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Drug Mechanisms and Reactions

Phase 1: Medication Metabolism

The whole selection of biochemical processes that occur in a organism, Metabolism consists both of anabolism and catabolism (the accumulation and break down of substances, respectively). The biochemical reactions are known as metabolic pathways and involve enzymes that transform one chemical into another product, either breaking down a material or building a new chemical substance. The term is commonly used to send specifically to the breakdown of food and its change into energy.

The liver organ is the principal site of medicine metabolism. Although metabolism typically inactivates drugs, some drug metabolites are pharmacologically energetic sometimes even more than the mother or father substance. An inactive or weakly effective substance that has an active metabolite is called a pro-drug, especially if made to deliver the effective moiety more effectively.

Drugs can be metabolized by oxidation, decrease, hydrolysis, hydration, conjugation, condensation, or isomerization, whatever the procedure, the goal is to make the medication simpler to excrete. The enzymes involved with metabolism are present in many tissue but generally will be more focused in the liver organ.

Drug metabolism rates vary among patients. Some patients metabolize a medicine so rapidly that therapeutically effective blood and structure concentrations aren't come to, in others, metabolism may be so poor that usual doses have toxic effects. Individual drug metabolism rates are inspired by genetic factors, coexisting disorders (especially chronic liver disorders and advanced heart failure), and medication interactions (especially those regarding induction or inhibition of metabolism).

For many drugs, metabolism occurs in two stages:

Phase I reactions: Which entail formation of a new or modified efficient group or cleavage, these reactions are nonsynthetic.

Phase II reactions

Which involve conjugation with an endogenous chemical, these reactions are man-made. Metabolites created in synthetic reactions are definitely more polar and even more immediately excreted by the kidneys (in urine) and the liver (in bile) than those developed in nonsynthetic reactions. Some drugs undergo only stage I or level II reactions, thus, phase amounts reflect functional somewhat than sequential classification.

Phase I Medicine Metabolism

Phase I metabolism includes oxidation, decrease, hydrolysis and hydration reactions, as well as other rarer miscellaneous reactions. Oxidations performed by the microsomal, mixed-function oxidase system (cytochrome P450-centered) is known as separately because of its importance and the variety of reactions performed by this enzyme system.

Classification of Phase I Reactions:

  • Oxidation
  • Reduction
  • Hydrolysis
  • Hydration
  • Dethioacetylation
  • Isomerization


Oxidations relating cytochrome P450 (the microsomal mixed-function oxidase)

The mixed-function oxidase system within microsomes (endoplasmic reticulum) of several cells (notably those of liver organ, kidney, lung and intestine) executes numerous functionalisation reactions.

CYP 450: The cytochrome P450(CYP) enzyme system involves a superfamily of hemoproteins that catalyse the oxidative metabolism of a multitude of exogenous chemicals including drugs, carcinogens, contaminants and endogenous ingredients such as steroids, essential fatty acids and prostaglandins. The CYP enzyme family performs an important role in phase-I metabolism of many drugs. The wide range of drugs that experience CYP mediated oxidative biotransformation is responsible for the large numbers of clinically significant drug connections during multiple medicine therapy.

All of these reactions require the presence of molecular air and NADPH as well as the

complete mixed-function oxidase system (cytochrome P450, NADPH-cytochrome

P450 reductase and lipid).

All reactions require the initial insertion of a single oxygen atom in to the drug molecule. A succeeding rearrangement and/or decomposition of this product may occur, leading to the final products development.

(i) Aromatic hydroxylation: That is an extremely common reaction for drugs and xenobiotics made up of an aromatic engagement ring. In this particular example the local anaesthetic and antidysrhythmic medicine, lignocaine, is changed into its 3-hydroxy derivative.

(ii) Aliphatic hydroxylation: Another very common effect, e. g. pentobarbitone hydroxylated in the pentyl side chain.

(iii) Epoxidation: Epoxides are normally unpredictable 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), creating dihydrodiols, however they could also spontaneously decompose to create hydroxylated products or quinones. It has been advised that epoxide development is the first step in aromatic hydroxylation.

(iv) Dealkylation: This response occurs very readily with drugs including a second or tertiary amine, an alkoxy group or an alkyl substituted thiol. The alkyl group is lost as the related aldehyde. The reactions are often referred to as N-, O- or S-dealkylations, depending on the type of atom the alkyl group is mounted on.

(v) Oxidative deamination: Amines filled with the composition -CH(CH3)-NH2 are metabolised by the microsomal mixed-function oxidase system to release ammonium ions and leave the corresponding ketone. As with dealkylation, oxidative deamination includes an intermediate hydroxylation step with succeeding decomposition to yield the ultimate products.

The product of the oxidative deamination of EPI or NE is 3, 4-didydroxyphenylclycoaldehyde (DOPGAL). DOPGAL is at the mercy of lowering to the matching liquor (3, 4-dihydroxyphenylethylene glycol, DOPEG) or oxidation to the corresponding carboxylic acidity (3, 4-dihydroxymandelic acid, DOMA), the second option being the major pathway.

(vi) N-oxidation: Hepatic microsomes in the existence of air and NADPH can develop N-oxides. These oxidation products may be shaped by the mixedfunction oxidase system or by separate flavoprotein N-oxidases. The enzyme involved in N-oxidation will depend on the substrate under study. Many different chemical substance groupings can be N-oxidised including amines, amides, imines, hydrazines and heterocyclic compounds.

(vii) S-oxidation: Phenothiazines can be changed into their S-oxides (sulfoxides (SјO) and sulfones (јSјO)) by the microsomal mixed-function oxidase system.

(viii) Phosphothionate oxidation: The substitute of a phosphothionate sulfur atom with oxygen is a effect common to the phosphothionate insecticides, e. g. parathion. The merchandise paraoxon is a powerful anticholinesterase and gives the potent insecticide action as well as the toxicity in humans.

Oxidations not catalysed by cytochrome P450 (Non-Microsomal)

A volume of enzymes in the torso not related to cytochrome P450 can oxidize drugs.

(i) Alcoholic beverages Oxidation by Alcoholic beverages dehydrogenase: This enzyme catalyses the oxidation of several alcohols to the corresponding aldehyde and it is localised in the soluble small fraction of liver organ, kidney and lung skin cells. This enzyme uses NAD+ as co-factor and is also a true dehydrogenase.

(ii) Aldehyde oxidation: Aldehydes can be oxidised by a number of enzymes involved with intermediary metabolism, e. g. aldehyde dehydrogenase, aldehyde oxidase and xanthine oxidase (the second option 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 matching uric acid derivative.

Metabolic Reduction

(i) Azo- and nitro-reduction can be catalysed by cytochrome P450 (but may also be catalysed by NADPH-cytochrome P450 reductase).

(ii) Ring cleavage: Epoxides can be modified back again to the mother or father hydrocarbon, e. g. benzo(a)anthracene- 8, 9-epoxide whereas some heterocyclic compounds can be diamond ring cleaved by decrease.

(iii) Reductive defluorination: Fluorocarbons of the halothane type can be defluorinated by liver organ microsomes in anaerobic conditions.

Metabolic Hydrolysis

Esters, amides, hydrazides and carbamates can immediately be hydrolysed by various enzymes.

(i) Ester hydrolysis: The hydrolysis of esters may take put in place the plasma (nonspecific acetylcholinesterases, pseudocholinesterases and other esterases) or in the liver organ (specific esterases for particular sets of chemical substances). 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 gradually than the equivalent esters) but will be hydrolysed by the liver organ amidases. Ethylglycylxylidide, the N-deethylated phase 1 product of lignocaine, is hydrolysed by the liver organ microsomal fraction to deliver xylidine and ethylglycine.

(iii) Hydrazide and carbamate hydrolysis: Less common efficient communities in drugs may also be hydrolysed, such as the hydrazide group in isoniazid or the carbamate group in the used hypnotic, hedonal.

Factors Influencing Metabolism

Many factors make a difference liver organ metabolism, such as:

In ageing, the amounts of hepatocytes and enzyme activity declines.

Diseases that reduce hepatic blood flow like heart inability or impact can also decrease the metabolic probable of the liver organ.

Also the use of other drugs as well as eating and environmental factors can influence liver organ metabolic function.

Metabolism may also be altered anticipated to a genetic deficiency of a specific enzyme.

Differences in metabolism that result from functional genetic polymorphisms can be accommodated by knowing the regularity of different genotypes, and by modifying either the enzyme great quantity (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 even be incorporated into the models to anticipate hepatic clearance in neonates, infants and children.


Metabolism is the breakdown of Drugs inside your body, to disable their activity, creating inactive metabolites, however some drugs are either not afflicted by metabolism or turned on by it, some even form dangerous metabolites Good examples:

Imipiramine not affected by metabolism:

Paracetamol produce Toxic Metabolite

Metabolism occurs in two stages, Period I Metabolism, and Stage II Metabolism.

Phase I Metabolism changes the medication into metabolite by creation of a new functional group or modifying it, while phase II Metabolism or reactions entail conjugation with indigenous material.

Phase I Reactions Include:

Oxidation, decrease, hydrolysis and hydration reactions, and other uncommon miscellaneous reactions.

Oxidation can be split into Microsomal or non Microsomal matching to whether it includes mitochondrial CYP 450 enzymes.

Oxidation includes:


Aromatic Hydroxylation, Aliphatic Hydroxylation, Epoxidation, Dealkylation, oxidative deamination, N- oxidation, S-oxidation and Phosphothionate oxidation.


Alcohol Oxidation by Liquor dehydrogenase, Aldehyde Oxidation and Oxidation by Xanthine oxidase.

Reduction will involve: Azo- and nitro-reduction, Band cleavage, Reductive defluorination

Hydrolysis includes: Ester hydrolysis, Amide hydrolysis, Hydrazide and carbamate hydrolysis

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