Perhexiline

Perhexiline structure

Perhexiline is a medication primarily used in the management of angina pectoris and heart failure. It works by inhibiting mitochondrial carnitine palmitoyltransferase-1, a key enzyme in fatty acid metabolism. This inhibition shifts the heart's energy substrate preference from fatty acids to glucose, which is more oxygen-efficient. This mechanism of action makes perhexiline useful in conditions where the heart's oxygen demand exceeds supply, thereby alleviating symptoms of angina and improving exercise tolerance.

Mechanism of Action

Perhexiline modulates the heart's metabolism by inhibiting the enzyme carnitine palmitoyltransferase-1 (CPT-1) located in the mitochondria. CPT-1 is crucial for the transport of long-chain fatty acids into the mitochondria, where they undergo beta-oxidation for energy production. By inhibiting this enzyme, perhexiline reduces fatty acid oxidation and promotes glucose oxidation. This metabolic shift is beneficial in ischemic conditions, as glucose oxidation requires less oxygen per ATP molecule generated than fatty acid oxidation, thus making it more efficient under oxygen-limited conditions.

Clinical Uses

Perhexiline is mainly used for the management of chronic angina pectoris that is not adequately controlled by other antianginal agents. It is also used in some cases of heart failure, where it can improve symptoms and exercise capacity. The use of perhexiline is guided by its efficacy in improving symptoms and quality of life in patients with angina and heart failure, despite its relatively uncommon use compared to other antianginal and heart failure medications.

Pharmacokinetics

The pharmacokinetics of perhexiline involve its metabolism primarily by the liver enzyme CYP2D6, leading to significant variability in drug levels among individuals. This variability necessitates therapeutic drug monitoring to ensure plasma concentrations are within the therapeutic range and to avoid toxicity. Patients with reduced CYP2D6 activity may have higher plasma levels of perhexiline, increasing the risk of side effects.

Adverse Effects

The use of perhexiline can be associated with several adverse effects, including peripheral neuropathy, hepatotoxicity, and nausea. Peripheral neuropathy is a significant concern with long-term use and is potentially irreversible. Hepatotoxicity, while less common, requires regular monitoring of liver function tests during treatment. The risk of adverse effects underscores the importance of therapeutic drug monitoring and patient selection in the use of perhexiline.

Contraindications

Perhexiline is contraindicated in patients with known hypersensitivity to the drug, severe liver impairment, and previous history of perhexiline-induced neuropathy or hepatotoxicity. Caution is advised in patients with moderate liver impairment or those with risk factors for liver disease.

Conclusion

Perhexiline remains a valuable tool in the management of angina pectoris and heart failure, particularly in patients who have not responded adequately to other treatments. Its unique mechanism of action, focusing on the metabolic modulation of the heart, offers a distinct therapeutic advantage. However, the need for careful patient selection, monitoring of drug levels, and awareness of potential adverse effects are critical in its use.