Perhexiline maleate neuropathy

Steven Herskovitz MD (Dr. Herskovitz of the Montefiore Medical Center has no relevant financial relationships to disclose.)
Louis H Weimer MD, editor. (Dr. Weimer of Columbia University has received consulting fees from Roche.)
Originally released January 10, 2002; last updated December 29, 2016; expires December 29, 2019

Key points

 

• Perhexiline is a prophylactic antianginal agent that enhances cardiac oxygen efficiency by inhibiting mitochondrial carnitine palmitoyltransferase-1, which results in an increase in glucose metabolism at the expense of fatty acid metabolism.

 

• The principal neurotoxic effect of perhexiline is a predominantly demyelinating sensorimotor polyneuropathy.

 

• The toxic mechanism is likely related to accumulation of lysosomal inclusions in Schwann cells and other tissues. Like amiodarone, perhexiline is a cationic amphiphilic drug that can penetrate lysosomes.

Historical note and terminology

Perhexiline maleate is an orally-administered prophylactic agent that was introduced in the 1970s for the treatment of angina pectoris and variant angina (Prinzmetal) (Lyon et al 1971; Raabe 1979). A beneficial effect has been suggested in elderly patients with severe aortic stenosis (Unger et al 1997) or congestive heart failure (Ashrafian et al 2007). Interest in this drug has increased in recent years. Its actions include coronary vasodilatation by a direct effect on vascular smooth muscle and blocking exercise-induced tachycardia. It acts as a cardiac metabolic agent, enhancing oxygen efficiency by inhibiting mitochondrial carnitine palmitoyltransferase-1, resulting in an increase in glucose metabolism at the expense of fatty acid metabolism (Kennedy et al 1996; Ashrafian et al 2007). The principal neurotoxic effect of perhexiline is a predominantly demyelinating peripheral neuropathy, an uncommon finding in toxic neuropathies. There are additional reports of raised intracranial pressure with papilledema and a proximal myopathy.

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