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Cibenzoline

A Review of its Pharmacological Properties and Therapeutic Potential in Arrhythmias

  • Drug Evaluation
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Summary

Synopsis

Cibenzoline is a class I antiarrhythmic drug with limited class III and IV activity which can be administered orally or intravenously. An elimination half-life of about 8 to 12 hours permits twice daily administration, although age and renal function must be considered when determining dosage. Cibenzoline has some activity in ventricular and supraventricular arrhythmias, including drug-refractory ventricular tachycardia or ventricular arrhythmias following recent acute myocardial infarction, although results in patients with sustained ventricular tachycardia are less promising. In comparative trials, cibenzoline has demonstrated efficacy similar to or better than that of a variety of other class I antiarrhythmic drugs and was at least as well tolerated, with a more convenient dosage schedule. However, further studies to clarify the proarrhythmic effects of cibenzoline and its use in patients with impaired left ventricular function are required, and the use of cibenzoline (and other class I antiarrhythmic agents) in patients with other than potentially lethal ventricular arrhythmias should be avoided following the results of the CAST studies.

Thus, cibenzoline is an effective antiarrhythmic agent with a favourable pharmacokinetic profile that may be considered with other class I drugs in patients requiring therapy for high risk arrhythmias.

Pharmacodynamic Properties

In isolated tissues cibenzoline exhibits class I and to a lesser extent, class III and IV antiarrhythmic activity. In intact animals intravenous cibenzoline increases atrial refractory periods, atrioventricular nodal, intraventricular and His-Purkinje (HV) conduction times, and ventricular refractory periods. Stroke volume decreases as a result of the direct negative inotropic action of cibenzoline combined with an increase in systemic vascular resistance.

In patients with arrhythmia cibenzoline produces dose-proportional increases in QRS (≤ 33%), QTc (≤ 12%), AH (≤ 14%), and HV (> -47%) intervals, and ventricular effective refractory period (≤ 9%). In conjunction with the pronounced decrease in maximum upstroke velocity of the action potential (Vmax), this indicates a predominantly class Ic profile. Contrary to the bradycardic effect seen in isolated tissues and intact animals, cibenzoline either increases or has no effect on heart rate in man. This may be due to vagolytic activity or to a baroreflex-mediated increase in heart rate due to reported decreases in blood pressure.

Cibenzoline also exerts a negative inotropic effect following single-dose intravenous administration, with significant transient decreases in the rate of change of left ventricular pressure, ejection fraction and stroke volume index, accompanied by an increase in vascular resistance, occurring within the therapeutic range of plasma concentrations. Afterload reduction in compensation for the negative inotropic effect appears to occur with longer term oral administration, but these effects require that cibenzoline be used with caution in patients with depressed left ventricular function.

Pharmacokinetic Properties

Cibenzoline can be administered both intravenously and orally; bioavailability after oral administration is about 85%, with peak plasma concentrations occurring 1 to 3 hours post dose. The plasma concentration-time profile is best described by a 3-compartment model in healthy subjects and a 2-compartment model in patients with acute myocardial infarction. The volume of distribution is large at 4.1 to 7.3 L/kg, and protein binding is 50 to 60%. In humans, 30 to 65% of cibenzoline is excreted unchanged in the urine; total clearance ranges from 30 to 50 L/h and renal clearance from 17 to 30 L/h. In patients with renal impairment and in the elderly, renal clearance of cibenzoline decreases and elimination half-life increases from about 7.5 to more than 20 hours. Plasma concentrations of cibenzoline associated with the abolition of arrhythmias ranged from 293 to 569 μg/L. In general, a trough plasma concentration greater than 300 μg/L was associated with antiarrhythmic activity.

Therapeutic Use

Cibenzoline has been evaluated in both ventricular and supraventricular tachyarrhythmias. Noncomparative and placebo-controlled trials have demonstrated the efficacy of cibenzoline in patients with arrhythmias, including patients with ventricular arrhythmias refractory to established antiarrhythmic agents. In small comparative studies, cibenzoline was at least as effective as quinidine, disopyramide, mexiletine, aprindine, lidocaine (lignocaine) and nadoxolol in patients with ventricular arrhythmias (cibenzoline response rate 38 to 78%), and as effective as flecainide, quinidine and disopyramide in patients with supraventricular arrhythmias (cibenzoline response rate 36 to 76%). However, results in patients with sustained ventricular tachycardia are less promising (cibenzoline response rate 28 to 54%).

Few studies have evaluated the effects of underlying organic cardiovascular disease on the response to cibenzoline therapy. While beneficial effects on haemodynamic functional parameters have been observed with short term cibenzoline administration in this patient group, the effects in patients with a reduced ejection fraction have been variable and considerable caution is recommended in these patients.

Tolerability

Cibenzoline has been relatively well tolerated in clinical trials and was usually at least as well tolerated as other antiarrhythmic agents in comparative studies. Gastrointestinal adverse effects, nervousness and tremulousness, and to a lesser extent blurred vision, dry mouth, urinary retention, hypotension/syncope, and asymptomatic increases in liver transaminases and decreases in white blood cell counts have been observed. Prolongation of PR and QRS intervals may also occur and occasional cases of bundle branch block and exacerbation of congestive heart failure have been noted. Limited studies suggest cibenzoline has proarrhythmic effects comparable to other antiarrhythmic agents. As cibenzoline influences the ECG and has a negative inotropic effect, care must be taken when administering other cardioactive agents concomitantly.

Dosage and Administration

Cibenzoline dosage should be individually titrated although in clinical trials most patients responded to 130 to 160mg twice daily orally. Cibenzoline is available as the 130mg formulation. In Japan 50 or 100mg 3 times daily of the cibenzoline succinate has been used. Dosage requirements are reduced in the elderly and it has been recommended that patients with renal dysfunction receive two-thirds the normal dosage once daily, while those with renal failure receive one-third the normal dose 12-hourly or the normal dose 36-to 48-hourly. Plasma concentrations should be monitored initially in patients with compromised renal function, and left ventricular function should be monitored in patients with a severely reduced ejection fraction.

Cibenzoline 1 to 1.75 mg/kg intravenously has been administered in patients with supraventricular arrhythmias and 1 to 3 mg/kg in patients with ventricular arrhythmias, but the use of intravenous cibenzoline has not been well characterised.

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Authors and Affiliations

  1. Department of Therapeutics and Pharmacology, The Queen’s University of Belfast, Belfast, Northern Ireland

    Dean W. G. Harron, Rex N. Brogden, Diana Faulds & Andrew Fitton

  2. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Dean W. G. Harron, Rex N. Brogden, Diana Faulds & Andrew Fitton

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Various sections of the manuscript reviewed by: M. Andrejak, Centre Hospitalier Regional et Universitaire D’Amiens, Amiens, France; H. Atarashi, First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan; F. Burkart, Departement Innere Medizin, Universitätskliniken, Kantonsspital Basel, Basel, Switzerland; M. Cooper, Department of Cardiology, Westmead Hospital, Westmead, New South Wales, Australia; B. Flouvat, Laboratoire de Toxicologie, Hopital Ambroise-Pare, Boulogne, France; H. Hayakawa, First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan; J.J. Heger, Krannert Institute of Cardiology, Indianapolis, Indiana, USA; D.E. Hilleman, The Cardiac Center of Creighton University, Omaha, Nebraska, USA; K. Kato, The Cardiovascular Institute, Tokyo, Japan; R. Kato, Department of Cardiology, Nagoya National Hospital, Nagoya, Japan; T. Katoh, First Department of Internal Medicine, Nippon Medical School, Tokyo, Japan; R.C. Klein, Veterans Administration Medical Center, Albuquerque, New Mexico, USA; V. Kühlkamp, Medizinische Klinik Abteilung III, Eberhard-Karls-Universität, Tübingen, Germany; S.M. Mohiuddin, The Cardiac Center of Creighton University, Omaha, Nebraska, USA; J. Morganroth, Center of Excellence for Cardiovascular Studies, Philadelphia, Pennsylvania, USA; T. Ozawa, Department of Biomedical Chemistry, University of Nagoya, Nagoya, Japan; A.C. Rankin, Department of Medical Cardiology, Royal Infirmary, University of Glasgow, Glasgow, Scotland; S. Saksena, Arrhythmia and Pacemaker Service, Eastern Heart Institute, New Jersey Medical School, Newark, New Jersey, USA; G. Schmidt, First Department of Medicine, Technische Universität München, München, Federal Republic of Germany; R.G. Shanks, Department of Therapeutics and Pharmacology, The Queen’s University of Belfast, Belfast, Northern Ireland.

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Harron, D.W.G., Brogden, R.N., Faulds, D. et al. Cibenzoline. Drugs 43, 734–759 (1992). https://doi.org/10.2165/00003495-199243050-00008

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