What are the categories of antiarrhythmic (anti-arrhythmic) drugs, their mechanisms, side effects, and clinical uses?

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Antiarrhythmic Drug Categories, Mechanisms, Side Effects, and Clinical Applications

The Vaughan Williams classification system categorizes antiarrhythmic drugs into four main classes based on their primary mechanisms of action, with each class having specific indications, contraindications, and side effect profiles that guide their clinical use in various arrhythmias. 1

Class I: Sodium Channel Blockers

Class I agents block the fast sodium channels, slowing conduction velocity. They are subdivided into three groups:

Class IA

  • Drugs: Quinidine, Procainamide, Disopyramide
  • Mechanism: Moderate sodium channel blockade with potassium channel blockade, prolonging action potential duration and QT interval
  • Side Effects:
    • QT prolongation with risk of torsades de pointes
    • Hypotension
    • GI disturbances (nausea, diarrhea)
    • Quinidine: thrombocytopenia, hemolytic anemia
    • Disopyramide: anticholinergic effects (dry mouth, urinary retention, glaucoma)
    • Heart failure exacerbation
  • Clinical Uses:
    • Atrial fibrillation/flutter
    • Ventricular tachyarrhythmias
    • Less commonly used now due to proarrhythmic risk 1

Class IB

  • Drugs: Lidocaine, Mexiletine
  • Mechanism: Weak sodium channel blockade, shortening action potential duration
  • Side Effects:
    • CNS effects (confusion, seizures, paresthesias)
    • Lidocaine: primarily IV use with minimal hemodynamic effects
  • Clinical Uses:
    • Lidocaine: Acute treatment of ventricular tachyarrhythmias 2
    • Less effective for atrial arrhythmias

Class IC

  • Drugs: Flecainide, Propafenone
  • Mechanism: Strong sodium channel blockade with minimal effect on repolarization
  • Side Effects:
    • Ventricular proarrhythmia (especially with structural heart disease)
    • QRS widening
    • Conversion to atrial flutter with rapid ventricular conduction
    • Heart failure exacerbation
  • Clinical Uses:
    • Supraventricular tachyarrhythmias in patients without structural heart disease
    • Contraindicated in patients with coronary artery disease or reduced ejection fraction 1

Class II: Beta-Blockers

  • Drugs: Propranolol, Metoprolol, Atenolol, etc.
  • Mechanism: Competitive inhibition of beta-adrenergic receptors, decreasing sympathetic effects on the heart
  • Side Effects:
    • Bradycardia
    • Hypotension
    • Bronchospasm
    • Fatigue
    • Depression
    • Masking of hypoglycemia symptoms
  • Clinical Uses:
    • Considered the mainstay of antiarrhythmic therapy 1
    • Effective for suppressing ventricular ectopy
    • Reducing sudden cardiac death in various cardiac disorders
    • Rate control in atrial fibrillation
    • Treatment of inappropriate sinus tachycardia

Class III: Potassium Channel Blockers (Repolarization Prolonging)

  • Drugs: Amiodarone, Sotalol, Dofetilide, Ibutilide, Bretylium
  • Mechanism: Block potassium channels, prolonging repolarization and refractory period
  • Side Effects:
    • QT prolongation with risk of torsades de pointes
    • Sotalol: also has beta-blocking properties, bradycardia, heart failure exacerbation
    • Amiodarone: multiple organ toxicities including pulmonary fibrosis, thyroid dysfunction, hepatotoxicity, photosensitivity, corneal deposits, peripheral neuropathy
    • Dofetilide: primarily QT prolongation risk
  • Clinical Uses:
    • Maintenance of sinus rhythm in atrial fibrillation
    • Treatment of ventricular arrhythmias
    • Amiodarone: most effective for maintaining sinus rhythm after cardioversion 1, 3

Special Note on Amiodarone

Amiodarone is unique as it possesses properties of all four Vaughan Williams classes:

  • Class I: Sodium channel blockade
  • Class II: Noncompetitive antisympathetic action
  • Class III: Potassium channel blockade (primary effect)
  • Class IV: Calcium channel blockade

This multi-channel activity explains its broad efficacy but also its extensive side effect profile 3, 4

Class IV: Calcium Channel Blockers

  • Drugs: Verapamil, Diltiazem (non-dihydropyridines)
  • Mechanism: Block L-type calcium channels, particularly in AV nodal tissue
  • Side Effects:
    • Hypotension
    • Heart failure exacerbation
    • Bradycardia
    • AV block
    • Constipation (verapamil)
  • Clinical Uses:
    • Rate control in atrial fibrillation
    • AV nodal reentrant tachycardias
    • Not effective for ventricular arrhythmias 1

Other Antiarrhythmic Agents

  • Adenosine:

    • Mechanism: Activates adenosine receptors, hyperpolarizing cells and slowing AV nodal conduction
    • Uses: Acute termination of PSVT
    • Side Effects: Transient dyspnea, chest pain, flushing

  • Digoxin:

    • Mechanism: Inhibits Na+/K+ ATPase, increases vagal tone
    • Uses: Rate control in atrial fibrillation
    • Side Effects: Nausea, visual disturbances, arrhythmias with toxicity

Proarrhythmic Risk Factors

Factors predisposing to drug-induced ventricular proarrhythmia include:

For Class IA and III agents:

  • Long QT interval (QTc ≥460 ms)
  • Structural heart disease
  • Female gender
  • Hypokalemia/hypomagnesemia
  • Bradycardia
  • Renal dysfunction
  • High doses or rapid dose increases 1

For Class IC agents:

  • Wide QRS duration (>120 ms)
  • Structural heart disease
  • Depressed LV function
  • Rapid ventricular response rates 1

Clinical Decision-Making Algorithm

  1. Identify the arrhythmia type:

    • Supraventricular vs. ventricular
    • Sustained vs. non-sustained
    • Presence of structural heart disease

  2. For atrial fibrillation/flutter:

    • Without structural heart disease: Class IC (flecainide, propafenone)
    • With structural heart disease: Amiodarone, sotalol, dofetilide
    • For rate control: Beta-blockers, calcium channel blockers, digoxin

  3. For ventricular arrhythmias:

    • Acute treatment: IV lidocaine, amiodarone
    • Long-term prevention with structural heart disease: Amiodarone
    • Without structural heart disease: Beta-blockers, sotalol

  4. For AV nodal reentrant tachycardias:

    • Acute termination: Adenosine
    • Prevention: Beta-blockers, calcium channel blockers

Important Caveats

  1. Proarrhythmic potential: All antiarrhythmic drugs can potentially worsen arrhythmias, especially in patients with structural heart disease or electrolyte abnormalities 2

  2. Monitoring requirements:

    • QT interval monitoring for Class IA and III drugs
    • Electrolyte monitoring (especially potassium and magnesium)
    • Organ function monitoring for amiodarone (thyroid, liver, lungs)

  3. Drug interactions: Many antiarrhythmics have significant interactions with other medications, particularly amiodarone which affects metabolism of numerous drugs

  4. Implantable cardioverter-defibrillators (ICDs) have largely replaced antiarrhythmic drugs as primary therapy for life-threatening ventricular arrhythmias, with drugs often used as adjunctive therapy 1

  5. Individualized risk assessment is essential before initiating any antiarrhythmic therapy, weighing the potential benefits against the risk of proarrhythmia and other adverse effects

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Research

Antiarrhythmic agents and proarrhythmia.

Critical care medicine, 2000

4
Research

Comparative mechanisms of action of antiarrhythmic drugs.

The American journal of cardiology, 1993

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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