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

· Intro

· List of drugs

· Table: genotype, phenotype, frequency, effect

Nature	· Microsomal enzyme
Where	· Liver > other
Alleles	· Two
Function	· Redox (especially O-demethylation)
Importance	· Affects 25% of clinically used drugs
Problem	· Polymorphism is common · Non-inducible

Activated

(prodrug)

· Codeine -> morphine (↑↑potency)

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

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

Inactivated

· Methadone

· SSRI

· TCA

· β-blocker

· Clonidine

Phenotype	Genotype	Frequency
Ultrarapid	>2 normal	30% Nth Africa, Ethiopia, Arab 10% Greece, Portugal 1-3% others
Normal	2 normal	80-90%
Intermediate	1 normal 1 reduced function	2-10%
Poor	2 reduced function	5-10% total 30% Hong Kong Chinese

Drug activated

· ↑Peak effect (~150%?), ↑toxicity

· ↑Duration

· High risk opioid toxicity: breastfeeding infant, sedated, sleep disordered breathing

Drug inactivated

· ↓Peak effect

· ↓Duration

Drug activated

· ↓Peak effect

· ↓Duration

Drug inactivated

· ±↑Peak effect, +/- ↑toxicity

· ↑Duration