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Metabolism of Drugs
PRESENTE MODERATO R Dr. R. Janarthanan R Dr. Jyoti Patil 1st Year MBBS ASSISTANT PROFESSOR Dept. of Pharmacology Dept. of Pharmacology BLDE BLDE INTRODUCTIO N • Termination of Drug Action - Biotransformation, Excretion and Tissue Reabsorption
• TERMS : Biotransformation, Detoxification, Drug Metabolism
• DEFINITION : Enzyme - catalyzed biochemical transformation of drugs within the
living organisms.
• The biotransformation reaction of any drug may have three different consequences ⚬ Active Drug to Inactive Drug ( Phenobarbitone to Hydroxyphenobarbitone) ⚬ Inactive Drug to Active Drug ( PRO - Drugs : L-DOPA to Dopamine) ⚬ Active Drug to Equally Active drug (Diazepam to Oxazepam) FIRST PASS METABOLISM • All drugs taken orally, first of all, pass through GIT wall and then through portal system,
before reaching the systemic circulation.
• First-Pass Metabolism - drug metabolism occurring before the drug enters the systemic
circulation. • Decreased bioavailability of the drug diminished therapeutic response, because a
significant amount of the drug is inactivated before reaching the systemic circulation. • The first-pass effect may be bypassed if the drug is administered parenterally or
sublingually PHASES OF DRUG METABOLISM Phase I Reactions
⚬ Degenerative reactions ⚬ Smaller Polar/Non-polar metabolites by introduction of new group (-OH, -NH2) ⚬ Oxidation, Reduction, Hydrolysis. ⚬ Metabolite formed may - Active/Inactive
Phase II Reactions
⚬ Synthetic/ Conjugation reactions
⚬ Catalyzed by Microsomal, Mitochondrial or Cytoplasmic enzymes ⚬ Metabolite formed is mostly Inactive ⚬ Drug which acquire reactive groups ( NH2, COOH or OH ) in Phase I reaction undergoes Phase II reaction DRUG METABOLIZING ENZYMES 1. Microsomal Enzymes:
⚬ Location: Smooth endoplasmic reticulum of liver, also in intestines, lungs, kidneys.
⚬ Functions: Phase II reactions (except glucuronidation), certain oxidations, reductions,
hydrolytic reactions.
⚬ Characteristics: Non-inducible, can be inhibited, show genetic variation.
ENZYMATIC BIOTRANSFORMATIO N PHASE I REACTIONS: OXIDATIONS • Microsomal Oxidations (CYP-dependent):
⚬ Aromatic Hydroxylations: Phenobarbitone to p-hydroxyphenobarbitone.
⚬ Aliphatic Hydroxylations: Pentobarbitone to hydroxypentobarbitone. ⚬ N-, O-, and S-Dealkylation: Morphine to normorphine. ⚬ N- and S-Oxidation: Trimethylamine to trimethylamine N-oxide. ⚬ Deamination: Amphetamine to phenylacetone derivative. ⚬ Desulfurisation: Parathion to paraoxon.
• Non-microsomal Oxidations:
⚬ Mitochondrial Oxidations: Epinephrine to vinyl-mandelic acid.
⚬ Cytoplasmic Oxidation: Alcohol to acetic acid. ⚬ Plasma Oxidation: Histamine to imidazole acetic acid. PHASE I REACTIONS: REDUCTIONS • Microsomal Reductions:
⚬ Nitro Reduction: e.g., Chloramphenicol to arylamine metabolite.
⚬ Azo Reduction: e.g., Prontosil to sulfanilamide. ⚬ Keto Reduction: e.g., Cortisone to hydroxycortisone.
• Non-microsomal Reductions:
⚬ Example: Chloral hydrate to trichloroethanol.
PHASE I REACTIONS: HYDROLYSIS
• Microsomal Hydrolysis:
⚬ Rare Example: Pethidine to pethidinic acid.
• Non-microsomal Hydrolysis:
⚬ Mainly for esters and amides Example: Procaine to PABA
PHASE II REACTIONS: CONJUGATIONS • Microsomal Conjugations:
