Antiarrhythmic drugs: Propafenone (Class 1C)

• Class: Class Ic antiarrhythmic (membrane-stabilizing Na+ channel blocker) with additional weak beta-blocking and calcium channel–blocking activity.
• What it does: Strongly slows conduction through the atria, AV node (to a lesser extent), His-Purkinje system, and ventricles. Minimal effect on repolarization.
• ECG effects: Marked QRS widening; PR prolongation; minimal QT change (any QT increase largely reflects QRS widening rather than APD prolongation).

Mechanism of Action

• Primary: Potent blockade of fast inward Na+ channels with slow unbinding kinetics → large reduction in phase 0 upstroke velocity → slowed conduction velocity and reduced automaticity.
• Secondary: Weak nonselective beta-blockade and mild calcium channel blockade → can add to bradycardia/AV nodal effects.Net electrophysiology:

• • Conduction: markedly prolonged (↑ QRS).
  • Refractoriness: relatively preserved in normal tissue; increased in diseased or accessory pathways (useful in WPW).
  • Repolarization/AP duration: little to no effect compared with class Ia/III.

Clinical Uses

Supraventricular arrhythmias:

• Paroxysmal atrial fibrillation (AF) and atrial flutter in patients without structural heart disease.
• AV re-entrant tachycardia (e.g., WPW) and other SVTs.

Ventricular arrhythmias:

• Selected sustained or symptomatic ventricular tachyarrhythmias in carefully chosen patients without ischemic or structural heart disease.

Pill-in-the-pocket (PITP) for AF conversion:

• Single-dose self-administration for recent-onset AF in pre-selected patients after in-hospital testing and only with concomitant AV nodal blockade.

Who Should Not Get It (Contraindications)

• Structural heart disease, prior MI, significant LV dysfunction, or heart failure (increased mortality/proarrhythmia risk; CAST trial lesson).
• Cardiogenic shock; severe hypotension.
• Clinically significant bradycardia, sick sinus syndrome, or AV block (>1st degree) without a pacemaker.
• Marked electrolyte abnormalities (uncorrected hypo-K/Mg).
• Brugada syndrome or history suggestive of it (can unmask Brugada ECG and provoke arrhythmias).
• Severe obstructive pulmonary disease or bronchospastic disease (due to beta-blocking effect).
• Known hypersensitivity to propafenone.

Key Warnings and Risks

• Proarrhythmia: QRS widening–mediated VT, 1:1 atrial flutter conduction, and exacerbation of existing arrhythmias. Avoid in structural heart disease.
• Conduction disturbances: Excessive PR and QRS prolongation → AV block or severe bradycardia.
• Negative inotropy: May worsen heart failure.
• Hematologic reactions (rare): Agranulocytosis; counsel patients to seek care for fever, sore throat, or signs of infection.
• Hepatic effects: Transaminase elevations; cholestasis (rare).
• Bronchospasm: Particularly in reactive airway disease.
• Taste disturbances (metallic taste), dizziness, visual blurring, nausea, constipation are common tolerability issues.
• Pacing thresholds: May increase pacemaker/ICD capture thresholds; device checks recommended after initiation or dose changes.

Pharmacokinetics and Pharmacogenomics

• Formulations: Immediate-release (IR) and extended-release (ER/SR).
• Metabolism: Hepatic; major via CYP2D6 (to 5‑hydroxypropafenone) and via CYP3A4/CYP1A2 (to N‑depropylpropafenone).
• Genetic variability: CYP2D6 poor metabolizers have higher propafenone levels and longer half-life (risk of exaggerated beta-blockade and conduction slowing).
• Half-life: ~2–10 h in extensive metabolizers; can exceed 10–30 h in poor metabolizers.
• Bioavailability increases with repeated dosing (saturable first-pass).
• Protein binding: High.

Dosing (Adults – typical ranges; follow local labeling)

Immediate-release (for suppression or conversion under supervision):

• Start 150 mg every 8 hours; titrate to 225–300 mg every 8 hours based on response and ECG.

Extended-release (maintenance of sinus rhythm in AF):

• 225–325 mg every 12 hours; may increase to 425 mg every 12 hours.

Pill-in-the-pocket conversion (only after in-hospital test dose and with AV nodal blocker):

• 450 mg once if body weight <70 kg; 600 mg once if ≥70 kg.
• Administer a beta-blocker or non-DHP calcium channel blocker 30 minutes prior to avoid 1:1 atrial flutter conduction.

Dose adjustments:

• Hepatic impairment: lower doses and slower titration; monitor closely.
• Elderly or those with conduction disease: start low, go slow.

Drug Interactions (high-yield)

• Propafenone is both a substrate and inhibitor (notably of CYP2D6) and inhibits P‑glycoprotein.
• Increases levels/effects of:

• Digoxin (P‑gp inhibition) → monitor levels and for toxicity.
• Warfarin (increased anticoagulant effect) → monitor INR closely and adjust dose.
• Beta-blockers metabolized by CYP2D6 (e.g., metoprolol, propranolol) → risk of bradycardia/hypotension.

• CYP inhibitors that raise propafenone levels: strong 2D6 inhibitors (fluoxetine, paroxetine), 3A4 inhibitors (ritonavir, certain azoles, macrolides), cimetidine, grapefruit juice.
• CYP inducers that lower levels: rifampin, carbamazepine, phenytoin, St John’s wort.
• Additive conduction/negative inotropy: with other AV nodal blockers (beta-blockers, verapamil/diltiazem), other antiarrhythmics, and agents prolonging QRS/QT.
• Alcohol can enhance hypotension and dizziness.

Monitoring

• Baseline and follow-up ECG: PR and QRS intervals; discontinue or down-titrate if QRS widens >25% from baseline or if significant PR prolongation/AV block develops.
• Heart rate, blood pressure, and symptoms.
• Liver function tests (periodically), especially with symptoms.
• CBC if infection symptoms (due to rare agranulocytosis).
• Electrolytes (keep K and Mg normal).
• Serum drug partners as indicated (INR with warfarin; digoxin levels).

Use in Special Populations

• Pregnancy/lactation: Use only if benefits outweigh risks; the drug passes into breast milk.
• Pediatrics: Used for SVT/WPW by specialists; weight-based dosing and close monitoring required.
• Geriatrics: Greater sensitivity to conduction effects; lower initial doses and careful titration.

Clinical Pearls and Exam Tips

• Memory aid: Class Ic = “I” for Intense Na+ block, “c” for Conduction slowing (QRS↑), minimal effect on repolarization (QT unchanged or slightly ↑).
• Only use for AF in patients without structural heart disease or ischemic heart disease.
• Always pair with an AV nodal blocker when using for AF conversion to prevent rapid 1:1 atrial flutter.
• Metallic taste is a classic side effect.
• Consider CYP2D6 phenotype and interacting drugs before dosing; poor metabolizers and strong CYP2D6 inhibitors can markedly raise exposure.
• Propafenone can unmask Brugada ECG patterns; avoid if suspected.

Comparison with Flecainide (quick)

• Both are class Ic with strong Na+ block and QRS widening; both contraindicated in structural heart disease.
• Propafenone has weak beta-blocking and calcium channel–blocking properties; flecainide does not.
• Taste disturbance more typical with propafenone; visual disturbances more noted with flecainide.

Patient Counseling Points

• Take exactly as prescribed; do not double up missed doses.
• Report new or worsening palpitations, fainting, chest pain, shortness of breath, or signs of infection immediately.
• Avoid grapefruit juice; limit alcohol; discuss all OTC/herbal products.
• If you have a pacemaker/ICD, ensure device checks after starting or changing dose.