Version May 2024
INTRODUCTION — 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 CCBs and their clinical indications in a variety of arrhythmias. More detailed discussions of the use of CCBs in specific arrhythmias, CCBs for nonarrhythmic conditions, and other treatment options for arrhythmias are presented separately.
●(See "Calcium channel blockers in the management of chronic coronary syndrome".)
●(See "Calcium channel blockers in heart failure with reduced ejection fraction".)
●(See "Choice of drug therapy in primary (essential) hypertension".)
●(See "Atrioventricular nodal reentrant tachycardia".)
●(See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome".)
●(See "Wide QRS complex tachycardias: Approach to management".)
●(See "Control of ventricular rate in atrial flutter".)
ELECTROPHYSIOLOGIC PROPERTIES — CCBs, considered class IV antiarrhythmic drugs (table 1), preferentially affect myocardial tissue with a slow action potential that is mediated by calcium currents. The sinoatrial and atrioventricular nodes depend on 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 on sodium channel currents. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".)
CCBs block the slow calcium channel in a dose-dependent fashion, resulting in the following direct effects [3,4]:
●Slowing of phase 4 depolarization and the conduction velocity of the sinoatrial (SA) and atrioventricular (AV) nodes
●Lengthening the antegrade and retrograde refractory periods of the AV node
●Slowing of the sinus rate and increased PR interval on the electrocardiogram (ECG) via the slowing of conduction through the AV node
Similar to sodium channel blockers, CCBs with antiarrhythmic activity (ie, verapamil and diltiazem) exhibit "use-dependence." This phenomenon is characterized by an increase in the extent of calcium channel blockade as the frequency of impulse generation and ventricular activation increases. CCBs can also cause significant peripheral vasodilation, an effect which can induce reflex activation of the sympathetic nervous system. As a result, the observed electropharmacologic and pharmacodynamic properties of CCBs represent a combination of direct effects and indirect sympathetic reflex actions. This is particularly important with dihydropyridines (ie, nifedipine), which are potent vasodilators and sympathetic activators. The serum concentration of dihydropyridine CCBs necessary to achieve electrophysiologic activity in humans is much higher than the concentration needed to induce potent vasodilation. Therefore, at prescribed doses, these agents do not exert measurable electrophysiologic effects and appear to be devoid of antiarrhythmic activity. In addition, the reflex activation of the sympathetic nervous system offsets any direct effect of the dihydropyridine CCBs on the sinoatrial and AV nodes.
Among nondihydropyridine CCBs, the effect on vasodilation is more apparent with diltiazem than verapamil, which results in verapamil having a more pronounced effect on the SA and AV nodes as its action is not offset by vasodilatory activation of sympathetic activity.
CLINICAL USE — Because verapamil and diltiazem primarily affect slow response tissues in the SA and AV nodes, these medications are primarily used for the management of supraventricular tachycardias dependent on conduction through the AV node (ie, atrioventricular nodal reentrant tachycardia and atrioventricular reentrant tachycardia) and for ventricular rate control in atrial fibrillation (AF), atrial flutter, and atrial tachycardia. They are largely ineffective for the direct prevention of most ventricular arrhythmias; however, there are some exceptions, such as the utility of verapamil for the treatment of idiopathic fascicular ventricular tachycardia. (See 'Ventricular arrhythmia' below.)
The antiarrhythmic effect of verapamil appears to be similar in adults and children, although less experience is available in children [1,2,5]. Verapamil and to a lesser degree diltiazem may be harmful in patients with hypotension or impaired ventricular function (especially those with a history of heart failure [HF]), and in general should not be used in patients with these conditions. In addition, CCBs should be used cautiously in patients already taking a beta blocker because of the combined negative inotropic and chronotropic effects of both classes of medications [5].
A brief review of these issues is provided here; the use of CCBs in the treatment of specific arrhythmias is discussed in detail elsewhere.
Supraventricular tachycardia — Both diltiazem and verapamil are accepted as treatments of choice for the termination of supraventricular tachycardias (SVT), such as AV nodal reentrant tachycardia and atrioventricular reciprocating tachycardia due to an accessory pathway. An important exception to the first-line use of these agents occurs in unstable patients with hemodynamic compromise. In an unstable patient with SVT, the preferred treatment is direct electrical cardioversion or intravenous adenosine, a very short-acting AV nodal blocking agent that rarely produces additional hypotension. (See "Atrioventricular nodal reentrant tachycardia".)
Another situation in which CCBs should be avoided or used with caution is in the presence of a wide QRS complex tachycardia. If there is no doubt that a wide QRS complex tachycardia is supraventricular in origin, therapy directed at the AV node and the SVT may be given. In such cases, management is similar to that described above for SVT with a normal QRS duration. However, with a wide QRS complex tachycardia that is potentially ventricular tachycardia, CCBs blockers should be avoided, as there is a risk for hemodynamic deterioration following the administration of these medications. (See "Wide QRS complex tachycardias: Approach to management".)
CCBs appear to be of limited value in other forms of reentrant and automatic SVT [2,3,5,6]. Limited data exist concerning their role in SA nodal reentrant tachycardia or in atrial tachycardia due to an ectopic focus or intraatrial reentry (except for rate control by AV nodal blockade). However, oral verapamil may convert paroxysmal atrial tachycardia with block to sinus rhythm under certain circumstances, such as digoxin toxicity.
Multifocal atrial tachycardia — Either a non-dihydropyridine calcium channel blocker (ie, verapamil and diltiazem) or a beta blocker is usually the treatment of choice for multifocal atrial tachycardia. These drugs impair AV nodal conduction and will therefore slow the ventricular rate in this disorder; they do not usually reverse or prevent this arrhythmia. (See "Multifocal atrial tachycardia".)
Atrial fibrillation and flutter — Verapamil and diltiazem are used both acutely (via the intravenous route) and chronically (via the oral route) to slow the ventricular response in AF and atrial flutter. Their efficacy for rate control is due to their direct action to slow conduction and prolonged refractoriness in the AV node. Verapamil and diltiazem reduce both the resting and the exercise-induced increases in heart rate, whereas the major effect of digoxin (which works on the AV node via enhancing vagal tone) is on the resting rate. Therefore, verapamil and diltiazem are generally preferred to digoxin as monotherapy (in the absence of underlying HF) [7]. However, for patients with inadequate ventricular rate control with monotherapy, the concurrent use of digoxin or a beta blocker with verapamil or diltiazem has an additive depressant effect on the AV node. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Control of ventricular rate in atrial flutter".)
AV nodal blocking medications that are normally used to control the ventricular rate during AF (most importantly) or atrial flutter, including the CCBs verapamil and diltiazem, are contraindicated in patients with an accessory pathway and preexcitation. This is discussed in further detail in another topic. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'When to avoid AV nodal blockers'.)
CCBs also have a propensity to convert atrial flutter to fibrillation in a small number of patients, presumably due to a shortening of the atrial effective refractory period [8]. CCBs have been regarded as having little value in the termination and prevention of AF. However, verapamil may prevent the atrial electrical remodeling that occurs in AF, and the combination of verapamil with another agent has been shown to be effective in preventing AF recurrence [9]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Verapamil'.)
Ventricular arrhythmia — The role of CCBs in ventricular arrhythmias is less well defined [10-15].
●CCBs inadequately suppress ventricular premature beats in patients with structurally normal or abnormal hearts. They also have no significant effect on arrhythmia frequency or arrhythmic mortality in patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, or mitral valve prolapse [1,2,16].
●As a class, CCBs have a limited role in the treatment of ventricular tachycardia (VT) or ventricular fibrillation (VF) in the setting of organic heart disease. They do not suppress nonsustained VT, nor do they prevent the inducibility of VT/VF after programmed electrical stimulation. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management".)
However, calcium blockers may have a role in the following clinical settings:
●They are often effective when ventricular tachycardia or fibrillation is due to transient coronary artery spasm [17]. (See "Vasospastic angina".)
●They may have a role for polymorphic VT in the structurally normal heart or in those with familial catecholaminergic polymorphic VT that is due to a RyR2 or calsequestrin gene mutation [18]. (See "Catecholaminergic polymorphic ventricular tachycardia".)
●Exercise-triggered VT (called repetitive monomorphic VT) having the morphologic pattern of left bundle branch block and an inferiorly directed axis deviation (right ventricular outflow tract tachycardia) or a pattern of right bundle branch block and rightward axis (left ventricular outflow tract tachycardia) may respond predictably and promptly to intravenous verapamil. Such an arrhythmia may occur in patients without identifiable cardiac disease [12,19,20]. (See "Ventricular tachycardia in the absence of apparent structural heart disease".)
●A relatively rare, sustained VT that occurs in patients without evidence of structural heart disease has the morphologic pattern of right bundle branch block with left axis deviation [21-23]. This arrhythmia, which is called an idiopathic fascicular ventricular tachycardia (primarily of the left posterior fascicle), verapamil sensitive tachycardia, or Belhassen tachycardia, appears to be a distinct clinical entity and, in most cases, responds to intravenous verapamil [21,24]. (See "Ventricular tachycardia in the absence of apparent structural heart disease".)
Arrhythmia mortality after myocardial infarction — Routine treatment of the post-MI patient with a calcium channel blocker is not justified. It is possible that CCBs might benefit selected patients after MI, particularly those with a non-Q wave infarct, without HF, and who are unable to take a beta blocker [25-27]. However, the level of benefit, if present, is small. Additionally, there are subsets of patients in whom certain CCBs may increase mortality (see "Overview of the nonacute management of ST-elevation myocardial infarction" and "Overview of the nonacute management of ST-elevation myocardial infarction", section on 'Calcium channel blockers' and "Major side effects and safety of calcium channel blockers" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction", section on 'Calcium channel blockers').
CCBs reverse coronary vasospasm and attenuate myocardial ischemic damage following experimental coronary occlusion [28]. These observations led to clinical studies assessing if these drugs might increase survival in patients with acute myocardial infarction (MI).
Numerous randomized controlled trials of CCBs (diltiazem, verapamil, and nifedipine) have been analyzed [29,30]. No agent was found to unequivocally and decisively decrease mortality; in fact, pooled data for five CCBs suggested an unfavorable trend in total mortality, particularly with the short-acting dihydropyridines (figure 1). This is in contrast to the clear benefit associated with other drugs such as beta blockers, statins, aspirin, and angiotensin converting enzyme inhibitors. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices" and "Society guideline links: Supraventricular arrhythmias".)
SUMMARY AND RECOMMENDATIONS
●In addition to adenosine, the calcium channel blockers (CCBs) diltiazem and verapamil are treatments of choice for the termination of supraventricular tachycardia. (See 'Supraventricular tachycardia' above and "Atrioventricular nodal reentrant tachycardia".)
●Diltiazem and verapamil can be used both acutely (via the intravenous route) and chronically (via the oral route) to slow the ventricular response in atrial fibrillation (AF), atrial tachycardia, and atrial flutter. (See 'Atrial fibrillation and flutter' above.)
●In patients with hypotension or impaired ventricular function, especially those with a history of heart failure, diltiazem and verapamil may be harmful, and are relatively contraindicated. (See 'Clinical use' above.)
●CCBs should be used cautiously in patients already taking a beta blocker because of the combined negative inotropic and chronotropic effects of both classes of medications. (See 'Clinical use' above.)
●In a patient with a wide QRS complex tachycardia that is potentially ventricular tachycardia, CCBs should be avoided, as there is a risk for hemodynamic deterioration following the administration of these medications. (See 'Supraventricular tachycardia' above and "Wide QRS complex tachycardias: Approach to management".)
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