metabolism and excretion

• Metabolism is the enzymatic or biochemical transformation of the drug substance to usually less toxic metabolic products, which may be eliminated more readily from the body.
• Drug metabolism refers solely to the chemical biotransformation of a drug by the biological environment.
• Regulation of Renal Blood Flow is achieved by adjusting the perfusion pressure across the vascular bed.
• Blood flow to an organ is directly proportional to the arteriovenous pressure difference (perfusion pressure) across the vascular bed and indirectly proportional to the vascular resistance.
• Xenobiotics is another term for drug metabolism, for foreign substances.
• Lipophilic drug/substrate and converts it to a more hydrophilic metabolite to facilitate its elimination.
• Metabolism serves three principal purposes: to supply energy for body functions and maintenance, to break down ingested (foreign) compounds and biosynthesis of more complex molecules, and to make compounds more polar and water-soluble.
• The liver is the principal site of metabolism, both synthesizing and eliminating organs.
• The liver lobule is the basic unit of the liver, containing parenchymal cells, a network of interconnected lymph and blood vessels.
• The liver has a large right lobe and a small left lobe.
• The hepatic artery carries oxygen in the liver.
• The hepatic portal vein collects blood from the various segments of the GIT that perfuse in the liver, carrying nutrients to the liver and is involved in the First-Pass Effect.
• The sinusoids are large vascular capillaries that facilitate drug and nutrient removal before the blood enters the general circulation.
• Three Major Components of a Drug Biotransformation include the Reactant (drug or xenobiotics), Product (metabolite), and Reaction catalyst (enzymes).
• Phase 1 Reaction is non-synthetic and involves small chemical changes in one or more functional drug groups.
• Liver has the highest concentration of drug-metabolizing enzymes.
• Oxidation is the most common reaction in Phase 1 Reaction.
• Glucuronic Acid Conjugation is the most common Phase 2 Reaction.
• Glucuronic Acid Conjugation is a condensation of the drug or its primary metabolite with d-glucuronic acid.
• The reaction requires activation of glucuronic acid by synthesis of UDP-GA (uridine diphosphate glucuronic acid).
• Enzyme: Glucuronyl transferase catalyzes Glucuronic Acid Conjugation.
• Glucuronides are more water-soluble than the parent structures due to the large hydrophilic carbohydrate moiety.
• Glucuronides are more acidic than the parent molecule and hence more ionized.
• Glucuronides are less easily permeate through membranes and are poorly reabsorbed by the kidney tubule.
• Kupffer cells are endothelial lining of the sinusoids, phagocytic macrophages, and part of the Reticulo Endothelial system.
• Bile acids are secreted by the liver.
• Limited enzyme: Coenzyme A.
• Conversion of hippuric acid to an active form is reduced in liver damage, newborn, and aged.
• Benzoic acid → hippuric acid is used for conjugation with organic acids such as phenylacetic and related acids.
• Factors that influence drug metabolism include chemical structure, genetic difference (polymorphism), disease state, gender, age, circadian rhythm, nutritional status, and interacting substances.
• Enzyme induction is a drug or chemical-stimulated increase in enzyme activity resulting in a faster rate of metabolism.
• Auto-induction is a drug that stimulates its own metabolism.
• Foreign-induction is when one enzyme inducer stimulates the rate of metabolism of another drug.
• Enzyme inhibition is the process where enzyme activity is increased, resulting in a decrease in metabolism and an increase in drug effect.
• Enzyme inhibitors include P-Phenytoin, P-Phenobarbital, R-Rifampicin, C-Carbamazepine, C-Cigarette smoking, C-Chronic alcoholism.
• The first pass effect is the initial biotransformation of an active drug before reaching the systemic circulation, which reduces the systemic availability of the drug.
• Drugs that undergo the first pass effect include Propanolol, NTG, Morphine, Pentazocine, Mepredone, Verapamil.
• Metabolizing enzymes occur in the soluble, the mitochondrial, or the microsomal fractions.
• Excretion is the final loss of the drug substance or its metabolites from the body, such as through the kidney (urine), intestines (feces), skin (sweat), saliva, and milk.
• Drug elimination is the irreversible removal of drug from the body by all routes of elimination.