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‫المحاضرة الثانية‬ ‫الدكتور قاسم صالح النعیمی‬ Distribution of drugs 1. Definition Penetration of a drug to the sites of action through the walls of blood vessels from the administered site after absorption is call...

‫المحاضرة الثانية‬ ‫الدكتور قاسم صالح النعیمی‬ Distribution of drugs 1. Definition Penetration of a drug to the sites of action through the walls of blood vessels from the administered site after absorption is called drug distribution. Drugs distribute through various body fluid compartments such as: (a) plasma (b) interstitial fluid compartment (c) trans-cellular compartment Apparent Volume of distribution (VD): The volume into which the total amount of a drug in the body would have to be uniformly distributed to provide the concentration of the drug actually measured in the plasma. It is an apparent rather than real volume. Factors determining the rate of distribution of drugs: 1. Protein binding of drug: A significant portion of absorbed drug may become reversibly bound to plasma proteins. The active concentration of the drug is that part which is not bound, because it is only this fraction which is free to leave the plasma and site of action. Protein binding reduces diffusion of drug into the cell and there by delays its metabolic degradation e.g. high protein bound drug like phenylbutazone is long acting. Low protein bound drug like thiopental sodium is short acting. 2. Plasma concentration of drug (PC):.The concentration of free drug in plasma does not always remain in the same level e.g. i) After I.V. administration plasma concentration falls sharply ii) After oral administration plasma concentration rises and falls gradually. 1 iii) After sublingual administration plasma concentration rise sharply and falls gradually. 3. Clearance: Volume of plasma cleared off the drug by metabolism and excretion per unit time. Protein binding reduces the amount of drug available for filtration at the glomeruli and hence delays the excretion, thus the protein binding reduces the clearance. 4. Physiological barriers to distribution: There are some specialized barriers in the body due to which the drug will not be distributed uniformly in all the tissues. These barriers are: a) Blood brain barrier (BBB) through which thiopental sodium is easily crossed but not dopamine. b) Placental barrier: which allows non-ionized drugs with high lipid/water partition coefficient by a process of simple diffusion to the foetus e.g. alcohol, morphine. 5. Affinity of drugs to certain organs: The concentration of a drug in certain tissues after a single dose may persist even when its plasma concentration is reduced to low. Thus the hepatic concentration of mepacrine is more than 200 times that of plasma level. Their concentration may reach a very high level on chronic administration. Iodine is similarly concentrated in the thyroid tissue. 2  Metabolism of drugs: Drugs are chemical substances, which interact with living organisms and produce some pharmacological effects and then, they should be eliminated from the body unchanged or by changing to some easily excretable molecules. The process by which the body brings about changes in drug molecule is referred as drug metabolism or biotransformation. First pass – metabolism of drugs may occur as they cross the intestine or transit the liver eg: nitroglycerin Other drugs may be destroyed before absorption eg: penicillin Such reactions decrease delivery to the target tissues Enzymes responsible for metabolism of drugs: a) Microsomal enzymes: Present in the smooth endoplasmic reticulum of the liver, kidney and GIT e.g. glucuronyl transferase, dehydrogenase , hydroxylase and cytochrome P450. b) Non-microsomal enzymes: Present in the cytoplasm, mitochondria of different organs. e.g. esterases, amidase, hydrolase. Types of biotransformation: The chemical reactions involved in biotransformation are classified as phase-I and phase – II (conjugation) reactions. In phase-I reaction the drug is converted to more polar metabolite. If this metabolite is sufficiently polar, then it will be excreted in urine. Some metabolites may not be excreted and further metabolised by phase –II reactions. Phase-I: Oxidation, reduction and hydrolysis. Phase-II: Glucuronidation, sulfate conjugation, acetylation, glycine conjugation and methylation reactions. 3 1- Phase - I reactions a) Oxidation: Microsomal oxidation involves the introduction of an oxygen and/or the removal of a hydrogen atom or hydroxylation, dealkylation or demethylation of drug molecule e.g. conversion of salicylic acid into gentisic acid. b) Reduction: The reduction reaction will take place by the enzyme reductase which catalyze the reduction of azo (-N=N-) and nitro (-NO2) compounds e.g. prontosil converted to sulfonamide. c) Hydrolysis: Drug metabolism by hydrolysis is restricted to esters and amines (by esterases and amidases) are found in plasma and other tissues like liver. It means splitting of drug molecule after adding water e.g. pethidine undergoes hydrolysis to form pethidinic acid. Other drugs which undergo hydrolysis are atropine and acetylcholine. Cytochrome P450; - is a family of isoenzymes - Drugs bind to this enzyme and are oxidized or reduced- - Can be found in the GI epithelium, lung and kidney - Cyp3A4 alone is responsible for more than 60% of the clinically prescribed drugs metabolized by the liver Cytochrome P450 enzyme induction Stimulation of hepatic drug metabolism by some drugs.Enzyme inducers stimulate their own metabolism and also accelerate metabolism of other drugs :Ex of inducers: phenobarbital, rifampin, phenytoin, carbamazepine, griseofulvin, cigarette smoking. Cytochrome P450 enzyme inhibition. Some drugs may decrease the activity of hepatic drug-metabolizing enzymes , this will lead to increase levels of active drug in the body 4 Ex of inhibitors: alcohol, allopurinol, grapefruit juice, cimetidine, amiodarone, ciprofloxacin, clarithromycin, erythromycin, fluoxetine, isoniazid, metronidazole, verapamil, omeprazole, oral contraceptives 2-Phase - II reactions (conjugation reactions): This is synthetic process by which a drug or its metabolite is combined with an endogenous substance resulting in various conjugates such as glucoronide, sulfate, glycine, methylated compound and amino acid. The endogenous substrates originate in the diet, so nutrition plays a critical role in the regulation of drug conjugation. a) Glucuronide conjugation. It is the most common and most important conjugation reaction of drugs. Drugs which contain a) Hydroxyl, amino or carboxyl group undergo this process e.g. phenobarbitone. b) Sulfate conjugation: Sulfotransferase present in liver, intestinal mucosa and kidney, which transfers sulfate group to the drug molecules e.g. phenols, catechols, etc. c) Acetyl conjugation: The enzyme acetyl transferase, which is responsible for acetylation, is present in the kupffer cells of liver. Acetic acid is conjugated to drugs via its activation by CoA to form acetyl CoA. This acetyl group is then transferred to-NH2 group of drug e.g. dapsone, isoniazid. d) Glycine conjugation: Glycine conjugation is characteristic for certain aromatic acids e.g. salicylic acid, isonicotinic acid, p-amino salicylic acid. These drugs are also metabolized by other path ways. e) Methylation: Adrenaline is methylated to metanephrine by catechol-o- methyl transferase. Here the source of methyl group is s – adenosyl methionine. 5 Variations in drug metabolism: 1-Biotransformation in the fetus or neonate: - These individuals are very vulnerable to the toxic effects of drugs - Their liver and metabolizing enzymes are under-developed - They also have poorly developed blood brain barrier - Can get hyperbilirubinemia which leads to encephalopathy - Have poorly developed kidneys which can alter excretion and cause jaundice 2-Biotransformation in the elderly: Hepatic enzymes and other organs deteriorate over time 3-Generally, men metabolize faster than women (ex: alcohol) 4-Diseases can affect drug metabolism (ex: hepatitis, cardiac (↓ blood flow to the liver), pulmonary disease). 5-Genetic differences; Ex: Slow acetylators (autosomal recessive trait mostly found in Europeans living in the high northern latitudes and in 50% of blacks and whites in the US). 6