Revised (2018) Vaughan Williams classification of antiarrhythmic drugs

Class	Subclass	Pharmacological targets	Electrophysiological effects	Examples of drugs	Major clinical applications	Corresponding likely therapeutic mechanism(s)
HCN channel blockers
0		HCN channel-mediated pacemaker current (I_f) block	Inhibition of I_f reducing SAN phase 4 pacemaker depolarization rate, thereby reducing heart rate; possible decreased AVN and Purkinje cell automaticity; increase in RR intervals	Ivabradine	Stable angina and chronic heart failure with heart rate ≥70 beats per minute Potential new applications for tachyarrhythmias	Reduction in SAN automaticity
Voltage-gated Na⁺ channel blockers
I	Ia	Nav1.5 open state; intermediate (Tau ≈ 1 to 10 seconds) dissociation kinetics; often concomitant K⁺ channel block	Reduction in peak I_Na, AP generation, and (dV/dt)_max with increased excitation threshold; slowing of AP conduction in atria, ventricles, and specialized ventricular conduction pathways; concomitant I_K block increasing APD and ERP; increase in QT intervals	Quinidine, ajmaline, disopyramide	Supraventricular tachyarrhythmias, particularly recurrent atrial fibrillation; ventricular tachycardia, ventricular fibrillation (including SQTS and Brugada syndrome)	Reduction in ectopic ventricular/atrial automaticity Reduction in accessory pathway conduction Increase in refractory period, decreasing reentrant tendency
	Ib	Nav1.5 open state; rapid dissociation (Tau ≈ 0.1 to 1 second); I_Na; window current	Reduction in peak I_Na, AP generation and (dV/dt)_max with increased excitation threshold; slowing of AP conduction in atria, ventricles, and specialized ventricular conduction pathways; shortening of APD and ERP in normal ventricular and Purkinje myocytes; prolongation of ERP and postrepolarization refractoriness with reduced window current in ischemic, partially depolarized cells Relatively little electrocardiographic effect; slight QTc shortening	Lidocaine, mexiletine	Ventricular tachyarrhythmias (ventricular tachycardia, ventricular fibrillation), particularly after myocardial infarction	Reduction in ectopic ventricular automaticity Reduction in DAD-induced triggered activity Reduced reentrant tendency by converting unidirectional to bidirectional block, particularly in ischemic, partially depolarized myocardium
	Ic	Nav1.5 inactivated state; slow dissociation (Tau >10 seconds)	Reduction in peak I_Na, AP generation and (dV/dt)_max with increased excitation threshold; slowing of AP conduction in atria, ventricles, and specialized ventricular conduction pathways; reduced overall excitability; prolongation of APD at high heart rates; increase in QRS duration	Propafenone, flecainide	Supraventricular tachyarrhythmias (atrial tachycardia, atrial flutter, atrial fibrillation, and tachycardias involving accessory pathways) Ventricular tachyarrhythmias resistant to other treatment in the absence of structural heart disease, premature ventricular contraction, catecholaminergic polymorphic ventricular tachycardia	Reduction in ectopic ventricular/atrial automaticity Reduction in DAD-induced triggered activity Reduced reentrant tendency by converting unidirectional to bidirectional block Slowed conduction and reduced of excitability particularly at rapid heart rates blocking reentrant pathways showing depressed conduction
	Id	Nav1.5 late current	Reduction in late Na⁺ current (I_NaL), affecting AP recovery, refractoriness, repolarization reserve, and QT interval	Ranolazine	Stable angina, ventricular tachycardia As a potential new class of drugs for the management of tachyarrhythmias	Decrease in AP recovery time Reduction in EAD-induced triggered activity
Autonomic inhibitors and activators
II	IIa	Nonselective beta- and selective beta1-adrenergic receptor inhibitors	Inhibition of adrenergically induced G_s protein-mediated effects of increased adenylyl kinase activity and [cAMP]_i with effects including slowed SAN pacemaker rate caused by reduced I_f and I_CaL; increased AVN conduction time and refractoriness, and decreased SAN pacing and triggered activity resulting from reduced I_CaL; and reduced RyR2-mediated SR Ca²⁺ release and triggered activity; increase in RR and PR intervals	Nonselective beta inhibitors: carvedilol, propranolol, nadolol Selective beta1-adrenergic receptor inhibitors: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol	Sinus tachycardia or other types of tachycardic, including supraventricular (atrial fibrillation, atrial flutter, atrial tachycardia), arrhythmias Rate control of atrial fibrillation and ventricular tachyarrhythmias (ventricular tachycardia, premature ventricular contraction) NOTE: atenolol, propranolol, and nadolol also used in LQTS; nadolol used in catecholaminergic polymorphic ventricular tachycardia	Reduction in SAN automaticity Reduction in AVN automaticity Reduction in ectopic ventricular/atrial automaticity Reduction in EAD-/DAD-induced triggered activity Reduced SAN reentry Reduction in AVN conduction terminating reentry
	IIb	Nonselective beta-adrenergic receptor activators	Activation of adrenergically induced G_s-protein effects of increasing adenylyl kinase activity and [cAMP]_i (refer to entry above); decrease in RR and PR intervals	Isoproterenol	Accelerating rates of ventricular escape rhythm in cases of complete atrioventricular block before definitive pacemaker implantation Acquired, often drug-related bradycardia-dependent torsades de pointes	Increased escape ventricular automaticity Suppression of bradycardia-dependent EAD-related triggered activity
	IIc	Muscarinic M₂ receptor inhibitors	Inhibition of supraventricular (SAN, atrial, AVN) muscarinic M₂ cholinergic receptors (refer to entry below); decreased RR and PR intervals	Atropine, anisodamine, hyoscine, scopolamine	Mild or moderate symptomatic sinus bradycardia Supra-His, AVN, conduction block, eg, in vagal syncope or acute inferior myocardial infarction	Increase in SAN automaticity Increase in AVN conduction
	IId	Muscarinic M₂ receptor activators	Activation of supraventricular (SAN, atrial, AVN) muscarinic M₂ cholinergic receptors activates K_ACh channels, hyperpolarizing the SAN and shortening APDs in atrial and AVN tissue, and reduces [cAMP]_i and therefore I_CaL and SAN I_f; inhibitory effects on adenylyl cyclase and cAMP activation, reducing its stimulatory effects on I_CaL, I_Ks, I_Cl, and I_ti in adrenergically activated ventricular tissue; increased RR and PR intervals	Carbachol, pilocarpine, methacholine, digoxin	Sinus tachycardia or supraventricular tachyarrhythmias	Reduction in SAN automaticity Reduced SAN reentry Reduction in AVN conduction, terminating reentry
	IIe	Adenosine A₁ receptor activators	Activation of adenosine A₁ receptors in supraventricular tissue (SAN, atrial, AVN) activates G protein-coupled inward rectifying K⁺ channels and I_KAdo current, hyperpolarizing the SAN and shortening APDs in atrial and AVN tissue, and reduces [cAMP]_i and therefore I_CaL and SAN I_f; inhibitory effects on adenylyl cyclase and cAMP activation, reducing its stimulatory effects on I_CaL, I_Ks, I_Cl, and I_ti in adrenergically activated ventricular tissue; increased RR and increased PR intervals	Adenosine, ATP; aminophylline acts as an adenosine receptor inhibitor	Acute termination of AVN tachycardia and cAMP-mediated triggered VTs Differentiation of sinus from atrial tachycardia	Reduction in SAN automaticity Reduction in AVN conduction, terminating reentry Reduction in EAD-/DAD-induced triggered activity
K⁺ channel blockers and openers
III
Voltage dependent K⁺ channel blockers	IIIa	Nonselective K⁺ channel blockers	Block of multiple K⁺ channel targets resulting in prolonged atrial, Purkinje, and/or ventricular myocyte AP recovery, increased ERP, and reduced repolarization reserve; prolonged QT intervals	Ambasilide, amiodarone, dronedarone	Ventricular tachycardia in patients without structural heart disease or with remote myocardial infarction; tachyarrhythmias with Wolff-Parkinson-White syndrome Atrial fibrillation with atrioventricular conduction via accessory pathway Ventricular fibrillation and premature ventricular contraction Tachyarrhythmias associated with supraventricular arrhythmias and atrial fibrillation	Increase in AP recovery time Increase in refractory period, with decreased reentrant tendency NOTE: amiodarone also slows sinus node rate and atrioventricular conduction
		Kv11.1 (HERG) channel-mediated rapid K⁺ current (I_Kr) blockers	Prolonged atrial, Purkinje, and ventricular myocyte AP recovery, increased ERP, and reduced repolarization reserve; prolonged QT intervals	Dofetilide, ibutilide, sotalol	Ventricular tachycardia in patients without structural heart disease or with remote myocardial infarction Tachyarrhythmias associated with Wolff-Parkinson-White syndrome Atrial fibrillation with atrioventricular conduction via accessory pathway, ventricular fibrillation, premature ventricular contraction Tachyarrhythmias associated with supraventricular arrhythmias and atrial fibrillation	Increase in AP recovery time Increase in refractory period with decreased reentrant tendency
		Kv7.1 channel-mediated, slow K⁺ current (I_Ks) blockers	Prolonged atrial, Purkinje, and ventricular myocyte AP recovery, increased ERP, and reduced repolarization reserve; prolonged QT intervals	No clinically approved drugs in use		Increase in AP recovery time Increase in refractory period with decreased reentrant tendency
		Kv1.5 channel-mediated, ultrarapid K⁺ current (I_Kur) blockers	Prolonged atrial AP recovery, increased ERP, and reduced repolarization reserve	Vernakalant	Immediate conversion of atrial fibrillation	Atrium-specific actions: increase in AP recovery time and increase in refractory period with decreased reentrant tendency
		Kv1.4 and Kv4.2 channel-mediated transient outward K⁺ current (I_to1) blockers	Prolonged atrial, Purkinje, and ventricular myocyte AP recovery, increased ERP, and reduced repolarization reserve, particularly in subepicardial as opposed to subendocardial ventricular cardiomyocytes	Blocker under regulatory review for the acute conversion of atrial fibrillation: tedisamil		Increase in AP recovery time; increase in refractory period, with decreased reentrant tendency
Metabolically dependent K⁺ channel openers	IIIb	Kir6.2 (I_KATP) openers	Opening of ATP-sensitive K⁺ channels (I_KATP), shortening AP recovery, refractoriness, and repolarization reserve in all cardiomyocytes apart from SAN cells; shortened QT intervals	Nicorandil, pinacidil	Nicorandil: treatment of stable angina (second line); pinacidil: investigational drug for the treatment of hypertension	Potential decrease in AP recovery time
Transmitter dependent K⁺ channel blockers	IIIc	GIRK1 and GIRK4 (I_KACh) blockers	Inhibition of direct or G_i protein βγ-subunit-mediated activation of I_KACh, particularly in SAN, AVN, and atrial cells, prolonging APD and ERP and decreasing repolarization reserve	Blocker under regulatory review for management of atrial fibrillation: BMS 914392		Reduction in SAN automaticity
Ca²⁺ handling modulators
IV
Surface membrane Ca²⁺ channel blockers	IVa	Nonselective surface membrane Ca²⁺ channel blockers	Block of Ca²⁺ current (I_Ca), resulting in inhibition of SAN pacing, inhibition of AVN conduction, prolonged ERP, increased AP recovery time, increased refractory period, diminished repolarization reserve, and suppression of intracellular Ca²⁺ signaling; increased PR intervals	Bepridil	Angina pectoris Potential management of supraventricular tachyarrhythmias	Reduction in AVN conduction, terminating reentry Reduction in EAD-/DAD-induced triggered activity
		Ca_v1.2 and Ca_v1.3 channel mediated L-type Ca²⁺ current (I_CaL) blockers	Block of Ca²⁺ current (I_Ca), resulting in inhibition of SAN pacing, inhibition of AVN conduction, prolonged ERP, increased AP recovery time, increased refractory period, diminished repolarization reserve, and suppression of intracellular Ca²⁺ signaling; increased PR intervals	Phenylalkylamines (eg, verapamil), benzothiazepines (eg, diltiazem)	Supraventricular arrhythmias and ventricular tachycardia without structural heart disease Rate control of atrial fibrillation	Reduction in AVN conduction, terminating reentry Reduction in EAD-/DAD-induced triggered activity
		Ca_v3.1 channel mediated T-type Ca²⁺ current (I_CaT) blockers	Inhibition of SAN pacing, prolonged His-Purkinje phase 4 repolarization, absent from ventricular cells	No clinically approved drugs in use
Intracellular Ca²⁺ channel blockers	IVb	SR RyR2-Ca²⁺ channel blockers	Reduced SR Ca²⁺ release: reduced cytosolic and SR [Ca²⁺]	Flecainide, propafenone	Catecholaminergic polymorphic ventricular tachycardia	Reduction in DAD-induced triggered activity
		IP₃R-Ca²⁺ channel blockers	Reduced atrial SR Ca²⁺ release; reduced cytosolic and SR [Ca²⁺]	No clinically approved drugs in use
Sarcoplasmic reticular Ca²⁺-ATPase activators	IVc	Sarcoplasmic reticular Ca²⁺ pump activators	Increased Ca²⁺-ATPase activity, increased SR [Ca²⁺]	No clinically approved drugs in use		Reduction in DAD-induced triggered activity
Surface membrane ion exchange inhibitors	IVd	Surface membrane ion exchanger (eg, SLC8A) inhibitors	Reduced Na⁺–Ca²⁺ exchange reduces depolarization associated with rises in subsarcolemmal [Ca²⁺]	No clinically approved drugs in use		Reduction in EAD-/DAD-induced triggered activity
Phosphokinase and phosphorylase inhibitors	IVe	Increased/decreased phosphorylation levels of cytosolic Ca²⁺ handling proteins	Includes CaMKII modulators: altered intracellular Ca²⁺ signaling	No clinically approved drugs in use		Reduction in EAD-/DAD-induced triggered activity
Mechanosensitive channel blockers
V		Transient receptor potential channel (TRPC3/TRPC6) blockers	Intracellular Ca²⁺ signaling	Blocker under investigation: N–(p-amylcinnamoyl) anthranilic acid		Reduction in EAD-/DAD-induced triggered activity
Gap junction channel blockers
VI		Cx (Cx40, Cx43, Cx45) blockers	Reduced cell-cell coupling and AP propagation; Cx40: atria, AVN, ventricular conduction system; Cx43: atria and ventricles, distal conduction system; Cx45: SAN, AVN, conducting bundles	Blocker under investigation: carbenoxolone		Reduction in ventricular/atrial conduction Reduction in accessory pathway conduction Reduction in AVN conduction
Upstream target modulators
VII		Angiotensin-converting enzyme inhibitors	Electrophysiological and structural (fibrotic, hypertrophic, or inflammatory) remodeling	Captopril, enalapril, delapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril	Management of hypertension, symptomatic heart failure Potential application reducing arrhythmic substrate	Reduction of structural and electrophysiological remodeling changes that compromise AP conduction and increase reentrant tendency
		Angiotensin receptor blockers	Electrophysiological and structural (fibrotic, hypertrophic, or inflammatory) remodeling	Losartan, candesartan, eprosartan, telmisartan, irbesartan, olmesartan, valsartan, saprisartan	Management of hypertension, symptomatic heart failure Potential application reducing arrhythmic substrate	Reduction of structural and electrophysiological remodeling changes that compromise AP conduction and increase reentrant tendency
		Omega-3 fatty acids	Electrophysiological and structural (fibrotic, hypertrophic, or inflammatory) remodeling	Omega-3 fatty acids: eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid	Post-myocardial infarct reduction of risk of cardiac death, myocardial infarct, stroke, and abnormal cardiac rhythms	Reduction of structural and electrophysiological remodeling changes that compromise AP conduction and increase reentrant tendency
		Statins	Electrophysiological and structural (fibrotic, hypertrophic, or inflammatory) remodeling	Statins	Post-myocardial infarct reduction of risk of cardiac death, myocardial infarct, stroke, and abnormal cardiac rhythms	Reduction of structural and electrophysiological remodeling changes that compromise AP conduction and increase reentrant tendency

HCN: hyperpolarization-activated cyclic nucleotide-gated; SAN: sino-atrial node; AVN: atrioventricular node; AP: action potential; APD: action potential duration; ERP: effective refractory period; SQTS: short-QT syndrome; DAD: delayed afterdepolarization; EAD: early afterdepolarization; RyR2: ryanodine receptor 2; SR: sarcoplasmic reticulum; CaMKII: calcium/calmodulin kinase II.

From: Lei M, Wu L, Terrar DA, et al. Modernized classification of cardiac antiarrhythmic drugs. Circulation 2018; 138:1879. Available at: https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.118.035455 (Accessed on January 29, 2019). Reproduced under the terms of the Creative Commons Attribution License.

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