Drug Metabolism Flashcards
Principle of drug metabolism
Converts lipid soluble and non-polar compounds to water soluble and polar compounds so that they can be excreted
Why so compounds have to be converted to water soluble and polar compounds?
Only water-soluble substances undergo excretion, whereas lipid soluble substances are reabsorbed from renal sites back into the blood
Important sites of metabolism
- Liver
- Lining of gut
What are prodrugs?
Drugs that are activated following metabolism
Examples of prodrugs
- Codiene
- Enalapril
Effects of metabolism
- No pharmacological activity
- Production of toxic metabolites - direct toxicity, carcinogenesis, teratogenesis
What happens in the Phase 1 of drug metabolism?
- Involves hydrolysis, oxidation or reduction
- Increased polarity of compounds
- Provides active sites for Phase 2
- Cytochrome P450 metabolising enzymes
What happens in Phase 2 of metabolism?
- Conjugation: increase water solubility
- Inactivates drug
- Molecule endogenous to body donates portion to foreign body
What does conjugation involve?
Attachment of:
- Glucuronic acid
- Glutathione
- Sulphate
- Acetate
Substrate for CYP1A2
Theophylline
Substrate for CYP2D6
Codeine, antidepressants
Substrate CYP3A4
Diazepam, methodone
-In liver
Factors affecting metabolism
- Genetics
- Hepatic blood flow
- Liver disease
- Age
- Sex
- Ethnicity
- Pregnancy
What is enzyme induction?
The drug metabolising enzymes can be induced (activity increased) - decreases drug effect
What are common enzyme inducers?
-Alcohol and smoking
Drugs and herbals:
-St John’s Wort
-Rifampicin
What inhibits enzymes?
Some drugs, herbal medicines and foods will inhibit metabolising enzymes
Explain influence of genetic diversity in metabolism of drugs
Proteins different - metabolising enzymes - therefore variation metabolism
Different response to drugs therefor therapeutic failure or ADR
Explain genetic polymorphism
Drug metabolising enzymes different in people due to gene expression - gene mutations can alter enzymes also
What does decreased activity of an enzyme cause?
Increased drug toxicity
Subpopulations of metabolisers
Poor - PM
Intermediates - IM
Extensive -EM
Ultrarapid - um
Who are more prone to polymorphisms?
Some ethnicities
Drug metabolism in children
- Enzyme deficient in the fetus
- Renal deficient
- 2yrs rapid metabolism
- By puberty rate greater than adults
Drug metabolism during pregnancy
- Metab. enzymes induced in 2nd & 3rd trimester
- Hormones affect metab.
- Females adapted to cope with increased levels in liver
Drug metabolism in the elderly
Plasma protein, body mass and liver weight decreased therefore altered metabolism.
Drug metabolism in different ethnicities
- Racial differences in genetic expression of cytochrome P-450 isoforms
- Asian slower at drug metab. than causasians
