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Subclassification of Class I antiarrhythmic drugs: Enhanced relevance after CAST

  • Antiarrhythmics
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Summary

Class I antiarrhythmic drugs are traditionally divided into three subclasses—Ia, Ib, and Ic—on the grounds of differences in kinetics of interaction with the sodium channel and different effects on the duration of the action potential. The CAST study has highlighted our growing awareness of the proarrhythmic potential of this group of agents, particularly the Class Ic subgroup. Class I drugs can cause arrhythmias either by slowing conduction to critical levels, thus enhancing the possibility of reentrant arrhythmias, or in some cases by prolonging action potential duration, leading to early afterdepolarizations, which probably underlie triggered automaticity. Evidence is presented that the Class Ic compounds may be inherently more proarrhythmic than the Ib compounds, because of their lesser ability to depress ischemic myocardium selectively. Arguments are advanced for the continued use of a slightly modified subclassification of Class I antiarrhythmic drugs.

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References

  1. Askey JM. Quinidine in the treatment of auricular fibrillation in association with congestive failure. Ann Intern Med 1946;24:317–384.

    Google Scholar 

  2. Selzer A, Wray HW. Quinidine syncope. Paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation 1964;30:17–26.

    Google Scholar 

  3. Nichoson WJ, Cartin CE, Gracey JG, Knoch HR. Disopyramide-induced ventricular fibrillation. Am J Cardiol 1979;43:1053.

    Google Scholar 

  4. Velebit V, Podrid PJ, Lown B, et al. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 1982;65:263–272.

    Google Scholar 

  5. Echt DS, Liebson PR, Mitchell LB, et al. and the CAST Investigators. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. N Engl J Med 1991;324: 781–788.

    Google Scholar 

  6. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: A meta-analysis of randomized control trials. Circulation 1990;82:1106–1116.

    Google Scholar 

  7. Morganroth J, Goin JE. Quinidine-related mortality in the short-to-medium-term treatment of ventricular arrhythmias: A meta-analysis. Circulation 1991;84:1977–1983.

    Google Scholar 

  8. Vaughan Williams EM. Classification of antiarrhythmic drugs. Symposium on Cardiac Arrhythmias. Astra, Denmark, 1970, pp 449–472.

    Google Scholar 

  9. Vaughan Williams EM. Subgroups of Class I antiarrhythmic drugs. Eur Heart J 1984;5:96–98.

    Google Scholar 

  10. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. The Sicilian Gambit: A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation 1991;84:1831–1851.

    Google Scholar 

  11. Bassett AL, Hoffman BF. Antiarrhythmic drugs: Electrophysiological actions. Ann Rev Pharmacol 1971;2:143–170.

    Google Scholar 

  12. Jensen RA, Katzung BG. Electrophysiological actions of diphenylhydantoin on rabbit atria. Circ Res 1970;26:17–27.

    Google Scholar 

  13. Singh BN, Vaughan Williams EM. Effect of altering potassium concentrations on the action of lidocaine and diphenylhydantoin on rabbit atrial and ventricular muscle. Circ Res 1971;29:286–295.

    Google Scholar 

  14. Singh BN, Hauswirth D. Comparative mechanisms of action of antiarrhythmic drugs. Am Heart J 1974;87:367–382.

    Google Scholar 

  15. Harrison DC, Winkle R, Sami M, Mason J. Encainide: A new and potent antiarrhythmic agent. Am Heart J 1980; 100:1046–1054.

    Google Scholar 

  16. Harrison DC, Winkle RA, Sami M, Mason JW. Encainide: A new and potent antiarrhythmic agent. In: Harrison DC, ed. Cardiac arrhythmias: A decade of progress. Boston: G. K. Hall Medical Publishers, 1981:315–330.

    Google Scholar 

  17. Campbell TJ. Kinetics of onset of rate-dependent effects of Class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc Res 1983;17:344–352.

    Google Scholar 

  18. Harrison DC. Antiarrhythmic drug classification: New science and practical applications. Am J Cardiol 1985;56: 185–187.

    Google Scholar 

  19. Pallandi RT, Campbell TJ. Selective depression of conduction of premature action potentials in canine Purkinje fibers by class IB antiarrhythmic drugs: Comparison with IA and IC drugs. Cardiovasc Res 1988;22:171–178.

    Google Scholar 

  20. Buchanan JW, Saito T, Gettes LS. The effects of antiarrhythmic drugs, stimulation frequency, and potassium-induced resting potential changes on condition velocity and dV/dt in guinea-pig myocardium. Circ Res 1985;56:696–703.

    Google Scholar 

  21. Davis J, Matsubara T, Scheinman MM, et al. Use-dependent effects of lidocaine on conduction in canine myocardium: Application of the modulated receptor hypothesis in vivo. Circulation 1986;74:205–214.

    Google Scholar 

  22. Weirich J, Antoni H. Differential analysis of the frequency-dependent effects of class I antiarrhythmic drugs according to periodical ligand binding: Implications for antiarrhythmic and proarrhythmic efficacy. J Cardiovasc Pharmacol 1990;15:998–1009.

    Google Scholar 

  23. Teo K, Yusuf S, Furberg C. Effect of antiarrhythmic drug therapy on mortality following myocardial infarction. Circulation 1990;82 (Suppl 4):III197.

    Google Scholar 

  24. Greene HL, Roden DM, Katz RJ, et al. The cardiac arrhythmia suppression trial: First CAST ... then CAST II. J Am Coll Cardiol 1992;19:894–898.

    Google Scholar 

  25. Hoffman BF, Rosen MR. Cellular mechanisms for cardiac arrhythmias. Circ Res 1981;49:1–15.

    Google Scholar 

  26. Campbell TJ. Proarrhythmic actions of antiarrhythmic drugs: A review. Aust NZ J Med 1990;20:275–282.

    Google Scholar 

  27. Spinelli W, Hoffman BF. Mechanisms of termination of reentrant atrial arrhythmias by Class I and Class II antiarrhythmic agents. Circ Res 1989;65:1565–1579.

    Google Scholar 

  28. Boersma L, Brugada J, Kirchhof C, Allessie M. Drug-induced acceleration of reentrant ventricular tachycardia by double wave reentry: Importance of the wavelength (abstract). Eur Heart J 1991;12 (Suppl):146.

    Google Scholar 

  29. Starmer CF, Lastra AA, Nesterenko VV, Grant AO. Proarrhythmic response to sodium channel blockade: Theoretical model and numerical experiments. Circulation 1991;84: 1364–1377.

    Google Scholar 

  30. Wald RW, Waxman MB, Downar E. The effect of antiarrhythmic drugs on depressed conductions and unidirectional block in sheep Purkinje fibers. Circ Res 1980;46:612–619.

    Google Scholar 

  31. Brugada J, Boersma L, Abdollah H, et al. Echo-wave termination of reentrant ventricular tachycardia (abstract). Eur Heart J 1991;12 (Suppl):84.

    Google Scholar 

  32. Wit AL, Rosen MR. Pathophysiologic mechanisms of cardiac arrhythmias. Am Heart J 1983;106:798–811.

    Google Scholar 

  33. Hondeghem LM. Antiarrhythmic agents: Modulated receptor applications. Circulation 1987;75:514–520.

    Google Scholar 

  34. Brugada J, Boersma L, Kirchhof C, Allessie M. Proarrhythmic effects of flecainide: experimental evidence for increased susceptibility to reentrant arrhythmias. Circulation 1991;84:1808–1818.

    Google Scholar 

  35. Cooper MT, Krall R, Moddrelle D, Anderson KP. Proarrhythmic effects of flecainide acetate in the normal canine heart. Aust NZ J Med 1991;21:546.

    Google Scholar 

  36. Jackman WM, Friday KJ, Anderson JL, et al. The long QT syndromes: A critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988;31:115–172.

    Google Scholar 

  37. Lui HK, Lee G, Dietrich P, et al. Flecainide-induced QT prolongation and ventricular tachycardia. Am Heart J 1982;103:567–569.

    Google Scholar 

  38. Hemsworth PD, Campbell TJ. Depression of maximum rate of depolarization of guinea-pig ventricular action potentials by metabolites of encainide. Br J Pharmacol 1989;97: 619–625.

    Google Scholar 

  39. January CT, Riddle JM. Early afterdepolarizations: Mechanism of induction and block. A role for L-type Ca2+ current. Circ Res 1989;64:977–990.

    Google Scholar 

  40. Hondeghem LM, Katzung BG. Antiarrhythmic agents: The modulated receptor mechanism of actions of sodium and calcium channel-blocking drugs. Ann Rev Pharmacol Toxicol 1984;24:387–423.

    Google Scholar 

  41. Kodama I, Toyama J, Takanaka C, Jamada K. Block of activated and inactivated sodium channels by class-I antiarrhythmic drugs studied by using the maximum upstroke velocity (Vmax) of action in guinea-pig cardiac muscles. J Mol Cell Cardiol 1987;19:367–377.

    Google Scholar 

  42. Toyama J, Honjo H, Kamiya K, et al. Classification of Class I drugs on the basis of the modulated receptor concept. In: Toyama J, Hondeghem LM, eds. Current topics in antiarrhythmic agents. Tokyo: Excerpta Medica, 1989:175–188.

    Google Scholar 

  43. Campbell TJ, Hemsworth PD. Selective depression of maximum rate of depolarization of guinea-pig ventricular action potentials by amiodarone and lignocaine in simulated ischaemia: Comparison with encainide. Clin Exp Pharm Physiol 1990;17:135–145.

    Google Scholar 

  44. Campbell TJ, Wyse KR, Hemsworth PD. Effects of hyperkalemia, acidosis, and hypoxia on the depression of maximum rate of depolarization by class I antiarrhythmic drugs in guinea-pig myocardium: Differential actions of class Ib and Ic agents. J Cardiovasc Pharmacol 1991;18:51–59.

    Google Scholar 

  45. Nakaya Y, Elharrar V, Surawicz B. Effect of mexiletine, amiodarone and disopyramide on cardiac excitability and refractoriness. Cardiovasc Drugs Ther 1987;1:141–153.

    Google Scholar 

  46. Pallandi RT, Campbell TJ. Resting and rate-dependent depression of Vmax of guinea-pig ventricular action potentials by amiodarone and desethylamiodarone. Br J Pharmacol 1987;92:97–103.

    Google Scholar 

  47. Mason JW, Hondeghem LM, Katzung BG. Block of inactivated sodium channels and of depolarization-induced automaticity in guinea-pig papillary muscle by amiodarone. Circ Res 1984;55:277–285.

    Google Scholar 

  48. Man RYK, Dresel PE. A specific effect of lidocaine and tocainide on ventricular conduction of mid-range extrasystoles. J Cardiovasc Pharmacol 1979;1:329–342.

    Google Scholar 

  49. Ranger S, Talajic M, Lemery R, et al. Kinetics of use-dependent ventricular conduction slowing by antiarrhythmic drugs in humans. Circulation 1991;83:1987–1994.

    Google Scholar 

  50. Hondeghem LM, Synders 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;81:686–690.

    Google Scholar 

  51. Cobbe SM. Sotalol. In: Vaughan Williams EM, Campbell TJ, eds. Antiarrhythmic drugs. Berlin: Springer-Verlag, 1989:365–387.

    Google Scholar 

  52. Wittig J, Harrison LA, Wallace AG. Electrophysiological effects of lidocaine on distal Purkinje fibers of canine heart. Am Heart J 1973;86:69–78.

    Google Scholar 

  53. Vaughan Williams EM. Some factors that influence the activity of antiarrhythmic drugs. Br Heart J 1978;40 (Suppl):52–61.

    Google Scholar 

  54. Impact Research Group. International Mexiletine and Placebo Antiarrhythmic Coronary Trial: I. Report on arrhythmia and other findings. J Am Coll Cardiol 1984;4:1148–1163.

    Google Scholar 

  55. Burkart F, Pfisterer M, Kiowski W, et al. Effect of antiarrhythmic therapy on mortality in survivors of myocardial infarction with asymptomatic complex ventricular arrhythmias: Basel Antiarrhythmic Study of Infarct Survival (BASIS). J Am Coll Cardiol 1990;16:1711–1718.

    Google Scholar 

  56. Ross DL, Cooper MJ, Davis LM, et al. Comparison of amiodarone and sotalol in the long term treatment of ventricular tachyarrhythmias based on coronary artery disease. Aust NZ J Med 1991;21:545.

    Google Scholar 

  57. Colatsky TJ, Follmer CH, Starmer CF. Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias. Circulation 1990;82:2235–2242.

    Google Scholar 

  58. Echt DS, Black JN, Barbey JT, et al. Evaluation of antiarrhythmic drugs on defibrillation energy requirements in dogs. Sodium channel block and action potential prolongation. Circulation 1989;79:1106–1117.

    Google Scholar 

  59. Dorian P, Fain ES, Davy JM, Winkle RA. Lidocaine causes a reversible, concentration-dependent increase in defibrillation energy requirements. J Am Coll Cardiol 1986;8: 327–332.

    Google Scholar 

  60. Hernandez R, Mann ME, Breckinridge S, et al. Effects of flecainide on defibrillation thresholds in the anesthetized dog. J Am Coll Cardiol 1989;14:777–781.

    Google Scholar 

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  1. Department of Cardiology, St. Vincent's Hospital, Sydney, Australia

    Terence J. Campbell

  2. Department of Clinical Pharmacology, St. Vincent's Hospital, Sydney, Australia

    Terence J. Campbell

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Campbell, T.J. Subclassification of Class I antiarrhythmic drugs: Enhanced relevance after CAST. Cardiovasc Drug Ther 6, 519–528 (1992). https://doi.org/10.1007/BF00055611

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