Lectures 9&10

Question 1

What are the sites of drug metabolism?

Answer 1

Liver, GI tract (gut bacteria and proteases), Intestinal wall (CYPs), Plasma, specialised tissues

Question 2

What results from drug metabolism?

Answer 2

A more H2O soluble metabolite
Less likely to diffuse into cells to reach receptors
Favours increased excretion into urine and bile
Frequently abolishes activity and terminates drug action
Can produce toxic metabolites

Question 3

What is an example of a drug which has increased activity after metabolism?

Answer 3

Prodrugs such as acetylsalicylate and zidovudine

Question 4

What is an example of a drug which has no change in activity after metabolism?

Answer 4

Diazepam converted to nordiazepam through removal of a methyl group

Question 5

What occurs in phase one of drug metabolism?

Answer 5

The addition or uncovering of a reactive group through oxidation, reduction or hydrolysis which makes the molecule more susceptible to phase 2 reactions

Question 6

What occurs in phase 2 of rug metabolism?

Answer 6

conjugation of endogenous molecule with drug through additions of glucuronide, sulphate, amino acids, acetylation/methylation
This makes the molecule more polar, ideal substrates for active transport and excretion

Question 7

What is the most important reaction for phase 1 metabolism of drugs?

Answer 7

Oxidation which requires O2, NADPH and cytochrome P450 reductase

Question 8

What are CYPs?

Answer 8

An important class of enzymes, the cytochrome P450 dependent mixed function oxidase system which are located on the smooth endoplasmic reticulum
There is a family of 18 gene families, where CYP 1,2,3 encode enzymes involved in most drug metabolism

Question 9

What is the metabolism of phenytoin?

Answer 9

Phase 1 is hydroxylation by CYP which is an inactive form of the drug and is slightly soluble in water
Phase 2 is conjugation by UDP glucuronosyl transferase to yield a product which is very soluble in water

Question 10

What are the factors influencing drug metabolism?

Answer 10

Patient genetic constitution,

age, sex, pregnancy, diet, cigarettes, alcohol, diseases and other drugs, organ function

Question 11

What is the effect of age on drug metabolism?

Answer 11

Neonates have reduced capacity to metabolise drugs
Children have a high metabolism rate
Adults have a lower metabolism rate

Question 12

What is the effect of smoking on drug metabolism?

Answer 12

Smokers typically have higher rates of drug metabolism

Question 13

What is the clinical significance of the high variance of drug metabolism rates between individuals?

Answer 13

Different dosages need to be applied to individuals as those with high drug metabolism will need a higher dose to have therapeutic benefit and those with low metabolism will need lower doses to avoid the adverse effects of an overdose

Question 14

How is drug metabolism induced?

Answer 14

Enzyme synthesis is initiated within 24 hours of exposure, increasing over 3-5 days leading to a reduced drug effect
The enzyme continues to remain in the body for over 1-3 weeks after the inducing agent is discontinued

Question 15

What are drugs that can induce drug metabolism?

Answer 15

Barbiturates, phenytoin, rifampicin, St Johns wort

Question 16

What are environmental factors that can induce drug metabolism?

Answer 16

Cigarette smoking, eating BBQ meat, cruciferous veges, high protein diet, ethanol, exposure to insecticides and PCBs

Question 17

How is drug metabolism inhibited?

Answer 17

Rapid onset within one day
exaggerated response with increased risk of toxicity
Reverse inhibitors, Heavy metals

Question 18

What are the reverse inhibitors that inhibit drug metabolism?

Answer 18

Cimetidine, ketoconazole, quinolone antibiotics, HIV protease inhibitors, grape fruit juice

Question 19

What is the typical outcome of a standard dose of most drugs in a patient population?

Answer 19

20% will gain no therapeutic benefit, 50-60% will gain some therapeutic benefit and 20% will get adverse effects