Perhexiline
- 1 March 2007
- journal article
- review article
- Published by Wiley in Cardiovascular Drug Reviews
- Vol. 25 (1), 76-97
- https://doi.org/10.1111/j.1527-3466.2007.00006.x
Abstract
The definitive version is available at www.blackwell-synergy.comPerhexiline, 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.Houman Ashrafian, John D. Horowitz, Michael P. FrenneauKeywords
This publication has 61 references indexed in Scilit:
- Myocardial Glucose Transport and Utilization in Patients With Type 2 Diabetes Mellitus, Left Ventricular Dysfunction, and Coronary Artery DiseaseJournal of the American College of Cardiology, 2006
- CYP2B6, CYP2D6, and CYP3A4 Catalyze the Primary Oxidative Metabolism of Perhexiline Enantiomers by Human Liver MicrosomesDrug Metabolism and Disposition, 2006
- The influence of CYP2D6 genotype on trough plasma perhexiline and cis‐OH‐perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemiaBritish Journal of Clinical Pharmacology, 2005
- Myocardial Substrate Metabolism in the Normal and Failing HeartPhysiological Reviews, 2005
- Development of a regimen for rapid initiation of perhexiline therapy in acute coronary syndromesInternal Medicine Journal, 2004
- Is perhexiline essential for the optimal management of angina pectoris?Australian and New Zealand Journal of Medicine, 1995
- Perhexiline maleate treatment for severe angina pectoris — correlations with pharmacokineticsInternational Journal of Cardiology, 1986
- Perhexiline [2-(2,2-dicyclohexylethyl)piperidine] maleateActa Crystallographica Section C Crystal Structure Communications, 1986
- Pharmacokinetics of perhexiline maleate in anginal patients with and without peripheral neuropathyEuropean Journal of Clinical Pharmacology, 1978
- Effects of Perhexiline on Coronary Hemodynamic and Myocardial Metabolic Responses to TachycardiaCirculation, 1974