TABLE 1.

Old and current Atrial Fibrillation antiarrhythmic drugs: therapeutic mechanisms and benefits.

Vaughan Williams class	Targets	Therapeutic mechanisms	Therapeutic benefits for Atrial Fibrillation
Voltage-gated Na+channel blockers
IA Quinidine Procainamide Disopyramide	Nav1.5	Open-state INa block Intermediate offset kinetics ↓ peak INa → ↓ non-AVN dV/dtmax, ↑ excitation threshold	Rhythm control ↓ atrial ectopic automaticity ↓ atrial excitability ↓ atrial conduction ↓ Purkinje conduction ↓ reentrant arrhythmias
	K+ channels	↓ multiple IK’s (Ito, IKr, IKs, IK1, IKATP)	↑ atrial ERP ↑ atrial APD
IC Flecainide Propafenone	Nav1.5 SR RyR2-Ca2+ channels	Inactivated-state, frequency-dependent INa block Slow offset kinetics ↓ peak INa → ↓↓ dV/dtmax (non-AVN APs), ↑ excitation threshold ↓ RyR2-mediated SR Ca2+ release → ↓ intracellular Ca2+ load	Rhythm control ↑ potency at rapid heart rates ↓ atrial ectopic automaticity ↓ atrial excitability ↓ DAD-induced triggered activity Converts unidirectional to bidirectional block → ↓ reentrant arrhythmias ↓ atrial conduction ↓ accessory pathway conduction ↑↑ atrial APD at rapid heart rates
β-Blockers
IIA Non-selective Carvedilol Propranolol Nadolol		↓ Gs-AC-cAMP signaling → ↓ If and ↓ ICaL → ↓ RyR2-mediated SR Ca2+ release, ↓ intracellular Ca2+ load	Rate control ↓ SAN automaticity and ↑ PR ↓ atrial ectopic automaticity ↓ EAD- and DAD-induced triggered activity ↓ AVN conduction ↑ AVN refractoriness ↑ RR ↓ reentrant arrhythmias Prevention of adrenergic AF 1st-line for HFpEF and HFrEF
	Non-selective β-adrenoceptors
Selective Atenolol Bisoprolol Esmolol Metoprolol	β1-adrenoceptors
Na+-K+pump inhibitor
IID Digoxin	Muscarinic M2 receptors (SAN, atrial, AVN) Na+-K+ pump	↑ vagal tone ↓ sympathetic tone Hyperpolarizing SAN	Rate control ↓ SAN automaticity ↓ AVN conduction ↑ AVN refractoriness Second-line for HFrEF
Voltage-gated K+channel blockers
III Non-selective Amiodarone Dronedarone	Nonselective K+ channels	↓ multiple IK’s (Ito, IKs, IK1, IKACh)	Rhythm control ↑ APD ↑ atrial ERP ↓ reentrant arrhythmias
Selective Sotalol Dofetilide	Kv11.1 (hERG)	↓ IKr	↓ SAN automaticity (amiodarone) ↓ AVN conduction (amiodarone)
Voltage-gated Ca2+ channel blockers
IV Diltiazem Verapamil	Cav1.2 Cav1.3	↓ ICaL → ↓ RyR2-mediated SR Ca2+ release, ↓ intracellular Ca2+ load	Rate control ↓ SAN automaticity ↑ atrial ERP ↓ AVN conduction ↓ EAD- and DAD-induced triggered activity ↓ reentrant arrhythmias

AC, adenylyl cyclase; AF, atrial fibrillation; AP, action potential; APD, action potential duration; AVN, atrioventricular node; cAMP, cyclic adenosine monophosphate; dV/dt_max, maximum action-potential upstroke velocity; EAD/DAD, early/delayed afterdepolarizations; ERP, effective refractory period; G_s, stimulatory G protein; HFpEF (HFrEF), heart failure with preserved (reduced) ejection fraction; RyR2, ryanodine receptor two; SAN, sinoatrial node; SR, sarcoplasmic reticulum.