Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress fast rhythms of the heart (cardiac arrhythmias), such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation.
While the use of antiarrhythmic agents to suppress atrial arrhythmias (atrial fibrillation and atrial flutter) is still in practice, it is unclear whether suppression of atrial arrhythmias will prolong life 1,2.
In the past, it was believed that suppression of the potentially dangerous ventricular arrhythmias, ventricular tachycardia and ventricular fibrillation would prolong life, but it was found in large clinical trials that suppression of these arrhythmias would paradoxically increase mortality3,4, which may happen due to the increased work load these drugs place on the heart.
In individuals with atrial fibrillation, antiarrhythmics are still used to suppress arrhythmias. This is often done to relieve the symptoms that may be associated with the loss of the atrial component to ventricular filling (atrial kick) that is due to atrial fibrillation or flutter.
In individuals with ventricular arrhythmias, antiarrhythmic agents are often still in use to suppress arrhythmias. In this case, the patient may have frequent arrhythmic events or at high risk for ventricular arrhythmias. Antiarrhythmic agents may be considered the first-line therapy in the prevention of sudden death in certain forms of structural heart disease, and failure of these agents to suppress arrhythmias may lead to implantation of an implantable cardioverter-defibrillator (ICD).
The use of antiarrhythmic agents in this population may be in conjunction with an ICD. In this case, the ICD is used to prevent sudden death due to ventricular fibrillation, while the antiarrhythmic agent(s) are used to suppress ventricular tachyarrhythmias so that the ICD doesn't shock the patient frequently.
The cardiac action potential
Many attempts have been made to classify antiarrhythmic agents. The problem arises from the fact that many of the antiarrhythmic agents have multiple modes of action, making any classification imprecise.
Vaughan Williams antiarrhythmic classification
The Vaughan Williams classification is one of the most widely used classification schemes for antiarrhythmic agents. This scheme classifies a drug based on the primary mechanism of its antiarrhythmic effect. However, its dependence on primary mechanism is one of the limitations of the VW classification, since many antiarrhythmic agents have multiple action mechanisms. Amiodarone, for example, has effects consistent with all of the first four classes. Another limitation is the lack of consideration within the VW classification system for the effects of drug metabolites. Procainamide, a class Ia agent whose metabolite – N-acetyl procainamide (NAPA) – has a class III action is one such example. A historical limitation was that drugs such as digoxin and adenosine – important antiarrhythmic agents – had no place at all in the VW classification system. This has since been rectified by the inclusion of class V.
There are five main classes in the Vaughan Williams classification of antiarrhythmic agents:
Class I agents
The class I antiarrhythmic agents interfere with the sodium (Na+) channel. Class I agents are grouped by what effect they have on the Na+ channel, and what effect they have on cardiac action potentials.
Class Ia agents
Class Ia agent decreasing Vmax
, thereby increasing action potential duration.
Class Ia agents block the fast sodium channel. Blocking this channel depresses the phase 0 depolarization (reduces Vmax), which prolongs the action potential duration by slowing conduction. Agents in this class also cause decreased conductivity and increased refractoriness.
Indications for Class Ia agents are supraventricular tachycardia, ventricular tachycardia, symptomatic ventricular premature beats, and prevention of ventricular fibrillation.
Class Ia agents include quinidine, procainamide and disopyramide .
Procainamide can be used in the treatment of atrial fibrillation in the setting of Wolff-Parkinson-White syndrome, and in the treatment of wide complex hemodynamically stable tachycardias.
While procainamide and quinidine may be used in the conversion of atrial fibrillation to normal sinus rhythm, they should only be used in conjunction with an AV node blocking agent (ie: digoxin, verapamil, or a beta blocker), because procainamide and quinidine can increase the conduction through the AV node and may cause 1:1 conduction of atrial fibrillation, causing an increase in the ventricular rate.
Class Ib agents
Effect of class Ib antiarrhythmic agents on the cardiac action potential.
Class Ib antiarrhythmic agents are sodium channel blockers. Class Ib agents have fast onset and offset kinetics, meaning that they have little or no effect at slower heart rates, and more effects at faster heart rates. Class Ib agents shorten the action potential duration and reduce refractoriness. These agents will decrease Vmax in partially depolarized cells with fast response action potentials. They either do not change the action potential duration, or they may decrease the action potential duration.
Class Ib agents are indicated for the treatment of ventricular tachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrillation.
Class Ib agents include lidocaine, mexiletine , tocainide , and phenytoin.
Class Ic agents
Effect of class Ic antiarrhythmic agent on cardiac action potential.
Class Ic antiarrhythmic agents markedly depress the phase 0 repolarization (decreasing Vmax). They decrease conductivity, but have a minimal effect on the action potential duration. Of the sodium channel blocking antiarrhythmic agents (the class I antiarrhythmic agents), the class Ic agents have the most potent sodium channel blocking effects.
Class Ic agents are indicated for life-threatening ventricular tachycardia or ventricular fibrillation, and for the treatment of refractory supraventricular tachycardia (ie: atrial fibrillation).
Class Ic agents include encainide , flecainide, moricizine , and propafenone.
Class II agents
Class II agents are conventional beta blockers. They act by slowing conduction through the AV node.
Class II agents include esmolol, propranolol, and metoprolol.
Class III agents
Effect of class III antiarrhythmic agent on cardiac action potential.
Class III agents predominantly block the potassium channels, thereby prolonging repolarization5. Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. (The re-entrant rhythm is more like to interact with tissue that has become refractory).
Class III antiarrhythmic agents exhibit reverse use dependent prolongation of the action potential duration (Reverse use-dependence)5. This means that the refractoriness of the ventricular myocyte increases at lower heart rates. This increases the susceptibility of the myocardium to early after-depolarizations (EADs) at low heart rates. Antiarrhythmic agents that exhibit reverse use-dependence are more efficacious at preventing a tachyarrhythmia that converting someone into normal sinus rhythm. Because of the reverse use-dependence of class III agents, at low heart rates class III antiarrhythmic agents may paradoxically be more arrhythmogenic.
Class III agents include amiodarone, azimilide , bretylium , clofilium , dofetilide, ibutilide , sematilide , and sotalol.
Amiodarone is indicated for the treatment of refractory VT or VF, particularly in the setting of acute ischemia. Amiodarone is also safe to use in individuals with cardiomyopathy and atrial fibrillation, to maintain normal sinus rhythm. However, it does not cardiovert individuals from atrial fibrillation to normal sinus rhythm.
Sotalol is indicated for the treatment of atrial or ventricular tachyarrhythmias, and AV re-entrant arrhythmias. Ibutilide is the only antiarrhythmic agent currently approved by the FDA for acute conversion of atrial fibrillation to sinus rhythm.
Class IV agents
Class IV agents are slow calcium channel blockers. They decrease conduction through the AV node.
Class IV agents include verapamil and diltiazem.
Class V agents
Class V agents include adenosine and digoxin.
- Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002 Dec 5;347(23):1825-33. (Medline abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=1
- Nichol G, McAlister F, Pham B, Laupacis A, Shea B, Green M, Tang A, Wells G. Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation. Heart. 2002 Jun;87(6):535-43. (Medline abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
- The Cardiac Arrhythmia Suppression Trial (CAST): The CAST investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomised trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989, 321:406–412.
- The Cardiac Arrhythmia Suppression Trial II (CAST II): The CAST II Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med. 1992 Jul 23;327(4):227-33. (Medline abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1
- Lenz TL, Hilleman DE, Department of Cardiology, Creighton University, Omaha, Nebraska. Dofetilide, a New Class III Antiarrhythmic Agent. Pharmacotherapy 20(7):776-786, 2000. (Medline abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
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