Vijay biotransformation
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Transcript of Vijay biotransformation
DR.VIJAYA KRISHNAPost graduate student
Department of PharmacologyGANDHI MEDICAL COLLEGE
Hyderabad, AP.
BIOTRANSFORMATION
01 AUG 2012
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
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.
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.
Why Biotransformation is necessary?:
• To easily eliminate the drug• To terminate drug action by
inactivating it By changing its physicochemical properties from:
Active /inactiveLipophilic UnionisedNonpolarPlasma protein bound
Inactive /activeHydrophilic IonisedPolarFree
Consequences of Biotransformation
• Active to Inactive: Phenobarbitone----
Hydroxyphenobarbitone• Inactive (prodrug) to Active : L-Dopa ---- Dopamine Parathion -- Paraoxon Talampicillin -- Ampicillin
• Active to equally active: Diazepam -- Oxazepam Amitriptyline -- Nortriptyline Imipramine -- Des-imipramine Codeine -- Morphine
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”.
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
• 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.
Drugs which undergo first pass effect:LI
VER • ISOSORBIDE
DINITRATE• GLYCERYL
TRINITRATE• MORPHINE• PETHIDINE• XYLOCAINE• IMIPRAMINE• AMITRIPTYLIN
E• PROPRANOLO
L
INTE
STIN
AL M
UCO
SA
• L-DOPA• ALPHA
METHYLDOPA• TESTOSTERON
E• PROGESTERON
E• CHLORPROMA
ZINE• CLONAZEPAM• MIDAZOLAM• CYCLOSPORIN
E
BRO
NCH
IAL
MU
COSA • NICOTIN
E• ISOPRIN
ALINE
With in the cell: Endoplasmic reticulum. smooth ER microsomal reactions rough ER protein synthesis
PHASES OF DRUG METABOLISM
PHASE I REACTION
PHASE II REACTION
1.Degradative reaction 1.Synthetic reaction
2.Introduction of functional group ( -OH, -NH2,-SH,-O -,-COOH)
2.Conjugates phase 1 metabolite with glucuronic acid,sulfate,acetyl, methyl groups.
3.Mainly microsomal 3.Microsomal, Mitochondrial & Cytoplasmic
4.Metabolites formed may be smaller, polar/non-polar Active/Inactive
4.Metabolites formed are usually larger,polar,water soluble & Inactive
DRUG METABOLIZING ENZYMESENZYMES REACTIONS
PHASE 1 “OXYGENASES”
CYP 450 C & O OXIDATION,DEALKYLATION,
FMO N, S & P OXIDATION
EPOXIDE HYDROLASES HYDROLYSIS OF EPOXIDES
PHASE 2 “TRANSFERASES”
SULFOTRANSFERASES(SULT) ADDITION OF SULFATE
UDP-GLUCURONOSYLTRANSFERASES(UGT) ADDITION OF GLUCURONIC ACID
GLUTATHIONE-S-TRANSFERASES(GST) ADDITION OF GLUTATHIONE
N-ACETYL TRANSFERASES(NAT) ADDITION OF ACETYL GROUP
METHYLTRANSFERASES(MT) ADDITION OF METHYL GROUP
OTHER ENZYMES
ALCOHOL DEHYDROGENASES REDUCTION OF ALCOHOLS
ALDEHYDE DEHYDROGENASES REDUCTION OF ALDEHYDES
NADPH-QUINONE OXIDOREDUCTASE(NQO) REDUCTION OF QUINONES
MICROSOMAL ENZYMES NON-MICROSOMAL ENZYMES
1.Smooth endoplasmic reticulum of cells of liver,git,kidney,lungs & skin.
1.Cytoplasm, mitochondria of hepatic & other tissues(plasma).
2.Non-specific,inducible. 2.Non-inducible.
3.PHASE-I: most oxidation & reduction, some hydrolysis.
3.PHASE-I: most hydrolysis, some oxidation & reduction.
4.PHASE-II: only glucuronide conjugation.
4.PHASE-II: all except glucuronide conjugation.
5.Mainly MFO’s like CYP 450, FMO’s, EH, UGT
5. Include MAO, esterases, amidases ,transferases , conjugases.
In the Oxido-reductase process 2 microsomal enzymes 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
CYTOCHROME P450
• Microsomal drug oxidations require p450,p450 reductase, NADPH ,O2
• Very low substrate specificity.High lipid solubility is the only common structural feature of most of substrates.
• P450 isoforms in liver –cyt1A2 ,2A6 ,2B6 ,2C8, 2C9, 2C18, 2C19, 2D6, 2E1,3A4,3A5
Of these isoforms 3A4/5 carry out biotransformation of about 50% of drugs.
P450 enzymes classified into families denoted by numbers -1,2,3 and sub families by A,B,C & D basis of AA sequence and c-DNA . Another number indicates –specific isoenzymes.
Electron flow in microsomal drug oxidizing system
CO
huCYP-Fe+2
Drug
CO
O2
e-
e-
2H+
H2O
Drug
CYPR-Ase
NADPH
NADP+
OHDrug
CYP Fe+3
Drug
CYP Fe+2
Drug
CYP Fe+2
Drug
O2
CYP Fe+3
OHDrug
CYP 450 SUBSTRATES
1A2 Acetaminophen, antipyrine, caffeine, clomipramine, phenacetin, tamoxifen, theophylline, tacrine, warfarin
2A6 Coumarin, tobacco nitrosamines, nicotine
2B6 Artemisin, bupropion, cyclophosphamide, efavirenz, ifosfamide, ketamine, mephobarbital, mephenytoin, nevirapine, propofol, selegiline, sertraline
2C8 Taxol, all-trans-retinoic acid
2C9 Celecoxib, flurbiprofen,hexobarbital,ibuprofen, losartan,phenytoin, tolbutamide, s-warfarin
2C18 Tolbutamide, phenytoin
2C19 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, ethanol
3A4, 3A5 Acetaminophen , cyclosporine, alfentanyl, cocaine, dapsone, diazepam, erythromycin, lidocaine, lovastatin, methadone ,midazolam, ethinyl estradiol, mifepristone, terfenadine,tamoxifen,saquinavir.
Microsomal: 1.oxidation – a.CYP dependent
b.CYP independent 2.reduction 3.hydrolysis
Non-microsomal: 1.oxidation 2.reduction 3.hydrolysis
PHASE-I REACTIONSReaction Structure Examples
Microsomal(Cyp 450 dependent): Oxidation
1.Aromatic hydroxylations
R- -------- R- -OH
Phenobarbitone, Phenytoin,propranolol, amphetamine, warfarin, 17α - ethenyl estradiol
2.Aliphatic hydroxylations
RCH2CH3-------> RCHOHCH3
digoxin,ibuprofen,secobarbital,chlorpropamide
PHASE-I REACTIONSReaction Structure Examples Microsomal(Cyp 450 dependent): oxidative Dealkylation
3.N-Dealkylation RN(CH3)2------ RNHCH3+CH3CHO
Mephobarbitone,amitriptyline,morphine, caffiene, theophylline
4.O-Dealkylation R-O-CH3------R-OH+HCHO
phenacetin, codiene, paranitroanisole
5.S-Dealkylation R-SCH3---- R-SH + HCHO
6-methylthiopurine
PHASE-I REACTIONSReaction Structure Example
Microsomal(Cyp 450 dependent): N-Oxidation
Primary amines RNH2------>RNHOH
Aniline, Chlorpentermine
Secondary amines R1-NH2-R2----> R1-NOH-R2
2-acetyl aminofluorene, acetaminophen
Tertiary amines NR1R2R3----> R1R2R3-N-O
nicotine, methaqualone
PHASE-I REACTIONS
Reaction Structure Examples
Microsomal(cyp 450 dependent):
S-Oxidation R1-S-R2--->R1 -SO-R2
cimetidine, chlorpromazine, omeprazole, thioridazine
Deamination R-CHNH2-R---->R-COR +NH3
Amphetamine, diazepam
Desulfurisation R1-PS-R2--->R1-PO-R2
Parathion,thiopental
Dechlorination CCl4---> [CCl3-]---> CHCl3 carbontetrachloride
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).
EPOXIDE HYDROLASE• Two types: soluble and microsomal
• Drug----------- epoxide-------- inactive metabolite.
• Ex:carbamazepine--carbamazepine-10-11-epoxide--Trans-dihydrodiol
• Valnoctamide,valproic acid inhibit mEH.
cyp EH
•Highly reactive electrophile•Binds to DNA,RNA.PROTEINS•Cell toxicity
PHASE-I REACTIONS
Reaction Structure Examples
Non-microsomal:Oxidation
Mitochondrial oxidation
R-CH(OH)CH2NH2- R-CH(OH)COOH+NH3
Epinephrine
Cytoplasmic oxidation(dehydrogenation)
C2H5OH-CH3CHO-CH3COOH
Alcohol
Plasma oxidative processes
Histamine-Imidazole acetic acidXanthine- Uric acid
PHASE-I REACTIONSReactions Structure Examples
Microsomal reductions
Nitro Reductions RNO2--RNH2 Chloramphenicol
Azo Reductions RN=NR1-RNH2+R1NH2
prontosilsulfasalazine
Keto Reduction R-CO-R1- R-CHOH-R1
cortisone, methadone, metyrapone
Non-microsomal Reductions:
C(Cl)3CH(OH)2- C(Cl)3CH2OH
Chloral hydrate
PHASE-I REACTIONSReaction Structure Examples
Microsomal Hydrolysis
Pethidine, Lidocaine
Non-Microsomal Hydrolysis
Procaine---PABAAtropine-- atropic acidPenicillin-GProcainamide
Non-Enzymatic Biotransformation
• Skeletal muscle relaxants like ATRACURIUM are metabolised in the plasma spontaneously through molecular rearrangement without involvement of any enzyme action.
ENZYME INDUCTIONXenobiotics can influence the extent of drug metabolism 1.by activating transcription 2.by inducing expression of genes
Mechanism of enzyme induction:
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.
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.
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.
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
Enzyme induction by decreased enzyme degradation(substrate s):
Troleandomycin, clotrimazole induces CYP3A Ethanol induces CYP2E1 Isosafrole induces CYP1A2
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.
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 INHIBITED
ALLOPURINOL XANTHINE OXIDASE
NSAIDS CYCLO-OXYGENASE
THEOPHYLLINE PHOSPHODIESTERASE
DISULFIRAM ALDEHYDE DEHYDROGENASE
PHASE-II REACTIONSGLUCURODINATION(microsomal): UDP-GA + substrate(Phase-I metabolite)
Glucuronides(glucopyranosiduronic acids)
Decojugated substrate
Ex: morphine, acetaminophen, diazepam, N-hydroxydapsone, digitoxin.
UGT
ALCOHOL & PHENOLIC HYDROXYL groupsCARBOXYL, SULFURYL, CARBONYL moietiesPrimary, Secondary & tertiary AMINE linkages.
Bacterial glucuronidase
• 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.
PHASE-II REACTIONSSULFATION(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.
• 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.
PHASE-II REACTIONSGLUTATHIONE 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
Electrophile-GlutathioneGST otherwise react with –O,-N,-S atoms leading to cell damage
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.
Its activity in cancerous tissue has been linked to development of resistance to chemotherapeutic agents.
Anticancer drug----> JNK &P38---->Apoptosis
-
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.
GST over expression In tumour cells
Resistance
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.”
Methylation(cytosol):
• Substrate: -N, -O, -S atoms containing compounds• Co-substrate: S-Adenosyl Methionine• Enzyme: Methyltransferase
N-Methyltransferases -Nicotinamide NMT- Serotonin, Tryptophan, Nicotinamide, Nicotine
Phenylethanolamine NMT - Norepinephrine
Histamine NMT - Histamine
Catechol-o-methyltransferase–>Dopamine,Norepinephrine, Methyldopa, Ecstasy
Phenol-o-methyltransferase –>Tyrosine metabolism
Thiopurine-s-methyltransferase ->Azathioprine, Thioguanine, 6-MP
Amino acid conjugation(mitochondria):
Substrate: aspirin, benzoic acid, nicotinic acid, deoxycholic acid Co-substrate: Glycine (or) Glutamine Enzyme: 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.
1. 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
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.
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.
FACTORS AFFECTING DRUG METABOLISM
• 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
• Genetic polymorphism: Autosomal recessive traits. PHASE-I: CYP2D6DRUG PHENOTYPE EFFECT
debrisoquin PM orthostatic hypotension
codeine PM dec. analgesic effect.
UM inc. respiratory depression
tramadol PM inc. seizure risk
nortriptyline PM inc. ADR
UM dec. therapeutic effect.
• PHASE-I: CYP2C19DRUG PHENOTYPE EFFECT
amitriptyline PM dec. clearance. inc. ADR
citalopram PM inc. GIT side effects
omeprazole EM inc. therapeutic effect
tamoxifen EM inc. endoxifen. inc. efficacy. reduces risk of relapse.
tamoxifen(cyp2d6)
PM dec. endoxifen- dec. therapeutic efficacy.
chlorproguanil EM inc. therapeutic efficacy.
• PHASE-I: CYP2C9DRUG PHENOTYPE EFFECT
CELECOXIB, DICLOFENAC
PM INC. ADR
WARFARIN PM INC. BLEEDING RISK
TOLBUTAMIDE PM CARDIOTOXICITY
PHENYTOIN PM NYSTAGMUS, DIPLOPIA, ATAXIA.
• PHASE-II:Genetic polymorphism
Drug Effect
Pseudocholine esterase
Succinylcholine Succinylcholine apnea
N-Acetyl transferase 2
Slow Acetylation
Isoniazid Pheripheral neuropathy
Sulfonamide Autoimmune response
Bicyclic Aromatic Amines
Bladder cancer
Fast Acetylation
Isoniazid Hepatotoxicity
PHASE-II:Genetic polymorphism
Drug Effect
Thiopurine-s-methyltransferase (TMPT)
Azathioprine6-MercaptopurineThioguanine
Thiopurine induced fatal Hematopoietic toxicity
UDP-Glucuronosyl transferase
Bilirubin Crigler-Najjer syndromeGilbert syndrome
Irinotecan Bone marrow toxicityLife threatening diarrhoea.
Glutathione S transferase(GST)
Acetaminophen Acetaminophen toxicity- hepatic necrosis.
Drug – Drug interaction during metabolism:
Enzyme inducer Drugs with Metabolism
Phenobarbital & other barbiturates
Barbiturates, choramphenicol, chlorpromazine, cortisol, coumarin anticoagulants, digitoxin, doxorubicin, estradiol, itraconazole, phenytoin, quinidine, testosterone, etc.
Phenytoin Cortisol, dexamethasone, digitoxin, itraconazle, theophylline.
Carbamazepine Carbamazepine, clonazepam, itraconazole
Rifampicin Coumarin anticoagulants, digitoxin, itraconazole, glucocorticoids, OC Pills, saquinavir.
St.john’s wort Alprazolam, cyclosporine, digoxin, OC Pills, indinavir, ritonavir, simvastatin, tacrolimus, warfarin
Ritonavir Acutely inhibitor of CYP3A4; Chronicly inducer-midazolam.
Drug – Drug interaction during metabolism:
Enzyme inhibitors Drugs with metabolism
Itraconazole Atorvastatin,cisapride,cyclosporine, diazepam,digoxin,indinavir, phenytoin, quinidine, sildenafil, verapamil, warfarin
Isoniazid,chloramphenicol, Allopurinol
Dicoumarol, probenecid, tolbutamide
Disulfiram Ethanol, phenytoin,warfarin
Chlorpromazine Propranolol
Grapefruit juice Alprazolam, atorvastatin, cyclosporine
Ethanol Methnol
Spironolactone Digoxin
Saquinavir Cisapride, ergots, midazolam.
OC Pills Antipyrine.
DISEASES: Liver diseases - chlordiazepoxide &
diazepam
Pulmonary diseases – procainamide, procaine,
antipyrine Hypothyroidism - antipyrine, digoxin,
methimazole, beta blockers
Cardiac diseases - hepatic blood flow – rate of metabolism - amitriptyline, desipramine, isoniazid, labetalol, propanolol, lidocaine, morphine, pentazocine, verapamil.
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