Title 4. DRUG ELIMINATION.pdf ✅

PHARMD GURU Page 1 INTRODUCTION: Drug elimination is the process of irreversible removal of drug from the body. Excretion and biotransformation are the two major components of drug elimination. Drug elimination is expressed as first-order elimination rate process. Excretion is a process of removal of the intact drug by renal or non-renal route from internal to external environment. The duration of drug action and rate of drug elimination is determined by excretion along with metabolism. The drug can be excreted by any pathway: i. If excretion of drug occurs through the kidney then it is referred as renal excretion. ii. If excretion of drug occurs by any other organ, then it is referred as non-renal excretion Biotransformation, is also called metabolism, is defined as the biochemical conversion of drug into another chemical form. Biotransformation includes enzymatically driven chemical conversion, but some of the drugs may be chemically changed by a non-enzymatic process. Xenobiotics, which are substances foreign to the body, are, metabolized or biotransformed to more water soluble compounds, because water soluble compounds are more readily excreted. Hence lipophilic drugs which are not readily eliminated or metabolized to more polar DRUG ELIMINATION As per PCA syllabus copy, the topic given was Drug elimination. Most of the students gets confused and study only Drug excretion and leave Drug Metabolism. Drug Elimination = Drug Metabolism + Drug Excretion. So we have to study Drug Metabolism also as in the name of Biotransformation.
PHARMD GURU Page 2 compounds. Without biotransformation, excretion of lipophilic xenobiotics would be extremely slow and they will eventually accumulate in the body and kill the organism. The biotransformation of drugs mainly occurs in the liver, other organ having significant metabolic capacity include the GIT, kidneys, lungs. DRUG METABOLISM The biotransformation of drugs generally occurs in two phases. Phase-I reactions & Phase-II reactions. SCHEMATIC PATHWAYS OF BIOTRANSFORMATION PHASES PHASE-I & PHASE-II REACTIONS
PHARMD GURU Page 3 Classification of Biotransformation Phases: TYPES OF REACTION ENZYME SUBCELLULAR LOCALIZATION PHASE-I OXIDATION Alcohol dehydrogenase Cytosol Aldehyde dehydrogenase Cytosol, mitochondria Aldehyde oxidase Cytosol Monoamine oxidase Mitochondria Xanthine oxidase Cytosol Diamine oxidase Cytosol Flavin monooxygenases Microsomes Cytochrome P450 Microsomes REDUCTION -Azo & -nitro reduction Microsomes, blood, cytosol Carbonyl reduction Cytosol Sulfoxide reduction Cytosol Disulfide reduction Microsomes Reductive dehalogenation Cytosol, microsomes Quinonne reduction Microsomes, lysosomes, cytosol HYDROLYSIS Esterase Microsomes, lysosomes, cytosol Peptidase Blood, lysosomes Epoxidase, hydrolase Microsomes, cytosol PHASE-II Sulphate conjugation Cytosol Glucuronide conjugation Microsomes Glutathione conjugation Cytosol, microsomes Amino acid conjugation Mitochondria, microsomes Acyltion Cytosol, mitochondria Methylation Cytosol, microsomes, blood
PHARMD GURU Page 4 PHASE-I REACTIONS: Phase-I reactions also termed as Non-synthetic reactions. The purpose of this phase is to introduce a polar functional group into the xenobiotic or drug molecule to increase its water solubility so that it can be easily excreted and /or conjugated and excreted. It involves oxidation, reduction and hydrolysis. This may result in activation, change or inactivation of drug. Phase I reactions introduce functional groups viz -0H, -SH, -NH, -COOH and slightly increase the hydrophilicity of drugs. The majority of phase-I metabolites are generated by a common hydroxylating enzyme system known as cytochrome P450. Cytochrome P: The cytochromes P (CYP) are a superfamily of enzymes, that are involved in the metabolism large number of dietary and zenobiotic agents. Among the diverse reactions carried out by mammalian cytochrome P are 0-dealkylation, N-dealkylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, dehalogenation. In human there are 12 CYPs known to be important for the metabolism of xenobiotics. Hence include CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19, 2E1, 3A4 and 3A5. PHASE-II REACTIONS: Phase-II reactions also termed as Synthetic reactions. It involves formation of conjugates with drug or its metabolites formed in phase l reaction. The conjugate is formed with an endogenous substance such as carbohydrates and amino acids. PHASE-I REACTIONS 1. OXIDATION: A common phase-I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts a pharmacologically inactive compound (a prodrug) to a pharmacologically active one. These reactions typically involve a cytochrome P450 monooxygenase, NADPH and oxygen. Reaction results in proton enriched products. There are two types: