Current Cardiology Reports

, Volume 3, Issue 4, pp 314–323 | Cite as

What niche will newer class III antiarrhythmic drugs occupy?

  • Bramah N. Singh
  • Jonnalagedda S. M. Sarma


The decline in the use of sodium channel blockers has led to an expanding use of β-blockers and complex class III agents such as sotalol and amiodarone for controlling cardiac arrhythmias. Success with these agents in the context of their side effects has spurred the development of compounds with simpler ion channel-blocking properties with less complex adverse reactions. The resulting so-called pure class III agents were found to have antifibrillatory effects in atrial fibrillation (AF) and flutter, as well as in ventricular tachyarrhythmias. Pure class III compounds are effective in inducing acute chemical conversion of AF, in preventing paroxysmal AF, and in maintaining sinus rhythm in patients with persistent AF restored to sinus rhythm. Examples of such compounds are dofetilide, which selectively blocks IKr, and ibutilide, available only as an intravenous agent, which blocks the IKr and augments the inactivated Na+ current in atrial myocytes. Dofetilide and ibutilide have been introduced into clinical practice. Azimilide is the first of the class III agents that blocks both components (IKr and IKs) of the delayed rectifier current, which may confer certain electrophysiologic advantages. The potential therapeutic niche of ibutilide, dofetilide, and azimilide in the control of cardiac arrhythmias forms the basis of this review.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Singh BN: Antiarrhythmic drugs: a re-orientation in light of recent developments in the control of disorders of rhythm. Am J Cardiol 1998, 81:3D-13D.PubMedCrossRefGoogle Scholar
  2. 2.
    Singh BN: Current antiarrhythmic drugs: an overview of mechanisms of action and potential clinical utility. J Cardiovasc Electrophysiol 1999, 10:283–301.PubMedCrossRefGoogle Scholar
  3. 3.
    Camm AJ, Yap Guan Yee: What should we expect from the next generation of antiarrhythmic drugs? J Cardiovasc Electrophysiol 1999, 10:317–317.CrossRefGoogle Scholar
  4. 4.
    Wei Sun, Sarma JSM, Singh BN: Electrophysiological effects of dronedarone (SR33589), a noniodinated benzofuran derivative, in the rabbit heart: comparison with amiodarone. Circulation 1999, 100:2276–2281. First of the detailed electrophysiologic comparisons of amiodarone and dronedarone in cardiac muscle after chronic pretreatment of the drugs in the rabbit and guinea pigs. The effects of the two compounds on various parameters of the action potential duration were found to be similar.Google Scholar
  5. 5.
    Singh BN: Historical development of the concept of controlling cardiac arrhythmias by lengthening repolarization: particular reference to sotalol. Am J Cardiol 1990, 65(Suppl 3):A11A.Google Scholar
  6. 6.
    Singh BN: Sotalol: current status and expanding indications. J Cardiovasc Pharmacol Therapeut 1999, 4:59–65.Google Scholar
  7. 7.
    Nattel S, Singh BN: Evolution, mechanisms, and classification of antiarrhythmic drugs: focus on class III actions. Am J Cardiol 1999, 84:11R-19R.PubMedCrossRefGoogle Scholar
  8. 8.
    Murray KT: Ibutilide. Circulation 1998, 97:493–497.PubMedGoogle Scholar
  9. 9.
    Torp-Pedersen C, Moller M, Bloch-Thomsen PE, et al., for the Danish Investigations of Arrhythmia and Moratlity on Dofetilide Study group: Dofetilide in patients with congestive heart failure and left ventricular dysfunction. N Eng J Med 1999, 341:857–865. The outcome results of the critical clinical trial of dofetilide on mortality in patients with heart failure and markedly reduced left ventricular ejection fraction. Compared with placebo, there was no adverse effect of the drug on mortality or sudden death; it also showed an antifibrillatory effect in patients in the trial who had AF.CrossRefGoogle Scholar
  10. 10.
    Fermini, B, Jurkiewicz NK, Jow B: Use dependent effect of the class III antiarrhythmic agent NE-10064 (azimilide) on cardiac repolarization block or delayed rectifier potassium and L-type calcium currents. J Cardiovasc Pharmacol 1995, 26:259–267.PubMedCrossRefGoogle Scholar
  11. 11.
    Salata JJ, Brooks RR: Pharmacology of azimilide dihydrochloride (NE-10064), a class III antiarrhythmic agent. Cardiovas Drug Rev 1997, 15:137–156. A comprehensive review of the electrophysiologic and antiarrhythmic actions of azimilide summarized on the basis of original investigative studies.CrossRefGoogle Scholar
  12. 12.
    Singh BN, Mody FV, Lopez B, Sarma JSM: Antiarrhythmic agents for atrial fibrillation: focus on prolonging atrial repolarization. Am J Cardiol 1999, 84:161R-173R, 92:1954-1968.PubMedCrossRefGoogle Scholar
  13. 13.
    Hohnloser S, Klingenheben T, Singh BN: Amiodarone-associated proarrhythmic effects: a review with special reference to torsades de pointes tachycardia. Ann Int Med 1994, 121:529–535.PubMedGoogle Scholar
  14. 14.
    Lee Ks, Gibson JK: Unique ionic mechanism of action of ibutilide on freshly isolated heart cells. Circulation 1995, 92:2755–2757.PubMedGoogle Scholar
  15. 15.
    Ellenbogen KA, Sambler BS, Wood MA, et al.: Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and flutter: a dose-response study. J Am Coll Cardiol 1996, 28:130–136. This paper and papers by Stambler et al. [16] and Ellenbogan et al. [17] are from controlled clinical trials with the intravenous formulation of ibutilide that clearly established the role of the drug in the acute conversion of recent-onset AF and AFL in patients. They also provide details of the proarrhythmic reactions induced by the drug.PubMedCrossRefGoogle Scholar
  16. 16.
    Stambler BS, Wood MA, Ellenbogen KA, et al.: Efficacy of safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Circulation 1996, 94:1613–1621.PubMedGoogle Scholar
  17. 17.
    Ellenbogen KA, Clemo HF, Stambler BS, et al.: Efficacy of ibutilide for termination of atrial fibrillation and flutter. Am J Cardiol 1996, 78:42–45.PubMedCrossRefGoogle Scholar
  18. 18.
    Buchanan LV, Kabell G, Brunden MN, et al.: Comparative assessment of ibutilide, d-sotalol, clofilium, E-4031, and UK-68,798 in a rabbit model of proarrhythmia. J Cardiovasc Pharmacol 1993, 22:540–549.PubMedGoogle Scholar
  19. 19.
    Naccarelli GV, Lee KS, Gibson JK, et al.: Electrophysiology and pharmacology of ibutilide. Am J Cardiol 1996, 78:12–16.PubMedCrossRefGoogle Scholar
  20. 20.
    Oral H, Souza HJ, Michaud GF, et al.: Facilitating transthoracic cardioversion of atrial fibrillation with ibutilide treatment. N Engl J Med 1999, 340:1849–1854. This is an elegant landmark paper from a very experienced group that found that a single injection of ibutilide facilitated DC cardioversion when the procedure had failed immediately prior to the drug infusion. The data support the notion that class III drugs lower threshold of conversion and raise the possibility that such drugs may need to be "on board" prior to attempted conversion in potentially refractory patients.PubMedCrossRefGoogle Scholar
  21. 21.
    Singh BN: Acute conversion of atrial flutter and fibrillation: direct current cardioversion versus intravenously administered pure class III agents. J Am Coll Cardiol 1997, 29:391–393.PubMedCrossRefGoogle Scholar
  22. 22.
    Roden DM: Ibutilide and the treatment of atrial arrhythmias. a new drug- almost unheralded — is now available to US physicians. Circulation 1996, 94:1499–1502.PubMedGoogle Scholar
  23. 23.
    Stambler BS, Wood MA, Ellenbogen KA: Comparative efficacy of intravenous ibutilide versus procainamide for enhancing termination of atrial flutter by atrial overdrive pacing. Am J Cardiol 1996, 77:960–966.PubMedCrossRefGoogle Scholar
  24. 24.
    Glatter K, Young Y, Chatterjee K et al.: Chemical cardioversion of atrial fibrillation or flutter with ibutilide in patients amiodarone therapy. Circulation 2001, 103:253–257. An important original study in which the authors showed that chemical conversion of patients with AF chronically treated with amiodarone is not only highly effective, but is safe.There was only one case of spontaneously terminating torsades de pointes in a series of about 70 patients.PubMedGoogle Scholar
  25. 25.
    Kowey PR, Vanderlugt JT, Luderer JR: Safety and risk/benefit analysis of ibutilide for acute conversion of atrial flutter and fibrillation. Am J Cardiol 1996, 78:46–52.PubMedCrossRefGoogle Scholar
  26. 26.
    Falk RH, Pollak A, Singh SN, Friederich T for Doefitilide Investigators: Intravenous dofetilide, a class III antiarrhythmic agent, for the termination of sustained atrial fibrillation or flutter. J Am Coll Cardiol 1997, 29:385–392.PubMedCrossRefGoogle Scholar
  27. 27.
    Pfizer Labs: Data on file. New York, NY.Google Scholar
  28. 28.
    Carmeliet E: Voltage- and time-dependent block of the delayed K current in cardiac myocytes by dofetilide. J Pharmacol Exp Ther 1992, 262:809–817.PubMedGoogle Scholar
  29. 29.
    Jurkiewicz NK, Sanguinetti MC: Rate-dependent prolongation of action potentials by a methanesulfonanilide class III antiarrhythmic agent: specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circ Res 1993, 72:75–83.PubMedGoogle Scholar
  30. 30.
    Singh SN, Zoble RG, Yellen L, et al., for the Dofetilide Atrial Fibrillation Investigators: Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or flutter: the symptomatic atrial fibrillation Investigative research on dofetilide (SAFIRE-D) study. Circulation 2000, 102:2383–2390. One of the two pivotal blinded, placebo-controlled, dose-ranging studies that established the efficacy of sotalol in patients with symptomatic AF and AFL.Google Scholar
  31. 31.
    Waldo AL, Camm AJ, D Ruyter H et al.: Effects of d-sotalol on mortality in patients with left ventricular function after recent and remote myocardial infarction. Lancet 1996, 348:7–12.PubMedCrossRefGoogle Scholar
  32. 32.
    Corey AE, Al-Khalidi H, Brezovic C, et al.: Azimilide pharmacokinetics and pharmacodynamics upon multiple oral dosing. Clin Pharmacol Ther 1997, 61:205–212.Google Scholar
  33. 33.
    Lamorgese M, Kirian M, Van Wagoner DR: Azimilide (NE-10064) blocks outward K currents in human atrial and ventricular myocytes. Circulation 1997, 92(8, Suppl l):I575.Google Scholar
  34. 34.
    Groh WJ, Gibson KJ, Maylie JG: Comparison of the rate-dependent properties of the class III antiarrhythmic agents azimilide (NE-10064) and E-4031: considerations on the mechanism of reverse-rate dependent action potential prolongation. J Cardiovasc Electrophysiol 1997, 8:529–536. This carefully conducted study drew attention to the fact that the rate-dependent effect of azimilide on the action potential duration and the effective refractory period differed from that of other pure class III agents, and appeared to be similar to those of amiodarone. This may be due to the nature of the ion-channel block that the drug produces in isolated cardiac myocytes.PubMedCrossRefGoogle Scholar
  35. 35.
    Restivo M, Hegazy M, El-Hamamy M: Antiarrhythmic efficacy of azimilide dihydrochloride on functional circus movement atrial flutter in the canine right atrial enlargement model. PACE 1996, 19(4, Part II):664.Google Scholar
  36. 36.
    Nattel S, Liu L, St George D: Effects of the novel antiarrhythmic agent azimilide on experimental atrial fibrillation and atrial electrophysiologic properties. Cardiovasc Res 1998, 37:627–635.PubMedCrossRefGoogle Scholar
  37. 37.
    Drexler AP, Micklas JM, Brooks RR: Effects of intravenously administered NE-10064 on programmed electrical stimulation (PES)-induced ventricular arrhythmias in anesthetized infarcted dogs. FASEB J 1993, 7:A97.Google Scholar
  38. 38.
    Black SC, Butterfield JL, Lucchesi BR: Protection against programmed electrical stimulation-induced ventricular tachycardia and sudden cardiac death by NE-10064, a class III antiarrhythmic drug. J Cardiovasc Pharmacol 1993, 22:810–823.PubMedCrossRefGoogle Scholar
  39. 39.
    Procter & Gamble Labs: Data on file.Cincinnati, OH.Google Scholar
  40. 40.
    Pritchett E, Page, R, Connolly Marcello, S and ASAP Investigators: Azimilide treatment of atrial fibrillation. Circulation 2000, 98:1–633.Google Scholar
  41. 41.
    Benditt DG, Williams JH, Jin J, et al., for the dl-Sotalol Atrial Fibrillation/Flutter Study Group: Maintenance of sinus rhythm with oral dl-sotalol therapy in patients with symptomatic atrial fibrillation and flutter: a dose-response study. Am J Cardiol 1999, 84:270. This is a carefully executed, placebo-controlled trial that examined the dose-ranging effect of dl-sotalol in preventing recurrences of AF in patients with paroxysmal AF. It is a landmark study that formed the basis for the approval of the drug in the United States.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2001

Authors and Affiliations

  • Bramah N. Singh
    • 1
  • Jonnalagedda S. M. Sarma
    • 1
  1. 1.Division of Cardiology 111EVA Medical Center of West Los AngelesLos AngelesUSA

Personalised recommendations