2017A Question 04

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

Examiner Report

7.1% of candidates achieved a pass in this question.

A discussion of genetic variations should address the different phenotypes and prevalence in different populations.

Any accurate discussion of clinical relevance gained marks. Relevant drugs that can be commented on include codeine, oxycodone, tramadol, methadone, beta-blockers, anti-emetics and tricyclic antidepressants. Whether the enzyme metabolises drugs into active or inactive metabolites is important – a number of candidates incorrectly proposed that ultra-rapid metabolisers should be prescribed higher doses of codeine. Discussion of ‘at risk’ groups such as children gained marks.

Model Answer

Structure:

  • Introduction
  • List of drugs
  • Table: Genotype, phenotype, frequency, effect

Introduction

Factor Detail
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

Mechanism Examples
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

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 Effect
Activation

- ↑ Peak effect (~150%?), ↑ toxicity

- ↑ Duration

- High risk opioid toxicity: Breastfeeding infant, sedated, sleep disordered breathing

Inactivation

- ↓ Peak effect

- ↓ Duration

Effect of Decreased Function

Drug Effect
Activation

- ↓ Peak effect

- ↓ Duration

Inactivation

- ±↑ Peak effect, +/- ↑ Toxicity

- ↑ Duration


Last updated 2021-08-23

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