New antiarrhythmia drugs

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1 ıœ fl» Œ Î «Î ª «Ì Hyung Wook Park, MD Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Korea New antiarrhythmia drugs ABSTRACT Antiarrhythmia drugs are designed to maintain sinus rhythm, prevent arrhythmia, and modulate ion channel function. Several classification of these drugs have been developed, mostly according to the targeted protein. One drug developmental strategy is to find tissue-specific ion channel s that are devoid of proarrhythmogenic risks. Treating ventricular arrhythmia is problematic, despite the development of implantable cardioverter-defibrillators. The currently available pharmacologic agents have limited efficacy and/or carry a risk of side effects. A major obstacle in the development of novel antiarrhythmia drugs is related to the complexity of electrical signaling, which in turn introduces safety concerns. Classic antiarrhythmia drugs are of limited effectiveness and post the risk of lifethreatening ventricular tachycardia/ventricular fibrillation. Very few antiarrhythmia drugs have been successful in the last few decades due to safety concerns or limited benefits in comparison with those of existing therapies. New antiarrhythmia drugs, such as atrial-specific and/or multichannel s, upstream therapy, and anti-remodeling drugs, are emerging. The different mechanisms of action of antiarrhythmia drugs may increase the therapeutic options available for the safe treatment of arrhythmia in a wide variety of pathophysiological situations. Key words: antiarrhythmia drug ion channel ıœó Œ «fl Î Õ Ÿÿ ÃÁÓffi Á,» œè µ ø Œ Œ «flã ˆ µ «Ì Ÿ. Œ Î Œ à Ό«Û œì, º fl «ª Ø Á, Received: April 08, 2012 Accepted: August 15, 2012 Correspondence: Hyung Wook Park, MD, Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Korea Tel: , Fax: , mdhwp@chol.com ˆÎº Ô Ô œ ø ffi Õ Œ ffi Ÿ. à ÿ Œ Ÿ«Â Ì, µ µ ˆ Ø Œß«Ô ª Ô œ Õ ª Ò Œ Ÿ. œˆ ÃØ Ò Ê Ûµ Œ à «Ì ÿ, Í- Ú Ã Û Œ Ø ˆ«Ì Ÿ flœ ßffi, Øà «Ì à œ«ó Ú Ã Û «ø ª π œ Ó ÏÁ ߌ Ì Œ Ϊ œ»ÿ. ı fl» Œ «Ã ˆ œì fl µ ªÙ«Â ÃØß. Ÿ fl«ì È Ò Œ œ Œ, «23

2 Ø, à Ό«flˆ µ fiû ŸÁ à Ό Îœ ßffi «Œ ʃ Œ œ Ó Ÿ. ˆÁ flã fl» È ª Ø Û œè ŸΩ Ÿ. Class IIIŒ «ıœó 1. Azimilide I Kr I Ks current ø œá, ʺø øˆ I Kr Ÿıø ß. à Á ÿ I Kr «Ã œá I Ks Õ Ÿ à Ό«Ã ÛÎ Œ ı œ ßffiß. ŸÊˆı «Ã œ» Ø 3,717̪ ÎÛ Œ» ALE (Azimilide Post-Infarct Survival Evaluation) 1, ıœó ʺø fl ª Ì ø ø Ø Ù Á ø ˆ Ÿ. ˆ ʺøª ÎÛ Œ A-STAR (Supraventricualr Tachy- Arrhythmia Reduction), A-COMET I, II (Cardioversion Maintenance Trial) ffi«œ ø È œ Ÿ. œ Œ ÁÎ«Ì Ÿ. Ÿ Œ Œ «Û Îœ ÁΫreverse use-dependent I Kr ÎŒ ß. Ê«Øø  Á, 1 ê«Ê ø 75% ø ø Ø«ˆ ʺ ø ø Ø ø È œÿ Dronedarone Amiodarone Ø Ã ÎŒ Îœˆ iodine Ó Œ Îà œá, I Kur, I Ks, I Kr, I to, I K1 ª Ô Ÿ. ATHENA appleá ÎÛ Ø Á ª ˆ Œ Ø ÎÛ Œ ANDROMEDA (Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease), PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy) «ÊÏ dronedarone ÁÎ Á à ı œ fl «Ÿ. Û Œ Ã, «Ã œ«ó Ø ÁÎÿ»»Ÿ. Œ Î ŸÌ À ffi amiodarone Òœ ø È Ï œˆ Ÿ Tedisamil Amiodarone صº I Kr, I to, I KATP Ó Ø ffi ÎŒ œá gap junction ª Î µõ µ ı ʺø «ª Ô œ ø Ÿ. Ê, «appleœ Îœˆ Ê Î Îà ı œÿ. œá 8~14 ß. 2 Ω ı Œ fl«œ ø Ωà ٠Ÿ. 1. Celivarone ffi, L-type ffi, ffi (I Kr, I Ks, I KACh ), -1 à Ό Î Ÿ. Ò Ê ØÃ Ã Ó Êºø ÊÛ ª ø ø Œ Øœ πêø Ÿ. -Á «ºø µ ø Ÿ. 3. Nifekalant 2. Budiodarone (ATI-2042) I Kr «œ Œ nifekalant œª fl» Œ œá, apple ºø (implantable cardioverter-defibrillator, ICD) apple Ø electrical storm fl ª Ô œ ø Ó amiodarone Ê Œ ı œá, 7 µœ Ì, à amiodarone Òœ œÿ. Amiodarone iodineª ØœÌ Ÿ. ø apple Ø Êºø «Ûµ Î flãÿ. 24 The Official Journal of Korean Heart Rhythm Society

3 3. PM101 Amiodarone ØÁ Ϊ ffiì Ÿ. ı œì, Î Ã Á Òffi Ÿ. Phase I æ» Û ÃŸ. Ê Á ÿ- Â Ê Á ÿ-  (atrial repolarizationdelaying drugs)«êï Î Œ I Kr Œ dofetilide, ibutilide Òœ Á» Ê ı ø ÃÁ, Û ø ø Øø Ùª Õ Œ Î«Ì Ÿ. 1. Vernakalant Âπ» flœ ÃÁ œì, Ê ºø«ø ø Øà œÿ. I Kur û ΠÈ I to, I na Ô ÎÃ Ì I Kr à I Ks Î «Ÿ. CRAFT (Controlled Randomized Atrial Fibrillation Trial), ACT (Atrial arrhythmia Con-version Trial) I- Ó 7œÃ ʺø«ø ø Ø 70% µãÿ. Ø ıœfl ʺø«ø ØÒ ŒÁÎœ ΫÁ, Ãπ À Ë(regulatory review) Ÿ Ê Á ÿ-  Table 1 Ê Á ÿ-  ffiœ Ÿ. ffi ÎŒ 1. Pilsicainide  ˆ µ à «Ÿ. Ÿ class Ic Õ Ò ø Õ Œ Ϊ ffiì Ÿ. 2. Ranolazine MERLIN-TIMI 36 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-elevation acute coronary syndrome-thrombolysis In Myocardial Infarction 36), ß Òœ Òˆ Û ı«ÿ. ƒ I Na «Ô ÃÁ, ıø µ Ÿ. ıœó «È 1. Ê I KACh Ô Ê «Ÿº Â Û ŸÁ à Όȫ, Á Ÿ Ÿ. I Kur, I KACh, I KAde Ê πã œ ʺø«πÊ ø ø Ø Ò ª ßœ fl «Ì Ÿ. Ê ± ffi à Ό Œ AZD 7009, AVE-0118, AVE-1231, Xen-D0101, ISQ-1, NIP-142 Ó Èà Ÿ. œœ ʺ Øà Œ ffi ÎŒ µ Îœ Õ Œ À ffi Table 1. Atrial repolarization-delaying drugs Agent Mode of action Route Limitations Vernakalant (RSD1235) I Kur, I to, I na, I Kr and oral High conversion efficacy limited to AF <72h; moderately effective in AF of <7 days; ineffective in atrial flutter AZD7009 I Na, I Kr, I kur, I to Potent I Kr blockade, QT prolongation and torsades de pointes AVE0118 I Kur, I to, I KACh Potential QT prolongation S9947 and S20951 I Kur Potential QT prolongation NIP-141/142 I Kur, I to, I KACh, I CaL Multiple-channel ; insufficient data XEN-D0101/1 I Kur and oral Insufficient data 25

4 Ÿ. Tertiapin I KACh Õ CA (constitutively active), I KACh appleœ Ô œ Ê ÂœÌ, ʺø fl ª Ô Ÿ. «Â Ê Øà M2 ˆÎº Œ cisatracurium Œ Ê Œ Œ ø ß ª πê Ÿ. I KACh «ÃØ Ã ÎŒ  µ Ÿ  πã œ «Œ Œ Î fl à Ÿ Õß Ca 2+ Overload º ª ffi à Ÿ Œ fl fl ª œ ˆ, Î Œ ffi Ê (class V) «Û Œ πê Îà ÃÃœŸ. à œ Œ ffi Ê Â Ø Ã Ã Ÿ ª Î Îà œ ßffiß. ffi -ffi Ø ffi -ˆ Ø Î fl«ì ÃÈ Ã ÎŒ«Ê «Ã fiû Ê Øà Œ «πê Ò Œ fl«ì Ÿ. ffi ffi Ø Ô Œ SEA0400, KB-R7943, SN-6, YM Õ Èà Ÿ. œœ digitalis Œ µ ø Ÿ. ffi -ˆ Ø Ô Œ cariporide Õ FR Á - Œ Øà ß. Gap Junction Modifier 1. Rotigaptide Gap junctionª Î µ ± ÃÎ apple«õ fi apple ʺøª Ô œ Ÿ. Ø Œ Ã Ê Ì «Êºø Ô œˆ œ Ÿ. 30 Late I Na Ito 1 I Kur 2 mv 0 0 I Na I CaL IKr 3 I K1 I KAch I K1-80 I KAch NCX ms 4 Inhibitors at therapeutic concentrations I KAch I K1 I Na I to I Cal I Kur I Ks I Kr NCX I f NIP-151, NIP141/142, AVE0118, celivarone Dronedarone Vernakalant, tedisamil, dronedarone, celivarone, ATI-2042, pilsicainide, ranolazine (late I Na ), AZD7009, NIP141/142 Vernakalant, tedisamil, dronedarone, AVE0118, AZD7009 JTV519, vernakalant, dronedarone, celivarone, ranolazine, NIP141/142 Vernakalant, XEN D0101, dronedarone, AVE0118, AVE1231, AZD7009, ATI-2042, NIP141/142 HMR1556 (selective), azimilide, dronedarone, celivarone, ATI-2042 Tedisamil, dronedarone, nifekalant, celivarone, ATI-2042, vernakalant, AZD7009 KB-R7943, SEA0400, ranolazine, SN-6, dronedarone Ivabradine, propafenone Figure 1. Ion currents determining the action potential and the occurrence of each current in relation to the action potential. The majority of new antiarrhythmia drugs block several ion currents. 26 The Official Journal of Korean Heart Rhythm Society

5 ıœó Œ ÎŒ Ã Ø Ã ÎŒ ø Œ ÔÌ Á, Øà Œ Œ ø Ò Œ fl«ì Ÿ. ÃÈ Œ Œ Ϊ œì ø ÿî œ ßœ fl«ˆáóˆ «π à Ÿ. «, Á ª πêœì Ô œ ß È Óˆ ø Î «ffiã πã ˆ, ıœó Êß«œ Œ «Ì Ó Œ π π ß(Figure 1). References 1. Camm AJ, Karam R, Pratt CM. The azimilide post-infarct survival evaluation (ALE) trial. Am J Cardiol. 1998;81: Hohnloser SH, Dorian P, Straub M, Beckmann K, Kowey P. Safety and efficacy of intravenously administered tedisamil for rapid conversion of recent-onset atrial fibrillation or atrial flutter. J Am Coll Cardiol. 2004;44: Morita N, Tanaka K, Yodogawa K, Hayashi M, Akutsu K, Yamamoto T, Satoh N, Kobayashi Y, Katoh T, Takano T. Effect of nifekalant for acute conversion of atrial flutter: the possible termination mechanism of typical atrial flutter. Pacing Clin Electrophysiol. 2007;30: Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, Avezum Á, Blomström P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A, Davy JM, Delacrétaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S, Gonzalez- Hermosillo A, Granger CB, Heidbüchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L, Tomcsányi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH; PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011;365: Camm AJ, Capucci A, Hohnloser SH, Torp-Pedersen C, Van Gelder IC, Mangal B, Beatch G; AVRO Investigators. A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol. 2011;57: Cha TJ, Ehrlich JR, Chartier D, Qi XY, Xiao L, Nattel S. Kir3-based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias. Circulation. 2006;113: