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Tocainide

A Review of its Pharmacological Properties and Therapeutic Efficacy

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Summary

Synopsis: Tocainide1 is an antiarrhythmic drug structurally related to lignocaine with similar electrophysiological, haemodynamic and antiarrhythmic effects. In contrast to lignocaine (lidocaine) it is well absorbed after oral administration and has a plasma half-life of about 15 hours.

In several open and controlled therapeutic trials in patients with ventricular arrhythmias, often following a myocardial infarction, tocainide has been relatively effective and usually well tolerated. In treating ventricular ectopic beats and/or ventricular tachycardia tocainide has demonstrated effective suppression in 60 to 70% of patients in both open and controlled studies. It has an acute effect when infused in patients with ventricular arrhythmias complicating myocardial infarction, as well as a prophylactic effect when given orally. The majority of these studies have demonstrated tocainide to be more effective than placebo, but trials against other antiarrhythmic agents are few in number and vary in design. One study combining an infusion of tocainide with oral therapy compared to a bolus injection of lignocaine followed by a constant infusion in patients after myocardial infarction, found the two agents to be of similar efficacy.

The most common adverse effects are neurological and gastrointestinal in nature, nausea and dizziness occurring most frequently. Adverse effects resulting in termination of therapy have been reported in about 16% of patients. Aggravation of pre-existing heart failure, increased ventricular arrhythmia, deterioration of conduction disturbances, convulsions, and cases of lupus erythematosus syndrome have occasionally been reported.

Thus, tocainide appears to offer a worthwhile addition to the other antiarrhythmic agents available for ventricular arrhythmias. However, its relative place in therapy compared with other antiarrhythmic drugs is not yet clearly established.

Pharmacodynamic Studies: In both animals and man, tocainide has electrophysiological and haemodynamic effects which are qualitatively similar to those of lignocaine. The electrophysiological effects of tocainide are small in magnitude, and involve a decrease in the rate of rise of the action potential; a decrease in the effective refractory periods of the atrium, AV node and right ventricle; and a general decrease in membrane excitability together with slight decreases in conduction velocity and automaticity of the sinus node. Electrocardiographic changes are also similar to those seen with lignocaine, with a slight decrease in the Q-Tc intervals, but no significant change in QRS duration.

In patients with Wolff-Parkinson-White syndrome, tocainide has been shown to increase the effective refractory period of the accessory pathway. In combination with a β-adrenoceptor blocking drug (β-blocker) tocainide depressed sinus node function and shortened the functional refractory period of the His-Purkinje system, but no significant change in the refractory periods of the atrium, AV node, or right ventricle were seen.

Haemodynamic studies in animals and healthy subjects did not demonstrate any alteration in heart rate or blood pressures after infusions of tocainide. However, patients with acute myocardial infarction showed small increases in both heart rate and blood pressures following tocainide infusion, but no overall increase was seen in a long term study of such patients on oral therapy. Studies in other patients with coronary artery disease or valvular heart disease have shown small elevations in blood pressure but no alteration in heart rate. Tocainide brought about a slight depression of myocardial function in most groups of patients studied although the results varied from group to group. When combined with a β-blocker tocainide decreased peak left ventricular rate of pressure rise and ejection fraction, but increased pulmonary wedge pressure. This combination of drugs produced a small depression of myocardial contractility which in patients with heart disease did not result in clinical sequelae; however in patients with ‘sick-sinus syndrome’ and impaired AV conduction significant depression of cardiac function may occur with such a combination.

Pharmacokinetic Studies: Oral administration of tocainide hydrochloride results in rapid and essentially complete absorption, bioavailability approaching 100%. Tocainide does not undergo significant hepatic first-pass metabolism. Peak plasma levels reached in healthy subjects 1 to 2 hours after a single dose of 400mg were approximately 1.8 ± 0.5 μg/ml. Patients with acute myocardial infarction, and other groups of patients, given tocainide 400mg 3 times daily, achieved mean plasma levels within the range 5 to 7 μg/ml. Increasing the dose in these patients to 600mg 3 times daily resulted in mean plasma concentrations of around 9 to 10 μg/ml. Intravenous administration of 500 or 750mg tocainide over 15 to 30 minutes to patients with acute myocardial infarction resulted in similar peak plasma levels of around 11 μg/ml. Studies on the extent of protein binding of tocainide have varied in their results, but it appears the free fraction in blood may be 0.8 to 0.9 or more. The apparent volume of distribution was found to be slightly greater in patients (3.2 L/kg) than in healthy subjects (2.9 L/kg).

28 to 55% of a dose of tocainide is excreted in the urine as unchanged drug, with the formation of the glucuronide of N-carboxytocainide the primary metabolic pathway for the remainder. The elimination rate in healthy subjects and various patient groups corresponds to an elimination half-life of between 12 and 15 hours. In severe renal dysfunction the half-life can double in value to around 27 hours.

Studies relating tocainide plasma levels with clinical effects vary in their findings, but it appears that a plasma concentration of about 4 to 10 μg/ml represents the likely desirable therapeutic range.

Therapeutic Trials: In several open studies with tocainide in the treatment of ventricular ectopic beats and/or ventricular tachycardia, often following myocardial infarction, oral doses of 1200 to 3200mg daily brought about significant suppression of arrhythmias in about 60% of patients. This suppression was maintained during long term therapy. Short term infusions of tocainide at 0.5 and 0.75 mg/kg/min in patients with ventricular arrhythmias complicating myocardial infarction resulted in a significant decrease in frequent and complex ventricular arrhythmias.

Placebo-controlled studies of tocainide in patients with ventricular ectopic beats have generally been single-blind in design and have demonstrated effective suppression in about 70% of patients. Studies on the usefulness of tocainide as a prophylactic agent in the prevention of ventricular arrhythmias after myocardial infarction have been mainly double-blind and placebo-controlled in design. The majority of these studies have demonstrated tocainide (given intravenously and orally) to be more effective than placebo in suppressing ventricular arrhythmias.

Intravenous or oral administration of tocainide has been shown to be as effective as procainamide in suppressing ventricular arrhythmias, and oral administration was possibly as effective as quinidine although divergent findings of relative efficacy have been reported in comparisons with quinidine. Importantly, tocainide 750mg intravenously over 15 minutes followed by 800mg orally, then subsequently 400mg 3 times daily orally, was found equally effective to lignocaine 75mg as an intravenous bolus, followed by an infusion of 2 mg/min, in suppressing ventricular tachycardia and ventricular ectopic beats after myocardial infarction. At present there are few data on the effect of tocainide on life-threatening arrhythmias.

Side Effects: Tocainide has been well tolerated in most patients. The most common adverse effects are neurological and gastrointestinal in nature, nausea and dizziness occurring in about 30% of patients. Adverse effects causing termination of therapy occurred in about 16% of patients. Infrequent adverse events reported included rash, hepatitis, elevated liver enzymes, acute pulmonary oedema, interstitial pulmonary oedema, polyarthritis, and pericarditis, both with possibly related elevated antinuclear antibody titres. Other important adverse effects of tocainide seen in a few patients involved aggravation of pre-existing heart failure, increased ventricular arrhythmia, deterioration of conduction disturbances, convulsions, and cases of lupus erythematosus syndrome. Isolated cases of ventricular fibrillation, interstitial pneumonitis and bradycardia have also been documented. Electrocardiographic changes have been limited to a decrease in QT duration.

Drug Interactions: The administration of tocainide and metoprolol to patients with heart disease results in a small depression of myocardial contractility, which is not clinically significant, but in patients with ‘sick sinus syndrome’, or impaired AV conduction this combination may produce more substantial depressant effects. In a single patient receiving tocainide 600 to 2400mg daily over 16 months, administration of propranolol on 2 separate occasions resulted in episodes of severe paranoia and confusion.

Dosage and Administration: The dosage of tocainide should be individualised for each patient on the basis of response and toleration. Plasma tocainide concentrations within the range 4 to 10 μg/ml can usually be maintained with a daily dose of 1200mg tocainide hydrochloride, given either as 400mg thrice daily or 600mg twice daily. Higher plasma concentrations around the upper limit of the therapeutic range are obtained by giving 600mg 3 times daily. Dosage may be increased to 2400mg daily where necessary. Time taken to achieve steady state levels is about 70 hours, so where it is necessary to give a loading dose, an extra dose given 4 to 6 hours after the first dose is recommended. Acute treatment can also be initiated by slow intravenous infusion of 500 to 750mg over a period of 15 to 30 minutes followed immediately by 600 to 800mg orally. Maintenance treatment can then be initiated after 8 hours.

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Authors and Affiliations

  1. ADIS Drug Information Services, PO Box 34-030, Birkenhead, Auckland 10, New Zealand

    Barbara Holmes, R. N. Brogden, R. C. Heel, T. M. Speight & G. S. Avery

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  1. Barbara Holmes
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  2. R. N. Brogden
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  3. R. C. Heel
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  4. T. M. Speight
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  5. G. S. Avery
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Additional information

Various sections of the manuscript reviewed by: C.E. Eiriksson, Cardiac Testing, Boise V.A. Medical Center, Boise, U.S.A.; C.I. Haffajee, Division of Cardiovascular Medicine, Worcester, Massachusetts, USA; D.C. Harrison, Cardiology Division, School of Medicine, Stanford University, USA; D.E. Jewitt, Cardiac Department, Kings College Hospital, London, England; D.M. Krikler, Cardiology Department, Hammersmith Hospital, London, England; D. Lalka, Department of Pharmaceutics, School of Pharmacy, State University of New York, New York, USA; T.D.V. Lawrie, Department of Cardiology, Royal Infirmary, Glasgow, Scotland; M.M. LeWinter, Cardiology Section, San Diego Veterans Administration Medical Centre, San Diego, USA; O. Nyquist, Department of Internal Medicine, Huddinge University Hospital, Huddinge, Sweden; M. Perelman, Cardiology Department, Hammersmith Hospital, London, England; B.M. Singh, Cardiology Section, V.A. Hospital (Wadsworth) Los Angeles, USA; G. Sloman, Department of Cardiology, Epworth Medical Centre, Richmond, Victoria, Australia.

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Holmes, B., Brogden, R.N., Heel, R.C. et al. Tocainide. Drugs 26, 93–123 (1983). https://doi.org/10.2165/00003495-198326020-00001

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