perhexiline-maleate and Angina-Pectoris

Approaches to the pharmacotherapy of angina pectoris have previously centred on the concept that a transient imbalance between myocardial oxygen "demand" and supply within the myocardium can best be addressed by reducing demand (for example, with β-adrenoceptor antagonist) or by increasing availability of blood (via coronary vasomotor reactivity adjustment or coronary revascularization). However, this principle is potentially challenged by the emergence of cases of angina unsuitable for such therapies (for example because of concomitant severe systolic heart failure) and by the recognition that impaired myocardial energetics may precipitate angina in the absence of fixed or variable coronary obstruction (for example in hypertrophic cardiomyopathy). The past 20 years have seen the re-emergence of a class of anti-anginal agents which act primarily by improving efficiency of myocardial oxygen utilization, and thus can correct impaired energetics, simultaneously treating angina and heart failure symptoms. We review the principles underlying the safe use of such agents, beginning with the prototype drug perhexiline maleate, which despite complex pharmacokinetics and potential hepato- or neuro-toxicity has emerged as an attractive management option in many "complicated" cases of angina pectoris.

Topics: Angina Pectoris; Animals; Cardiovascular Agents; Fatty Acids; Glucose; Humans; Mitochondria; Myocardium; Perhexiline

The ever-increasing burden of ischaemic heart disease and its common manifestation chronic angina pectoris calls for the exploration of other treatment options for those patients who despite the maximum conventional pharmacological and surgical interventions continue to suffer. Such exploration has led to the increasing use of new metabolically acting antianginal agents and the re-emergence of an old and somewhat forgotten pharmacological agent, perhexiline maleate. This review aims to update the cardiac nurse with knowledge to manage the care a patient receiving perhexiline maleate treatment and provide a brief review of three new metabolic agents: trimetazidine, ranolazine and etomoxir.

Topics: Acetanilides; Angina Pectoris; Calcium Channel Blockers; Cardiovascular Agents; Carnitine O-Palmitoyltransferase; Drug Monitoring; Epoxy Compounds; Fatty Acids; Half-Life; Humans; Metabolic Clearance Rate; Nurse's Role; Nursing Assessment; Patient Education as Topic; Patient Selection; Perhexiline; Piperazines; Randomized Controlled Trials as Topic; Ranolazine; Treatment Outcome; Trimetazidine; Vasodilator Agents

Despite large gains in the medical and surgical treatment of angina pectoris in the past two decades, many patients are refractory to conventional medical therapy and are unsuitable for a first or, more commonly, repeat coronary revascularization procedure. We evaluated the efficacy of perhexiline maleate, a drug with an antianginal mechanism of action in humans that is as yet unknown, by using a randomized double-blind placebo-controlled crossover design in 17 patients with refractory angina who continued to receive maximal antianginal therapy, typically including nitrates, a beta-blocker, and a calcium channel antagonist. In view of perhexiline's potential for hepatic and neurological toxicity, plasma drug levels were monitored and maintained in the 150-600 ng/ml range. Sixty-three percent of patients were judged perhexiline responders by objective exercise testing criteria, as compared with 18% of patients on placebo (p less than 0.05). By blinded review of subjective measures of anginal frequency and severity, 65% of patients noted an improvement while on perhexiline, whereas no patient identified the placebo phase with improvement. Side effects observed in 29% of patients were minor and related to transient elevations of blood levels of more than 600 ng/ml; no patient suffered hemodynamic or cardiac conduction abnormalities attributable to perhexiline. With attention to the pharmacokinetics of perhexiline's elimination in individual patients, this novel antianginal agent seems to be safe and effective and deserves further evaluation in patients already receiving maximal antianginal therapy who are not candidates for revascularization procedures.

Topics: Aged; Angina Pectoris; Clinical Trials as Topic; Double-Blind Method; Exercise Test; Female; Half-Life; Humans; Male; Middle Aged; Perhexiline; Prospective Studies

We report on a case of perhexiline maleate-induced hepatitis secondary to a long-term administration of recommended daily dosages of 300 mg. The patient had a spectacular weight loss of 29 kg. He developed hepatitis, which subsided after drug withdrawal. Our electron-microscopic findings with the typical inclusion bodies and impaired hydroxylation capacity point to an underlying metabolic disorder as the pathogenetic mechanism.

Topics: Angina Pectoris; Biopsy; Chemical and Drug Induced Liver Injury; Debrisoquin; Humans; Liver; Male; Microscopy, Electron; Middle Aged; Perhexiline; Time Factors

Perhexiline maleate, which causes inhibition of myocardial fatty acid catabolism with a concomitant increase in glucose utilization, is particularly useful in the management of patients with severe angina pectoris. While perhexiline exerts no significant negative inotropic or dromotropic effects, its short- and long-term use has hitherto been restricted because of complex pharmacokinetics and the eventual development, in many patients, of hepatitis and peripheral neuropathy. Correlations between perhexiline dose, plasma drug concentrations, efficacy and development of toxicity were examined prospectively in 3 groups of patients. The first group (n = 29) were patients in whom perhexiline was added to previously prescribed anti-anginal medication for short-term (pre-surgical or post-myocardial infarction) control of angina pectoris. Over a mean treatment period of 18 +/- 2 (SEM) days, 13 patients experienced a marked reduction in frequency and severity of attacks. No adverse effects occurred. A second group of patients (n = 19) were treated chronically with 50-400 mg/day of perhexiline, dosage being adjusted to minimize symptoms. Over a mean treatment period of 8.8 +/- 1.7 months, 5 patients became asymptomatic, while 9 developed evidence of hepatitis or neurotoxicity, with concomitant plasma perhexiline concentrations of 720-2680 ng/ml. Subsequently, a further group of similar patients (n = 22) were treated for 12.4 +/- 2.6 months, perhexiline dosage being adjusted to maintain plasma perhexiline concentrations below 600 ng/ml. Nine patients became asymptomatic, while none developed adverse effects. It is concluded that perhexiline is useful both as a short-term adjunct to anti-anginal therapy and in the long-term management of patients unsuitable for coronary artery bypass grafting. The risk of long-term toxicity can be reduced markedly by maintenance of plasma drug concentrations below 600 ng/ml without significantly compromising anti-anginal efficacy.

Topics: Adult; Aged; Angina Pectoris; Angina, Unstable; Drug Administration Schedule; Female; Humans; Kinetics; Male; Middle Aged; Perhexiline; Prospective Studies; Time Factors

Experience is reported with 41 patients taking perhexiline maleate for angina pectoris for periods of up to 70 months, while serum concentrations of the drug were monitored, and liver function tests and electromyographic tests were made before and during treatment. Severe side effects did not occur unless serum perhexiline levels were greater than 1.5 mg/L. The drug seems effective for prolonged dosage, and the monitoring of weight, liver function test results, and serum concentrations should prevent or reduce toxicity. A starting dose of 100 mg daily is recommended. The drug is not recommended for routine use in angina pectoris.

Topics: Adult; Aged; Angina Pectoris; Electromyography; Female; Humans; Male; Middle Aged; Monitoring, Physiologic; Perhexiline

Patients taking oral doses of perhexiline maleate have been examined. Measurement of serum perhexiline concentrations established that different dose requirements between patients were necessary due to the different doses at which drug saturation was achieved. Measurement of serum perhexiline concentrations are essential if side-effects from the drug are to be avoided.

Topics: Angina Pectoris; Humans; Male; Perhexiline

We performed a double-blind controlled crossover trial of perhexiline maleate versus identical placebo in daily doses of 100-400 mg in 20 male patients who were severely limited with angina pectoris despite therapy with beta-adrenoreceptor blockers. All patients had documented coronary artery disease and were awaiting coronary artery bypass grafting. Beta-blocker therapy was continued unchanged. A significant response compared to placebo was evident after 100 mg of perhexiline, and incremental therapeutic effects were evident up to 400 mg. The mean weekly angina rate fell from 18.2 +/- 2.8 basal to 6.2 +/- 1.5 on 200 mg (P less than 0.05) to 2.8 +/- 0.9 on 400 mg perhexiline (P less than 0.05). Nitroglycerin consumption fell in parallel. The mean exercise duration increased from 261 +/- 57 sec to 384 +/- 75 sec (P less than 0.05). Five patients became asymptomatic on perhexiline, and the number of pain-free days increased 100% (P less than 0.01) compared to placebo. No patient experienced hypotension or heart failure. This study shows that the addition of perhexiline to beta-adrenoreceptor antagonists in patients with severe angina pectoris is effective and represents an alternative therapy.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Angina Pectoris; Double-Blind Method; Drug Resistance; Humans; Male; Middle Aged; Perhexiline; Piperidines

Two cases of sensory-motor neuropathy attributed to perhexilene maleate are described. The clinical and pathological features of perhexilene neuropathy are discussed. The use of perhexilene should be tempered with caution. Nerve conduction studies may be useful in confirming early neuropathy.

Topics: Angina Pectoris; Female; Humans; Leg; Male; Middle Aged; Neural Conduction; Pain; Paresthesia; Perhexiline; Peripheral Nervous System Diseases

Topics: Angina Pectoris; Humans; Perhexiline; Piperidines; Premedication

Perhexiline maleate is a potent anti-anginal drug which may cause alcoholic-type hepatitis and cirrhosis. We report a case of a patient who developed cirrhosis on a relatively low dose within 16 mth.

Topics: Aged; Angina Pectoris; Female; Humans; Liver; Liver Cirrhosis; Perhexiline; Piperidines

Topics: Adult; Aged; Angina Pectoris; Female; Humans; Liver Cirrhosis; Male; Perhexiline; Peripheral Nervous System Diseases; Piperidines

Topics: Angina Pectoris; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Female; Genes; Hepatitis, Alcoholic; HLA Antigens; HLA-B Antigens; Humans; Middle Aged; Perhexiline; Piperidines

The use of perhexiline maleate as an antianginal agent is occasionally associated with side effects, particularly neuropathy and liver damage. The reason why some individuals develop these toxic reactions is not clear, though some evidence suggests that they may result from impaired oxidative metabolism, due to genetic or hepatic factors, and consequential accumulation of the drug in toxic concentrations. Drug oxidation was measured with an oxidation phenotyping procedure in 34 patients treated with perhexiline, 20 of whom had developed neuropathy and 14 of whom had not. Most of the 20 patients with neuropathy, but not the unaffected patients, showed an impaired ability to effect metabolic drug oxidation. This impairment was independent of hepatic function, concurrent drug therapy, or tobacco or alcohol consumption. The fact that the ability to oxidise several drugs is genetically controlled points to a genetic susceptibility to developing neuropathy in response to perhexiline. Routine determination of the drug oxidation phenotype might lead to safer use of perhexiline by predicting patients who may be more at risk of developing a neuropathic reaction associated with its long-term use.

Topics: Adult; Aged; Alcohol Drinking; Angina Pectoris; Debrisoquin; Female; Humans; Isoquinolines; Liver Function Tests; Male; Middle Aged; Oxidation-Reduction; Perhexiline; Peripheral Nervous System Diseases; Piperidines; Smoking

Perhexiline maleate is an agent currently under investigation in Canada that is used for angina unresponsive to other treatment. This paper describes a possible side effect previously unreported--papilledema not associated with peripheral neuropathy.

Topics: Adult; Angina Pectoris; Fluorescein Angiography; Humans; Male; Papilledema; Perhexiline; Piperidines; Visual Fields

In a 78-year-old woman receiving perhexiline maleate for intractable angina pectoris, a syndrome of parkinsonism and peripheral neuropathy developed. The neuropathy was confirmed by electromyographic and nerve conduction studies. The parkinsonism and peripheral neuropathy disappeared when perhexiline maleate was discontinued.

Topics: Aged; Angina Pectoris; Female; Humans; Parkinson Disease, Secondary; Perhexiline; Peripheral Nervous System Diseases; Piperidines

Topics: Angina Pectoris; Humans; Perhexiline; Piperidines