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Pharmacokinetics - II.pptx

  1. Dr. Arun.S First year Post Graduate Department of Pharmacology Government Medical College Ananthapuramu
  2. SPECIFIC LEARNING OBJECTIVES - AT THE END OF THE SEMINAR THE LEARNER WILL BE ABLE TO 1. Define and Describe Biotransformation of drugs and Factors affecting it 2. Describe first pass metabolism 3. Describe the drug metabolizing enzymes 2. Describe Enzyme induction and inhibition 3. Describe the process of elimination of drugs
  3. DEFINITION • Pharmacokinetics deals with Absorption, Distribution, Metabolism an Excretion of the drugs. • Pharmacon - drug • kinesis - movement • It is a branch which deals with “what the body does to the drug”. • It is also called ADME study.
  4. BIOTRANSFORMATION OF DRUGS • Enzyme catalysed biochemical transformation of drugs within the living organism. • Lipid soluble to lipid insoluble - Not reabsorbed in kidney. • Sites: Liver (m.c) Kidney Lungs Intestine (small & large) Adrenal cortex Placenta Skin
  5. 4 CONSEQUENCES OF BIOTRANSFORMATION 1. Inactive metabolite from active drug: Eg - Paracetamol, propranolol, phenobarbitone, morphine, etc 2. Active metabolite from inactive (prodrug) or a less active drug: / Eg - L-Dopa Dopamine (in basal ganglia) Prednisone Prednisolone Enalapril Enalaprilat Dipivefrine Epinephrine
  6. 3. Active metabolite from an equally active drug: Eg - Digitoxin Digoxin Morphine Morphine - 6 - glucuronide Allopurinol Alloxanthine 4. Formation of toxic metabolite: Eg: Paracetamol N-acetyl-p-benzoquinoneimine (NAPQI) Cyclophosphamide Acrolein
  8. FIRST PASS METABOLISM • Pre-systemic metabolism • First pass effect
  11. Attributes of drugs with high first pass metabolism: (a) Oral dose >> sublingual or parenteral dose. (b) Marked individual variation in the oral dose due to differences in the extent of first pass metabolism. (c) Oral bioavailability is apparently increased in patients with severe liver disease. (d) Oral bioavailability of a drug is increased if another drug competing with it in first pass metabolism is given concurrently, e.g. chlorpromazine and propranolol.
  13. PHASE - 1 REACTIONS • Degradative reactions • Metabolite formed - active / inactive • Mostly CYP mediated. • Introduction of a new group - smaller non-polar / polar
  14. PHASE - 2 REACTIONS • Conjugation reactions • Catalysed by Microsomal, mitochondrial or cytoplasmic enzymes • Metabolite - polar, water soluble - inactive
  16. Summarise the reactions
  17. PHASE - 3 • ATP-binding cassette (ABC) and solute linked carrier (SLC) transporters. • ABC transporters - efflux (Primary active transport) • SLC - Uptake and efflux (Secondary active transport - symport and antiport) • Uptake transporters: 1. Na+-taurocholate cotransporting polypeptide (NTCP) 2. OCT 1 3. OAT 2 4. organic anion-transporting polypeptides • Efflux transporters: 1. P-gp efflux system 2. bile salt export pump (BSEP) 3. multidrug resistance-associated protein (MRP) 2
  20. CYP 450 SYSTEM • Superfamily of heme containing sozymes located primarily in the smooth endoplasmic reticulum of liver and GI tract. • Metabolism of 1. Endogenous compounds (steroids and lipids) 2. Exogenous compounds - drugs, carcinogens, and environmental pollutants • Metabolize only lipid soluble drugs • Phase 1 (oxi, red, hyd) and phase 2 (glucuronyl conj)
  22. NON-MICROSOMAL ENZYMES • Located in cytoplasm, mitochondria - liver cells (m.c) and plasma • Eg - MAO, Esterases, amidases, transferases • Phase 2 reactions (except glucuronide conj) • Few Phase 1 reactions (oxi, red, hyd) • Non-inducible • Can be inhibited
  23. NON-ENZYMATIC BIOTRANSFORMATION (HOFFMANS ELIMINATION) • Inactivation of the drug in body fluids spontaneously by molecular rearrangement. • Eg - Atracurium, Cisatracurium, Gantacurium
  24. ENZYME INDUCTION • Many drugs, insecticides and carcinogens interact with DNA and increase the synthesis of microsomal enzyme protein, especially cytochrome P-450 and UGTs.
  25. CLINICAL SIGNIFICANCE OF ENZYME INDUCTION: 1. Decreased intensity and/or duration of action of drugs. e.g. Unwanted pregnancy - failure of contraception with oral contraceptives, Phenytoin - ↑ metabolism of Vit D - Osteomalacia 2. Increases intensity of drug action - Acute paracetamol toxicity in alcoholics 3. Tolerance - due to autoinduction - increase dose after 2 weeks. Eg - Carbamazepine, rifampin, nevirapine 4. Faster metabolism of endogenous substrates. 5. Interference with chronic toxicity testing
  26. USES OF ENZYME INDUCTION 1. Congenital nonhaemolytic jaundice: deficient glucuronidation of bilirubin - phenobarbitone hastens clearance of jaundice. 2. Cushing’s syndrome: phenytoin - enhances degradation of adrenal steroids. 3. Chronic poisonings: by faster metabolism of the accumulated poisonous substance.
  27. ENZYME INHIBITION • Rapid process, usually reversible • Irreversible - secobarbital (antoinhibition of its own metabolism) - overdose • Enzymes involved - Hepatic Microsomal mixed function oxidase (MFO), MAO, Xanthine oxidase, etc.
  28. CLINICAL RELEVANCE OF ENZYME INHIBITION POTENTIALLY ADVERSE CONSEQUENCES: • Nausea / vomitting - Theophylline + Erythromycin • ↑ Bleeding - cimetidine + warfarin • Severe RS depression - Morphine + MAO inhibitors • Ataxia & drowsiness - Phenytoin + Warfarin / chloramphenicol • Cardiac arrhythmias - Terfenadine + ketoconazole / chloramphenicol
  29. THERAPEUTICALLY BENEFICIAL CONSEQUENCES: • ↑ L-dopa in brain when given with Carbidopa • Alcohol deaddiction with disulfiram • d-tubocurarine induced skeletal muscle paralysis - reversed by neostigmine
  30. DRUG CLEARANCE THROUGH METABOLISM • Drug enters the body - elimination begins (Elimination - Biotransformation + excretion) • 3 major pathways: hepatic metabolism, biliary elimination, urinary excretion. Clearance (CL) estimates the volume of blood from which the drug is cleared per unit of time. Total CL - reflects all mechanisms of drug elimination CL = Rate of elimination / plasma conc. CL = 0.693 × Vd / t1/2
  31. RATE OF ELIMINATION (R) OF PARTICULAR ORGAN R = Amount of drug entering the organ per unit time -- Amount of drug leaving the organ per unit time R = Q.CA – Q.CV Q is Rate of blood flow to that organ CA is Concentration of drug in arteries entering that organ CV is Concentration of drug in veins leaving that organ Thus, R = Q. (CA – CV) Since, CL = Rate of elimination / plasma conc. CL = Q. (CA – CV) = Q. = Q x Extraction ratio. Q. CA Extraction ratio = CL / Q
  32. HEPATIC EXTRATION RATIO • Fraction of the absorbed drug prevented by the liver from reaching systemic circulation. • Both presystemic metabolism as well as direct excretion into bile determine ERLiver, • Orally given drugs - active metabolites reach the blood • Parenterally give drug - directly reaches the blood • So if active metabolites cause more ADR than the parent drug, Oral is less safe than parenteral route.
  33. EXCRETION OF DRUGS Major routes 1. Renal 2. Biliary 3. Faecal 4. Alveolar Minor routes 1. Breast milk 2. Skin 3. Hair 4. Sweat 5. Saliva
  35. RENAL EXCRETION GLOMERULAR FILTRATION Non selective and unidirectional process Factors affecting it: • Molecular size • Plasma protein binding • Renal blood flow
  36. RENAL EXCRETION ACTIVE TUBULAR SECRETION 80% drugs eliminated PPB - doesnt interfere
  37. RENAL EXCRETION TUBULAR REABSORPTION • Passive diffusion - lipid solubility, pH of urine and pKa of the drug. • Acidic drugs are more reabsorbed - urinary pH - acidic Significance: • In poisonings, 1. Acidification of urine by Ammonium chloride / Ascorbic acid / Acetazolamide 2. Alkalinization of urine by Sodium bicarbonate / sodium citrate
  38. BILIARY EXCRETION AND ENTEROHEPATIC CIRCULATION  Drugs > 500 Da weight are secreted in bile  Conjugation with glucuronic acid increases the molecular weight of the substrate by almost 200 Da, so bile is an important route for eliminating glucuronide conjugates.  Drugs eliminated via bile into feces: • Quinine • colchicine • d-tubocurarine • corticosteroids • erythromycin Biliary Clearance = Biliary excretion rate Plasma drug conc.
  39. ENTEROHEPATIC CIRCULATION • A drug can be recycled between the gut lumen, hepatic portal vein, liver, bile and back to the gut lumen; • This is described as enterohepatic circulation. • Some of the reabsorbed drug may escape hepatic extraction and proceed into the hepatic vein, maintaining the drug concentrations in the general circulation.
  40. FAECAL ELIMINATION • Orally ingested drugs - not absorbed throughout the gut • Examples 1. Magnesium sulfate 2. Streptomycin 3. Neomycin 4. Bacitracin 5. Cholestyramine 6. Laxatives
  41. ALVEOLAR EXCRETION • Gases and volatile liquids - breath • Excretion depends on partial pressure of the gaseous drug in the blood, not on lipid solubility • Essential oils - eucalyptus oil and garlic oil - via cough / mucous expectoration.
  42. EXCRETION THROUGH BREAST MILK • pH partition principle • Basic drugs - trapped in relatively acidic pH of breast milk. • Basc drugs secreted via breast milk: 1. Chloramphenicol 2. Tetracyclines 3. Morphine 4. Metronidazole 5. Cytotoxic drugs 6. Diazepam 7. Oral contraceptives 8. Anti-histamines 9. Purgatives 10. Carbimazole • Non electrolytes: Ethanol, urea - independent of milk pH. • Acidic drugs secreted 1. Sulfonamides 2. Penicillins 3. Ampicillin 4. Dapsone 5. Phenobarbitone 6. Theophylline
  43. DRUGS TO BE AVOIDED IN LACTATING MOTHER • Chloramphenicol • Chloroquine • Primaquine • quinine • Procainamide • Nitrofurantoin • Nalidixic acid • Dapsone • Isoniazid • Probenicid • Sulfonamides
  44. EXCRETION VIA SKIN, HAIR, SWEAT AND SALIVA • Keratin precursor cells - Griseofulvin • Hair follicles - Arsenic, mercury salts, iodides • Saliva - Phenytoin, lithium, iodine, potassium iodide, Metronidazole, Disulfiram, Metoclopramide, Clarithromycin • Sweat - Amines & urea derivatives, Iodides, rifamipicin, heavy metals.
  46. TOTAL BODY CLEARANCE • The total body (systemic) clearance, CLtotal, is the sum of all clearances from the drug- metabolizing and drug-eliminating organs. Care should be exercised while administering: • renally excreted drugs; • drugs with a narrow therapeutic index—digoxin; • drugs which produce active metabolites benzodiazepines (diazepam + chlordiazepoxide), antipsychotics (risperidone, thioridazine), and opioids (morphine, pethidine, dextropropoxyphene); and • drugs that may further reduce renal function—NSAIDs.
  47. FACTORS AFFECTING DRUG METABOLISM 1. Age 2. Sex 3. Species 4. Race 5. Genetic variation 6. Nutrition and diet 7. Pregnancy 8. Thyroid imbalance 9. Temporal factors 10. Diseases 11. Drug-Drug interactions - Enzyme induction / inhibition
  48. FACTORS AFFECTING DRUG METABOLISM 1. AGE: Neonates and infants - low microsomal enzymes and glucuronyl transferase. The activity of CYP450 enzymes in neonates is <<< adult human Grey baby syndrome - chloramphenicol Floppy baby syndrome - Diazepam Elderly age - ↓ Hepatic blood flow - slow metabolism of propranolol and pethidine - toxicity 2. SEX: Males - ↑ BMR - efficient metabolism - salicylates, alcohol, propranolol and benzodiazepines.
  49. FACTORS AFFECTING DRUG METABOLISM 3. SPECIES Atropine metabolism - Rabbits > Man 4. RACE Eskimos metabolize drugs faster than Asians. Chinese - ↑ alcohol dehydrogenase, ↓ Aldehyde dehydrogenase - More aldehydes in blood - more symptoms of headache, palpitation. 5. NUTRITION AND DIET: Protein rich diet - ↑ Metabolism of drugs Carb rich diet - ↓ Metabolism of drugs Starvation - enzyme inhibition.
  51. FACTORS AFFECTING DRUG METABOLISM 7. PREGNANCY CYP2D6, CYP3A4, CYP2B6, and CYP2C9 increase. Phenytoin, midazolam, metoprolol - short t1/2 CYP1A2 and CYP2C19 decrease. (Caffiene - reduced metabolism) UGT-1A4 - ↑ N-acetyl Transferase - ↓ 8. THYROID IMBALANCE Hypothyroidism - ↓ Elimination of many drugs. Eg - Propranolol, digoxin, etc Hyperthyroidism - ↑ Metabolism. Eg - Low dose of warfarin is enough - increased turnover of Vit K dependent clotting factors. 9. TEMPORAL FACTORS Enzyme actions - ↑ in early morning
  53. KINETICS OF METABOLISM Terminologies: • Plasma Half life (t1/2) • Biological half life • Biological effect half life • Terminal half life • Steady state concentration • Plasma half life and Vd is very important to consider dosing schedule for any drug. • 3 types of kinetics  First order  Zero order  Mixed order kinetics
  54. PLASMA T1/2 • Significance of Plasma t½: To know the, The duration of action of the drug The frequency of administration The time needed for attainment of steady state concentration (SSC)—longer the t½, longer is the time needed to attain SSC. To calculate the loading and maintenance doses of the drug
  56. STEADY STATE CONCENTRATION • Repeated administration of drug at short intervals before complete elimination - Drug accumulation in the body - rate of elimination equals rate of administration. • It takes 4 - 5 half-lives for the plasma concentration to reach the plateau level.
  59. FIRST ORDER KINETICS • Drugs obey Michaelis–Menten kinetics, where Km is Michaelis constant (the substrate concentration at half maximal velocity). • In most clinical situations, Km >> [C] • Rate of drug metabolism and elimination - directly proportional - concentration of free drug. • A constant fraction of drug is metabolized per unit of time (with each half-life, the concentration decreases by 50%). • Linear kinetics
  61. ZERO ORDER KINETICS • Here [C] >> Km • Fixed amount of the drug is eliminated per unit time • The rate of elimination is constant and does not depend on the drug concentration • Non-linear kinetics • Repeated drug administration over short intervals - lead to toxicity. • The only way to speed the elimination process is to go for dialysis • The enzyme is saturated by a high free drug concentration, and the rate of metabolism remains constant over time.
  62. MIXED ORDER KINETICS OR MICHAELIS MENTON KINETICS OR SATURATION KINETICS • Low dose - first order kinetics • High doses - Zero order kinetics • Eg - Aspirin, warfarin, digoxin, tolbutamide etc. • Most of the drugs like phenytoin, undergo both first and zero order kinetics at normal doses due to saturation of enzymatic process
  63. REFERENCES 1. Goodman and Gilman - The pharmacological basis of therapeutics - 14th edition 2. Lippincott’s Pharmacology - First South Asian edition 3. K.D.Tripathi - Medical Pharmacology - 8th edition 4. Padmaja Udaykumar - Medical Pharmacology - 7th edition 5. HL & KL Sharma - Principles of Pharmacology - 3rd edition 6. Review of Pharmacology - Gobind Rai Gag - 14th edition 7. Brenner and Steven’s Pharmacology - 6th edition

Hinweis der Redaktion

  1. Metabolism of a drug can begin even before a drug is absorbed: Gut bacteria represent the first metabolic interface between orally administered drugs and the body. Interindividual differences in composition of the gut flora could influence drug action and contribute to differences in drug response Xenobiotic-metabolizing enzymes can produce electrophilic metabolites that react with nucleophilic cellular macromolecules such as DNA, RNA, and protein. This can cause cell death and organ toxicity – Carcinogenesis. This potential for carcinogenic activity makes testing the safety of drug candidates vitally important. Testing for cancer-causing potential is particularly critical for drugs that will be used for the treatment of chronic diseases.
  2. Other organs that contain significant xenobiotic metabolizing enzymes include tissues of the nasal mucosa and lung, which play important roles in the metabolism of drugs that are administered through aerosol sprays. These tissues are also the first line of contact with hazardous substances that are airborne.
  3. Prodrugs bioactivated by CYPs are the antitumor drug cyclophosphamide, which is bioactivated to a cell-killing electrophilic derivative. Anti-thrombotic agent clopidogrel, which is activated to 2-oxo-clopidogrel and further metabolized to an irreversible inhibitor of platelet ADP P2Y12 receptors.
  4. The liver is the major “metabolic clearinghouse” for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, and proteins) and xenobiotics.
  5. The phase 1 enzymes lead to the introduction of functional groups, such as –OH, –COOH, –SH, –O–, or NH2. The phase 1 oxidation reactions are carried out by CYPs, FMOs, and epoxide hydrolases (EHs). The CYPs and FMOs are composed of superfamilies and subfamilies encoded by multiple genes. The phase 2 enzymes include several superfamilies of conjugating enzymes. Among the more important are the glutathione-S-transferase (GSTs), UGTs, sulfotransferases (SULTs), N-acetyltransferases (NATs), and methyltransferases (MTs). The conjugation reactions of the phase 2 enzymes usually require the substrate to have oxygen (hydroxyl or epoxide groups), nitrogen, or sulfur atoms that serve as acceptor sites for a hydrophilic moiety, such as glutathione, glucuronic acid, sulfate, or an acetyl group, that can be covalently conjugated to an acceptor site on the substrate.
  6. Induction involves microsomal enzymes in liver as well as other organs and increases the rate of metabolism by 2–4 fold. Induction takes 4–14 days to reach its peak and is maintained till the inducing agent is being given. Thereafter the enzymes return to their original value over 1–3 weeks.
  7. Carbidopa - Decarboxylase inhibitor Disulfiram - Aldehyde dehydrogenase inhibitor
  8. Mol wt > 20000 - not filtered. Eg - Heparin, Insulin, Dextran.
  9. Plasma half-life (t½) is the time taken for the plasma concentration of a drug to be reduced to half its value Biological half-life is the time required for total amount of drug in the body to be reduced to half. Biological effect half-life is the time required for the biological effect of the drug to reduce to half. Terminal half-life: On long-term use, certain drugs may remain in secondary compartments and they get gradually released into the circulation as the plasma concentration of drugs fall.