2017A04 Outline the genetic variations on the cytochrome P450 2D6 enzyme
and discuss the clinical relevance for drugs used in the peri-operative period.

List:

· Intro

· List of drugs

· Table: genotype, phenotype, frequency, effect

Intro: CYP2D6

Nature	· Microsomal enzyme · Mostly in liver
Function	· Redox (especially O-demethylation)
Importance	· Affects 25% of clinically used drugs
Allelic variants	·
Problem	· Polymorphism is common · Non-inducible enzyme

Relevant drugs:

Activated

(i.e. prodrugs)

· Codeine -> morphine (↑↑potency)

· Tramadol -> M1 (4 x analgesic efficacy, 200x MOP affinity)

· Oxycodone -> oxymorphone (10-15x ↑potency)

· Tamoxifen

Inactivated

· Antidepressants (SSRIs, TCAs)

· Antipsychotics (haloperidol, risperidone)

· Metoprolol

· Clonidine

Genetics:

Allelic variants

· ‘Normal’ (1,2)

· ‘Reduced activity’ (9,10,41)

· ‘No activity’ (4,5,6)

Phenotypes

By number of ‘Normal’ copies:

· Ultra-rapid: >2

· Extensive: 2 (i.e. usual)

· Intermediate: 1 (or 2x ‘Reduced activity’)

· Poor: 0

Prevalence

· Ultra-rapid: 30% Nth Africa, Arabs; 10% Greek/Portuguese; 1-3% others

· Extensive: 80-90%

· Intermediate: 2-10%

· Poor: 5-10% Caucasians, 30% Hong Kong Chinese

Effect of increased function:

Drug activated

· ↑Peak effect, ↑toxicity

· ↑Duration

· e.g. codeine toxicity (N.B. if given to UM mother -> neonatal fatality)

Drug inactivated

· ↓Peak effect

· ↓Duration

· e.g. clonidine effective shortened (?)

Effect of decreased function: