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
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
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
4
Q
Purpose
A
- Increase water solubility and aid excretion
- Deactivate compounds
5
Q
Prodrugs
A
- Activate following metabolism or form active metabolites e.g. codeine, enalapril
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
7
Q
Phases of metabolism
A
- Phase 1: oxidation, reduction, hydrolysis
- Phase 2: conjugation
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
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
10
Q
CYP3A4
A
- in liver and also in gut
- Drugs: diazepam, methadone, simvastatin, CCBs
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
12
Q
CYP1A2
A
- Induced by smoking, need a higher dose for many antidepressants
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
14
Q
Factors that affect metabolism
A
- Other drugs/herbals/natural substances
- Genetics
- Hepatic blood flow
- Liver disease
- Age
- Sex
- Ethnicity
- Pregnancy
15
Q
Examples of interfering herbals/natural substances
A
- St John’s Wort
- Grapefruit
- Herbals often have active compounds
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
