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Classs drug metabolism

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Dr. RAGHU PRASADA M S
MBBS,MD
ASSOCIATE PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.
1

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It is chemical alteration of drug in the body, wherein
Non polar lipid soluble compounds are made
polar lipid insoluble, s...

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Drug Biotransformation –convert lipophilic /
hydrophobic drug (to enter cells) to hydrophilic
metabolites.
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Classs drug metabolism

  1. 1. Dr. RAGHU PRASADA M S MBBS,MD ASSOCIATE PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1
  2. 2. It is chemical alteration of drug in the body, wherein Non polar lipid soluble compounds are made polar lipid insoluble, so that they are easily excreted. Drugs which do not undergo biotransformation – Streptomycin, neostigmine….(highly polar drugs) Primary site – Liver Others – Kidney, Intestine, Lungs, Plasma
  3. 3. Drug Biotransformation –convert lipophilic / hydrophobic drug (to enter cells) to hydrophilic metabolites. Advantages Termination of drug action - (↓ toxicity) Reduced lipophilicity. Renal / biliary excretion ↑ - (↓renal reabs)
  4. 4. Metabolic changes by Enzymes ( Microsomal, Cytoplasmic, Mitochondrial) Spontaneous Molecular rearrangement – HOFMANN ELIMINATION Excreted unchanged (highly polar drugs) - Aminoglycosides, Methotrexate, Neostigmine
  5. 5. A) Drug inactivation - inactive or less active Propranolol, Pentobarbitone, Morphine, Chloramphenicol, Paracetamol, Ibuprofen, lignocaine B) Active drug to Active metabolite- active metabolite Effect is due to parent drug and its active metabolite
  6. 6. Phenacetin - Paracetamol Phenyl butazone - Oxyphenbutazone Primidone - Phenobarbitone Diazepam - Oxazepam Digitoxin - Digoxin Amitriptyline - Nortriptyline Codeine - Morphine Spironolactone - Canrenone Allopurinol - Alloxanthine Cefotaxime - Des acetyl cefotaxime Morphine - Morphine 6 glucuronide
  7. 7. C) Inactive drug (Prodrug) - Active drug Prodrugs are inactive drugs which need BT in the body to form active metabolites. ADV More stable Better BA Less toxicity Examples Levodopa - Dopamine Enalapril - Enalaprilat Dipivefrine - Epinephrine
  8. 8. TYPES BIOTRANSFORMATION REACTIONS - 2 TYPES Phase I / Non synthetic / Functionalization A functional group is generated Metabolite – active or inactive Phase II / Synthetic / Conjugation An endogenous radical is conjugated Metabolite is usually inactive
  9. 9. Phase I Reactions Oxidation Reduction Hydrolysis Cyclization Decyclization
  10. 10. Phase II Reactions Glucuronide conjugation Acetylation Methylation Sulfate conjugation Glycine conjugation Glutathione conjugation Ribonucleotide / Ribonucleoside synthesis
  11. 11. OXIDATION Addition of Oxygen / negatively charged radical or removal of Hydrogen / Positively charged radical Oxidation is the main process of metabolism Produces unstable intermediates - Epoxides, Superoxides, Quinones Oxidation – 9 types
  12. 12. 1.OXIDATION AT NITROGEN ATOM Chlorpheniramine Dapsone Meperidine 2.OXIDATION AT SULPHUR ATOM Chlorpromazine Chloramphenicol
  13. 13. ALIPHATIC HYDROXYLATION Hydroxyl group added to drug Salicylic acid to Gentisic acid Ibuprofen Tolbutamide, Chlorpropamide, AROMATIC HYDROXYLATION Phenytoin Phenobarbitone Propranolol
  14. 14. DEALKYLATON AT OXYGEN ATOM Phenacetin to Paracetamol 6.DEALKYLATON AT NITROGEN ATOM Amitriptyline to Nortriptyline DEALKYLATON AT SULPHUR ATOM 6Methyl thiopurine to Mercaptopurine 8.OXIDATIVE DEAMINATION Amphetamine 9.DESULFURATION Parathion to Paraoxon
  15. 15. Main enzymes are the Oxygenases – MICROSOMAL MONOOXYGENASES in liver ( Cytochrome p450/CYP )- drugs CYP( 450)s require NADPH & Oxygen Drug Metabolizing Enzymes – 2 types Microsomal – CYP 450, UDPGT Non microsomal – Flavoprotein oxidases,esterases…
  16. 16. NONMICROSOMAL OXIDATION Mitochondrial enzymes -MAO—Oxidative deamination of Adrenaline,5HT,Tyramine Cytoplasmic enzymes – Dehydrogenases Alcohol Oxidation to Acetaldehyde & Acetic Acid Plasma oxidative enzymes- Histaminase, Xanthine oxidas
  17. 17. b) REDUCTION Addition of Hydrogen / positively charged radical or removal of Oxygen / negatively charged radical MICROSOMAL REDUCTION by Monooxygenases need NADPH & cytochrome c reductase. A.NITRO Reduction- Chloramphenicol to aryl amine metabolite B.KETO Reduction – Cortisone to Hydrocortisone,
  18. 18. c) HYDROLYSIS Drug is split combining with water Ester + water Esterases Alcohol & Acid Microsomal hydrolysis Pethidine to meperidinic acid Non microsomal hydrolysis – Esterases, Amidases & Peptidases Atropine to Tropic acid
  19. 19. AZO Reduction Prontosil to Sulfanilamide NON MICROSOMAL REDUCTION Chloral hydrate to Trichloro ethanol
  20. 20. d) CYCLIZATION Formation of ring structure from a straight chain compound. Eg: Proguanil e) DE CYCLIZATION Ring structure opened Phenytoin, Barbiturates
  21. 21. CONJUGATION / TRANSFER Drug / phase I metabolite combines with endogenous substance derived from carbohydrates/ proteins. covalent bond formation between functional group of drug & endogenous substrate Endogenous-Glucuronic acid, Amino acids, Sulfates, Acetates, Glutathione Represent terminal inactivation – True detoxification reactions
  22. 22. Conjugates-hydrophilic, ionized, ↑mol.weight, Inactive Excreted in urine/ bile/ faeces. Phase II- need energy 7 types of reactions
  23. 23. 1.CONJUGATION WITH GLUCURONIC ACID UDP glucuronyl transferases Conjugates with OH & COOH are conjugated with glucuronic acid derived from glucose Drug + UDPGA Microsomal Glucuronyl transferase Drug glucuronide + UDP Drugs - Aspirin, Paracetamol, PABA, Metronidazole, Morphine, Diazepam
  24. 24. ↑Mol.weight – favours biliary excretion Drug glucuronides excreted in bile are hydrolyzed by intestinal microfloral enzymes - parent drug released - reabsorbed into systemic circulation- ↓excretion ↑duration of action Oral contraceptives, Phenolphthalein Endogenous substrates - Steroid, Thyroxine, Bilirubin
  25. 25. ACETYLATION Drugs with Amino or Hydrazine groups - INH, PAS, Hydralazine, Sulfonamides Procainamide, Dapsone. ( Code - SHIP) N Acetyl transferase Acetyl CoA Genetic polymorphism Acetylation- Rapid / Slow
  26. 26. 3. CONJUGATION WITH SULFATE Drug groups-Amino, Hydroxyl Cytoplasmic Enzymes - Sulfotransferases / Sulfokinases. Methyl dopa, Steroids, Chloramphenicol, Warfarin
  27. 27. CONJUGATION WITH GLYCINE Drug group – Carboxylic acid Salicylic acid , Benzoic acid 5. CONJUGATION WITH GLUTATHIONE Drug groups-Epoxide, Quinone Toxic metabolites of Paracetamol, Ethacrynic acid Cytoplasmic Enzyme - Glutathione S- Transferase
  28. 28. 6. METHYLATION Drugs with Amino & Phenol groups Histamine, Adrenaline, Nicotinic acid, Dopamine, Methyl dopa, Captopril Enzyme- Methyl transferase Endogenous substance- Cysteine, Methionine
  29. 29. 7. RIBONUCLEOTIDE /RIBONUCLEOSIDE SYNTHESIS Action of Purine & Pyrimidine antimetabolites 6 Mercaptopurine
  30. 30. INHIBITION OF DRUG METABOLISM One drug can inhibit the metabolism of another drug ↑ in circulating levels of slowly metabolised drug Prolongation or potentiation of its effects Consequences Precipitate toxicity of the object drug. can be therapeutically beneficial. Eg: Aversion of alcohol with disulfiram, Reversal of Skeletal Muscle paralysis of d-tc by Neostigmine
  31. 31. Valproate Ketoconazole Cimetidine Ciprofloxacin Erythromycin INH
  32. 32. MICROSOMAL ENZYME INDUCTION Drugs, insecticides, carcinogens will induce the synthesis of microsomal enzyme proteins Accelerated metabolism and reduced pharmacological response Consequences Drug- drug interactions Can lead to toxicity. Eg: Alcoholics more prone to hepatotoxicity of paracetamol due to↑ production of NABQI , Pptn of a/c intermittent porphyria by barbiturate
  33. 33. Therapeutic benefit. Eg: To treat neonatal jaundice Decreased duration of action. Eg: OCP failure Griseofulvin Phenytoin, Primidone Rifampicin Smoking Carbamazepine Phenobarbitone
  34. 34.  Metabolism - major 1) Phase I and II reactions 2) Function: change a lipid soluble to more water soluble molecule to excrete in kidney 3) Possibility of active metabolites with same or different properties as parent molecule  Biliary Secretion – active transport, 4 categories
  35. 35. Portal circulation Liver gall bladder Gut Bile duct Drug Biotransformation; glucuronide produced Bile formation Hydrolysis by beta glucuronidase
  36. 36. Liver enzymes inactivate some drug molecules First pass effect (induces enzyme activity) P450 activity is genetically determined: Some persons lack such activity  leads to higher drug plasma levels (adverse actions) Some persons have high levels  leads to lower plasma levels (and reduced drug action) Other drugs can interact with the P450 systems Either induce activity (apparent tolerance) Inactivate an enzyme system
  37. 37. Enzyme (CYP) Substrate Inhibitor Inducer 1A2 Clozapine, haloperidol Cimetidine Tobacco smoke 2B6 Bupropion Thiotepa Phenobarbital 2C19 Citalopram Fluoxetine Prednisone 2C9 Fluoxetine Paroxetine Secobarbital 2D6 Most ADs, Aps CPZ, ranitidine Dexamethasone 2E1 Gas anesthetics Disulfiram Ethanol 3A4,5,7 Alprazolam Grapefruit juiceGlucocorticoid
  38. 38.  Multiple CYP gene families have been identified in humans, and the categories are based upon protein sequence homology  Most of the drug metabolizing enzymes are in CYP 1, 2, & 3 families .  CYPs have molecular weights of 45-60 kDa.  Frequently, two or more enzymes can catalyze the same type of oxidation, indicating redundant and broad substrate specificity.  CYP3A4 is very common to the metabolism of many drugs; its presence in the GI tract is responsible for poor oral availabilty of many drugs
  39. 39.  Monoamine Oxidase (MAO), Diamine Oxidase (DAO) - MAO (mitochondrial) oxidatively deaminates endogenous substrates including neurotransmitters (dopamine, serotonin, norepinephrine, epinephrine); drugs designed to inhibit MAO used to affect balance of CNS neurotransmitters (L-DOPA); MPTP converted to toxin MPP+ through MAO-B. DAO substrates include histamine and polyamines.  Alcohol & Aldehyde Dehydrogenase - non-specific enzymes found in soluble fraction of liver; ethanol metabolism  Xanthine Oxidase - converts hypoxanthine to xanthine, and then to uric acid. Drug substrates include theophylline, 6- mercaptopurine. Allopurinol is substrate and inhibitor of xanthine oxidase; delays metabolism of other substrates; effective for treatment of gout.
  40. 40. ~60% ~35% CYP2E1* CYP1A2 CYP3A11 NAPQI N-acetyl-p-benzoquinone imine *induced by ethanol, isoniazid Protein adducts, Oxidative stress Toxicity HN COCH3 OH HN COCH3 O SO3H HN COCH3 O O CO2H OH OH HO N O COCH3

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