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

Where

·   Liver > other

Alleles

·   Two

Function

·   Redox (especially O-demethylation)

Importance

·   Affects 25% of clinically used drugs

Problem

·   Polymorphism is common

·   Non-inducible

 

Relevant drugs:

Activated (prodrug)

Inactivated

·   Codeine -> morphine (↑↑potency)

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

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

·   Methadone

·   SSRI

·   TCA

·   β-blocker

·   Clonidine

 

Genetics:

Phenotype

Genotype

Frequency

Ultrarapid

>2 normal

1-2% total

30% Ethiopians, Saudis

Normal

2 normal

80-90%

Intermediate

1 normal

1 reduced function

2-10%

Poor

2 reduced function

5-10% total

30% Hong Kong Chinese

 

Effect of increased function:

Drug activated

·   ↑Peak effect (~150%?), ↑toxicity

·   ↑Duration

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

Drug inactivated

·   ↓Peak effect

·   ↓Duration

 

Effect of decreased function:

Drug activated

·   ↓Peak effect

·   ↓Duration

Drug inactivated

·   ±↑Peak effect, +/- ↑toxicity

·   ↑Duration

 

 

Feedback welcome at ketaminenightmares@gmail.com