Pharmacology and Drug Treatment of Arrhythmias

1. Overview

2. Mechanisms of Arrhythmogenesis

1. Abnormal automaticity – Enhanced or suppressed spontaneous pacemaker discharge (e.g., accelerated junctional rhythm, sick sinus syndrome)
2. Triggered activity – Afterdepolarizations, either:
   • Early afterdepolarizations (EADs): occur during Phase 2/3 of the action potential; linked to QT prolongation and torsades de pointes
   • Delayed afterdepolarizations (DADs): occur after full repolarization; linked to digitalis toxicity, catecholamine excess
3. Reentry – The most common mechanism; requires a unidirectional block and a pathway permitting slow conduction to re-excite previously depolarized tissue (e.g., atrial flutter, AV nodal reentrant tachycardia, WPW syndrome)

3. Vaughan-Williams Classification

4. Class-by-Class Drug Details

Class I — Sodium Channel Blockers

• Short τ: drug dissociates quickly (Class IB — selective for rapidly firing/diseased tissue)
• Intermediate τ: Class IA
• Long τ: Class IC — accumulates at high heart rates, dangerous in ischemic myocardium

Class IA

• Blocks Na⁺ channels + outward K⁺ channels (IKr), prolonging APD and QT
• Vagolytic (can increase AV nodal conduction and paradoxically accelerate ventricular rate in atrial flutter)
• Adverse effects: Cinchonism (tinnitus, visual disturbances, headache), hemolytic anemia, QT prolongation → torsades de pointes, esophagitis

• Analogue of procaine; blocks open Na⁺ channels (intermediate τ); also blocks K⁺ channels
• Active metabolite: N-acetyl procainamide (NAPA) — prolongs APD but lacks Na⁺ channel block
• Short t½ (~3–4 h) requires slow-release formulation; NAPA accumulates in renal failure
• Major adverse effect: Drug-induced lupus syndrome (antinuclear antibodies in nearly all patients with long-term use; 25–50% develop symptoms). Also: bone marrow aplasia (0.2%), hypotension, torsades
• Acetylator phenotype determines lupus risk: slow acetylators develop lupus earlier

• Similar to procainamide but with significant antimuscarinic effects (urinary retention, dry mouth, constipation, glaucoma precipitation)
• Concentration-dependent protein binding; negative inotrope — can precipitate acute heart failure
• Eliminated via hepatic and renal routes

Class IB

• Very fast τ_recovery; selectively blocks activated and inactivated channels at rapid rates and depolarized potentials (ischemic tissue)
• Only available IV; extensive hepatic first-pass metabolism
• Dose-dependent CNS toxicity: perioral numbness → tremor → seizures → coma
• Reduce dose in heart failure and liver disease

• Orally active congener of lidocaine; shortens Phase 3 repolarization
• Used in ventricular arrhythmias and some channelopathies (Long QT syndrome Type 3)
• GI adverse effects (nausea, dyspepsia) are common

Class IC

• Markedly slows Phase 0; very slow dissociation from Na⁺ channels — effect is rate-dependent (worse at fast rates)
• Effective for supraventricular arrhythmias, paroxysmal AF in structurally normal hearts
• Contraindicated post-MI and in ischemic heart disease — the CAST trial showed 2-3× increase in mortality
• Oral; hepatic and renal metabolism; t½ ~20 h

• Similar to flecainide + weak β-blocking activity
• Hepatically metabolized; extensive polymorphism (poor vs. extensive metabolizers via CYP2D6)
• Adverse: bronchospasm (due to β-block), proarrhythmia, rare agranulocytosis

The CAST lesson: Suppressing ventricular ectopy with Na⁺ channel blockers post-MI increases mortality. Treating an asymptomatic arrhythmia marker is not the same as treating the patient. Among all antiarrhythmic drugs, only β-blockers demonstrably reduce mortality in long-term therapy. — Goodman & Gilman's

Class II — β-Adrenergic Receptor Blockers

• Rate control in atrial fibrillation/flutter
• Post-MI sudden death prevention
• Suppression of exercise-induced and catecholamine-mediated arrhythmias
• Ventricular arrhythmias in structural heart disease (reduced sudden cardiac death)

Class III — Potassium Channel Blockers

• A structural analogue of thyroid hormone; highly lipophilic; concentrated in fat, liver, and lungs
• Multi-channel blocker: Na⁺ (inactivated channels), K⁺ (IKr, IKs), Ca²⁺, plus non-competitive β-adrenergic block
• Prolongs APD in most tissues; slows conduction; reduces automaticity
• Extremely long t½ (40–55 days) — loading doses required; adverse effects resolve slowly
• First-line IV drug for VT/VF causing cardiac arrest; widely used for AF
• Organ toxicities (necessitate monitoring):
  • Pulmonary toxicity — interstitial pneumonitis/fibrosis (5–10%); can be fatal
  • Thyroid dysfunction — hyper- or hypothyroidism (iodine-rich; ~37% by weight iodine)
  • Hepatotoxicity — elevated transaminases; rarely cirrhosis
  • Corneal microdeposits — nearly universal but rarely impair vision
  • Photosensitivity/skin discoloration — slate-grey/blue-grey
  • Neurological — peripheral neuropathy, tremor, ataxia

• Both Class III (K⁺ block) and Class II (non-selective β-blocker) effects
• Renally eliminated; dose reduction in renal failure is essential
• Risk of torsades proportional to QTc prolongation; women at higher risk
• Used for maintenance of sinus rhythm in AF/flutter and for VT

• Potent, "pure" IKr blocker — no extracardiac effects
• Effective for AF/flutter cardioversion and maintaining sinus rhythm
• Strict initiation protocol: requires in-hospital monitoring with QTc surveillance
• Renally cleared; contraindicated with severe renal failure and with renal cation transport inhibitors
• Torsades de pointes: 1–3% even in controlled settings

• IV only; used for acute cardioversion of AF/flutter
• Also enhances slow inward Na⁺ current during plateau phase
• Torsades de pointes occurs in ~4–8%

• Non-iodinated analogue of amiodarone; fewer organ toxicities but significantly less effective
• Blocks IKr, IKs, IK1, acetylcholine-activated K⁺, peak Na⁺ current, and L-type Ca²⁺ current; stronger antiadrenergic effect than amiodarone
• Inhibits CYP3A4 and P-glycoprotein; significant drug interactions
• Increased mortality in permanent AF (ATHENA trial subset) and in severe heart failure (ANDROMEDA trial)
• GI adverse effects common (diarrhea, nausea, abdominal pain)

Class IV — Calcium Channel Blockers (Non-Dihydropyridine)

• Acute termination of AVNRT (PSVT)
• Rate control in AF/flutter
• Verapamil-sensitive VT (fascicular VT — responds to verapamil)

Other Agents

• Activates A₁ receptors → increases IKAch (K⁺ inward) and inhibits I_f → hyperpolarization and AV nodal block
• Drug of choice for acute termination of AVNRT (PSVT) — given as rapid IV bolus (6–12 mg)
• t½ of seconds (cellular uptake and deamination); adverse effects are transient
• Adverse: transient asystole, chest fullness/dyspnea, rarely AF or bronchospasm
• Potentiated by dipyridamole (adenosine uptake inhibitor); antagonized by theophylline and caffeine
• Increased sensitivity in cardiac transplant recipients (denervation hypersensitivity)

• Inhibits Na⁺/K⁺-ATPase → ↑ intracellular Ca²⁺ → positive inotropy
• Antiarrhythmic effect mediated mainly via enhanced vagal tone → ↓ AV nodal conduction
• Used for rate control in AF (especially with heart failure)
• Narrow therapeutic index; toxicity: nausea, visual disturbances (yellow-green halos), various arrhythmias (DAD-mediated)
• Absolute contraindication in WPW — may accelerate accessory pathway conduction

• Drug of choice for torsades de pointes (regardless of serum Mg²⁺ level)
• Also used for digoxin toxicity arrhythmias and refractory VF

5. Mechanistic Approach to Arrhythmia Treatment

6. Principles of Clinical Use

1. Identify and remove precipitating factors — electrolyte imbalances (hypokalemia, hypomagnesemia), ischemia, drug interactions, hypoxia, and thyroid disease are common contributors
2. Establish clear goals — Symptom relief vs. mortality benefit are different endpoints. Rate control vs. rhythm control must be consciously chosen (e.g., in AF)
3. Minimize risks — Proarrhythmia is real. Do not treat asymptomatic arrhythmias unless mortality benefit is established (the CAST lesson). Assess QTc, renal function, and structural heart disease before prescribing
4. Consider structural heart disease — Most Na⁺ channel blockers (Class IC) and some Class III agents are dangerous in ischemic or severely dysfunctional hearts. Only β-blockers and amiodarone have demonstrated safety data in structural heart disease
5. Drug combinations — Amiodarone + a Na⁺ channel blocker (e.g., flecainide) is the most studied combination for refractory ventricular arrhythmias. The HARMONY trial examined ranolazine + low-dose dronedarone for AF burden reduction. However, additive QT prolongation risk must always be anticipated

7. Proarrhythmic Risk Summary