Lecture 13

Question 1

Describe drug metabolism and its two phases

Answer 1

Phase I
Drug->Active (Pro-Drug)
->Inactive
->Toxic
Oxidation (P450 cytochrome), reduction, hydrolysis (esterases)

Phase II
Drug solubilisation by conjugation:
Glucuronidation, acetylation, Sulfation and methylation
->Elimination in urine or bile

Question 2

Describe a prodrug

Answer 2

A Prodrug is a drug or compound that is metabolised into a pharmacologically active drug.
Egs. 
 - Enalapril to Enalaprilat
 - Codeine into Morphine
 - Levodopa to Dopamine

Question 3

State cytochrome P450 inhibitors that have the rapid process

Answer 3

Amiodarone

Ciprofloxacin

Erythromycin/Clarithromycin

Metronidazole

Fluconazole

Isoniazid

Alcohol (acute)

Grapefruit juice

Question 4

State cytochrome P450 inducers that have the slow process

Answer 4

Carbamazepine

Phenytoin

Rifampicin

Alcohol (Chronic)

Question 5

Define therapeutic index

Answer 5

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

Question 6

Define genetic polymorphisms

Answer 6

Multiple genetic variants (allele combos) which result in different phenotypes.

Question 7

Define extensive metaboliser

Answer 7

Two active ‘normal’ alleles

Question 8

Intermediate metaboliser

Answer 8

One normal and one abnormal allele

Question 9

Poor metaboliser

Answer 9

Two abnormal alleles

Question 10

Ultrarapid metabolisers

Answer 10

Duplication of normal alleles

Question 11

Describe CYP2D6 metabolism

Answer 11

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

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

Question 12

Describe phase II reactions

Answer 12

Drug+Glucuronidation/acetylation/sulfation/methylation-> water soluble conjugate

Activity of N-acetyltransferase is genetically determined

Fast acetylators at increased risk of isoniazid hepatotoxicity

Slow acetylators at increased risk of isoniazid neuropathy

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

Question 13

What is the difference between non saturable and saturable metabolism

Answer 13

Non saturable metabolism (first order kinetics) is when drug concentration is directly proportional to the dose whereas for saturable metabolism (zero-order kinetics) drug concentrations rise disproportionately (non-linear) compared with dose