Antiarrhythmic Drugs

Definition

Antiarrhythmic drugs (AADs) modify cardiac ion channel function, automaticity, conduction, or refractoriness to suppress or prevent arrhythmias. The Vaughan Williams classification groups them into Class I (Na⁺ channel blockers: IA, IB, IC), Class II (beta-blockers), Class III (K⁺ channel blockers/prolonging agents), and Class IV (Ca²⁺ channel blockers). Most clinically important AADs have actions across multiple classes. All AADs carry proarrhythmic potential; drug selection depends on arrhythmia mechanism, underlying cardiac substrate, and comorbidities.

Key Concepts

Class IC — Flecainide

• Primary mechanism: Blocks fast inward Na⁺ current (INa) with slow unbinding (t½ >10 s) → post-repolarisation refractoriness (PRR). PRR prolongs atrial effective refractory period beyond APD, reducing sustainable re-entrant circuits in AF without requiring APD prolongation — accounting for minimal TdP risk. Effects are use- and rate-dependent: most potent at high AF rates (300–600 bpm), less potent during sinus rhythm. (sources/flecainide-af-europace-2011 — medium; COI declared)
• Atrial cardioversion: IV flecainide restores sinus rhythm in up to 95% of recent-onset AF (<48h) within 1h; superior to IV amiodarone and propafenone in head-to-head RCT (90% vs 72% vs 64%). Oral loading dose ("pill-in-the-pocket") achieves 50–60% conversion at 3h, 75–85% at 6–8h. (sources/flecainide-af-europace-2011 — medium)
• SR maintenance: 65% short-term, 49% long-term response; superior symptom control vs placebo (31% complete symptom freedom vs 9%). (sources/flecainide-af-europace-2011)
• RyR2 open-state blockade (CPVT mechanism): Flecainide inhibits cardiac RyR2 Ca²⁺ release channels, reducing diastolic Ca²⁺ sparks and preventing triggered arrhythmias — mechanistically distinct from Na⁺ channel blockade; the basis for its off-label use in CPVT. (sources/flecainide-af-europace-2011 — medium)
• Class 1C flutter — proarrhythmia: Slows AF to atrial flutter at ~200 bpm without slowing AV conduction → 1:1 AV conduction producing bizarre wide-QRS tachycardia. Concurrent AV nodal blocking drug is mandatory. QRS widening on ECG is a premonitory sign of ventricular proarrhythmia; regular monitoring required. (sources/flecainide-af-europace-2011)
• CAST contraindication: CAST (1991) demonstrated increased mortality in post-MI patients receiving flecainide — proarrhythmia from use-dependent Na⁺ blockade interacting with ischaemic scar. Absolute contraindications: CAD, prior MI, LVEF <35%, structural cardiomyopathy, Brugada syndrome. Late proarrhythmia can occur at any time if cardiac substrate changes after initial selection. (sources/flecainide-af-europace-2011 — medium; COI declared)

Class III — Amiodarone

• Mechanism (multichannel): Amiodarone has actions across all four Vaughan Williams classes. Primary effect: IKr blockade (class III) → prolonged APD and QTc, mediated by the active metabolite desethylamiodarone after loading. Additional: INa blockade (class I; slows phase 0 conduction velocity); non-competitive β-blockade (class II; reduces automaticity and AV nodal conduction); L-type Ca²⁺ channel blockade (class IV; slows AV node). Acute IV amiodarone acts mainly via Na/Ca/β mechanisms; the class III effect emerges only after desethylamiodarone accumulates. (sources/amiodarone-cvdrug-2020, rating: high)
• Low TdP risk despite QTc prolongation: Unlike quinidine and sotalol, amiodarone does not increase transmural dispersion of repolarisation — this accounts for its relatively low incidence of Torsades de Pointes despite significant QTc prolongation. (sources/amiodarone-cvdrug-2020, sources/drug-arrhythmia-aha-2020)
• Pharmacokinetics: Oral bioavailability 30–50% (enhanced 2.4–3.8× with food — take with meals). Three-phase distribution: central (~24 h) → peripheral/solid organ (~7 days) → deep fat tissue (~4 weeks). Full ventricular antiarrhythmic effect at ~10 weeks of loading. Half-life 50–60 days; drug effect persists up to 3 months post-discontinuation. No renal dose adjustment required. (sources/amiodarone-cvdrug-2020)
• VF / Cardiac arrest (Class IA): Only antiarrhythmic in the ACLS algorithm. ARREST trial: higher survival to hospital admission vs placebo (44% vs 34%; P=0.03). ALIVE trial: superior to lidocaine in shock-resistant VF (22.8% vs 12.0%; P=0.009). Kudenchuk 2016 (n=3,026): no overall survival benefit; benefit signal in witnessed arrest subgroup only. (sources/amiodarone-cvdrug-2020)
• VT — ICD storm / recurrent VT prevention: First-line for recurrent ICD shocks. OPTIC study: amiodarone + β-blocker had lowest ICD shock rate vs β-blocker alone or sotalol. VANISH trial: catheter ablation superior to drug escalation (including amiodarone) in ischaemic cardiomyopathy with recurrent VT. (sources/amiodarone-cvdrug-2020)
• AF — rhythm control: Acute pharmacologic cardioversion: 35–65% (lower than electrical cardioversion 70–90%). Long-term SR maintenance (pooled AFFIRM + AF-CHF, n=3,307): 84% at 1 year, 45% at 5 years. In AF + HFrEF, amiodarone is the only safe antiarrhythmic — propafenone, flecainide, and dronedarone are associated with worse outcomes. Maintenance dose 200 mg/day (100 mg/day in elderly). Catheter ablation superior to amiodarone for AF + HF (Di Biase 2016 RCT: 70% vs 34% AF-free at 2 years). (sources/amiodarone-cvdrug-2020, sources/HF-ESC-2021)
• SCD-HeFT — no mortality benefit in HFrEF: n=2,521; LVEF ≤35%; NYHA II–III. Overall HR 1.06 vs placebo (P=0.53) — no survival benefit. Prespecified NYHA interaction (P=0.004): NYHA II HR 0.85 (neutral); NYHA III HR 1.44 (97.5% CI 1.05–1.97) — statistically significant increased mortality. Amiodarone does not replace ICD for primary prevention; caution in NYHA III. (sources/icd-hfref-scdheft-nejm-2005, sources/amiodarone-cvdrug-2020)
• Toxicity — structured monitoring required:

• Key drug interactions: Warfarin (↓ CYP2C9/3A4 → reduce warfarin 30–50%); simvastatin (max 20 mg; CYP3A4 inhibition); digoxin (P-gp inhibition → toxicity); flecainide (reduce dose 50%; CYP2D6); Class Ia/III AADs (contraindicated or avoid — additive QTc); β-blockers/non-DHP CCBs (additive bradycardia); sofosbuvir (FDA black box — fatal bradycardia). (sources/amiodarone-cvdrug-2020)
• See entities/Amiodarone for full pharmacology, dosing, thyroid/pulmonary toxicity management, and drug interactions. See concepts/Amiodarone-Induced-Thyroid-Disorders and concepts/Amiodarone-Pulmonary-Toxicity for dedicated toxicity frameworks.

Class III — Dronedarone

• Structure vs amiodarone: Non-iodinated benzofuran derivative; loss of iodine eliminates thyroid and pulmonary toxicity. Half-life ~24h (vs 40–55 days for amiodarone). Multichannel blockade: IKr, IKs, IK1, IK-Ach, INa, ICa-L, plus non-competitive beta-adrenergic antagonism. (sources/dronedarone-circ-2009 — medium)
• IK-Ach blockade: 100-fold more potent than amiodarone (IC50 ~10 nmol/L); therapeutically relevant as IK-Ach is constitutively active in chronic AF and drives vagally mediated AF. (sources/dronedarone-circ-2009 — medium)
• ATHENA (n=4,628): 24.2% relative risk reduction in the composite of CV hospitalisation or all-cause death (HR 0.76; p<0.001); stroke reduced 34%; CV death reduced 29%. All-cause mortality HR 0.84 (NS). First AAD to demonstrate morbidity-mortality benefit in a high-risk AF population. (sources/dronedarone-circ-2009 — medium)
• ANDROMEDA — mortality hazard in severe HF (TERMINATED): n=627; excess mortality dronedarone 8.1% vs placebo 3.8% (HR 2.13) in NYHA III/IV + LVEF ≤35%. Mechanism: potent INa blockade (10× more potent than amiodarone) impairs ventricular contractility in the failing myocardium. Absolute contraindication in NYHA III/IV systolic HF. (sources/dronedarone-circ-2009 — medium)
• Drug interactions: CYP3A4 inhibitors can increase dronedarone exposure up to 25-fold (contraindicated). Increases digoxin levels 1.7–2.5-fold; simvastatin levels 2–4-fold (myopathy risk). Inhibits tubular creatinine secretion → apparent creatinine elevation not reflecting GFR reduction. (sources/dronedarone-circ-2009)

General Principles

• Substrate dependence: AAD safety and efficacy are critically dependent on the underlying cardiac substrate. Drugs safe in structurally normal hearts (flecainide, dronedarone) become proarrhythmic in ischaemic or failing myocardium. (sources/flecainide-af-europace-2011, sources/dronedarone-circ-2009)
• Genotype-specific pharmacology: Drug response can differ markedly by mutation — mexiletine for LQT3 (INaLate blockade); amiodarone and sotalol are ineffective in SQTS1 despite being IKr blockers (ion channel mutations alter drug-channel gating). Precision pharmacotherapy requires variant-level characterisation. (sources/channelopathies-jaha-2025)
• Rate-control AADs (Class II/IV): Beta-blockers and non-dihydropyridine calcium channel blockers (verapamil, diltiazem) slow AV conduction for ventricular rate control in AF but do not restore sinus rhythm. Digoxin is effective at rest but not during exertion.

Contradictions / Open Questions

• Amiodarone in HFrEF — NYHA III harm signal vs "only safe AAD" designation: SCD-HeFT showed overall HR 1.06 (neutral) in LVEF ≤35%, establishing amiodarone as the "only safe antiarrhythmic in HFrEF." However, the prespecified NYHA class interaction (P=0.004) revealed HR 1.44 (97.5% CI 1.05–1.97) in NYHA III — a statistically significant increased mortality risk. Guidelines have not stratified this safety designation by NYHA class. Whether this reflects drug toxicity or disease severity confounding remains unresolved. (sources/icd-hfref-scdheft-nejm-2005, sources/amiodarone-cvdrug-2020, sources/HF-ESC-2021)
• Amiodarone vs procainamide for hemodynamically stable VT: PROCAMIO RCT (n=62) showed procainamide superior to amiodarone for acute termination and safety; however procainamide is unavailable as a long-term oral agent in the USA, limiting practical applicability. Amiodarone remains widely used due to clinical familiarity despite this trial evidence. (sources/amiodarone-cvdrug-2020)
• Dronedarone vs amiodarone efficacy: Dronedarone is safer (no thyroid/pulmonary toxicity) but less efficacious for rhythm control; the DIONYSOS trial confirmed lower rhythm efficacy. No head-to-head RCT with hard mortality endpoints definitively resolves the superiority question in patients without severe LV dysfunction. (sources/dronedarone-circ-2009)
• Flecainide late proarrhythmia: CAST mortality was attributed to proarrhythmia in structural heart disease. Late proarrhythmia can occur at any time if cardiac substrate changes (e.g., patient develops CAD). Ongoing substrate monitoring after initial selection is required but not systematically performed. (sources/flecainide-af-europace-2011)
• Amiodarone/sotalol inefficacy in SQTS1: Mechanistically unexpected — both are IKr blockers but ineffective in SQTS1 (KCNH2 GOF). Suggests that channel mutations alter drug-binding affinity or kinetics in ways not predictable from drug class alone. (sources/channelopathies-jaha-2025)

Connections

• Related to entities/Amiodarone
• Related to entities/Flecainide
• Related to entities/Dronedarone
• Related to entities/Atrial-Fibrillation
• Related to entities/Heart-Failure
• Related to entities/CPVT
• Related to concepts/Drug-Induced-Arrhythmia
• Related to concepts/Cardiac-Action-Potential
• Related to concepts/Torsades-de-Pointes
• Related to concepts/Amiodarone-Induced-Thyroid-Disorders
• Related to concepts/Amiodarone-Pulmonary-Toxicity
• Related to concepts/Precision-Medicine-LQTS
• Related to concepts/Ion-Channel-Mutations

Sources

• sources/amiodarone-cvdrug-2020
• sources/dronedarone-circ-2009
• sources/flecainide-af-europace-2011
• sources/icd-hfref-scdheft-nejm-2005
• sources/channelopathies-jaha-2025