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 (If) block | Inhibition of If reducing SAN phase 4 pacemaker depolarization rate, thereby reducing heart rate; possible decreased AVN and Purkinje cell automaticity; increase in RR intervals | Ivabradine |
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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 INa, AP generation, and (dV/dt)max with increased excitation threshold; slowing of AP conduction in atria, ventricles, and specialized ventricular conduction pathways; concomitant IK block increasing APD and ERP; increase in QT intervals | Quinidine, ajmaline, disopyramide |
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Ib | Nav1.5 open state; rapid dissociation (Tau ≈ 0.1 to 1 second); INa; window current | Reduction in peak INa, 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 |
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Ic | Nav1.5 inactivated state; slow dissociation (Tau >10 seconds) | Reduction in peak INa, 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 |
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Id | Nav1.5 late current | Reduction in late Na+ current (INaL), affecting AP recovery, refractoriness, repolarization reserve, and QT interval | Ranolazine |
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Autonomic inhibitors and activators | ||||||
II | IIa | Nonselective beta- and selective beta1-adrenergic receptor inhibitors | Inhibition of adrenergically induced Gs protein-mediated effects of increased adenylyl kinase activity and [cAMP]i with effects including slowed SAN pacemaker rate caused by reduced If and ICaL; increased AVN conduction time and refractoriness, and decreased SAN pacing and triggered activity resulting from reduced ICaL; 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 |
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IIb | Nonselective beta-adrenergic receptor activators | Activation of adrenergically induced Gs-protein effects of increasing adenylyl kinase activity and [cAMP]i (refer to entry above); decrease in RR and PR intervals | Isoproterenol |
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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 |
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IId | Muscarinic M2 receptor activators | Activation of supraventricular (SAN, atrial, AVN) muscarinic M2 cholinergic receptors activates KACh channels, hyperpolarizing the SAN and shortening APDs in atrial and AVN tissue, and reduces [cAMP]i and therefore ICaL and SAN If; inhibitory effects on adenylyl cyclase and cAMP activation, reducing its stimulatory effects on ICaL, IKs, ICl, and Iti in adrenergically activated ventricular tissue; increased RR and PR intervals | Carbachol, pilocarpine, methacholine, digoxin |
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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 IKAdo current, hyperpolarizing the SAN and shortening APDs in atrial and AVN tissue, and reduces [cAMP]i and therefore ICaL and SAN If; inhibitory effects on adenylyl cyclase and cAMP activation, reducing its stimulatory effects on ICaL, IKs, ICl, and Iti in adrenergically activated ventricular tissue; increased RR and increased PR intervals | Adenosine, ATP; aminophylline acts as an adenosine receptor inhibitor |
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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 |
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Kv11.1 (HERG) channel-mediated rapid K+ current (IKr) blockers | Prolonged atrial, Purkinje, and ventricular myocyte AP recovery, increased ERP, and reduced repolarization reserve; prolonged QT intervals | Dofetilide, ibutilide, sotalol |
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Kv7.1 channel-mediated, slow K+ current (IKs) blockers | Prolonged atrial, Purkinje, and ventricular myocyte AP recovery, increased ERP, and reduced repolarization reserve; prolonged QT intervals | No clinically approved drugs in use |
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Kv1.5 channel-mediated, ultrarapid K+ current (IKur) blockers | Prolonged atrial AP recovery, increased ERP, and reduced repolarization reserve | Vernakalant |
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Kv1.4 and Kv4.2 channel-mediated transient outward K+ current (Ito1) 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 |
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Metabolically dependent K+ channel openers | IIIb | Kir6.2 (IKATP) openers | Opening of ATP-sensitive K+ channels (IKATP), shortening AP recovery, refractoriness, and repolarization reserve in all cardiomyocytes apart from SAN cells; shortened QT intervals | Nicorandil, pinacidil |
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Transmitter dependent K+ channel blockers | IIIc | GIRK1 and GIRK4 (IKACh) blockers | Inhibition of direct or Gi protein βγ-subunit-mediated activation of IKACh, 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 |
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Ca2+ handling modulators | ||||||
IV | ||||||
Surface membrane Ca2+ channel blockers | IVa | Nonselective surface membrane Ca2+ channel blockers | Block of Ca2+ current (ICa), 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 |
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Cav1.2 and Cav1.3 channel mediated L-type Ca2+ current (ICaL) blockers | Block of Ca2+ current (ICa), 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) |
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Cav3.1 channel mediated T-type Ca2+ current (ICaT) 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 |
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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 |
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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 |
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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 |
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Mechanosensitive channel blockers | ||||||
V | Transient receptor potential channel (TRPC3/TRPC6) blockers | Intracellular Ca2+ signaling | Blocker under investigation: N–(p-amylcinnamoyl) anthranilic acid |
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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 |
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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 |
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Angiotensin receptor blockers | Electrophysiological and structural (fibrotic, hypertrophic, or inflammatory) remodeling | Losartan, candesartan, eprosartan, telmisartan, irbesartan, olmesartan, valsartan, saprisartan |
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Omega-3 fatty acids | Electrophysiological and structural (fibrotic, hypertrophic, or inflammatory) remodeling | Omega-3 fatty acids: eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid |
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Statins | Electrophysiological and structural (fibrotic, hypertrophic, or inflammatory) remodeling | Statins |
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