Calcium channel blockers in the treatment of cardiac arrhythmias
- Philip J Podrid, MD, FACC
Philip J Podrid, MD, FACC
- Professor of Medicine, Professor of Pharmacology and Experimental Therapeutics
- Boston University School of Medicine
- Lecturer, Harvard Medical School
Calcium channel blockers (CCBs) are useful antiarrhythmic agents in the management of certain arrhythmias, primarily supraventricular tachyarrhythmias [1-3]. They have diverse electrophysiologic properties and are therefore of variable antiarrhythmic efficacy. The primary settings in which they are useful can be best appreciated from an understanding of their mechanism of action.
This topic will review the electrophysiological properties of calcium channel blockers and their clinical indications in a variety of arrhythmias. More detailed discussions of their use in specific arrhythmias and other treatment options for arrhythmias are presented separately. (See "Atrioventricular nodal reentrant tachycardia" and "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy" and "Control of ventricular rate in atrial flutter" and "Treatment of symptomatic arrhythmias associated with the Wolff-Parkinson-White syndrome" and "Approach to the management of wide QRS complex tachycardias".)
Calcium channel blockers (CCBs), considered class IV antiarrhythmic drugs (table 1), preferentially affect myocardial tissue that mediates its electrophysiologic properties with a slow action potential (which is mediated by calcium currents) rather than myocardial tissue that mediates its electrophysiologic properties via a fast action potential (mediated by the rapid influx of sodium currents). The sinoatrial and atrioventricular nodes depend upon calcium currents to generate slowly propagating action potentials. In contrast, fast response myocardial tissues (the atria, specialized infranodal conducting system, the ventricles, and accessory pathways) depend upon sodium channel currents. (See "Myocardial action potential and action of antiarrhythmic drugs".)
Certain disorders, such as an acute myocardial infarction, may convert tissue generating a fast action potential, including ventricular myocardium and Purkinje fibers, into tissue that generates a slow action potential. In an animal model, low doses of mibefradil, a T-type CCB with weak effects on the L-type calcium channel, prevented the reduction in the ventricular fibrillation threshold with ischemia, without depressing left ventricular contractility . Higher doses of both mibefradil and verapamil prevented ischemic and reperfusion arrhythmias, an effect associated with depression of left ventricular contractility. It is not clear, however, if CCBs are clinically useful in these settings. Furthermore, mibefradil has been withdrawn from the US market because of toxicity, and it is not known if other T-type calcium channel blockers will be developed.
Calcium channel blockers block the slow calcium channel in a dose-dependent fashion, resulting in the following direct effects [3,5]:
- Haines DE, DiMarco JP. Current therapy for supraventricular tachycardia. Curr Probl Cardiol 1992; 17:411.
- Singh BN, Ellrodt G, Peter CT. Verapamil: a review of its pharmacological properties and therapeutic use. Drugs 1978; 15:169.
- Singh BN, Hecht HS, Nademanee K, Chew CY. Electrophysiologic and hemodynamic effects of slow-channel blocking drugs. Prog Cardiovasc Dis 1982; 25:103.
- Muller CA, Opie LH, McCarthy J, et al. Effects of mibefradil, a novel calcium channel blocking agent with T-type activity, in acute experimental myocardial ischemia: maintenance of ventricular fibrillation threshold without inotropic compromise. J Am Coll Cardiol 1998; 32:268.
- Cranefield PF, Aronson RS, Wit AL. Effect of verapamil on the noraml action potential and on a calcium-dependent slow response of canine cardiac Purkinje fibers. Circ Res 1974; 34:204.
- Singh BN, Nademanee K, Baky SH. Calcium antagonists. Clinical use in the treatment of arrhythmias. Drugs 1983; 25:125.
- Boriani G, Bertaglia E, Carboni A, et al. A controlled study on the effect of verapamil on atrial tachycaarrhythmias in patients with brady-tachy syndrome implanted with a DDDR pacemaker. Int J Cardiol 2005; 104:73.
- Tsuneda T, Yamashita T, Fukunami M, et al. Rate control and quality of life in patients with permanent atrial fibrillation: the Quality of Life and Atrial Fibrillation (QOLAF) Study. Circ J 2006; 70:965.
- Singh BN. Control of cardiac arrhythmias by modulation of the slow myocardial channel. In: Calcium channels, their properties, functions, regulation, and clinical relevance, Horowitz L, Partridge LD, Leach JK (Eds), CRC Press, Boca Raton 1991. p.327.
- De Simone A, De Pasquale M, De Matteis C, et al. VErapamil plus antiarrhythmic drugs reduce atrial fibrillation recurrences after an electrical cardioversion (VEPARAF Study). Eur Heart J 2003; 24:1425.
- Belhassen B, Horowitz LN. Use of intravenous verapamil for ventricular tachycardia. Am J Cardiol 1984; 54:1131.
- Wellens HJ, Bär FW, Lie KI, et al. Effect of procainamide, propranolol and verapamil on mechanism of tachycardia in patients with chronic recurrent ventricular tachycardia. Am J Cardiol 1977; 40:579.
- Gill JS, Blaszyk K, Ward DE, Camm AJ. Verapamil for the suppression of idiopathic ventricular tachycardia of left bundle branch block-like morphology. Am Heart J 1993; 126:1126.
- Sung RJ, Shapiro WA, Shen EN, et al. Effects of verapamil on ventricular tachycardias possibly caused by reentry, automaticity, and triggered activity. J Clin Invest 1983; 72:350.
- Sclarovsky S, Strasberg B, Fuchs J, et al. Multiform accelerated idioventricular rhythm in acute myocardial infarction: electrocardiographic characteristics and response to verapamil. Am J Cardiol 1983; 52:43.
- Grenadier E, Alpan G, Maor N, et al. Polymorphous ventricular tachycardia in acute myocardial infarction. Am J Cardiol 1984; 53:1280.
- McKenna WJ, Harris L, Perez G. Hypertrophic cardiomyopathy: Comparison of verapamil and amiodarone in the treatment of arrhythmia. Br Heart J 1980; 45:354.
- Kimura E, Tanaka K, Mizuno K, et al. Suppression of repeatedly occurring ventricular fibrillation with nifedipine in variant form of angina pectoris. Jpn Heart J 1977; 18:736.
- Swan H, Laitinen P, Kontula K, Toivonen L. Calcium channel antagonism reduces exercise-induced ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia patients with RyR2 mutations. J Cardiovasc Electrophysiol 2005; 16:162.
- Palileo EV, Ashley WW, Swiryn S, et al. Exercise provocable right ventricular outflow tract tachycardia. Am Heart J 1982; 104:185.
- Wu D, Kou HC, Hung JS. Exercise-triggered paroxysmal ventricular tachycardia. A repetitive rhythmic activity possibly related to afterdepolarization. Ann Intern Med 1981; 95:410.
- Lin FC, Finley CD, Rahimtoola SH, Wu D. Idiopathic paroxysmal ventricular tachycardia with a QRS pattern of right bundle branch block and left axis deviation: a unique clinical entity with specific properties. Am J Cardiol 1983; 52:95.
- German LD, Packer DL, Bardy GH, Gallagher JJ. Ventricular tachycardia induced by atrial stimulation in patients without symptomatic cardiac disease. Am J Cardiol 1983; 52:1202.
- Belhassen B, Shapira I, Pelleg A, et al. Idiopathic recurrent sustained ventricular tachycardia responsive to verapamil: an ECG-electrophysiologic entity. Am Heart J 1984; 108:1034.
- Nogami A. Idiopathic left ventricular tachycardia: assessment and treatment. Card Electrophysiol Rev 2002; 6:448.
- Singh BN, Nayler WG. The role of calcium antagonists in acute myocardial infarction. In: Early interventions in acute myocardial infarction, Rapaport E (Ed), Kluwer Academic Publications, Boston 1989. p.123.
- Held PH, Yusuf S. Impact of calcium channel blockers on mortality. In: Cardiovascular pharmacology and therapeutics, Singh BN, Dzau VJ, Vanhoutte PM, Woosley RL (Eds), Churchill Livingtion, New York 1993. p.525.
- Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol 1991; 67:1295.
- Verapamil in acute myocardial infarction. The Danish Study Group on Verapamil in Myocardial Infarction. Eur Heart J 1984; 5:516.
- Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II--DAVIT II). Am J Cardiol 1990; 66:779.
- Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988; 319:385.