Pharmacotherapy of Arrhythmias

Physiological Basis

1. Abnormal automaticity - ectopic pacemaker discharge (enhanced or abnormal phase 4 depolarization)
2. Triggered activity - afterdepolarizations (early [EADs] or delayed [DADs]) from abnormal Ca²⁺ handling or prolonged action potentials
3. Reentry - unidirectional block with slow conduction in a circuit, allowing a wavefront to re-excite tissue it has already passed

The Vaughan-Williams Classification

Class I: Sodium Channel Blockers

Class IA

• Broadest Class IA agent; also blocks K⁺ channels (prolongs QT), α-adrenergic receptors, and has anticholinergic properties
• Uses: AF maintenance, ventricular arrhythmias
• Toxicity: Cinchonism (tinnitus, headache), GI upset (diarrhea), torsades de pointes (due to QT prolongation), vagolytic effects can increase ventricular rate in AF if used without an AV nodal agent

• Similar to quinidine; active metabolite N-acetylprocainamide (NAPA) has additional Class III effects
• Uses: Acute VT, WPW with AF (preferred IV agent in some guidelines)
• Toxicity: Drug-induced lupus erythematosus (slow acetylators at risk), agranulocytosis; chronic use avoided

• Strongly anticholinergic (urinary retention, dry mouth, glaucoma risk)
• Strong negative inotrope - contraindicated in heart failure
• Uses: Vagally-mediated AF, hypertrophic obstructive cardiomyopathy

Class IB

• IV only (extensive first-pass metabolism)
• Binds preferentially to depolarized (ischemic) tissue - excellent for ventricular arrhythmias post-MI/reperfusion
• Minimal effect on normal tissue; does not affect atrial arrhythmias significantly
• Toxicity: CNS (perioral numbness, tremor, seizures at toxic levels)

• Oral analogue of lidocaine
• Uses: Chronic ventricular arrhythmia suppression, often combined with amiodarone
• Notable use: Long QT syndrome type 3 (blocks the pathological late Na⁺ current)
• Toxicity: Tremor, nausea

Class IC

• Potent Na⁺ channel blocker with slow recovery - markedly slows conduction
• Uses: AF/flutter in structurally normal hearts; "pill-in-the-pocket" for paroxysmal AF
• CAST Trial Warning: Significantly increased mortality in patients with structural heart disease (post-MI) - contraindicated in ischemic heart disease or LV dysfunction
• Toxicity: Pro-arrhythmia (can convert AF to atrial flutter with 1:1 AV conduction if given without AV nodal blockade)

• IC agent with mild β-blocking properties
• Similar indications and contraindications to flecainide
• Metabolized by CYP2D6 (variable effects in poor metabolizers)

Class II: Beta-Blockers

• Metoprolol, Atenolol - oral, cardioselective; rate control in AF/flutter, prevention of SVT
• Esmolol - ultra-short-acting IV (t½ ~9 min); ideal for acute rate control intraoperatively or in emergency settings
• Propranolol - non-selective; also used in long QT syndrome, thyrotoxic arrhythmias, CPVT

Class III: Potassium Channel Blockers

• Properties across all 4 classes (I, II, III, IV)
• Extremely long half-life (40-55 days); large volume of distribution
• Most effective AAD for maintaining sinus rhythm in AF; effective for VT/VF
• Multiorgan toxicity with long-term use:
  • Pulmonary toxicity (fibrosis/pneumonitis) - most serious
  • Thyroid dysfunction (hypo- or hyperthyroidism - contains 37% iodine)
  • Hepatotoxicity
  • Corneal microdeposits (nearly universal, usually asymptomatic)
  • Photosensitivity (blue-grey skin discoloration)
  • Peripheral neuropathy
• Drug interactions: Inhibits CYP3A4, CYP2C9, and P-glycoprotein → increases warfarin, digoxin, flecainide, procainamide levels significantly

• Class III + significant β-blocking (Class II) properties
• Uses: AF maintenance, ventricular arrhythmias
• Risk of torsades de pointes (especially with bradycardia, hypokalemia, renal failure)
• Must be initiated in-hospital with QT monitoring

• "Pure" IKr blocker - selective Class III
• Uses: AF/flutter cardioversion and maintenance
• Significant torsades risk; requires 3-day in-hospital initiation with renal dose adjustment
• Eliminated renally - contraindicated in severe renal impairment

• Rapid-acting Class III agent for acute cardioversion of AF/flutter
• Effective in ~50-70% of flutter cases
• Requires cardiac monitoring for 4 hours post-dose (torsades risk)

• Structural analogue of amiodarone without iodine moieties - less thyroid/pulmonary toxicity
• Effects across all 4 classes (milder than amiodarone)
• Uses: AF rate/rhythm control in patients with preserved EF
• Contraindicated in decompensated heart failure and permanent AF (increased mortality shown in ANDROMEDA and PALLAS trials)

Class IV: Calcium Channel Blockers

• Block L-type Ca²⁺ channels in nodal tissue (SA, AV)
• Rate control in AF/flutter (acute and chronic)
• Terminate AVNRT and AVRT (reentry involving AV node)
• Contraindicated in WPW - blocking the AV node may force conduction through the accessory pathway at dangerous rates, potentially precipitating VF
• Verapamil is contraindicated in VT - can cause hemodynamic collapse (famous clinical pitfall of misidentifying VT as SVT)

Other Important Agents

• Endogenous nucleoside; activates K⁺ channels and inhibits adenylyl cyclase in AV node → transient complete AV block (seconds)
• Drug of choice for acute termination of AVNRT and AVRT (diagnostic and therapeutic)
• Half-life: ~10 seconds - administer as rapid IV bolus
• Contraindicated in cardiac transplant recipients (denervated heart is hypersensitive), severe asthma
• Common side effects: Flushing, dyspnea, chest discomfort (transient)

• Inhibits Na⁺/K⁺-ATPase → indirect vagomimetic effect → slows AV node conduction
• Uses: Rate control in AF with heart failure (where beta-blockers/CCBs may be poorly tolerated)
• Narrow therapeutic index; toxicity manifests as bradyarrhythmias, AV block, or paradoxically ventricular arrhythmias
• Contraindicated in WPW (same reason as CCBs)

• Treatment of torsades de pointes (even when Mg levels are normal)
• Adjunct in digoxin toxicity

• Inhibits late Na⁺ current (Class IB-like) and IKr
• Primary indication: Chronic angina
• Notable antiarrhythmic use: AF in ischemic heart disease, adjunct in ventricular arrhythmias

Mechanistic Approach to Specific Arrhythmias

Drug Selection Algorithm for AF (Rhythm Control)

Key Contraindications Summary

Proarrhythmia: A Critical Concept

• QT prolongation → Torsades de pointes: Class IA (quinidine, procainamide), Class III agents - risk amplified by hypokalemia, hypomagnesemia, bradycardia, female sex, and drug interactions
• Flecainide/propafenone: Can convert AF to organized atrial flutter with 1:1 conduction (extreme tachycardia) - always co-prescribe an AV nodal agent
• Proarrhythmia in structural heart disease: The CAST trial established that flecainide/encainide increased sudden death in post-MI patients with asymptomatic PVCs
• Amiodarone: Despite QT prolongation, torsades is relatively uncommon - possibly due to its multiple channel-blocking effects providing balance

Clinical Principles of AAD Use

1. Identify and remove precipitating factors - electrolyte abnormalities (K⁺, Mg²⁺), ischemia, thyroid disease, hypoxia
2. Establish the arrhythmia diagnosis precisely before treating - misidentifying VT as SVT can be fatal
3. Match drug to mechanism - e.g., AV nodal agents are not useful for AF termination, only rate control
4. Use non-pharmacologic therapy when appropriate - catheter ablation is now first-line for many arrhythmias (AVNRT, atrial flutter, WPW, paroxysmal AF)
5. Monitor for toxicity - plasma levels (digoxin, procainamide), QT intervals (all Class I/III agents), organ function (amiodarone monitoring: TFTs, LFTs, PFTs, ophthalmic exam)
6. Consider the "moving target" - cardiac electrophysiology changes with ischemia, rate, and autonomic tone, altering drug effects unpredictably

Recent evidence note: A 2024 meta-analysis (PMID 38727662) comparing rhythm vs. rate control strategies for AF found no significant mortality difference between strategies, reinforcing that symptom burden and patient preference guide the choice. A 2026 analysis (PMID 40803485) comparing AADs vs. catheter ablation found ablation superior to drugs for maintaining sinus rhythm in AF, consistent with the growing shift toward earlier ablation.