Pharmacokinetics 3

Question 1

Define drug metabolism

Answer 1

Occurs in 2 phases
Phase 1 - breaking down, enzymatic process, Oxidation (P450 cytochrome), reduction and hydrolysis. Broken into active (pro-drug), inactive or toxic product. Depends on the drug
Phase 2 - Drug solubilisation by conjunction, elimination in urine or bile. (Glucuronidation, acetylation, sulfation, methylation)

Question 2

What is a prodrug?

Answer 2

A Prodrug is a drug or compound that is metabolised into a pharmacologically active drug.

Question 3

Give the importance of the order of phase reactions

Answer 3

Can occur in either order

Question 4

Give some examples of prodrugs

Answer 4

• Enalapril to Enalaprilat
• Codeine into Morphine
• Levodopa to Dopamine

Question 5

Give some examples of cytochrome p450 inhibitors

Answer 5

Amiodarone

Ciprofloxacin

Erythromycin/Clarithromycin

Metronidazole

Fluconazole

Isoniazid

Alcohol (acute)

Grapefruit juice

Question 6

What do cytochrome P450 inhibitors do to the drug?

Answer 6

Reduce the metabolism of the drug so increases the amount of drug available
Rapid process

Question 7

What do cytochrome P450 inhibitors do to the drug?

Answer 7

Increase the metabolism of the drug. Less drug in plasma so more active form produced.
Slower process

Question 8

Give some examples of P450 inducers

Answer 8

Carbamazepine

Phenytoin

Rifampicin

Alcohol (Chronic)

Question 9

What is the difference between the effect of consumption of alcohol on cytochrome P450

Answer 9

Alcohol (Acute)- INHIBITOR

Alcohol (Chronic)- INDUCER

Question 10

What may drugs Drug metabolised by CYP450 with narrow therapeutic index/window
Eg. warfarin, aminophylline
combined with cytochrome P450 inhibitor lead to?

Answer 10

Adverse side effects

Question 11

What is the therapeutic index?

Answer 11

Ratio of concentration associated with toxicity (MTC) vs concentration associated with efficacy (MEC).

Question 12

How do genetics affect drug metabolism?

Answer 12

Genetic Polymorphisms are multiple genetic variants (allele combinations) which result in different phenotypes.
Polymorphisms of drug metabolising enzymes can affect drug handling.

Question 13

Define extensive metaboliser

Answer 13

Two active ‘normal’ alleles

Question 14

Define intermediate metaboliser

Answer 14

One normal and one abnormal allele

Question 15

Define poor metaboliser

Answer 15

Two abnormal alleles

Question 16

Define ultrarapid metaboliser

Answer 16

Duplication of normal alleles

Question 17

Describe the effect of the CYP2D6 polymorphisms in ultrarapid metaboliser

Answer 17

CYP2D6 polymorphism with ultrarapid metaboliser effect causes opiate toxicity in some individuals even at low dose. This causes an exaggerated response to codeine.

Question 18

Describe the effect of the CYP2D6 polymorphisms in poor metaboliser

Answer 18

CYP2D6 polymorphism with poor metaboliser effect causes inadequate pain relief by codeine in some individuals.

Question 19

What are Fast acetylators at increased risk of?

Answer 19

Fast acetylators at increased risk of isoniazid hepatotoxicity

Question 20

What are Slow acetylators at increased risk of?

Answer 20

Slow acetylators at increased risk of isoniazid neuropathy

Slow acetylators at increased risk of drug-induced lupus with hydralazine

Question 21

What phase is the N-acetyltransferase involved in?

Answer 21

Phase 2

Genetically determined

Question 22

Describe the relationship between the drug concentration and dose for most drugs

Answer 22

Linear relationship
First order kinetics
Higher the dose of drug the higher the concentration

Question 23

Describe the relationship between the dose and drug concentration for saturable metabolism

Answer 23

Not a linear relationship
Drug concentrations rise disportionately compared with the dose
Zero order kinetics

Question 24

Give some examples of drugs that have saturable metabolism

Answer 24

Phenytoin Alcohol
Aspirin
Methotrexate
Fluoxetine
Verapamil