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PoD > Drug metabolism > Flashcards

Drug metabolism Flashcards

1
Q

What is drug metabolism?

A
  • 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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2
Q

What do drugs have to become polar or water soluble

A

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

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3
Q

Site of metabolism

A
  • 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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4
Q

Purpose

A
  • Increase water solubility and aid excretion

- Deactivate compounds

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5
Q

Prodrugs

A
  • Activate following metabolism or form active metabolites e.g. codeine, enalapril
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6
Q

Effects of metabolism

A
  • 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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7
Q

Phases of metabolism

A
  • Phase 1: oxidation, reduction, hydrolysis

- Phase 2: conjugation

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8
Q

Phase 1 of metabolism

A
  • 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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9
Q

Cytochrome P-450 isoforms

A
  • CYP3A4 is major constitutive enzyme in human liver, contributes to wide range of drugs, also found in gut
  • CYP2D6
  • CYP1A2
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10
Q

CYP3A4

A
  • in liver and also in gut

- Drugs: diazepam, methadone, simvastatin, CCBs

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11
Q

CYP2D6

A
  • 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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12
Q

CYP1A2

A
  • Induced by smoking, need a higher dose for many antidepressants
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13
Q

Phase 2

A
  • 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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14
Q

Factors that affect metabolism

A
  • Other drugs/herbals/natural substances
  • Genetics
  • Hepatic blood flow
  • Liver disease
  • Age
  • Sex
  • Ethnicity
  • Pregnancy
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15
Q

Examples of interfering herbals/natural substances

A
  • St John’s Wort
  • Grapefruit
  • Herbals often have active compounds
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16
Q

Genetic factors affecting metabolism

A
  • 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
17
Q

Genetic polymorphism affecting metabolism

A
  • 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
18
Q

Children: drug metabolism

A
  • 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
19
Q

Elderly: drug metabolism

A
  • 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
20
Q

Sex

A
  • Differs between men and women

- Pregnancy: hormonal changes have profound effect on drug metabolism

21
Q

Enzyme induction:

A
  • 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
22
Q

Enzyme inhibition

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

PoD (33 decks)

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