What is propafenone (class IC antiarrhythmic), including its mechanism, indications, dosing, contraindications, adverse effects, monitoring, and alternative therapies?

Propafenone: Class IC Antiarrhythmic Agent

Classification and Mechanism of Action

Propafenone is a Class IC antiarrhythmic drug that blocks sodium channels, slows cardiac conduction, and possesses mild beta-blocking activity at approximately 1/40th the potency of propranolol. 1

• Sodium channel blockade: Reduces Phase 0 upstroke velocity of the cardiac action potential, slowing conduction in atrial and ventricular tissue 1
• Electrophysiologic effects: Prolongs PR interval and QRS duration in a dose-dependent manner, increases AV nodal conduction time (AH interval) and His-Purkinje conduction time (HV interval), but does not significantly affect QTc interval 1
• Beta-blocking properties: Causes approximately 8% reduction in resting heart rate at therapeutic concentrations, with clinically significant beta-blockade at 600 mg doses 1, 2
• Weak calcium channel antagonism: Present at very high concentrations but likely does not contribute to antiarrhythmic efficacy 1

FDA-Approved Indications

In patients WITHOUT structural heart disease, propafenone is indicated for: 1

• Paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms—to prolong time to recurrence
• Paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms
• Documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia)

Critical limitation: Propafenone should NOT be used to control ventricular rate during atrial fibrillation, and its use in chronic atrial fibrillation has not been evaluated 1

Dosing Regimens

For Cardioversion of Recent-Onset Atrial Fibrillation:

• Oral loading: 450-600 mg single dose, with conversion expected within 2-6 hours (success rate 56-83%) 3
• Intravenous: 2 mg/kg, with faster conversion than oral administration 3

For Maintenance Therapy (Prevention of Recurrence):

• Immediate-release: 150-300 mg three times daily (450-900 mg/day total) 3
• Sustained-release formulation: 225-425 mg twice daily 3

For Ventricular Arrhythmias:

• Standard dosing: 450-900 mg/day in divided doses 3
• Therapeutic plasma levels: 0.2-1.5 µg/mL provide good suppression of ventricular ectopy 1

Absolute Contraindications

Propafenone is absolutely contraindicated in: 1

• Heart failure (uncontrolled congestive heart failure or any degree of systolic dysfunction) 3, 4
• Cardiogenic shock 1
• Structural heart disease (including ischemic heart disease, coronary artery disease, left ventricular hypertrophy) 3
• Conduction system disease: Sick sinus syndrome, AV block, intraventricular conduction disorders without pacemaker 1
• Bradycardia 1
• Marked hypotension 1
• Brugada syndrome (risk of sudden death from idiopathic ventricular fibrillation) 3
• Severe obstructive lung disease 3
• Manifest electrolyte imbalance 1

Mandatory Combination Therapy

Before initiating propafenone, a beta-blocker or nondihydropyridine calcium channel antagonist MUST be given to prevent rapid AV conduction during atrial flutter. 3, 5

• Timing: Administer AV nodal blocking agent at least 30 minutes before propafenone for acute cardioversion, or prescribe as continuous background therapy 3, 5
• Rationale: Propafenone can convert atrial fibrillation to atrial flutter with paradoxical 1:1 AV conduction, causing dangerously rapid ventricular rates (risk 0.3-5%) 5, 6
• Propafenone's intrinsic beta-blocking activity is insufficient for rate control and should never be relied upon alone 5

Major Adverse Effects and Proarrhythmia

Cardiovascular Proarrhythmic Effects:

• Ventricular tachycardia/fibrillation: 1-5% incidence depending on dose 7
• Rapid atrial flutter with 1:1 AV conduction: 0.3-5% risk 5, 6
• QRS prolongation >25% from baseline indicates proarrhythmic risk 7, 4
• Intraventricular conduction disturbances 3
• Bradycardia at conversion (especially in patients with sinus/AV node dysfunction) 3
• Hypotension 3

Non-Cardiovascular Effects:

• Neurological: CNS side effects (5% discontinuation rate) 3
• Gastrointestinal: Nausea, diarrhea 8
• Negative inotropic effects: Can precipitate or worsen heart failure 3, 6

Mandatory Monitoring Requirements

Initial conversion trial MUST occur in hospital before any outpatient "pill-in-the-pocket" use: 3, 5

• ECG monitoring: Regular monitoring during initiation and dose adjustments to detect QRS widening (should not exceed 150% of baseline) 3, 5, 7
• Watch for bradycardia: Conversion may be associated with significant bradycardia requiring permanent pacing 5
• Assess for proarrhythmia: Monitor for ventricular tachycardia, conduction abnormalities 5
• Drug interactions: Monitor digoxin levels if used concomitantly, as propafenone increases digoxin concentrations 5

"Pill-in-the-Pocket" Strategy

This outpatient self-administration approach is ONLY appropriate for highly selected patients: 3

Eligibility Criteria (ALL must be met):

• Lone AF without structural heart disease 3
• No sinus or AV node dysfunction 3
• No bundle-branch block 3
• No QT-interval prolongation 3
• No Brugada syndrome 3
• Successful supervised in-hospital trial demonstrating safe conversion without bradycardia or proarrhythmia 3, 5
• Already on beta-blocker or calcium channel antagonist as background therapy 3, 5

Alternative Therapies

For Patients WITH Structural Heart Disease:

• Amiodarone is the preferred antiarrhythmic agent in patients with heart failure or structural heart disease 4
• Sotalol may be used in ischemic heart disease without severe heart failure 4

For Cardioversion of Recent-Onset AF:

• Flecainide: Similar efficacy to propafenone (Class IC agent with same contraindications) 3
• Ibutilide (IV): Effective for cardioversion, 4% risk of torsades de pointes, requires 4-hour monitoring 3
• Amiodarone: Safer in structural heart disease but slower onset than propafenone 3

For Maintenance of Sinus Rhythm:

• Amiodarone: More effective than propafenone/sotalol but greater organ toxicity 3
• Sotalol: Comparable efficacy to propafenone in patients without contraindications 3
• Dofetilide: Effective but requires QT monitoring and dose adjustment for renal function 3

Non-Pharmacologic Options:

• Catheter ablation: Consider for severely symptomatic recurrent AF after failure of ≥1 antiarrhythmic drug plus rate control 3
• Direct-current cardioversion: For persistent AF when pharmacologic conversion fails 3

Critical Clinical Pitfalls to Avoid

1. Never use propafenone without AV nodal blockade in patients at risk for atrial flutter 3, 5
2. Never initiate outpatient therapy without supervised hospital trial to assess for bradycardia and proarrhythmia 3, 5
3. Never use in ANY patient with structural heart disease or heart failure—this is an absolute contraindication despite propafenone's beta-blocking properties 3, 4, 2
4. Never assume propafenone's intrinsic beta-blockade is sufficient for rate control—it is not 5
5. Never use for rate control during established atrial fibrillation—this is not an approved indication 1
6. Screen for Brugada syndrome before initiating therapy, as propafenone can trigger sudden death in these patients 3