B.Pharm. Class Notes and Handouts

• Conservation is the process of management of biosphere in order to obtain the greatest benefit for the present generation and maintaining the potential for future. • Conservation of medicinal plant resources is of global concern because we don't know what we are losing and what we will need in future. DRUG METABOLISM Presented by Saroj kanta Bisoyi Asst.Professor RCPHS, BAM INTRODUCTION Biotransformation: Chemical alteration of the drug in body that converts nonpolar or lipid soluble compounds to polar or lipid insoluble compounds. Drug metabolism may be defined as the biochemical modification of one chemical form to another, occurring usually through specialised enzymatic systems. It often involves the conversion of lipophilic chemical compounds (drugs) into highly polar derivatives that can be easily excreted from the body. FUNCTION OF BIOTRANSFORMATION 1) It causes conversion of an active drug to inactive or less active metabolite(s) called as pharmacological inactivation. Example of drug follow by this mechanism. Phenobarbitone P-hhdroxy phenobarbitone Phenytoin P-Hydroxy phenytoin Procaine P-amino benzoic acid 2) It causes conversion of an active to more active metabolite(s) called as bioactivation or toxicological activation. Codeine Morphine Halothane Trifluoro acetic acid paracetamol N –Hydroxylation derivative 3) It causes conversion of an Inactive drug active metabolite. Ex of drug follow by this mechanism. Levodopa- dopamine SITE/ORGANS OF DRUG METABOLISM The major site of drug metabolism is the liver (microsomal enzyme systems of hepatocytes). Secondary organs of biotransformation ➢ kidney (proximal tubule) ✓ lungs ➢ testes ➢ skin ➢ intestines LIVER The primary site for metabolism of almost all drugs because it is relatively rich in a large variety of metabolising enzymes. Metabolism by organs other than liver (called as extra- hepatic metabolism) is of lesser importance because lower level of metabolising enzymes is present in such tissues. A few drugs are also metabolised by non-enzymatic means called as nonenzymatic metabolism. The drug metabolising enzymes can be broadly divided into two groups: microsomal and non-microsomal enzymes. TYPE OF DRUG METABOLISM The metabolism of drug in the body is achieved by two types of reactions .these reactions are 1) Phase-I reaction 2) Phase-II reaction Phase 1 reaction. (Non synthetic phase). ➢ a change in drug molecule. generally results in the introduction of a functional group into molecules or the exposure of new functional groups of molecules. PHASE –I REACTION ❖ In this reaction a functional polar group (ie-OH,COOH,NH2,SH) is introdused to drug or in xenobiotics to convert them into more water soluble compounds so they are easily excreted out from the body. Phase-1 reaction convert the parent drug into polar metabolites by three ways. a) Oxidation reaction b) Reduction reaction C) Hydrolysis reaction A) OXIDATION REACTIONS Addition of oxygen/ negatively charged radical or removal of hydrogen/ positvely charged radical. Reactions are carried out by group of enzyme monooxygenases in the liver. Fianl step: Involves cytochrome P-450 haemoprotein, NADPH, cytochrome P-450 reductase and O2 CYTOCHROME P FAMILY Multiple CYP gene families have been identified in humans, and the categoriezed based on protein sequence homology Most of the drug metabolizing enzymes are in CYP 1, 2, & 3 families . CYP3A4 is very common to the metabolism of many drugs. CYTOCHROMES: METABOLISM OF DRUGS CYP Enzyme Examples of substrates 1A1 Caffeine, Testosterone, R-Warfarin 1A2 Acetaminophen, Caffeine, Phenacetin, R-Warfarin 2A6 Estradiol, Testosterone 2B6 Cyclophosphamide, Erythromycin, Testosterone 2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, SWarfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin, Zidovudine (2C8,9,19); 2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane 2D6 Acetaminophen, Codeine, Debrisoquine 3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine, Cortisol, Erythromycin, Cyclophosphamide, S- and R Warfarin, Phenytoin, Testosterone, Halothane NON-CYP DRUG OXIDATIONS Monoamine Oxidase (MAO), Diamine Oxidase (DAO) ➢ MAO (mitochondrial) oxidatively deaminates endogenous substrates including neurotransmitters’ ➢ Dopamine, serotonin, norepinephrine, epinephrine Alcohol & Aldehyde Dehydrogenase ➢ Non-specific enzymes found in soluble fraction of liver ➢ Ethanol metabolism TYPES OF DRUG METABOLISM OXIDATION REACTIONS Aromatic and side chain hydroxylation. Oxidation of benzylic carbon atom Oxidation of allylic carbon atom Oxidation at the carbon alpha to carbonyl and imino group. Oxidatiive N and O-dealkylation N- oxidation and sulphur oxidation. Desulphuration 1) AROMATIC AND SIDE CHAIN HYDROXYLATION. Hydroxylation means addition of –OH group to the aromatic ring. The reaction involves the formation of an epoxides as an intermediate and under goes rearrangement to form phenolic products 1) AROMATIC AND SIDE CHAIN HYDROXYLATION. 5) OXIDATIVE N AND O-DEALKYLATION oxidative N and O-dealkylation involves hydroxylation of alpha carbon adjecent to amino group and oxygen to form carbinolamine or hemiactal as an intermedite than undergoes clevage to release the alkyl group and the drug metabolites. 5) OXIDATIVE N AND O-DEALKYLATION REDUCTION Nitro,azo and carbonyl group containg drug are easily redused by various enzyme present in the body (reductase enzyme). reduction of aromatic nitro group reduced to primary amine as metabolites. AZO GROUP CONTAINING DRUGS UNDERGOES ENZYMATIC REDUCTION GIVE TWO AMINES. CARBONYL CONTINING DRUG ON ENZYMATIC REDUCTION GIVES ALCOHOL AS METABILITES. HYDROLYSIS REACTION Drugs containing ester or amide functional group undergoes metabolism by this pathways. HYDROLYSIS Drugs containing ester or amide functional group undergoes metabolism by this pathways. AMIDE DRUGS LIKE LIGNOCAINE UNDERGOES HYDROLYSIS TO FORM AMINE Hydrolysis of amide is very slow as compared to esters. The drug produced by hydrolysis get easily excreted as compared to parent drugs. These products have high polarity and easily show conjugation reactions. PHASE-II DRUG METABOLISAM These are also called conjugation reaction. Last step in detoxification reactions and almost always results in loss of biological activity of a compound. May be preceded by one or more of phase I reaction . The products formed after phase-II reactions are generally inactive. It involve conjugation with various endogeneous substances like glucuronic acid,amino acids,glutathion etc. PHASE –II METABOLISM OCCURS BY FOLLOWING PATHWAYS 1) Glucuronidation 2) Glutathione conjugation 3) Sulphate conjugation 4) Methylation 5) Acetylation 6) Aminoacid conjugation 1) GLUCURONIDATION Also known as glucuronic acid conjugation. Phase-1 metabolites having free alcoholic or phenolic groups cojugates with glucuronic acid to form ether or ester glucuronides. This process is done by the help of the enzyme glucuronyl transferase. 1) GLUCURONIDATION The transfer of glucuronyl group to the drug takes place by the coenzyme UDPGA (uridine diphospho-α-d-glucuronic acid). Glucuronides formed are normally non toxic,highly polar and easily excreted in the urine or biles. It mainly occurs in many tissues like kidney,skin,intenstine,lungs and brain. 4-HYDROXY PHENYTOIN FORM IN PHASE-1 REACTION FORM PHENYTOIN –O- GLUCURONIDE MORPHINE PRODUCES MORPHINE GLUCURONIDES. GLUTATHIONE CONJUGATION Also known as mercaptouric acid is a thiol containing tripeptide.γ-glutamyl cysteine glycine Electron deficient metabolites like alkyl aryl halides,sulphates,sulphonates,nitrates produced by phase-I metabolism conjugates with glutathione. That catalysed by the enzyme glutathione transferase. METABOLISM OF ETHACRYNIC ACIDS SULPHATE CONJUGATION Drug having hydroxy groups,phenols and aromatic amines under goes sulphate conjugation. It occurs by the enzyme sulphotransferase and coenzyme PAPS(Phosphoadenosine phosphosulphate). Mostly the steroidal drugs undergoes by this reaction The proces occurs mostly in the liver ,kidney and intenstine. Ex-Estrone on metabolism produces estrone sulphate. ESTRONE METABOLISM METHYLATION Most of the endogeneous amine are metabolise by this methylation conjugation. Mostly methyl group is attached with the help of coenzyme SAM(S-adenosyl methionine) and enzyme methyl transferase. ACETYLATION Acetylation inlvoves conjugation reaction with acetyl coA by using the enzyme N-Acetyl transferase present in liver ,lngs,spleen and gastric cell and red blood cells. Drug contains Hydrazino functional group undergoes acetylation. Ex- Isoniazid gets acetylted to form acetyl isoniazid AMINO ACIDS CONJUGATION Drugs having aromatic acids and aryl alkyl acids as functional group undergoes conjugation with amino acids like glycine and glutamic acids. Metabolites of phase-I reaction having carboxyl group also conjugates with glycine. Ex-Benzoic acid conjugates with glycine to form hippuric acid DIPHENHYDRAMINE METABOLISM FACTROR AFFECTING METABOLISM Some physical,chemical and biological factors affects the metabolism of a drugs. These are 1) Physiochemical properties of the drug molecules. ✓ physiochemical properties like size,,shape,acidity and basicity,lipophilicity,solubility,pka value of drugs molecules affects drug metabolism. 2) CHEMICAL FACTORS Various chemical affects the metabolism of the drugs. these are a) Enzyme inducer b) Enzyme inhibitors A) ENZYME INDUCER These are the chemical which increases metabolism. Ex-3-methyl cholanthrene and cigarette smoke increases

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