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Flashcards in Drug metabolism Deck (22):
1

What is drug metabolism?

- Biochemical modification of pharmaceutical substances by living organisms usually through specialised enzymatic activity
- Essential pharmacokinetic process that limits life of a substance in the body rending lipid soluble and non-polar compounds to water soluble and polar compounds so they can be excreted

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What do drugs have to become polar or water soluble

so they can be excreted. Can't do it if they're lipid soluble or non-polar

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Site of metabolism

- Important sites: liver, lining of gut, kidneys and lungs
- Metabolised by enzymes: drugs can often be metabolised by more than one enzyme due to number of active sites
- Some enzymes are expressed constitutively and others are induced in the presence of a particular substrate

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Purpose

- Increase water solubility and aid excretion
- Deactivate compounds

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Prodrugs

- Activate following metabolism or form active metabolites e.g. codeine, enalapril

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Effects of metabolism

- Loss of pharmacological activity
- Decrease in activity, with metabolites that show some activity
- Increase activity -> prodrug
- Production of toxic metabolites: direct toxicity, carcinogenesis, teratogenesis

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Phases of metabolism

- Phase 1: oxidation, reduction, hydrolysis
- Phase 2: conjugation

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Phase 1 of metabolism

- Oxidation
-Reduction
- Hydrolysis
- Increases the polarity of the compound and provides an active site for phase 2 metabolism
- Cytochrome P-450 enzymes is most important super family of metabolising enzymes

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Cytochrome P-450 isoforms

- CYP3A4 is major constitutive enzyme in human liver, contributes to wide range of drugs, also found in gut
- CYP2D6
- CYP1A2

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CYP3A4

- in liver and also in gut
- Drugs: diazepam, methadone, simvastatin, CCBs

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CYP2D6

- Metabolism for some antidepressants, antipsychotics and conversion of codeine to morphine
- Reduced or absent expression is found in 5-10%
- Can also be induced by smoking

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CYP1A2

- Induced by smoking, need a higher dose for many antidepressants

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Phase 2

- Conjugation: increases water solubility and enhances excretion of metabolised compound
- Involves attachment of glucaronic acid, glutahione, sulphate or acetate to metabolite generated by Phase 1
- Endogenous molecule donates a portion of itslef to the foreign molecule

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Factors that affect metabolism

- Other drugs/herbals/natural substances
- Genetics
- Hepatic blood flow
- Liver disease
- Age
- Sex
- Ethnicity
- Pregnancy

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Examples of interfering herbals/natural substances

- St John's Wort
- Grapefruit
- Herbals often have active compounds

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Genetic factors affecting metabolism

- Can lead to therapeutic failure or adverse drug reaction
- Pharmacokinetic and pharmadynamic responses can change
- Drug-metabolising enzymes are expressed in multiple forms -> inter-individual difference
- Genetic polymorphism

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Genetic polymorphism affecting metabolism

- Gene mutations resulting in absence or deficiency of particular metabolising enzyme. Can lead to increasing drug toxicity
- Can increase expressions of particular metabolising enzymes. Enhanced metabolism, reduced effect
- CYP2D6 polymorphism: poor metabolisers, intermediate metabolisers, extensive metabolisers, ultrarapid metabolisers. Wafarin, pheytoin

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Children: drug metabolism

- Children: metabolising enzymes can often be deficient or reduced in foetus or premmys
- Renal function is also deficient, metabolites build up to toxic levels
- However, 2yo can metabolise quicker than adults and it slows again in puberty

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Elderly: drug metabolism

- Plasma protein, lean body mass and liver mass all decrease significantly and alter drug metabolism
- Chronic disease is more common -> multiple drug therapy. High risk individual

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Sex

- Differs between men and women
- Pregnancy: hormonal changes have profound effect on drug metabolism

21

Enzyme induction:

- Many drug metabolising enzymes can be induced by other compounds
- Resulting in increased metabolism of drug and decreased drug effect
- Most common enzyme inducers include alcohol and smoking
- Process may take weeks or months to happen

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Enzyme inhibition

- Many commonly used drugs, herbal medicines and foodstuffs can inhibit enzymes: reversible or irreversible binding to the enzyme
- Inhibition can take immediate effect