biotransformation Vijaykrishna
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  • 1. DR.VIJAYA KRISHNA Post graduate studentDepartment of Pharmacology GANDHI MEDICAL COLLEGE Hyderabad, AP. 01 AUG 2012
  • 2. PLAN OF PRESENTATION• INTRODUCTION• DEFINITION• SITES OF BIOTRANSFORMATION• PHASES OF DRUG METABOLISM• PHASE-I REACTIONS• PHASE-II REACTIONS• ENZYME INDUCTION• ENZYME INHIBITION• FACTORS AFFECTING DRUG METABOLISM• REFERENCES
  • 3. INTRODUCTION• Biotransformation/Xenobiotic metabolism/ drug metabolism/detoxification.• Xenobiotics: a wide variety of foreign compounds to which humans get exposed in day to day life.• It includes unknown compounds, drugs, environmental pollutants, toxins.• Many xenobiotics can evoke bilogical responses.
  • 4. DEFINITION• The biochemical alteration of drug or xenobiotic in the presence of various enzymes that acts as a catalyst which themselves not consumed in the reaction and there by may activate or deactivate the drug is called biotransformation.
  • 5. Why Biotransformation is necessary?:• To easily eliminate the drug• To terminate drug action by inactivating it By changing its physicochemical properties from: Active /inactive Inactive /active Lipophilic Hydrophilic Unionised Ionised Nonpolar Polar Plasma protein Free bound
  • 6. Consequences of Biotransformation• Active to Inactive: Phenobarbitone---- Hydroxyphenobarbitone• Inactive (prodrug) to Active : L-Dopa ---- Dopamine Parathion -- Paraoxon Talampicillin -- Ampicillin
  • 7. • Active to equally active: Diazepam -- Oxazepam Amitriptyline -- Nortriptyline Imipramine -- Des-imipramine Codeine -- Morphine
  • 8. Sites of biotransformation• In the body: Liver, small and large intestines, lungs, skin, kidney, nasal mucosa & brain.• Liver is considered “metabolite clearing house” for both endogenous substances and xenobiotics.• Intestines are considered “initial site of drug metabolism”.
  • 9. FIRST PASS METABOLISM:• First pass metabolism or presystemic metabolism or ‘first pass effect’• After oral administeration many drugs are absorbed from the small intestine - transported first via portal system to the liver, where they undergo extensive metabolism before reaching systemic circulation. 26
  • 10. • First pass effect :Liver-90%, Git-9% and Portal circulation-1%• Partially metabolised drugs - nitroglycerine,propranolol,salbutamol- high oral dose is required.• Complete first pass metabolism - isoprenaline, hydrocortisone, insulin.• Liver diease- increased bioavailability of drugs.
  • 11. Drugs which undergo first pass effect:LIVER • L-DOPA • NICOTINE BRONCHIAL MUCOSA INTESTINAL MUCOSA • ISOSORBIDE DINITRATE • ALPHA • ISOPRINA METHYLDOPA LINE • GLYCERYL • TESTOSTERONE TRINITRATE • PROGESTERONE • MORPHINE • CHLORPROMAZI • PETHIDINE NE • XYLOCAINE • CLONAZEPAM • IMIPRAMINE • MIDAZOLAM • AMITRIPTYLINE • CYCLOSPORINE • PROPRANOLOL
  • 12.  With in the cell: Endoplasmic reticulum. smooth ER  microsomal reactions rough ER  protein synthesis
  • 13. PHASES OF DRUG METABOLISM PHASE I REACTION PHASE II REACTION1.Degradative reaction 1.Synthetic reaction2.Introduction of functional group 2.Conjugates phase 1 metabolite( -OH, -NH2,-SH,-O -,-COOH) with glucuronic acid,sulfate,acetyl, methyl groups.3.Mainly microsomal 3.Microsomal, Mitochondrial & Cytoplasmic4.Metabolites formed may be 4.Metabolites formed are usuallysmaller, polar/non-polar larger,polar,water soluble & InactiveActive/Inactive
  • 14. DRUG METABOLIZING ENZYMESENZYMES REACTIONSPHASE 1 “OXYGENASES”CYP 450 C & O OXIDATION,DEALKYLATION,FMO N, S & P OXIDATIONEPOXIDE HYDROLASES HYDROLYSIS OF EPOXIDESPHASE 2 “TRANSFERASES”SULFOTRANSFERASES(SULT) ADDITION OF SULFATEUDP-GLUCURONOSYLTRANSFERASES(UGT) ADDITION OF GLUCURONIC ACIDGLUTATHIONE-S-TRANSFERASES(GST) ADDITION OF GLUTATHIONEN-ACETYL TRANSFERASES(NAT) ADDITION OF ACETYL GROUPMETHYLTRANSFERASES(MT) ADDITION OF METHYL GROUPOTHER ENZYMESALCOHOL DEHYDROGENASES REDUCTION OF ALCOHOLSALDEHYDE DEHYDROGENASES REDUCTION OF ALDEHYDESNADPH-QUINONE OXIDOREDUCTASE(NQO) REDUCTION OF QUINONES
  • 15. MICROSOMAL ENZYMES NON-MICROSOMAL ENZYMES1.Smooth endoplasmic reticulum 1.Cytoplasm, mitochondria ofof cells of liver,git,kidney,lungs & hepatic & other tissues(plasma).skin.2.Non-specific,inducible. 2.Non-inducible.3.PHASE-I: most oxidation & 3.PHASE-I: most hydrolysis,reduction, some hydrolysis. some oxidation & reduction.4.PHASE-II: only glucuronide 4.PHASE-II: all exceptconjugation. glucuronide conjugation.5.Mainly MFO’s like CYP 450, 5. Include MAO, esterases,FMO’s, EH, UGT amidases ,transferases , conjugases.
  • 16. CYTOCHROME P450In the Oxido-reductase process 2 microsomalenzymes play a key role Flavo proteins ,NADPH –cyt p-450 oxido-reductase Haemoprotein,cyt p-450 serves as terminal oxidase • P450 heme reduction is rate limiting step
  • 17. • Microsomal drug oxidations require p450,p450 reductase, NADPH ,O2• Very low substrate specificity.High lipid solubilityis the only common structural feature of most ofsubstrates.• P450 isoforms in liver –cyt1A2 ,2A6 ,2B6 ,2C8,2C9, 2C18, 2C19, 2D6, 2E1,3A4,3A5
  • 18. Of these isoforms 3A4/5 carry outbiotransformation of about 50% of drugs.P450 enzymes classified into families denoted bynumbers -1,2,3 and sub families by A,B,C & Dbasis of AA sequence and c-DNA . Anothernumber indicates –specific isoenzymes.
  • 19. NADP+ Drug CYP CYP Fe+3 e- R-Ase Drug Drug OHNADPH CO CYP Fe+3 COCYP-Fe+2 CYP Fe+2 Drug OH Drug hu Drug e- O2 CYP Fe+2 H2O O2 Drug 2H+ Electron flow in microsomal drug oxidizing system
  • 20. CYP 450 SUBSTRATES1A2 Acetaminophen, antipyrine, caffeine, clomipramine, phenacetin, tamoxifen, theophylline, tacrine, warfarin2A6 Coumarin, tobacco nitrosamines, nicotine2B6 Artemisin, bupropion, cyclophosphamide, efavirenz, ifosfamide, ketamine, mephobarbital, mephenytoin, nevirapine, propofol, selegiline, sertraline2C8 Taxol, all-trans-retinoic acid2C9 Celecoxib, flurbiprofen,hexobarbital,ibuprofen, losartan,phenytoin, tolbutamide, s-warfarin2C18 Tolbutamide, phenytoin2C19 Diazepam, s-mephenytoin, naproxen, nirvanol, omeprazole, propranolol.2D6 Bufurolo, clozapine, debrisoquin, dextromethorphan, encainaide, fluoxetine, haloperidol, metoprolol, selegiline, tamoxifen, tricyclic antidepressants.2E1 Acetaminophen, chlorzoxazone, enflurane, halothane, ethanol3A4, 3A5 Acetaminophen , cyclosporine, alfentanyl, cocaine, dapsone, diazepam, erythromycin, lidocaine, lovastatin, methadone ,midazolam, ethinyl estradiol, mifepristone, terfenadine,tamoxifen,saquinavir.
  • 21.  Microsomal: 1.oxidation – a.CYP dependent b.CYP independent 2.reduction 3.hydrolysis Non-microsomal: 1.oxidation 2.reduction 3.hydrolysis
  • 22. PHASE-I REACTIONSReaction Structure ExamplesMicrosomal(Cyp 450 dependent):Oxidation1.Aromatic R- -------- Phenobarbitone,hydroxylations Phenytoin, R- -OH propranolol, amphetamine, warfarin, 17α - ethenyl estradiol2.Aliphatic RCH2CH3-------> digoxin,ibuprofen,shydroxylations RCHOHCH3 ecobarbital,chlorpr opamide
  • 23. PHASE-I REACTIONSReaction Structure ExamplesMicrosomal(Cyp 450 dependent):oxidative Dealkylation3.N-Dealkylation RN(CH3)2------ Mephobarbitone, RNHCH3+CH3CHO amitriptyline, morphine, caffiene, theophylline4.O-Dealkylation R-O-CH3------ phenacetin, codiene, R-OH+HCHO paranitroanisole5.S-Dealkylation R-SCH3---- R-SH + 6-methylthiopurine HCHO
  • 24. PHASE-I REACTIONSReaction Structure ExampleMicrosomal(Cyp 450 dependent):N-OxidationPrimary amines RNH2------>RNHOH Aniline, ChlorpentermineSecondary amines R1-NH2-R2----> 2-acetyl R1-NOH-R2 aminofluorene, acetaminophenTertiary amines NR1R2R3----> nicotine, R1R2R3-N-O methaqualone
  • 25. PHASE-I REACTIONSReaction Structure ExamplesMicrosomal(cyp 450dependent):S-Oxidation R1-S-R2---> cimetidine, R1 -SO-R2 chlorpromazine, omeprazole, thioridazineDeamination R-CHNH2-R----> Amphetamine, diazepam R-COR +NH3Desulfurisation R1-PS-R2---> Parathion, R1-PO-R2 thiopentalDechlorination CCl4---> [CCl3-]---> CHCl3 carbontetrachloride
  • 26. Flavin Monooxygenases• Also known as zeigler’s enzyme. Neither inducible nor inhibited.• six families-FMOs(FMO3 being the most abundant in liver.)• FMO3 is able to metabolize nicotine,cimetidine and ranitidine,clozapine and itopride.• A genetic deficiency in this enzyme causes the fish-odor syndrome due to a lack of metabolism of trimethylamine N-oxide (TMAO) to trimethylamine (TMA).
  • 27. EPOXIDE HYDROLASE• Two types: soluble and microsomal cyp EH• Drug----------- epoxide-------- inactive metabolite. •Highly reactive electrophile •Binds to DNA,RNA.PROTEINS •Cell toxicity• Ex:carbamazepine--carbamazepine-10-11- epoxide--Trans-dihydrodiol• Valnoctamide,valproic acid inhibit mEH.
  • 28. PHASE-I REACTIONSReaction Structure ExamplesNon-microsomal:OxidationMitochondrial R-CH(OH)CH2NH2- Epinephrineoxidation R-CH(OH)COOH+NH3Cytoplasmic C2H5OH-CH3CHO- Alcoholoxidation CH3COOH(dehydrogenation)Plasma oxidative Histamine-Imidazoleprocesses acetic acid Xanthine- Uric acid
  • 29. PHASE-I REACTIONSReactions Structure ExamplesMicrosomalreductionsNitro Reductions RNO2--RNH2 ChloramphenicolAzo Reductions RN=NR1- prontosil RNH2+R1NH2 sulfasalazineKeto Reduction R-CO-R1- R- cortisone, CHOH-R1 methadone, metyraponeNon-microsomal C(Cl)3CH(OH)2- Chloral hydrateReductions: C(Cl)3CH2OH
  • 30. PHASE-I REACTIONSReaction Structure ExamplesMicrosomal Pethidine,Hydrolysis LidocaineNon-Microsomal Procaine---Hydrolysis PABA Atropine-- atropic acid Penicillin-G Procainamide
  • 31. Non-Enzymatic Biotransformation• Skeletal muscle relaxants like ATRACURIUM are metabolised in the plasma spontaneously through molecular rearrangement without involvement of any enzyme action.
  • 32. ENZYME INDUCTIONXenobiotics can influence the extent of drug metabolism1.by activating transcription2.by inducing expression of genes
  • 33. Mechanism of enzyme induction:
  • 34. Aryl hydrocarbon Receptor(AHR):• Induces CYP1A1,1A2,1B1--> activates procarcinogens• Omeprazole is ligand.• AHR is a member of super family of transcription factors (PERIOD,SIMPLEMINDED,HIF).• AHR has regulatory role in the development of mammalian CNS – modulating the response to chemical & oxidative stress.
  • 35. Pregnane X Receptor:• Structurally similar to steroid hormone receptors.• Induces CYP3A4 ,Drug Transporters, SULT’s, UGT’s• LIGANDS: Pregnanolone-16-carbonitrile, Rifampin, Troleandomycin, Nifidipine, Mevastatin, troglitazone, Ritonavir, paclitaxel, hyperforin.• Basis for contraceptive failure.
  • 36. Constitutive Androstane Receptor(CAR):• Can activate genes even in absence of their ligands.• LIGANDS: Pesticide 1,4-bisbenzene, 5-pregnane-3,20-dione.• Induces CYP2B6, 2C9, 3A4, GST, UGT, SULT, Drug & endobiotic transporters.• Inverse agonists-androstanol, clotrimazole,meclizine PXR & CAR exhibits species differenceEx: 1.Rifampicin activates human PXR but not that of Rat.2.Pregnanolone-16-carbonitrile- activates mouse,rat PXR.3.Meclizine inhibits human CAR but activates mouse CAR.
  • 37. Peroxisome Proliferator Activated Receptor α(PPARα):• Highly expressed in liver & kidney.• LIGAND: 1.fibrates(gemfibrozil, fenofibrate), 2. hypoglycemic drugs(rosiglitazone, pioglitazone)• Induces 1.enzymes- fatty acids(Arachidonic acid) 2.CYP4A - oxidation of FA & drugs with FA side chain(leukotiene analogues)• PPARα does not induce xenobiotic metabolism
  • 38. Enzyme induction by decreased enzyme degradation(substrate s): Troleandomycin, clotrimazole induces CYP3A Ethanol induces CYP2E1 Isosafrole induces CYP1A2
  • 39. ENZYME INHIBITION• It is basis for several drug interactions. It is a rapid process.• Microsomal: 1.Reversible – cimetidine & ketoconazole binds tightly to cyp450 heme iron and inhibits metabolism of testosterone.• Troleandomycin & Erythromycin--> CYP3A4--> cyp3A4-metabolite complex.• Proadifen(SKF-525-A)--> bind tightly to heme iron and partially irreversibly inhibits enzyme.
  • 40. 2. Irreversible(suicidal inhibitors)- intermediate metabolite bind covalently with P450 apoprotien. Ex: spironolactone, ethinyl estradiol, ritonavir But Secobarbital inhibits CYP2B1 by binding to heme & protein moieties.Non-microsomal:DRUG ENZYME INHIBITEDALLOPURINOL XANTHINE OXIDASENSAIDS CYCLO-OXYGENASETHEOPHYLLINE PHOSPHODIESTERASEDISULFIRAM ALDEHYDE DEHYDROGENASE
  • 41. PHASE-II REACTIONSGLUCURODINATION(microsomal): UDP-GA + substrate(Phase-I metabolite) ALCOHOL & PHENOLIC HYDROXYL groups CARBOXYL, SULFURYL, CARBONYL moieties Primary, Secondary & tertiary AMINE linkages. UGT Glucuronides(glucopyranosiduronic acids) Bacterial glucuronidase Decojugated substrateEx: morphine, acetaminophen, diazepam, N- hydroxydapsone, digitoxin.
  • 42. • UGT are encoded by 19 genes(9genes on UGT1 locus- chr.2 & 10genes on UGT2 locus-chr.4)• UGT1- Glucuronidation of Bilirubin-rate limiting step.• UGT2 have greater specificity for endogenous substances(steroids) glucurodination.
  • 43. PHASE-II REACTIONSSULFATION(cytosolic): Sulfotransferase(SULT) conjugates sulfate- PAPS to the hydroxyl groups & less frequently to aromatic and aliphatic amine groups (acetaminophen, hydroxycoumarins). SULT has 13 isoforms. SULT play an important role in normal human homeostasis. SULT2B1b –skin-cholesterol-cholesterol sulfate- regulates keratinocyte differentiation & skin development.
  • 44. • SULT2A1-fetal adrenal gland -dehydroepiandrosterone - DHEA sulfate-essential for placental Estrogen biosynthesis during 2nd half of pregnancy.• SULT1A3- highly selective for catecholeamines.• SULT1E1-sulfates endogenous & exogenous steroids. Ex:-Estrogen(17-estradiol)-estrogen sulfate.• In humans significant fractions of circulating catecholamines,estrogens,iodothryronines, DHEA are exist in sulfate form.
  • 45. PHASE-II REACTIONSGLUTATHIONE CONJUGATION :Glutathione(GSH) is a tripeptide of glycine - glutamic acid - cysteine.• GSH exists in cell as oxidized form(GS-SH) and reduced form(GSH).• GSH:GSSH ratio is critical in maintaining cellular environment to be in reduced state.• GSH + Electrophilic compound GST otherwise react with –O,-N,-S atoms leading to cell damage Electrophile-Glutathione
  • 46. GLUTATHIONE-S-TRANSFERASE(GST):• exists in 20 isoforms.• Cytosolic GST isoforms -7classes - exogenous drugs & xenobiotics (acetaminophen, ethacrynic acid, bromobenzene)• Microsomal GST isoforms-endogenous leukotrienes & prostaglandins.• GST play an important role in cellular detoxification.
  • 47.  Its activity in cancerous tissue has been linked to development of resistance to chemotherapeutic agents. Anticancer drug----> JNK &P38---->Apoptosis - Resistance GST over expression In tumour cells Inhibition of GST activity sensitises tumour cells to anticancer drugs. TLK199(GSH analogue) activated by plasma esterase to TLK117(GST inhibitor) which potentiates toxicity of anticancer drugs.
  • 48.  N-Acetylation(cytosol):• Substrate- Aromatic amine groups & Hydrazine group such as sulfonamides,isoniazid,clonazepam, dapsone,etc.• Co-substrate- acetyl coenzyme A• Enzyme- N-Acetyl Transferase NAT1 & NAT2 – 25 Allelic variants are identified. NAT2 mutation – slow & fast acetylation. Field of pharmacogenetics has established by the identification of “The characterisation of an Acetylator phenotype.”
  • 49.  Methylation(cytosol):• Substrate: -N, -O, -S atoms containing compounds• Co-substrate: S-Adenosyl Methionine• Enzyme: Methyltransferase Nicotinamide NMT- Serotonin, Tryptophan, Nicotinamide, NicotineN-Methyltransferases - Phenylethanolamine NMT - Norepinephrine Histamine NMT - HistamineCatechol-o-methyltransferase–>Dopamine,Norepinephrine, Methyldopa, EcstasyPhenol-o-methyltransferase –>Tyrosine metabolismThiopurine-s-methyltransferase ->Azathioprine, Thioguanine, 6-MP
  • 50. Amino acid conjugation(mitochondria):Substrate: aspirin, benzoic acid, nicotinic acid, deoxycholic acidCo-substrate: Glycine (or) GlutamineEnzyme: acyl coenzyme A-glycinetransferase Riboside & Riboside phosphates: Many purines & pyrimidines form their active metabolites by forming ribonucleosides and ribonucleotides. Purines and pyrimidines are used as antimetabolites in cancer chemotherapy.
  • 51. FACTORS AFFECTING DRUG METABOLISM1. AGE: Neonates-low microsomal enzymes & glucuronyl transferase enzyme activity. ex: chloramphenicol-poor glucuronyl conjugation- Gray baby syndrome. Elderly persons- reduced hepatic blood flow. Ex: propranolol & pethidine
  • 52. FACTORS AFFECTING DRUG METABOLISM• Sex: male rats metabolise the drugs much faster than female rats and prepubertal male rats. male rats sleep for a shorter duration than female rats after receiving hexobarbital. In Humans similar sex differences exist for propranolol, ethanol, estrogens, salicylates.
  • 53. FACTORS AFFECTING DRUG METABOLISM• Species: Rabbits metabolise Atropine faster than man as they have high Atropine esterase activity in the liver and plasma.• Race: Chinese- high alcohol dehydrogenase activity & low Aldehyde dehydrogenase activity- high plasma aldehyde conc.- headache, palpitation after consuming alcohol.
  • 54. • Diet and environment: Low carbohydrate-high protein diet- metabolism. High carbohydrate-low protien diet- metabolism. Starvation – enzyme inhibition. Charcoal- broiled foods & cruciferous vegetables induce CYP1A. Grapefruit juice inhibit CYP3A. Cigarette smokers metabolise some drugs more rapidly than non-smokers
  • 55. • Genetic polymorphism: Autosomal recessive traits. PHASE-I: CYP2D6DRUG PHENOTYPE EFFECTdebrisoquin PM orthostatic hypotensioncodeine PM dec. analgesic effect. UM inc. respiratory depressiontramadol PM inc. seizure risknortriptyline PM inc. ADR UM dec. therapeutic effect.
  • 56. • PHASE-I: CYP2C19DRUG PHENOTYPE EFFECTamitriptyline PM dec. clearance. inc. ADRcitalopram PM inc. GIT side effectsomeprazole EM inc. therapeutic effecttamoxifen EM inc. endoxifen. inc. efficacy. reduces risk of relapse.tamoxifen PM dec. endoxifen- dec.(cyp2d6) therapeutic efficacy.chlorproguanil EM inc. therapeutic efficacy.
  • 57. • PHASE-I: CYP2C9DRUG PHENOTYPE EFFECTCELECOXIB, PM INC. ADRDICLOFENACWARFARIN PM INC. BLEEDING RISKTOLBUTAMIDE PM CARDIOTOXICITYPHENYTOIN PM NYSTAGMUS, DIPLOPIA, ATAXIA.
  • 58. • PHASE-II:Genetic Drug EffectpolymorphismPseudocholine esterase Succinylcholine Succinylcholine apneaN-Acetyl transferase 2 Slow Acetylation Isoniazid Pheripheral neuropathy Sulfonamide Autoimmune response Bicyclic Aromatic Bladder cancer Amines Fast Acetylation Isoniazid Hepatotoxicity
  • 59. PHASE-II:Genetic Drug EffectpolymorphismThiopurine-s- Azathioprine Thiopurine inducedmethyltransferase 6-Mercaptopurine fatal Hematopoietic(TMPT) Thioguanine toxicityUDP-Glucuronosyl Bilirubin Crigler-Najjertransferase syndrome Gilbert syndrome Irinotecan Bone marrow toxicity Life threatening diarrhoea.Glutathione S Acetaminophen Acetaminophentransferase(GST) toxicity- hepatic necrosis.
  • 60. Drug – Drug interaction during metabolism:Enzyme inducer Drugs with MetabolismPhenobarbital & other Barbiturates, choramphenicol, chlorpromazine,barbiturates cortisol, coumarin anticoagulants, digitoxin, doxorubicin, estradiol, itraconazole, phenytoin, quinidine, testosterone, etc.Phenytoin Cortisol, dexamethasone, digitoxin, itraconazle, theophylline.Carbamazepine Carbamazepine, clonazepam, itraconazoleRifampicin Coumarin anticoagulants, digitoxin, itraconazole, glucocorticoids, OC Pills, saquinavir.St.john’s wort Alprazolam, cyclosporine, digoxin, OC Pills, indinavir, ritonavir, simvastatin, tacrolimus, warfarinRitonavir Acutely inhibitor of CYP3A4; Chronicly inducer- midazolam.
  • 61. Drug – Drug interaction during metabolism:Enzyme inhibitors Drugs with metabolismItraconazole Atorvastatin,cisapride,cyclosporine, diazepam,digoxin,indinavir, phenytoin, quinidine, sildenafil, verapamil, warfarinIsoniazid,chloramphenicol, Dicoumarol, probenecid, tolbutamideAllopurinolDisulfiram Ethanol, phenytoin,warfarinChlorpromazine PropranololGrapefruit juice Alprazolam, atorvastatin, cyclosporineEthanol MethnolSpironolactone DigoxinSaquinavir Cisapride, ergots, midazolam.OC Pills Antipyrine.
  • 62. DISEASES: Liver diseases - chlordiazepoxide & diazepam Cardiac diseases - hepatic blood flow – rate of metabolism - amitriptyline, desipramine, isoniazid, labetalol, propanolol, lidocaine, morphine, pentazocine, verapamil. Pulmonary diseases – procainamide, procaine, antipyrine Hypothyroidism - antipyrine, digoxin, methimazole, beta blockers
  • 63. REFERENCES• Goodman Gilman - The Pharmacological Basis of Therapeutics, 12th Edition• Katzung – Basic & Clinical Pharmacology, 12th Edition• Sharma – Priciples of Pharmacology, 2nd Edition• www.google .com