboratory Tests Go to page 363, Chapter 12.

  12. SMA 6 Versus SMA 12 Both us automated continuous- flow blood chemistry assays. SMA 6 (Profile 1)

  13. Total proteins 6 to 8 g/dL Bilirubin up to 1 mg/dL  reported as total, conjugated and unconjugated Alkaline phosphatase 30-85 IU Calcium 10 mg/dL (5mEq/L) (does not indicate body supply of Ca) Creatinine (SCr) 1 mg/dL Albumin 3.5 to 5 g/dL SMA 12 (Profile 2) includes all of the above, plus:

  14. Sodium - fluid status – “water follows sodium” Sodium is the main extracellular cation. • Decreased values may be caused by diarrhea, heat exhaustion, kidney disorders, or ileostomates. • also dilutional hyponatremia – excess fluid intake • Symptoms include nausea, vomiting, anorexia, blurred vision, muscle cramps, and CNS changes. Both sodium and water are retained in such chronic disease states as congestive heart failure, cirrhosis, and nephrosis. Hypernatremia caused by dehydration. This is major problem of the geriatric population. Individual Test Values: Electrolytes

  15. Potassium is found mainly in cells and not serum. • Decreased values may be caused by diarrhea, kidney disease, prolonged vomiting, administration of insulin and glucose in diabetes, prolonged IV therapy, or use of thiazides or loop diuretics. • Lowered values may cause cardiac arrhythmias, confusion, muscle weakness, fatigue, and dizziness. • Symptoms of increased values include arrhythmias, depression, lethargy, coma, and electrocardiographic changes. • Drugs causing hyperkalemia: ACE – inhibitors, ARBs, K+ sparring diuretics, K+ supplements Potassium

  16. An increase in carbonic acid results in metabolic alkalosis and respiratory acidosis. • A decrease in carbonic acid results in metabolic acidosis and respiratory alkalosis. must also evaluate pH and pCO2 to determine true acid-base status • The most common therapeutic use of sodium bicarbonate injection is to overcome metabolic acidosis. Bicarbonate

  17. Calcium is important for bone formation, muscle contractions, blood clotting, nerve conduction, and effective enzyme function. • Low values may be caused by celiac disease, sprue, and certain kidney disease. • High values may be caused by hyperparathyroidism, certain respiratory diseases, multiple myeloma, during vitamin D toxicity, and drug therapy with thiazides. • Corrected calcium (mg/dl) = 4 – [patient albumin (g/dl)  [0.8 ] + current patient calcium Patients on long-term steroid therapy experience a deficiency in calcium. Calcium

  18. Phosphatase is a group of enzymes that split phosphoric acid from organic phosphate esters (alkaline phosphatase). normally present in small amounts in serum, elevation indicates tissue/cell damage and death causing release Increased values may cause bone disease (e.g., Paget disease), bone fractures, liver disease, or bile duct obstruction. Creatine phosphokinase (CK or CPK) has normal values of 1 to 10 IU/L; CPK is used to diagnose myocardial infarction or muscular dystrophy. • There are 3 subunits: CK-MB (cardiac), CK-MM (skeletal muscle), and CK-BB (brain and kidney). • Evaluations using CPKs have been replaced in many settings by the assays for troponins. Enzyme Tests

  19. These enzymes catalyze transfer of amino acid groups: • Aspartate aminotransferase (AST) or SGOT • Alanine aminotransferase (ALT) or SGPT • Known as “liver function tests (LFTs),” along with LDH. ALT is most sensitive and specific for liver damage. • Significant when elevated >3 upper limit of normal SerumTransaminases

  20. Endogenous substance that will reflect kidney function. Normal value is 1 mg/dL (range 0.8 – 1.2 mg/dL). Values above 2 mg/dL indicate either renal or hepatic disease. Creatinine clearance (CLCr) Allows determination of kidney glomerular function; Normal range is 100 to 140 mL/min Values for females are approximately 85% that of males. Cockroft and Gault equation: CLCr = (140 – age [in years])  body weight (in KG) 72  serum creatinine (mg/dL) Serum Creatinine Remember to multiply by 0.85 for females.

  21. Blood Counts CBC = complete blood count. Red blood cells (RBCs) Erythrocytes contain hemoglobin, which carries oxygen. Decreased values are caused by hemorrhage or anemia. Increased values are caused by polycythemia. White blood cells (WBCs) Leukocytes are the defense mechanism against micro-organisms. Normal counts are 4,000 (range of 4 – 10k) Decreased values are caused by blood dyscrasias or drug or chemical toxicities. Increased values (leukocytosis) are caused by infections or blood disorders.

  22. WBC differential counts aid in diagnosis • Neutrophils • Lymphocytes • Eosinophils • Basophils • Monocytes Platelets Thrombocytes necessary for blood clotting. Normal is 150-300,000; low levels can cause bruising, bleeding.

  23. Miscellaneous Blood Tests Hematocrit (Hct)  % of packed red blood cells Hemoglobin test (Hgb) – amount of hemoglobin Mean corpuscular volume (MCV) – average of volume of RBC Mean corpuscular hemoglobin (MCH) – hemoglobin content of the average RBC Desirable blood TOTAL cholesterol level is < 200 mg/dL. Desirable volume of low density lipoproteins (LDL) and very low-density lipoproteins (VLDL) are < 130 mg/dL. High density lipoproteins (HDL) are desirable.

  24. Coagulation Times • • Heparin • Activated partial thromboplastin time (APTT or PTT) • An accurate, low-cost test with normal values of 35 to 45 • seconds. Used in hospitals to monitor heparin therapy. • Antidote for excessive anticoagulant activity of heparin is protamine sulfate • • Warfarin • • Prothrombin time (PT or pro-time) • •International normalized ration (INR) • A ratio obtained by comparing a patient’s PT value with the mean normal PT value. Values in the range of 2.0 to 3.0 • are desired.

  25. Blood Glucose Normal fasting values range from 70 to 100 mg/dL. Glucose is the main source of energy in body. Hyperglycemia is present in diabetes mellitus and Cushing syndrome. Glucose tolerance test – measure BG 2 h after glucoseload is ingested HbA1c - % of Hgb molecules with a glucose molecule attached. Provides average BG over the past three months

  26. Blood Urea Nitrogen (BUN) • Test kidney function • Urea is produced by the liver from ammonia. • Normal range is 9-20 mg/dL • High N, resulting in mental confusion, may be caused by: • Kidney malfunction • Cardiac function • High protein intake (Atkins diet) • Low levels: may indicate liver disease

  27. Therapeutic Drug Plasma Levels Digoxin – 1 to 2 ng/mL ( >2 ng/mL may be toxic) Phenytoin – 10 to 20 μg/mL ( >30 g/mL may be toxic) Lithium – 0.5 to 1.5 mEq/L Aminoglycosides (gentamicin, tobramycin, netilmicin) – peaks of 5 to 8 ug/mL; troughs <2 μg/mL; measure approximately 1 h before next dose Vancomycin – 24 to 40 μg/mL; trough <10 g/mL (synergistic nephrotoxicity with aminoglycosides)

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