Chapter 8  ·  Module 2

Class I Agents: Sodium Channel Blockers

Use-dependence, three kinetic subclasses, and the structural heart disease contraindication

Class I Subclasses — Kinetics and Electrocardiogram Effects

Class Recovery Kinetics Prototype Drugs ECG Effect Key Proarrhythmia Risk
Ia Intermediate; also blocks potassium channels Quinidine, procainamide, disopyramide QRS widening + QT prolongation Torsades de pointes
Ib Rapid; fully relieves between beats at rest Lidocaine, mexiletine Minimal change at rest Low — central nervous system toxicity at high levels
Ic Slow; block not relieved between beats Flecainide, propafenone Marked QRS widening Ventricular tachycardia/fibrillation in structural disease; atrial flutter with 1:1 conduction

Class Ia Agents

Class Ia

Quinidine

  • Sodium + potassium channel block + anticholinergic
  • Brugada syndrome; short QT syndrome
  • Torsades de pointes (reverse use-dependent)
  • Cinchonism: tinnitus, visual disturbance, confusion
  • Gastrointestinal toxicity — common cause of discontinuation

Class Ia

Procainamide

  • Sodium channel block; active metabolite has Class III activity
  • Intravenous: stable ventricular tachycardia; Wolff-Parkinson-White with atrial fibrillation
  • Drug-induced lupus (chronic oral use) — anti-histone antibodies
  • Torsades de pointes; hypotension with rapid intravenous infusion

Class Ia

Disopyramide

  • Sodium channel block + strong anticholinergic + strongest negative inotropy
  • Hypertrophic obstructive cardiomyopathy; vasovagal syncope
  • Urinary retention, dry mouth, constipation (anticholinergic)
  • Contraindicated in reduced ejection fraction

Class Ib vs Class Ic

Class Ib — Rapid Kinetics

Lidocaine & Mexiletine

  • Block relieves rapidly between beats — minimal effect in normal tissue at rest
  • Selective for ischemic, depolarized, or rapidly firing tissue
  • Shorten action potential duration; no QT prolongation
  • Lidocaine: intravenous only; second-line for ventricular tachycardia/ventricular fibrillation
  • Mexiletine: oral; chronic ventricular arrhythmias; adjunct in Long QT Syndrome Type 3
  • Toxicity: central nervous system (perioral numbness → seizures); gastrointestinal (mexiletine)
Safe in ischemia

Class Ic — Slow Kinetics

Flecainide & Propafenone

  • Block not relieved between beats — tonic conduction depression at all rates
  • Marked QRS widening; no significant QT change
  • Highly effective for atrial fibrillation/flutter in structurally normal hearts
  • Pill-in-the-pocket strategy for paroxysmal atrial fibrillation
  • Propafenone: additional weak beta-blocker activity — avoid in asthma
  • Always co-prescribe atrioventricular nodal blocker to prevent 1:1 atrial flutter conduction
Contraindicated in structural heart disease

The Cardiac Arrhythmia Suppression Trial — Core Lesson

Critical Safety Principle

The Cardiac Arrhythmia Suppression Trial (1991): encainide and flecainide suppressed ventricular premature beats after myocardial infarction but increased arrhythmic death 2.5-fold vs placebo. Mechanism: use-dependent sodium channel blockade converts non-sustained micro-re-entrant circuits in peri-infarct scar into sustained, fatal ventricular tachycardia or ventricular fibrillation. Ventricular premature beat suppression is a surrogate endpoint — not a clinical benefit. Class Ic (and Class Ia) agents are contraindicated in structural heart disease regardless of arrhythmia type.

Drug Selection for Atrial Fibrillation Rhythm Control by Substrate

Cardiac Substrate Acceptable Agents Contraindicated
No structural heart disease Flecainide, propafenone, sotalol, dronedarone, amiodarone None of the above
Left ventricular hypertrophy Amiodarone, dofetilide Flecainide, propafenone
Coronary artery disease / prior myocardial infarction Sotalol, dofetilide, amiodarone Flecainide, propafenone
Heart failure with reduced ejection fraction Amiodarone, dofetilide Flecainide, propafenone, sotalol, dronedarone