Drug Metabolism

Question 1

Principle of drug metabolism

Answer 1

Converts lipid soluble and non-polar compounds to water soluble and polar compounds so that they can be excreted

Question 2

Why so compounds have to be converted to water soluble and polar compounds?

Answer 2

Only water-soluble substances undergo excretion, whereas lipid soluble substances are reabsorbed from renal sites back into the blood

Question 3

Important sites of metabolism

Answer 3

• Liver

- Lining of gut

Question 4

What are prodrugs?

Answer 4

Drugs that are activated following metabolism

Question 5

Examples of prodrugs

Answer 5

• Codiene

- Enalapril

Question 6

Effects of metabolism

Answer 6

• No pharmacological activity

- Production of toxic metabolites - direct toxicity, carcinogenesis, teratogenesis

Question 7

What happens in the Phase 1 of drug metabolism?

Answer 7

• Involves hydrolysis, oxidation or reduction
• Increased polarity of compounds
• Provides active sites for Phase 2
• Cytochrome P450 metabolising enzymes

Question 8

What happens in Phase 2 of metabolism?

Answer 8

• Conjugation: increase water solubility
• Inactivates drug
• Molecule endogenous to body donates portion to foreign body

Question 9

What does conjugation involve?

Answer 9

Attachment of:

• Glucuronic acid
• Glutathione
• Sulphate
• Acetate

Question 10

Substrate for CYP1A2

Answer 10

Theophylline

Question 11

Substrate for CYP2D6

Answer 11

Codeine, antidepressants

Question 12

Substrate CYP3A4

Answer 12

Diazepam, methodone

-In liver

Question 13

Factors affecting metabolism

Answer 13

• Genetics
• Hepatic blood flow
• Liver disease
• Age
• Sex
• Ethnicity
• Pregnancy

Question 14

What is enzyme induction?

Answer 14

The drug metabolising enzymes can be induced (activity increased) - decreases drug effect

Question 15

What are common enzyme inducers?

Answer 15

-Alcohol and smoking
Drugs and herbals:
-St John’s Wort
-Rifampicin

Question 16

What inhibits enzymes?

Answer 16

Some drugs, herbal medicines and foods will inhibit metabolising enzymes

Question 17

Explain influence of genetic diversity in metabolism of drugs

Answer 17

Proteins different - metabolising enzymes - therefore variation metabolism

Different response to drugs therefor therapeutic failure or ADR

Question 18

Explain genetic polymorphism

Answer 18

Drug metabolising enzymes different in people due to gene expression - gene mutations can alter enzymes also

Question 19

What does decreased activity of an enzyme cause?

Answer 19

Increased drug toxicity

Question 20

Subpopulations of metabolisers

Answer 20

Poor - PM
Intermediates - IM
Extensive -EM
Ultrarapid - um

Question 21

Who are more prone to polymorphisms?

Answer 21

Some ethnicities

Question 22

Drug metabolism in children

Answer 22

• Enzyme deficient in the fetus
• Renal deficient
• 2yrs rapid metabolism
• By puberty rate greater than adults

Question 23

Drug metabolism during pregnancy

Answer 23

• Metab. enzymes induced in 2nd & 3rd trimester
• Hormones affect metab.
• Females adapted to cope with increased levels in liver

Question 24

Drug metabolism in the elderly

Answer 24

Plasma protein, body mass and liver weight decreased therefore altered metabolism.

Question 25

Drug metabolism in different ethnicities

Answer 25

• Racial differences in genetic expression of cytochrome P-450 isoforms
• Asian slower at drug metab. than causasians