Drug Mechanisms and Reactions

Drug Mechanisms and ReactionsPhase 1 Drug MetabolismThe whole range of biochemical processes that occur within an organism, Metabolism consists both of anabolism and dissimilation (the buildup and breakdown of substances, respectively). The biochemical reactions be known as metabolic pathways and involve enzymes that transform one substance into another substance, any breaking down a substance or building a new chemical substance. The term is commonly used to refer specifically to the breakdown of food and its transformation into energy.The liver is the principal site of medicate metabolism. Although metabolism typically inactivates drugs, many drug metabolites ar pharmacologically active sometimes even to a greater extent than the parent compound. An unreactive or weakly active substance that has an active metabolite is called a pro-drug, especially if designed to deliver the active moiety more usefully.Drugs piece of tail be metabolized by oxidation, reduction, hydrolys is, hydration, conjugation, condensation, or isomerization, whatever the process, the goal is to make the drug easier to excrete. The enzymes manifold in metabolism are present in umteen tissues but generally are more concentrated in the liver.Drug metabolism rates vary among patients. Some patients metabolize a drug so rapidly that therapeutically effective blood and tissue concentrations are not reached, in others, metabolism may be so slow that usual doses have toxic effects. Individual drug metabolism rates are influenced by genetic factors, coexisting disorders (particularly chronic liver disorders and advanced heart failure), and drug interactions (especially those involving induction or inhibition of metabolism).For many drugs, metabolism occurs in two phasesPhase I reactions Which involve formation of a new or modified structural group or cleavage, these reactions are nonsynthetic.Phase II reactionsWhich involve conjugation with an endogenous substance, these reactions a re synthetic. Metabolites formed in synthetic reactions are more polar and more pronto excreted by the kidneys (in urine) and the liver (in bile) than those formed in nonsynthetic reactions. Some drugs undergo only phase I or phase II reactions, thus, phase subprograms hypothecate functional rather than sequential classification.Phase I Drug MetabolismPhase I metabolism includes oxidation, reduction, hydrolysis and hydration reactions, as well as other rarer confused reactions. oxidisations performed by the microsomal, mixed-function oxidase administration (cytochrome P450-dependent) is considered separately because of its importance and the diversity of reactions performed by this enzyme system.Classification of Phase I ReactionsOxidationReductionHydrolysisHydrationDethioacetylationIsomerizationOxidations involving cytochrome P450 (the microsomal mixed-function oxidase)The mixed-function oxidase system plant in microsomes (endoplasmic reticulum) of many cells (notably those o f liver, kidney, lung and intestine) performs many different functionalisation reactions.CYP 450 The cytochrome P450(CYP) enzyme system consists of a superfamily of hemoproteins that catalyse the oxidative metabolism of a wide variety of exogenous chemicals including drugs, carcinogens, toxins and endogenous compounds such as steroids, fatty acids and prostaglandins. The CYP enzyme family plays an important role in phase-I metabolism of many drugs. The broad range of drugs that undergo CYP mediated oxidative biotransformation is responsible for the large number of clinically signifi so-and-sot drug interactions during multiple drug therapy.All of these reactions require the presence of molecular oxygen and NADPH as well as thecomplete mixed-function oxidase system (cytochrome P450, NADPH-cytochromeP450 reductase and lipid).All reactions involve the initial insertion of a single oxygen atom into the drug molecule. A subsequent rearrangement and/or decomposition of this product may o ccur, leading to the final products formation.(i) Aromatic hydroxylation This is a very common reaction for drugs and xenobiotics containing an aromatic ring. In this example the local anaesthetic and antidysrhythmic drug, lignocaine, is converted to its 3-hydroxy derivative.(ii) Aliphatic hydroxylation another(prenominal) very common reaction, e.g. pentobarbitone hydroxylated in the pentyl side chain.(iii) Epoxidation Epoxides are normally unstable intermediates but may be stable enough to be isolated from polycyclic compounds (e.g. the precarcinogenic polycyclic hydrocarbons). Epoxides are substrates of epoxide hydrolase (discussed later), forming dihydrodiols, but they may withal spontaneously decompose to form hydroxylated products or quinones. It has been suggested that epoxide formation is the first step in aromatic hydroxylation.(iv) Dealkylation This reaction occurs very readily with drugs containing a secondary or tertiary amine, an alkoxy group or an alkyl substituted thi ol. The alkyl group is lost as the corresponding aldehyde. The reactions are often referred to as N-, O- or S-dealkylations, depending on the type of atom the alkyl group is attached to.(v) Oxidative deaminization Amines containing the structure -CH(CH3)-NH2 are metabolised by the microsomal mixed-function oxidase system to rid ammonium ions and leave the corresponding ketone. As with dealkylation, oxidative deamination involves an intermediate hydroxylation step with subsequent decomposition to yield the final products.The product of the oxidative deamination of EPI or NE is 3,4-didydroxyphenylclycoaldehyde (DOPGAL). DOPGAL is subject to reduction to the corresponding alcohol (3,4-dihydroxyphenylethylene glycol, DOPEG) or oxidation to the corresponding carboxylic acid (3,4-dihydroxymandelic acid, DOMA), the latter being the major pathway.(vi) N-oxidation liverwort microsomes in the presence of oxygen and NADPH bum form N-oxides. These oxidation products may be formed by the mix edfunction oxidase system or by separate flavoprotein N-oxidases. The enzyme involved in N-oxidation depends on the substrate under study. Many different chemical groups can be N-oxidised including amines, amides, imines, hydrazines and heterocyclic compounds.(vii) S-oxidation Phenothiazines can be converted to their S-oxides (sulfoxides (SO) and sulfones (SO)) by the microsomal mixed-function oxidase system.(viii) Phosphothionate oxidation The replacement of a phosphothionate sulfur atom with oxygen is a reaction common to the phosphothionate insecticides, e.g. parathion. The product paraoxon is a potent anticholinesterase and gives the potent insecticide action as well as the toxicity in humans.Oxidations not catalysed by cytochrome P450 (Non-Microsomal)A number of enzymes in the body not related to cytochrome P450 can oxidize drugs.(i) Alcohol Oxidation by Alcohol dehydrogenase This enzyme catalyses the oxidation of many alcohols to the corresponding aldehyde and is localised in the disintegrable fraction of liver, kidney and lung cells. This enzyme uses NAD+ as co-factor and is a true dehydrogenase.(ii) Aldehyde oxidation Aldehydes can be oxidised by a variety of enzymes involved in intermediary metabolism, e.g. aldehyde dehydrogenase, aldehyde oxidase and xanthine oxidase (the latter two being soluble metalloflavoproteins).(iii) Oxidation by Xanthine oxidase This enzyme will metabolise xanthine-containing drugs, e.g. caffeine, theophylline and theobromine, and the purine analogues to the corresponding uric acid derivative.Metabolic Reduction(i) Azo- and nitro-reduction can be catalysed by cytochrome P450 (but can also be catalysed by NADPH-cytochrome P450 reductase).(ii) Ring cleavage Epoxides can be converted back to the parent hydrocarbon, e.g. benzo(a)anthracene- 8,9-epoxide whereas some heterocyclic compounds can be ring cleaved by reduction.(iii) Reductive defluorination Fluorocarbons of the halothane type can be defluorinated by liver microsomes i n anaerobic conditions.Metabolic HydrolysisEsters, amides, hydrazides and carbamates can readily be hydrolysed by various enzymes.(i) Ester hydrolysis The hydrolysis of esters can take place in the plasma (nonspecific acetylcholinesterases, pseudocholinesterases and other esterases) or in the liver (specific esterases for particular groups of compounds). Procaine is metabolised by the plasma esterase, whereas pethidine (meperidine) is only metabolised by the liver esterase.(ii) Amide hydrolysis Amides may be hydrolysed by the plasma esterases (which are so non-specific that they will also hydrolyse amides, although more slowly than the corresponding esters) but are more likely to be hydrolysed by the liver amidases. Ethylglycylxylidide, the N-deethylated phase 1 product of lignocaine, is hydrolysed by the liver microsomal fraction to yield xylidine and ethylglycine.(iii) Hydrazide and carbamate hydrolysis Less common functional groups in drugs can also be hydrolysed, such as the hy drazide group in isoniazid or the carbamate group in the previously used hypnotic, hedonal.Factors affect MetabolismMany factors can affect liver metabolism, such asIn aging, the numbers of hepatocytes and enzyme activity declines.Diseases that reduce hepatic blood flow like heart failure or shock can also reduce the metabolic potential of the liver.Also the use of other drugs as well as dietary and environmental factors can influence liver metabolic function.Metabolism can also be altered due to a genetic privation of a particular enzyme.Differences in metabolism that result from functional genetic polymorphisms can be accommodated by knowing the frequency of different genotypes, and by modifying either the enzyme abundance (null alleles, for example, in the case of CYP2D6 poor metabolizers) or the intrinsic enzyme activity (for example, CYP2C9 variants). Data on developmental changes in the abundance and activity of different CYPs can also be incorporated into the models to pred ict hepatic clearance in neonates, infants and children.ConclusionMetabolism is the breakdown of Drugs inside the body, to disable their activity, forming inactive metabolites, however some drugs are either not affect by metabolism or activated by it, some even form toxic metabolites ExamplesImipiramine not affected by metabolismParacetamol produce Toxic MetaboliteMetabolism occurs in two phases, Phase I Metabolism, and Phase II Metabolism.Phase I Metabolism converts the drug into metabolite by formation of a new functional group or modifying it, while phase II Metabolism or reactions involve conjugation with natal substance.Phase I Reactions IncludeOxidation, reduction, hydrolysis and hydration reactions, and other rare miscellaneous reactions.Oxidation can be divided into Microsomal or non Microsomal according to whether it involves mitochondrial CYP 450 enzymes.Oxidation involvesMicrosomalAromatic Hydroxylation, Aliphatic Hydroxylation, Epoxidation, Dealkylation, oxidative deam ination, N- oxidation, S-oxidation and Phosphothionate oxidation.Non-MicrosomalAlcohol Oxidation by Alcohol dehydrogenase, Aldehyde Oxidation and Oxidation by Xanthine oxidase.Reduction involves Azo- and nitro-reduction, Ring cleavage, Reductive defluorinationHydrolysis involves Ester hydrolysis, Amide hydrolysis, Hydrazide and carbamate hydrolysis