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:

Drug activated

·  ↓Peak effect

·  ↓Duration

·  e.g. codeine and tramadol ineffective

Drug inactivated

·  ±↑Peak effect, +/- ↑toxicity

·  ↑Duration

·  e.g. clonidine effect prolonged (?)

 

 

Feedback welcome at ketaminenightmares@gmail.com