Perhexiline

Perhexiline, 2-(2,2-dicyclohexylethyl)piperidine, was originally developed as an anti-anginal drug in the 1970s. Despite its success, its use diminished due to the occurrence of poorly understood side effects including neurotoxicity and hepatotoxicity in a small proportion of patients. Recently, perhexiline's mechanism of action and the molecular basis of its toxicity have been elucidated. Perhexiline reduces fatty acid metabolism through the inhibition of carnitine palmitoyltransferase, the enzyme responsible for mitochondrial uptake of long-chain fatty acids. The corresponding shift to greater carbohydrate utilization increases myocardial efficiency (work done per unit oxygen consumption) and this oxygen-sparing effect explains its antianginal efficacy. Perhexiline's side effects are attributable to high plasma concentrations occurring with standard doses in patients with impaired metabolism due to CYP2D6 mutations. Accordingly, dose modification in these poorly metabolizing patients identified through therapeutic plasma monitoring can eliminate any significant side effects. Herein we detail perhexiline's pharmacology with particular emphasis on its mechanism of action and its side effects. We discuss how therapeutic plasma monitoring has led to perhexiline's safe reintroduction into clinical practice and how recent clinical data attesting to its safety and remarkable efficacy led to a renaissance in its use in both refractory angina and chronic heart failure. Finally, we discuss the application of pharmacogenetics in combination with therapeutic plasma monitoring to potentially broaden perhexiline's use in heart failure, aortic stenosis, and other cardiac conditions.