Perhexiline
The mechanism of action of perhexiline in the treatment of angina is unclear; it was originally labelled as a calcium channel blocker. It has a saturable rate of hepatic metabolism, which means that dose increases can lead to disproportionate changes in plasma concentration. The metabolism of perhexiline is genetically determined. Approximately 10% of the population are slow metabolisers of perhexiline and require very low maintenance doses (eg 50 to 100 mg once a week).
A relationship exists between perhexiline blood concentration and toxicity, and a therapeutic range of 0.15 to 0.6 mg/L (0.5 to 2 micromol/L) has been established. Patients who remain symptomatic on perhexiline within this range may require careful dose titration to achieve plasma concentrations in the range of 0.6 to 1.2 mg/L. Monitor within 3 to 5 days of the initial starting dose to identify slow metabolisers, then every 1 to 2 weeks until stabilised (the half-life is 7 to 14 days), and thereafter every 3 to 6 months. Perhexiline is metabolised by CYP2D6, so more careful monitoring is required if drugs that affect CYP2D6 are added or stopped, as this can affect plasma concentration and the risk of toxicity, or decrease efficacy.
Adverse effects, precautions and interactions:
Serious hepatic and neurological adverse effects limit the use of perhexiline. It is relatively contraindicated in patients with pre-existing liver or peripheral nerve disease. Careful therapeutic drug monitoring, together with clinical monitoring for the advent of peripheral neuropathy or hepatotoxicity, has reduced the incidence of serious adverse effects associated with perhexiline therapy. An interaction with some selective serotonin reuptake inhibitors (SSRIs) (eg fluoxetine, paroxetine) can result in a rise in the perhexiline plasma concentrations, with an increased risk of toxicity
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