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BySteven Lome, MD
Fact checked byProfessional Communications, Inc.

Antiarrhythmic Drug Topic Review

BySteven Lome, MD
Fact checked byProfessional Communications, Inc.

Antiarrhythmic drugs act on the electrical conduction system of the heart. The most common use of these drugs is as part of a rhythm control strategy to maintain sinus rhythm. The Vaughan Williams classification system divides these agents based on their mechanisms of action at the cell membrane ― ion channels and sympathetic receptors ― and their effects on the action potential. The classification includes four broad classes, with further subdivisions, as presented below.

Class IA Drugs: Quinidine, Amiodarone, Procainamide, Disopyramide

Class IA drugs block cardiac sodium channels and depress phase 0 of the action potential.

The class IA drugs are effective for the treatment of atrial fibrillation (AF), but are not commonly used in routine practice due to associated adverse events and significant pro-arrhythmia.

Procainamide may be used for the management of ventricular and supraventricular tachyarrhythmia. It may be used to manage AF in patients with Wolff-Parkinson-White syndrome. Significantly, chronic exposure to procainamide may cause drug-induced lupus erythematosus.

Disopyramide may be used for vagally mediated AF and obstructive hypertrophic cardiomyopathy.

Quinidine is associated with QT interval prolongation and is rarely used — occasionally in patients with Brugada syndrome and idiopathic ventricular fibrillation (VF). Quinidine also may cause cinchonism, a syndrome that includes tinnitus, reversible hearing loss, flushing, confusion, diarrhea and visual disturbances. [Barton AK, et al. Prescriber. 2020;2b][Mahajan A, et al. Antiarrhythmic Drugs. 2011;4a-b,6b]

Amiodarone has more class III properties than class I and is used primarily for AF and ventricular tachycardia (VT). Amiodarone toxicity, particularly pulmonary toxicity, is a concern.

Class IB Drugs: Lidocaine, Mexiletine, Tocainide, Phenytoin

Class IB drugs are rapid [Barton AK, et al. Prescriber. 2020;2a] cardiac sodium channel blockers which shorten the action potential.

Lidocaine is used intravenously to treat VT and VF. Lidocaine toxicity, notably seizures, can occur at higher doses.

Mexiletine, an oral lidocaine analog, may be used for long-term prevention of VT. [Barton AK, et al. Prescriber. 2020;3a]

Tocainide is generally avoided because of a very high incidence of adverse neurologic and cardiovascular effects. [Denaro CP, et al. Med Toxicol Adverse Drug Exp. 1989;4a]

Phenytoin preferentially blocks inactivated sodium channels and also blocks inactivated T-type calcium channels in ventricular myocytes. [Mahajan A, et al. Antiarrhythmic Drugs. 2011;5a]

Class IC Drugs: Flecainide, Propafenone, Encainide, Moricizine

Class IC drugs block cardiac sodium channels and have no effect on the action potential.

Class IC drugs are commonly used to maintain sinus rhythm in patients with AF, typically paroxysmal AF. Significant coronary artery disease is a contraindication to their use because of an increased risk for proarrhythmia and sudden cardiac death. Because class IC agents increase AV nodal conduction, they must be used in combination with an AV blocking agent in order to prevent rapid AF or atrial flutter conduction (1:1 conduction) through the AV node, which may result in very rapid ventricular response rates. Class IC drugs may be proarrhythmic in the setting of left ventricular hypertrophy (wall thickness > 1.4 cm).

Flecainide or propafenone may be used on an as-needed basis in the outpatient setting with a “pill-in-the-pocket” treatment strategy, if its safety and efficacy have been documented in hospital. [Markman TM, et al. JACC Clin Electrophysiol. 2022;1a]

Note that propafenone is hepatically cleared (not recommended with liver disease) while flecainide is renally cleared.

Encainide and moricizine are very rarely used.

Class II Drugs: Metoprolol, Carvedilol, Atenolol, Propranolol, Bisoprolol, Timolol, Esmolol, Acebutolol

Class II drugs are beta-adrenergic receptor blockers. They inhibit the effect of the sympathetic nervous system resulting in decreased chronotropy (heart rate), inotropy (contractility) and dromotropy (conductivity). Beta-blockers may be used for:[Mahajan A, et al. Antiarrhythmic Drugs. 2011;10b]

  • enhanced adrenergic state-related arrhythmias;
  • ventricular rate control during AF and atrial flutter;
  • supraventricular arrhythmias (esmolol and propranolol);
  • multifocal atrial tachycardia (esmolol and metoprolol);
  • frequent premature ventricular beats (acebutolol);
  • VT (propranolol);
  • control of torsades de pointes in patients with long QT intervals;
  • prevention of sudden cardiac death after myocardial infarction (acebutolol, metoprolol, atenolol, propranolol and timolol); and/or
  • preeclampsia-related ventricular arrhythmias.

Class II drugs are contraindicated in patients with obstructive lung disease with significant reversibility on spirometry and in patients with higher degrees of AV block. Common adverse events include fatigue and sleep disturbance. [Barton AK, et al. Prescriber. 2020;3a]

Class III Drugs: Amiodarone, Sotalol, Bretylium, Dofetilide, Dronedarone, Ibutilide, Azimilide

Class III drugs block cardiac potassium channels and prolong repolarization. [Mahajan A, et al. Antiarrhythmic Drugs. 2011;5b]

Class III drugs are primarily used for rhythm control in AF/atrial flutter and in the management of hemodynamically stable VT. [Barton AK, et al. Prescriber. 2020;3a-b]

Amiodarone is very effective in the treatment of VT, VF and supraventricular arrhythmias. [Mahajan A, et al. Antiarrhythmic Drugs. 2011;8a-b] Amiodarone is FDA-approved only for the treatment of VT and VF. Amiodarone toxicity is a concern. The half-life of amiodarone is 42 days. As mentioned above, amiodarone also has some class I activity, as well as class II and class IV activity. [Barton AK, et al. Prescriber. 2020;3b]

Sotalol is used in the management of sustained VT or VF and atrial tachyarrhythmias. [Mahajan A, et al. Antiarrhythmic Drugs. 2011;9b] Sotalol is proarrhythmic in the setting of left ventricular hypertrophy (wall thickness > 1.4 cm). Sotalol is contraindicated in patients with cardiac conduction abnormalities. It has some nonselective class II activity. [Barton AK, et al. Prescriber. 2020;3b] Amiodarone and dofetilide are preferred in patients with left ventricular systolic dysfunction (reduced ejection fraction).

Dronedarone, a class III agent with some class I, II and IV activity, is also used for rhythm control in AF. It is not safe with systolic heart failure (HF) or in the setting of permanent AF.

Dofetilide is useful for maintenance of normal sinus rhythm in patients with AF, and for conversion of AF to normal sinus rhythm. It is contraindicated in patients with long QT syndromes.

Ibutilide can be used as a one-time intravenous infusion for pharmacologic cardioversion of AF to sinus rhythm.

Bretylium and azimilide are not commonly used.

Class IV Drugs: Verapamil, Diltiazem, Nifedipine

Class IV drugs are known as calcium channel blockers and act by blocking cardiac calcium uptake. They are used to slow AV nodal conduction, decreasing heart rate. They have less of an effect on sinus node activity. Class IV agents — predominantly verapamil and diltiazem — are primarily used for the prevention and treatment of supraventricular tachycardia. They are not usually useful for ventricular arrhythmias. [Barton AK, et al. Prescriber. 2020;4a-b][Mahajan A, et al. Antiarrhythmic Drugs. 2011;4b-5a]

Class IV drugs are contraindicated in patients with HF, since they reduce cardiac contractility. [Barton AK, et al. Prescriber. 2020;4a-b] Concomitant use with beta-blockers and quinidine is also contraindicated. Class IV antiarrhythmics may cause bradycardia, AV block, dizziness, flushing and headaches; verapamil may also cause constipation, rash and nausea.

Class V Drugs: Digoxin, Adenosine, Ranolazine

Class V drugs are agents whose mechanism of action is either unknown, or cannot be easily classified into one of the four Vaughan Williams classes; examples include digoxin, adenosine and ranolazine. [Barton AK, et al. Prescriber. 2020;4b-5a] Digoxin can be used for rate control in AF, adenosine for AV node blockade for AV (nodal) re-entrant tachycardia, and ranolazine has been investigated as an adjunctive agent for rhythm conversion in AF. [Barton AK, et al. Prescriber. 2020;4b-5a][Rayner-Hartley E, et al. J Am Heart Assoc. 2016]

Guidelines and Recommendations

Currently two guidelines are available for the use of antiarrhythmic drugs in patients with arrythmias: the 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death  [Al-Khatib SM, et al. J Am Coll Cardiol. 2017] and the 2023 ACC/AHA/HRS/American College of Clinical Pharmacy Guideline for the Diagnosis and Management of Atrial Fibrillation. [Joglar JA, et al. J Am Coll Cardiol. 2023]

Recommendations on the use of antiarrhythmic agents for rhythm control from the 2023 AF guidelines include:[Joglar JA, et al. J Am Coll Cardiol. 2023;85a]

The following antiarrhythmic drugs are recommended (Class 2a recommendation except as noted) in patients with AF for long-term maintenance of sinus rhythm, depending on underlying heart disease and comorbidities:

  • amiodarone
  • dofetilide
  • dronedarone
  • flecainide
  • propafenone
  • sotalol (Class 2b recommendation)
  • Because of its potential toxicities, amiodarone should (Class 2a recommendation) only be used after consideration of risks and when other agents have failed or are contraindicated.
  • Dronedarone should not (Class III recommendation: Harm) be used for treatment of AF in patients with New York Heart Association (NYHA) class III and IV HF or patients who have had an episode of decompensated HF in the past 4 weeks.
  • Flecanide and propafenone should not (Class 3 recommendation: Harm) be used in patients with previous MI and/or significant structural heart disease, including HF with ejection fraction 40% or less, due to risk for worsening HF, potential proarrhythmia and mortality.

The 2023 AF guidelines contain the following recommendations on the use of antiarrhythmic agents for rate control:[Joglar 2023;67a,70a]

  • Control of the ventricular rate using a beta-blocker or non-dihydropyridine calcium channel antagonist is recommended (Class 1 recommendation) for patients with paroxysmal, persistent or permanent AF; the agent chosen should depend on underlying substrate and comorbid conditions.
  • Intravenous administration of a beta-blocker or non-dihydropyridine calcium channel blocker is recommended (Class 1 recommendation) to slow the ventricular heart rate in the acute setting in patients without pre-excitation. In hemodynamically unstable patients, electrical cardioversion is indicated.
  • Intravenous amiodarone may be considered (Class 2b recommendation) for acute rate control in patients with AF and rapid ventricular response who are critically ill and/or in decompensated AF and in whom beta-blockers or non-dihydropyridine calcium channel blockers are ineffective or contraindicated. However, consider the risk for stroke and cardioversion when using amiodarone as a rate-control agent.
  • In patients with AF with rapid ventricular response in whom beta-blockers and nondihydropyridine calcium channel blockers are ineffective or contraindicated, digoxin may be considered (Class 2a recommendation) for acute rate control, either alone or in combination with beta-blockers and nondihydropyridine calcium channel blockers.
  • In patients with AF and rapid ventricular response, adding intravenous magnesium to standard rate-control measures is reasonable (Class 2a recommendation).
  • In patients with AF and HF, digoxin is reasonable (Class 2a recommendation) for long-term rate control in combination with other agents or as monotherapy if other agents are not tolerated, not preferred or contraindicated.
  • Non-dihydropyridine calcium channel antagonists should not (Class 3 recommendation: Harm) be used in patients with decompensated HF, as these may lead to further hemodynamic compromise.
  • Dronedarone should not (Class 3 recommendation: Harm) be used to control the ventricular rate in patients with permanent AF as it increases the risk of the combined endpoint of stroke, MI, systemic embolism or cardiovascular death.

The 2017 Ventricular Arrhythmia guidelines contain too many recommendations on the use of antiarrhythmics to prevent VT, VF and sudden cardiac death (SCD) to list here. [Al-Khatib SM, et al. J Am Coll Cardiol. 2017] In general, the guidelines state that:

  • Class I agents have a limited role in the prevention of VT and SCD outside of specific situations (eg, quinidine for patients with Brugada syndrome).
  • Class II agents are the preferred first-line antiarrhythmic option for the treatment of VT/VF and the prevention of SCD.
  • Amiodarone (with unclear survival benefit) and sotalol (with no known survival benefit) are the only class III agents that may be useful in suppressing some ventricular arrhythmias.
  • Class IV agents have no role for the treatment of most ventricular arrhythmias; oral or intravenous verapamil is effective in the treatment of idiopathic interfascicular re-entrant left VT.

References:


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anti-arrhythmia agent
arrhythmia disorder
sinus tachycardia
atrial fibrillation
metoprolol
 

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