Drug Idiosyncrasy - Part II

 

Cytochrome P450 variants

The cytochrome P to be metabolised by more than one sub-type of enzyme, but clinically important reductions in metabolism will be seen if there are reductions in the activity of an enzyme that normally predominates in the metabolism of the drug. Those polymorphisms that produce an increase in enzyme activity are associated with rapid drug clearance and inadequate therapeutic effect. 450 group of enzymes are responsible for the great majority of microsomal phase I oxidation reactions. Four classes of cytochrome P450 enzymes (CYP1-4) each with several sub-groups have been identified. Polymorphisms in at least four cytochrome P450 enzymes have been found that are associated with increased, reduced or even absent enzyme activity. Most drugs have the potential to be metabolised by more than one sub-type of enzyme, but clinically important reductions in metabolism will be seen if there are reductions in the activity of an enzyme that normally predominates in the metabolism of the drug. Those polymorphisms that produce an increase in enzyme activity are associated with rapid drug clearance and inadequate therapeutic effect.

CYP 2D6

This enzyme is involved in metabolism of approximately 25% of drugs, many of which are relevant to anaesthetists. The drugs include beta-blockers (metoprolol, propranolol), anti-arrhythmics (amiodarone, flecainide), anti-depressants (nearly all tricyclics and selective serotonin re-uptake inhibitors), neuroleptics (phenothiazines and butyrophenones). It has been estimated that approximately 6% of Caucasians and 1% of Asians have reduced CYP 2D6 activity.

CYP 2C9

This enzyme is involved in the metabolism of warfarin. Individuals with deficient CYP 2C9 activity are prone to haemorrhagic complications of warfarin administered in otherwise standard dosage regimens.

CYP 2C19

This enzyme is responsible for oxidation of diazepam and the proton pump inhibitors such as omeprazole. Reduced activity of this enzyme is especially prevalent in Asians (20% versus 3% in Caucasians). Affected individuals require reduced doses of diazepam but have a beneficial therapeutic effect when given proton pump inhibitors in the treatment of Helicobacter pylori infection.

 

CYP 3A4-5

The CYP 3A enzymes are responsible for 50% of drug oxidation reactions. Polymorphisms leading to reduced activity occur in approximately 6% of Caucasians. Of relevance to anaesthesia is that they account for individuals who are slow metabolisers of midazolam.

1. Barta C, Sasvari-Szekely M, Devai A, Kovacs E, Staub M, Enyedi P. Analysis of mutations in the plasma cholinesterase gene of patients with a history of prolonged neuromuscular block during anesthesia. Molecular Genetics and Metabolism 2001; 74: 484-8.

2. Robinson RL, Anetseder MJ, Brancadoro V et al. Recent advances in the diagnosis of malignant hyperthermia susceptibility: how confident can we be of genetic testing? European Journal of Human Genetics 2003; 11: 342-8.

3. Hopkins PM. Malignant hyperthermia – pharmacology of triggering. British Journal of Anaesthesia 2011; 107: 48-56.