dronedarone" and "Amiodarone and thyroid dysfunction".) Ibutilide, which is available in intravenous form, is approved for the acute termination of atrial flutter and atrial fibrillation, and it prolongs the QT interval by enhancing the slow, delayed inward sodium current as well as blocking potassium channels during repolarization. (See "Therapeutic use of ibutilide".) Some of the class III agents, such as sotalol, dofetilide, and ibutilide, exhibit reverse use- dependent effects on repolarization [20]. This pharmacologic property is characterized by a dynamic increase in the repolarization time and the refractory period during slower heart rates. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 11/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Clinically, this property manifests as an increased QT interval at slower heart rates, which can increase the risk of torsades de pointes [20]. The new classification scheme ( table 2 and table 3) adds subclass IIIb and IIIc agents. + Subclass IIIb agents (metabolically dependent K channel openers, eg, pinacidil) may shorten the action potential but do not have antiarrhythmic activity [11]. Subclass IIIc agents (transmitter-dependent K-channel blockers, such as acetylcholine) activate potassium channels, but there are no clinically available drugs in this subclass. Class IV The class IV drugs are calcium channel blockers. Verapamil has a more pronounced inhibitory effect on the slow response SA and AV nodes than diltiazem. In comparison, the dihydropyridines, such as nifedipine, have little electrophysiologic effect on the heart. Verapamil and diltiazem can slow the sinus rate (usually in the presence of sinus node dysfunction or beta blockade), increase the refractoriness of and prolong conduction through the AV node, occasionally prolong the PR interval, and depress LV function. The newer classification scheme ( table 2 and table 3) calls this class "Ca handling modulators" and divides it into five subclassifications of targets, of which Class IVa is the classic Vaughan Williams surface channel blockers [11]. The additional classes IVb through IVe for the most part do not yet contain clinically available drugs, but this scheme does serve as a template for further research. An exception to this are the Class I drugs flecainide and propafenone, which qualify as class IVd ryanodine receptor blockers and are active against catecholaminergic polymorphic ventricular tachycardia. Additional proposed classes include Class V (mechanosensitive channel blockers) and Class VI (gap junction blockers), which have drugs under investigation. Class VII (upstream target modulators) includes angiotensin converting enzyme inhibitors and angiotensin receptor blockers that may have antiarrhythmic action by their effects on cardiac remodeling. A position paper on antiarrhythmic drugs produced by international societies provides additional detail [4]. SUMMARY AND RECOMMENDATIONS Antiarrhythmic drugs target ion channels and receptors in the heart, generally blocking or inhibiting function. (See 'Cardiac excitability' above.) Classification of antiarrhythmic drugs is generally done by their predominant action and target ( table 2 and table 3). Note that nearly all clinically used drugs act on multiple https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 12/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate targets. (See 'Classification of antiarrhythmic drugs' above.) The multiple electrophysiologic actions of antiarrhythmic drugs interacting with the variable underlying substrate present in each patient determine whether the clinical effect will be proarrhythmic or antiarrhythmic. (See 'Classification of antiarrhythmic drugs' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Arnsdorf MF. The cellular basis of cardiac arrhythmias. A matrical perspective. Ann N Y Acad Sci 1990; 601:263. 2. Fozzard HA, Arnsdor MF. Cardiac electrophysiology. In: The Heart and Cardiovascular Syste m, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York 1991. p.63. 3. Grant AO. Cardiac Ion Channels. Circ Arrythm Electrophysiol 2009; 2:185. 4. Dan GA, Martinez-Rubio A, Agewall S, et al. Antiarrhythmic drugs-clinical use and clinical decision making: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP). Europace 2018; 20:731. 5. Catterall WA. Structure and function of voltage-sensitive ion channels. Science 1988; 242:50. 6. St hmer W, Conti F, Suzuki H, et al. Structural parts involved in activation and inactivation of the sodium channel. Nature 1989; 339:597. 7. Fozzard HA, Danck DA. Sodium channels. In: The Heart and Cardiovascular System, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York 1991. p.1091. 8. The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. Circulation 1991; 84:1831. 9. Liu DW, Gintant GA, Antzelevitch C. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle. Circ Res 1993; 72:671. 10. Pelzer D, Pelzer S, McDonald TF. Calcium channels in heart. In: The Heart and Cardiovascular System,, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York1 991. p.1049. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 13/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate 11. Lei M, Wu L, Terrar DA, Huang CL. Modernized Classification of Cardiac Antiarrhythmic Drugs. Circulation 2018; 138:1879. 12. Arnsdorf MF. Arnsdorf's paradox. J Cardiovasc Electrophysiol 1990; 1:42. 13. Arnsdorf MF. Cardiac excitability, the electrophysiologic matrix and electrically induced ventricular arrhythmias: order and reproducibility in seeming electrophysiologic chaos. J Am Coll Cardiol 1991; 17:139. 14. Snyders DJ, Hondeghem LM, Bennett PB. Mechanisms of drug-channel interaction. In: The H eart and Cardiovascular System, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, N ew York 1991. p.2165. 15. Hondeghem LM, Katzung BG. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol 1984; 24:387. 16. Antzelevitch C, Nesterenko V, Shryock JC, et al. The role of late I Na in development of cardiac arrhythmias. Handb Exp Pharmacol 2014; 221:137. 17. Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of ventricular arrhythmia. Circulation 1990; 82:I103. 18. Frishman W, Silverman R. Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 2. Physiologic and metabolic effects. Am Heart J 1979; 97:797. 19. Naccarelli GV, Lukas MA. Carvedilol's antiarrhythmic properties: therapeutic implications in patients with left ventricular dysfunction. Clin Cardiol 2005; 28:165. 20. Hondeghem LM, Snyders DJ. Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 1990; 81:686. Topic 895 Version 30.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 14/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate GRAPHICS Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 15/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Normal conduction system Schematic representation of the normal intraventricular conduction system (His- Purkinje system). The Bundle of His divides into the left bundle branch and right bundle branch. The left bundle branch divides into anterior, posterior, and, in some cases, median fascicles. AV: atrioventricular; RA: right atrium; LA: left atrium; RV: right ventricle; LV: left ventricle. Graphic 63340 Version 6.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 16/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Myocardial action potential Representation of a ventricular action potential. There are 5 phases of the action potential beginning with phase 0, rapid depolarization by sodium influx. Phase 1 is a rapid repolarization via potassium efflux followed by phase 2 or the plateau phase. The plateau phase results from entry of calcium into the cell and potassium efflux. Phase 3 repolarization is dominated by potassium currents which polarize the cell and potassium inward rectifier maintains the resting potential or phase 4. See text for full description. Graphic 71390 Version 4.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 17/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Action potentials generated by different parts of conduction system The sinoatrial (SA) and atrioventricular (AV) nodes generate a slow action potential, mediated by calcium ions. In comparison, the tissues of the atria, ventricles, and the His-Purkinje system generate a fast action potential mediated by sodium ions. Sequential activation of these structures results in the characteristic waveforms visible on the surface electrocardiogram (ECG). The AV node and bundle of His are small structures; as a result, no electrical activity is recorded on the surface ECG during their activation. Graphic 61989 Version 4.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 18/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Fast versus slow response cardiac tissues Properties Fast response tissues Slow response tissues Atria, specialized infranodal SA and AV nodes, depolarized fast Location conducting system, ventricles, AV bypass tracts response tissues in which phase 0 depends upon calcium current Passive cellular properties Normal resting 80 to -95 mV 40 to -65 mV potential Active cellular properties Phase 0 current Sodium Primarily calcium Phase 0 channel kinetics Fast Slow activation; inactivation depends upon voltage and cell calcium concentration Peak overshoot +20 to +40 mV 5 to + 20 mV Action potential amplitude 90 to 135 mV 30 to 70 mV Properties dependent upon active and passive properties Threshold voltage 60 to -75 mV 40 to -60 mV Conduction 0.5 to 5 m/second 0.01 to 0.1 m/second velocity Conducive to reentry Only with inactivation of sodium channels with marked slowing of conduction velocity Present in normal tissue Yes Yes Automaticity Comparison of the major electrophysiologic characteristics of "fast" and "slow" response tissues. AV: atrioventricular; SA: sinoatrial. Graphic 71831 Version 3.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 19/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Mechanisms of tachyarrhythmias (A) Enhanced automaticity: nodal action potentials with normal automaticity (solid orange line) compared wit (dotted blue line) as would be seen with increased pacemaker current (I ) and/or decreased inward rectifier c enhanced automaticity arrhythmia, atrial tachycardia, is shown in the figure. f (B) Reentry: a schematic of a reentrant circuit with fast and slow conduction adjacent to a fixed core. An exam of ventricular tachycardia is shown below the figure. (C) Triggered activity, DADs: DADs with the first DAD (solid orange line) not reaching threshold to trigger an a subsequent DADs reaching threshold (dotted blue line). Bidirectional ventricular tachycardia from a catechola ventricular tachycardia patient is depicted and thought to initiate with DADs. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 20/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate (D) Triggered activity, EADs: reverence action potentials (solid black line) with a prolonged action potential an a long interval, which sets up conditions for a single EAD (dotted blue line) or oscillatory EADs. Typical short-l torsade de pointes in a patient with drug-induced long QT syndrome. AP: action potential; DAD: delayed afterdepolarization; EAD: early afterdepolarization. Courtesy of Lee Eckhardt, MD. Graphic 120258 Version 2.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 21/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs Pharmacological Electrophysiological Examples of Class Subclass targets effects drugs HCN channel blockers 0 HCN channel- mediated Inhibition of I reducing SAN phase 4 pacemaker Ivabradine f pacemaker current (I ) block depolarization rate, thereby reducing heart f rate; possible decreased AVN and Purkinje cell automaticity; increase in RR intervals + Voltage-gated Na channel blockers https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 22/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate I Ia Nav1.5 open state; intermediate (Tau 1 to 10 seconds) dissociation kinetics; Reduction in peak I AP generation, and , Quinidine, ajmaline, Na (dV/dt) increased excitation with disopyramide max often concomitant K channel block threshold; slowing of AP conduction in atria, + ventricles, and specialized ventricular conduction pathways; concomitant I block increasing APD and ERP; K increase in QT intervals https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 23/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Ib Nav1.5 open state; rapid dissociation (Tau 0.1 to 1 second); I Reduction in peak I AP generation and , Lidocaine, mexiletine Na (dV/dt) increased excitation with max ; window Na current 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 Ic Nav1.5 inactivated state; slow dissociation (Tau >10 Reduction in peak I AP generation and (dV/dt) , Propafenone, flecainide Na with max seconds) 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 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 24/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate + Id Nav1.5 late current Reduction in late Na Ranolazine current (I NaL AP recovery, ), affecting refractoriness, repolarization reserve, and QT interval Autonomic inhibitors and activators https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 25/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate II IIa Nonselective beta- and selective beta1- Inhibition of adrenergically induced Nonselective beta inhibitors: adrenergic receptor inhibitors G protein-mediated effects of increased carvedilol, propranolol, s adenylyl kinase activity and [cAMP] with effects i including slowed SAN nadolol Selective beta1- adrenergic receptor pacemaker rate caused by reduced I and I ; f CaL inhibitors: increased AVN conduction time and atenolol, bisoprolol, betaxolol, refractoriness, and decreased SAN pacing celiprolol, and triggered activity esmolol, metoprolol resulting from reduced ; and reduced RyR2- I CaL mediated SR Ca release and triggered activity; increase in RR and PR intervals 2+ https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 26/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 27/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate IIb Nonselective beta- adrenergic receptor Activation of adrenergically induced Isoproterenol activators G -protein effects of increasing adenylyl s kinase activity and [cAMP] (refer to entry i above); decrease in RR and PR intervals IIc Muscarinic M receptor inhibitors Inhibition of supraventricular (SAN, atrial, AVN) muscarinic M cholinergic receptors (refer to entry below); Atropine, anisodamine, hyoscine, scopolamine 2 2 decreased RR and PR intervals IId Muscarinic M Activation of Carbachol, 2 receptor activators supraventricular (SAN, atrial, AVN) muscarinic M cholinergic receptors channels, activates K ACh hyperpolarizing the SAN pilocarpine, methacholine, digoxin 2 and shortening APDs in atrial and AVN tissue, and reduces [cAMP] and therefore I i and SAN CaL I ; inhibitory effects on f adenylyl cyclase and cAMP activation, reducing its stimulatory effects on I , I , CaL Ks Cl , I and I in adrenergically activated ventricular ti tissue; increased RR and PR intervals https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 28/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate IIe Adenosine A receptor activators Activation of adenosine A receptors in Adenosine, ATP; aminophylline 1 1 supraventricular tissue (SAN, atrial, AVN) acts as an adenosine activates G protein- coupled inward receptor inhibitor + rectifying K channels and I hyperpolarizing the SAN current, KAdo and shortening APDs in atrial and AVN tissue, and reduces [cAMP] and therefore I i and SAN CaL I ; inhibitory effects on f adenylyl cyclase and cAMP activation, reducing its stimulatory effects on I and I in adrenergically activated ventricular tissue; increased RR and increased PR intervals , I , CaL Ks Cl , I ti + 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, Ambasilide, amiodarone, dronedarone + and reduced repolarization reserve; prolonged QT intervals https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 29/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Kv11.1 (HERG) Prolonged atrial, Dofetilide, channel-mediated rapid K current (I Purkinje, and ventricular myocyte AP recovery, ibutilide, sotalol + ) Kr blockers increased ERP, and reduced repolarization reserve; prolonged QT intervals Kv7.1 channel- Prolonged atrial, No clinically + mediated, slow K current (I Purkinje, and ventricular myocyte AP recovery, approved drugs in use ) blockers Ks increased ERP, and reduced repolarization reserve; prolonged QT intervals https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 30/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Kv1.5 channel- mediated, ultrarapid Prolonged atrial AP recovery, increased ERP, Vernakalant + K current (I blockers ) and reduced repolarization reserve Kur Kv1.4 and Kv4.2 Prolonged atrial, Blocker under channel-mediated transient outward Purkinje, and ventricular myocyte AP recovery, regulatory review for the acute + K current (I ) increased ERP, and conversion of to1 blockers reduced repolarization reserve, particularly in subepicardial as atrial fibrillation: tedisamil opposed to subendocardial ventricular cardiomyocytes Metabolically + dependent K channel IIIb Kir6.2 (I ) openers Opening of ATP- Nicorandil, pinacidil KATP + sensitive K channels ), shortening AP (I KATP openers recovery, refractoriness, and repolarization reserve in all cardiomyocytes apart from SAN cells; shortened QT intervals Transmitter dependent K channel blockers IIIc GIRK1 and GIRK4 (I Inhibition of direct or G protein -subunit- mediated activation of , particularly in I Blocker under regulatory review for management of atrial i + ) blockers KACh KACh SAN, AVN, and atrial cells, prolonging APD fibrillation: BMS 914392 and ERP and decreasing repolarization reserve 2+ Ca handling modulators IV 2+ Surface IVa Nonselective surface Block of Ca current Bepridil 2+ membrane membrane Ca (I ), resulting in Ca 2+ Ca channel blockers channel blockers inhibition of SAN pacing, inhibition of AVN conduction, prolonged ERP, increased AP https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 31/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate recovery time, increased refractory period, diminished repolarization reserve, and suppression of intracellular Ca 2+ signaling; increased PR intervals 2+ Ca 1.2 and Ca 1.3 channel mediated L- Block of Ca current ), resulting in (I Phenylalkylamines (eg, verapamil), v v Ca 2+ type Ca current ) blockers (I inhibition of SAN pacing, inhibition of AVN benzothiazepines (eg, diltiazem) CaL conduction, prolonged ERP, increased AP recovery time, increased refractory period, diminished repolarization reserve, and suppression of intracellular Ca signaling; increased PR intervals 2+ Ca 3.1 channel mediated T-type Ca current (I blockers Inhibition of SAN pacing, prolonged His- Purkinje phase 4 repolarization, absent No clinically approved drugs in use v 2+ ) CaT from ventricular cells 2+ 2+ Intracellular Ca channel blockers IVb SR RyR2-Ca channel blockers Reduced SR Ca release: reduced 2+ cytosolic and SR [Ca ] Flecainide, propafenone 2+ 2+ IP R-Ca channel blockers 2+ Reduced atrial SR Ca release; reduced No clinically approved drugs in 3 2+ cytosolic and SR [Ca ] use 2+ Sarcoplasmic 2+ reticular Ca - ATPase IVc Sarcoplasmic 2+ Increased Ca -ATPase No clinically reticular Ca pump activators activity, increased SR 2+ [Ca ] approved drugs in use activators + 2+ Surface IVd Surface membrane Reduced Na Ca No clinically membrane ion exchange ion exchanger (eg, SLC8A) inhibitors exchange reduces depolarization approved drugs in use inhibitors associated with rises in 2+ subsarcolemmal [Ca ] https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 32/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Phosphokinase and IVe Increased/decreased phosphorylation Includes CaMKII modulators: altered No clinically approved drugs in 2+ phosphorylase inhibitors levels of cytosolic Ca handling intracellular Ca signaling use 2+ proteins Mechanosensitive channel blockers 2+ V Transient receptor Intracellular Ca Blocker under potential channel (TRPC3/TRPC6) signaling investigation: N (p-amylcinnamoyl) blockers anthranilic acid Gap junction channel blockers VI Cx (Cx40, Cx43, Cx45) blockers Reduced cell-cell coupling and AP Blocker under investigation: propagation; Cx40: atria, AVN, ventricular conduction system; carbenoxolone Cx43: atria and ventricles, distal conduction system; Cx45: SAN, AVN, conducting bundles Upstream target modulators https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 33/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate VII Angiotensin- converting enzyme Electrophysiological and structural (fibrotic, Captopril, enalapril, delapril, inhibitors hypertrophic, or inflammatory) ramipril, quinapril perindopril, remodeling lisinopril, benazepril, imidapril, trandolapril, cilazapril Angiotensin receptor blockers Electrophysiological and structural (fibrotic, Losartan, candesartan, hypertrophic, or eprosartan, inflammatory) remodeling telmisartan, irbesartan, olmesartan, valsartan, saprisartan Omega-3 fatty acids Electrophysiological and Omega-3 fatty structural (fibrotic, hypertrophic, or inflammatory) remodeling acids: eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid Statins Electrophysiological and structural (fibrotic, hypertrophic, or Statins inflammatory) remodeling 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. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 34/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate From: Lei M, Wu L, Terrar DA, et al. Modernized classi cation 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. Graphic 120226 Version 2.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 35/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 36/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 37/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Contributor Disclosures Jonathan C Makielski, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. L Lee L Eckhardt, MD, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 38/38