Perhexiline maleate neuropathy

Steven Herskovitz MD

Peripheral Neuropathies

Updated 12.29.2023
Released 01.10.2002
Expires For CME 12.29.2026

Perhexiline maleate neuropathy

Author: Steven Herskovitz MD

See Contributor Disclosures

Editor: Louis H Weimer MD

Perhexiline maleate neuropathy

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Introduction

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) (14; 19). A beneficial effect has been suggested in elderly patients with severe aortic stenosis (27) or congestive heart failure (01). 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 (10; 01). 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.

Biological basis

Etiology and pathogenesis

The clinical profile, electrophysiologic studies, nerve biopsy data, and experimental animal studies are consistent with a primary demyelinating polyneuropathy with associated axonal degeneration. 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. It is postulated that such compounds form tight but not irreversible complexes with polar lipids, leading to impairment of degradation as well as to intralysosomal accumulation (13). The inclusions resemble those found in patients with various inherited storage diseases.

Perhexiline is absorbed within 6 to 12 hours of ingestion and has a half-life of 3 to 12 days. It is a lipophilic drug, can be found unchanged along with its metabolites in all tissues examined, and is eliminated in urine and feces after metabolic oxidation in the liver (cytochrome P450 2D6) to the more polar mono- and di-hydroxylated metabolites (29).

When fed perhexiline orally at 80 mg/kg per day for 4 to 10 weeks, dark Agouti rats, who are poor debrisoquine hydroxylators, develop cytoplasmic lipid inclusions similar to those in humans (15). These are most prominent in sensory and autonomic ganglia as well as in Schwann cells with primary demyelination in spinal roots and mixed demyelination and axonal degeneration in distal nerve segments. The number of inclusions are related to the duration of treatment as well as to the tissue and plasma concentration of perhexiline. There is a mild but statistically significant prolongation of motor latencies in sciatic nerve. Withdrawal of the drug 2 weeks before sacrificing the animal results in a decrease in inclusion bodies, indicating at least some degree of reversibility. Sprague Dawley rats, which are vigorous hydroxylators, show only mild accumulations of inclusion bodies, only after prolonged duration of treatment. In another study of adult Swiss NMRI-strain mice fed perhexiline for 10 to 18 weeks at 100 mg/kg per day to 200 mg/kg per day, inclusions were present in Schwann and perineurial cells of sciatic nerve as well as in gastrocnemius muscle biopsies (04). In both studies changes in animal weight, behavior, or nonquantitative measures of neurologic function were not noted. Perhexiline can induce polymorphous inclusions in the neurons, satellite, Schwann cells, and fibroblasts of cultured mice spinal ganglia (08).

References

01: Ashrafian H, Horowitz JD, Frenneaux MP. Perhexilene. Cardiovasc Drug Rev 2007;25(1):76-97. PMID 17445089
02: Barclay ML, Sawyers SM, Begg EJ, et al. Correlation of CYP2D6 genotype with perhexilene phenotypic metabolizer status. Pharmacogenetics 2003;13(10):627-32. PMID 14515061
03: Cooper RG, Evans DA, Whibley EJ. Polymorphic hydroxylation of perhexiline maleate in man. J Med Genet 1984;21:27-33. PMID 6694182
04: Fardeau M, Tome FM, Simon P. Muscle and nerve changes induced by perhexiline maleate in man and mice. Muscle Nerve 1979;2:24-36. PMID 232538
05: Fraser DM, Campbell IW, Miller HC. Peripheral and autonomic neuropathy after treatment with perhexiline maleate. Br Med J 1977;2:675-6. PMID 198058
06: Gibson JM, Fielder AR, Garner A, Millac P. Severe ocular side effects of perhexiline maleate: case report. Br J Ophthalmol 1984;68:553-60. PMID 6743625
07: Gilutz H, Frennneaux MP, Horowitz JD. A case series of concomitant treatment of perhexiline with amiodarone. Ther Drug Monit 2012;34:227-31. PMID 22322401
08: Hauw JJ, Mussini JM, Boutry JM, et al. Perhexiline maleate induced lipidosis in human peripheral nerve and tissue culture: ultrastructural and biochemical changes. Clin Toxicol 1981;18:1405-9. PMID 6277551
09: Horowitz JD, Sia ST, Macdonald PS, Goble AJ, Louis WJ. Perhexiline maleate treatment for severe angina pectoris – correlations with pharmacokinetics. Int J Cardiol 1986;13:219-29. PMID 3793279
10: Kennedy JA, Unger SA, Horowitz JD. Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexilene and amiodarone. Biochem Pharmacol 1996;52(2):273-80. PMID 8694852
11: Lhermitte F, Fardeau M, Chedru F, Mallecourt J. Polyneuropathy after perhexiline maleate therapy. Br Med J 1976;1:1256. PMID 178402
12: Lorentz IT, Shortall M. Perhexiline neuropathy: a report of two cases. Aust NZ J Med 1983;13:517-8. PMID 6316889
13: Lullmann H, Lullmann-Rauch R. Perhexiline induces generalized lipidosis in rats. Klinische Wochenschrift 1978;56:309-10. PMID 205704
14: Lyon LJ, Nevins MA, Fisch S, Henry S. Perhexiline maleate in treatment of angina pectoris. Lancet 1971;1:1272-4. PMID 4104721
15: Meier C, Wahllaender A, Hess CW, Preisig R. Perhexiline-induced lipidosis in the dark agouti (DA) rat. An animal model of genetically determined neurotoxicity. Brain 1986;109:649-60. PMID 3730809
16: Phuong H, Choi BY, Chong CR, Raman B, Horowitz JD. Can perhexiline be utilized without long-term toxicity? A clinical practice audit. Ther Drug Monit 2016;38(1):73-8. PMID 26309031
17: Pilcher J, Chandrasekhar KP, Russell Rees J. Long term assessment of perhexiline maleate in angina pectoris. Postgrad Med J 1973;49:115-8. PMID 4587027
18: Pollet S, Hauw JJ, Escourolle R, Baumann N. Peripheral nerve lipid abnormalities in patients on perhexiline maleate. Lancet 1977;1:1258. PMID 68353
19: Raabe DS Jr. Treatment of variant angina pectoris with perhexiline maleate. Chest 1979;75:152-6. PMID 105837
20: Said G. Perhexiline neuropathy; a clinicopathological study. Ann Neurol 1978;3:259-66. PMID 208453
21: Sebille A. Prevalence of latent perhexiline neuropathy. Br Med J 1978;2:1321-2. PMID 647257
22: Shah RR, Oates NS, Idle JR, Smith RL, Lockhart JD. Impaired oxidation of debrisoquine in patients with perhexiline neuropathy. Br Med J 1982;1:295-99. PMID 6277419
23: Shah RR, Oates NS, Idle JR, Smith RL, Lockhart JD. Prediction of subclinical perhexiline neuropathy in a patient with inborn error of debrisoquine hydroxylation. Am Heart J 1983;105:159-61. PMID 6295127
24: Singlas E, Goujet MA, Simon P. Pharmacokinetics of perhexiline maleate in anginal patients with and without peripheral neuropathy. Eur J Clin Pharmacol 1978;14:195-201. PMID 729614
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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Steven Herskovitz MD

Dr. Herskovitz of Montefiore Medical Center, Albert Einstein College of Medicine, has no relevant financial relationships to disclose.
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Editor

Louis H Weimer MD

Dr. Weimer of Columbia University has no relevant financial relationships to disclose.
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Patient Profile

Age range of presentation: 0-01 month

01-23 months

02-05 years

06-12 years

13-18 years

19-44 years

45-64 years

65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Perhexiline maleate neuropathy

Differential Diagnosis

chronic inflammatory demyelinating polyneuropathy

Also Relevant

Drug-induced myopathies
Drug-induced neuropathies

Clinical Categories

Peripheral Neuropathies

Perhexiline maleate neuropathy

Perhexiline maleate neuropathy

Introduction

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

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to access the full version.

Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Chronic inflammatory demyelinating polyradiculoneuropathy

Amyotrophic lateral sclerosis

Amiodarone neuropathy

Autoimmune autonomic neuropathy

Leukodystrophies

Neuroacanthocytosis

Peripheral nerve injuries

Perhexiline maleate neuropathy

Introduction

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

References

Contributors

Author

Editor

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Chronic inflammatory demyelinating polyradiculoneuropathy

Amyotrophic lateral sclerosis

Amiodarone neuropathy

Autoimmune autonomic neuropathy

Leukodystrophies

Neuroacanthocytosis

Peripheral nerve injuries

This is an article preview.
Start a Free Account
to access the full version.