Perhexiline
A potent metabolic anti-anginal that inhibits carnitine palmitoyltransferase-1 (CPT-1), shifting cardiac metabolism from fatty acids to glucose. Highly effective but with a narrow therapeutic window: it caused hepatotoxicity and peripheral neuropathy in the past, and modern use requires plasma-level monitoring.
01 Overview
Perhexiline inhibits carnitine palmitoyltransferase-1 (and CPT-2), the rate-limiting step of mitochondrial fatty-acid uptake, forcing a metabolic shift toward more oxygen-efficient glucose oxidation. It is one of the most effective anti-anginal drugs for refractory angina and is used in some hypertrophic cardiomyopathy and heart-failure settings.
Its historic reputation was destroyed by cases of hepatotoxicity and disabling peripheral neuropathy, which occurred in slow CYP2D6 metabolisers who accumulated the drug. It fell out of favour but survives in specialist centres (notably Australia and New Zealand) where mandatory therapeutic drug monitoring keeps plasma concentrations within a safe 0.15-0.6 mg/L window.
02 Mechanism
Inhibits carnitine palmitoyltransferase-1 (CPT-1), blocking mitochondrial long-chain fatty-acid uptake and forcing more oxygen-efficient glucose oxidation in the myocardium.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Starting dose | 100 mg/day | Oral | 100 mg/day, then adjusted by plasma-level monitoring. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Potent anti-anginal effectHighly effective for refractory angina where other agents fail. | strong | Clinical | |
| Symptom relief in HCM/heart failureImproves exercise capacity in selected hypertrophic cardiomyopathy and heart-failure patients. | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| HypoglycaemiaCan lower blood glucose, especially in diabetics on other agents. | Moderate | Uncommon | Clinical | |
| HepatotoxicityCan cause steatohepatitis and liver injury at supratherapeutic plasma levels. | Severe | Dose/level-dependent | Clinical | |
| Peripheral neuropathySensorimotor peripheral neuropathy with chronic toxic levels. | Severe | With accumulation | Clinical |