What are the classes of anti-arrhythmic (anti-rhythm) drugs?

Antiarrhythmic Drug Classification

Antiarrhythmic drugs are classified using the Vaughan Williams system into four main classes (I-IV) based on their primary mechanism of action on cardiac ion channels and receptors. 1, 2

Class I: Sodium Channel Blockers

Class I agents block fast sodium channels in cardiac myocytes, slowing phase 0 depolarization and conduction velocity. 1, 3 These are further subdivided based on their kinetics of sodium channel binding and effects on action potential duration:

Class IA

• Drugs: Quinidine, Procainamide, Disopyramide 1, 2
• Key characteristics: Moderate sodium channel blockade with intermediate dissociation kinetics; prolong action potential duration and QT interval 1, 2
• Critical warning: Associated with QT prolongation and risk of torsades de pointes 2

Class IB

• Drugs: Lidocaine, Mexiletine 1, 2
• Key characteristics: Weak sodium channel blockade with rapid dissociation kinetics; minimal effect on action potential duration 1
• Primary use: Ventricular tachyarrhythmias, particularly acute settings 2

Class IC

• Drugs: Flecainide, Propafenone 1, 2
• Key characteristics: Potent sodium channel blockade with slow dissociation kinetics; minimal effect on action potential duration 1
• Absolute contraindication: Structural heart disease due to increased mortality demonstrated in the CAST trial 1, 4
• Specific risk: Can convert atrial fibrillation to atrial flutter with rapid ventricular response 2

Critical limitation of all Class I agents: Except in specific circumstances, sodium channel blockers have a limited role in preventing ventricular tachycardia/sudden cardiac death due to lack of survival benefit and increased mortality in patients with ischemic heart disease. 1

Class II: Beta-Adrenergic Blockers

• Drugs: Propranolol, Metoprolol, Carvedilol 1, 2
• Mechanism: Competitive antagonism of beta-adrenergic receptors, reducing sympathetic effects on cardiac automaticity and conduction 3
• Unique distinction: Beta-blockers are the only antiarrhythmic class proven to reduce sudden cardiac death and overall mortality across multiple patient populations 1, 2, 4
• Clinical priority: First-line therapy for most arrhythmias and should be used in all patients unless contraindicated 4

Class III: Potassium Channel Blockers (Repolarization Prolonging Agents)

• Drugs: Amiodarone, Sotalol, Dofetilide, Ibutilide, Bretylium 1, 2
• Mechanism: Block potassium channels (primarily delayed rectifier current), prolonging action potential duration and refractory period 1, 3
• Key effect: Prolong QT interval with associated risk of torsades de pointes 2

Amiodarone - Special Considerations

Amiodarone is unique among antiarrhythmics because it possesses electrophysiologic characteristics of all four Vaughan Williams classes. 5, 6

• Blocks sodium channels (Class I effect) 5
• Exerts noncompetitive antisympathetic action (Class II effect) 5
• Blocks myocardial potassium channels, prolonging action potential (Class III effect) 5
• Blocks calcium channels (Class IV effect) 5
• Safety profile: Safe in heart failure but causes frequent extracardiac toxicity requiring monitoring of thyroid function, liver enzymes, pulmonary function, and ophthalmologic exams 4

Sotalol - Proarrhythmia Risk

Sotalol exhibits dose-related risk of torsades de pointes, with incidence ranging from 0.5% at 160 mg daily to 5.8% at doses >640 mg daily in patients with sustained VT/VF. 7

• Risk factors include: female gender, excessive QTc prolongation (>500 ms), history of cardiomegaly or heart failure, hypokalemia, and hypomagnesemia 7
• QTc monitoring is mandatory: Incidence of torsades de pointes increases from 1.3% with QTc <500 ms to 10.8% with QTc >550 ms 7

Class IV: Calcium Channel Blockers

• Drugs: Verapamil, Diltiazem (nondihydropyridines only) 1
• Mechanism: Block L-type calcium channels in nodal tissue 3
• Primary indication: Supraventricular tachyarrhythmias, particularly for rate control 2
• Key effects: Slow AV nodal conduction and prolong AV nodal refractoriness 1

Critical Safety Considerations Across All Classes

Proarrhythmia Risk Factors

Before initiating any antiarrhythmic, correct the following risk factors for torsades de pointes: 4

• Hypokalemia and hypomagnesemia 7
• Bradycardia (increases risk with Class IA and III agents) 7
• Female gender (higher risk with QT-prolonging agents) 7
• Structural heart disease 7

Required Monitoring Parameters

• Class IA and III agents: QT interval monitoring 4
• Class IC agents: QRS widening (discontinue if >150% baseline) 4
• All AV nodal blocking agents: PR interval 4

Clinical Selection Algorithm

For Atrial Fibrillation Without Structural Heart Disease

First-line options: Flecainide, Propafenone, or Sotalol 2, 4

• Beta-blockers should be added before Class IC agents to prevent rapid ventricular response if atrial flutter develops 1

For Atrial Fibrillation With Structural Heart Disease or Heart Failure

Preferred agents: Amiodarone or Dofetilide 2, 4

• Class IC agents are absolutely contraindicated 4

For Ventricular Arrhythmias

Beta-blockers are first-line for all patients 4

• Amiodarone for symptomatic/sustained VT in heart failure patients 4
• Sodium channel blockers have limited role except: IV lidocaine for refractory VT/cardiac arrest, oral mexiletine for long QT syndrome, quinidine for Brugada syndrome, flecainide for catecholaminergic polymorphic VT 1

Important Clinical Pitfalls

Drug interactions: Class I or III antiarrhythmic agents should be withheld for at least three half-lives before starting another antiarrhythmic 7

Combination therapy caution: Concomitant use of drugs that prolong QT interval is not recommended and has not been adequately studied 7

Amiodarone exception: In clinical trials, oral amiodarone for >1 month in the previous three months was an exclusion criterion for other antiarrhythmic initiation 7