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 |