Klinisch-pharmakologisches und elektrophysiologisches Profil von Dronedaron

Zusammenfassung

Dronedaron ist ein Benzofuranderivat, das strukturell mit Amiodaron verwandt ist, aber keine Jodkomponente enthält. Die Entwicklung der Substanz erfolgte mit dem Ziel, die antiarrhythmische Potenz von Amiodaron zu erhalten, aber die extrakardialen Nebenwirkungen dieses Medikaments zu reduzieren. Dronedaron ist weniger lipophil als Amiodaron. Dies führt unter anderem zu einer wesentlich kürzeren Zeit bis zum Erreichen des Fließgleichgewichts (Steady State, 4 – 8 Tage statt 1 – 3 Wochen unter Amiodaron) bzw. einer rascheren Elimination (Halbwertszeit 25 – 30 Stunden). Die hier berichteten in vitro und in vivo dokumentierten elektrophysiologischen Eigenschaften von Dronedaron ähneln denen von Amiodaron. Dronedaron hat antiarrhythmische Eigenschaften aller 4 Vaughan-Williams-Klassen. So blockiert es unter anderem Natriumkanäle bei höherer Stimulationsfrequenz, verlängert das kardiale Aktionspotential und hat Eigenschaften eines Kalziumkanalblockers. Außerdem zeigt Dronedaron nicht-kompetitive antiadrenerge Eigenschaften. Die antiarrhythmische Wirkung lässt mit steigender Herzfrequenz nicht nach (keine „reverse-use dependence”Diese Effekte erklären die antiarrhythmischen und frequenzstabilisierenden Eigenschaften von Dronedaron bei Patienten mit Vorhofflimmern.

Abstract

Dronedarone is a benzofuran derivative structurally similar to amiodarone but non-iodinated. The agent was systematically developed with the aim to maintain the antiarrhythmic potency of amiodarone while reducing the extracardiac side effects of the drug. Dronedarone is less lipophilic compared to the mother compound, which manifests in a substantial lower time to steady state (4 – 8 days compared to 1 – 3 weeks with amiodarone), and a more rapid elimination (half life 25 – 30 hours). Dronedarone has antiarrhythmic properties of all Vaughan-Williams classes. Among other channel blocking effects, It blocks sodium ion channels at higher stimulation frequency, prolongs the cardiac action potential, and has properties of a calcium channel blocker. Further, dronedarone has non-competitive antiadrenegic effects. No reverse use dependence has been documented at higher heart rate. These effects explain the antiarrhythmic and rate control properties of dronedarone in patients with atrial fibrillation.

Schlüsselwörter

Antiarrhythmika - Vorhofflimmern - Klinische Pharmakologie - Elektrophysiologie

Keywords

antiarrhythmics - atrial fibrillation/flutter - clinical pharmacology - electrophysiology

Literatur

• 1 Aimond F, Beck L, Gautier P. et al . Cellular and in vivo electrophysiological effects of dronedarone in normal and postmyocardial infarcted rats.  J Pharmacol Exp Ther. 2000;  292 415-424
• 2 Altomare C, Barbuti A, Viscomi C. et al . Effects of dronedarone on acetylcholine-activated current in rabbit SAN cells.  Br J Pharmacol. 2000;  130 1315-20
• 3 Celestino D, Medei E, Moro S. et al . Acute in vitro effects of dronedarone, an iodine-free derivative, and amiodarone, on the rabbit sinoatrial node automaticity: a comparative study.  J Cardiovasc Pharmacol Ther. 2007;  12 248-257
• 4 Chatelain P, Meysmans L, Matteazzi J R. et al . Interaction of the antiarrhythmic agents SR 33 589 and amiodarone with the beta-adrenoceptor and adenylate cyclase in rat heart.  Br J Pharmacol. 1995;  116 1949-1956
• 5 Damy T, Pousset F, Caplain H. et al . Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects.  Fundam Clin Pharmacol. 2004;  18 113-123
• 6 Djandjighian L, Planchenault J, Finance O. et al . Hemodynamic and antiadrenergic effects of dronedarone and amiodarone in animals with a healed myocardial infarction.  J Cardiovasc Pharmacol. 2000;  36 376-383
• 7 Doggrell S A, Hancox J C. Dronedarone: an amiodarone analogue.  Expert Opin Investig Drugs. 2004;  13 415-426
• 8 Finance O, Manning A, Chatelain P. Effects of a new amiodarone-like agent, SR 33 589, in comparison to amiodarone, D,L-sotalol, and lignocaine, on ischemia-induced ventricular arrhythmias in anesthetized pigs.  J Cardiovasc Pharmacol. 1995;  26 570-576
• 9 Fuster V, Ryden L E, Cannom D S. et al . ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation).  J Am Coll Cardiol. 2006;  48 e149-246
• 10 Gautier P, Guillemare E, Marion A, Bertrand J P, Tourneur Y, Nisato D. Electrophysiologic characterization of dronedarone in guinea pig ventricular cells.  J Cardiovasc Pharmacol. 2003;  41 191-202
• 11 Go A S, Hylek E M, Phillips K A. et al . Prevalence of Diagnosed Atrial Fibrillation in Adults: National Implications for Rhythm Management and Stroke Prevention: the AnTicoagulation and Risk Factors In Atrial Fibrillation (ATRIA) Study.  JAMA. 2001;  285 2370-2375
• 12 Guillemare E, Marion A, Nisato D, Gautier P. Inhibitory effects of dronedarone on muscarinic K+ current in guinea pig atrial cells.  J Cardiovasc Pharmacol. 2000;  36 802-805
• 13 Hodeige D, Heyndrickx J P, Chatelain P, Manning A. SR 33 589, a new amiodarone-like antiarrhythmic agent: anti-adrenoceptor activity in anaesthetized and conscious dogs.  Eur J Pharmacol. 1995;  279 25-32
• 14 Kathofer S, Thomas D, Karle C A. The novel antiarrhythmic drug dronedarone: comparison with amiodarone.  Cardiovasc Drug Rev. 2005;  23 217-230
• 15 Kober L, Torp-Pedersen C, McMurray J JV. et al . Increased Mortality after Dronedarone Therapy for Severe Heart Failure.  N Engl J Med. 2008;  358 2678-2687
• 16 Kowey P. Preliminary data show dronedarone safer alternative to amiodarone. Late-breaking clinal trial session. 25. Jahrestagung der Heart Rhythm Society. San Francisco; 2004
• 17 Lalevee N, Nargeot J, Barrere-Lemaire S. et al . Effects of amiodarone and dronedarone on voltage-dependent sodium current in human cardiomyocytes.  J Cardiovasc Electrophysiol. 2003;  14 885-890
• 18 Laughlin J C, Kowey P R. Dronedarone: a new treatment for atrial fibrillation.  J Cardiovasc Electrophysiol. 2008;  19 1220-1226
• 19 Manning A, Thisse V, Hodeige D. et al . SR 33 589, a new amiodarone-like antiarrhythmic agent: electrophysiological effects in anesthetized dogs.  J Cardiovasc Pharmacol. 1995;  25 252-261
• 20 Manning A S, Bruyninckx C, Ramboux J, Chatelain P. SR 33 589, a new amiodarone-like agent: effect on ischemia- and reperfusion-induced arrhythmias in anesthetized rats.  J Cardiovasc Pharmacol. 1995;  26 453-461
• 21 Naccarelli G V, Wolbrette D L, Khan M. et al . Old and new antiarrhythmic drugs for converting and maintaining sinus rhythm in atrial fibrillation: comparative efficacy and results of trials.  Am J Cardiol. 2003;  91 15D-26D
• 22 Patel C, Yan G -X, Kowey P R. Dronedarone.  Circulation. 2009;  120 636-644
• 23 Pitt A D, Fernandes C, Bewick N L. et al . Chronic amiodarone-induced inhibition of the Na+-K+ pump in rabbit cardiac myocytes is thyroid-dependent: comparison with dronedarone.  Cardiovasc Res. 2003;  57 101-108
• 24 Rochetaing A, Barbe C, Kreher P. Beneficial effects of amiodarone and dronedarone (SR 33589b), when applied during low-flow ischemia, on arrhythmia and functional parameters asssessed during reperfusion in isolated rat hearts.  J Cardiovasc Pharmacol. 2001;  38 500-511
• 25 Sanofi-Aventis .Multaq (dronedarone) briefing document for the Advisory Committee meeting of the Cardiovascular and Renal Drugs Division of the US Food and Drug Administration, March 18, 2009. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM134981.pdf (Zugriff am 4.3.2010)
• 26 Sanofi-Aventis .Fachinformation Multaq 400 mg Filmtabletten. Stand Dezember 2009. http://www.fachinformation.de (Zugriff am 4.3.2010)
• 27 Singh B N, Connolly S J, Crijns H J. et al . Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter.  N Engl J Med. 2007;  357 987-999
• 28 Sun W, Sarma J S, Singh B N. Electrophysiological effects of dronedarone (SR33589), a noniodinated benzofuran derivative, in the rabbit heart: comparison with amiodarone.  Circulation. 1999;  100 2276-2281
• 29 Sun W, Sarma J S, Singh B N. Chronic and acute effects of dronedarone on the action potential of rabbit atrial muscle preparations: comparison with amiodarone.  J Cardiovasc Pharmacol. 2002;  39 677-684
• 30 Thomas D, Kathofer S, Zhang W. et al . Acute effects of dronedarone on both components of the cardiac delayed rectifier K+ current, HERG and KvLQT1/minK potassium channels.  Br J Pharmacol. 2003;  140 996-1002
• 31 Touboul P, Brugada J, Capucci A, Crijns H J, Edvardsson N, Hohnloser S H. Dronedarone for prevention of atrial fibrillation: a dose-ranging study.  Eur Heart J. 2003;  24 1481-1487
• 32 van Opstal J M, Schoenmakers M, Verduyn S C. et al . Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome.  Circulation. 2001;  104 2722-2727
• 33 Varro A, Takacs J, Nemeth M. et al . Electrophysiological effects of dronedarone (SR 33 589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone.  Br J Pharmacol. 2001;  133 625-634
• 34 Verduyn S C, Vos M A, Leunissen H D. et al . Evaluation of the acute electrophysiologic effects of intravenous dronedarone, an amiodarone-like agent, with special emphasis on ventricular repolarization and acquired torsade de pointes arrhythmias.  J Cardiovasc Pharmacol. 1999;  33 212-222
• 35 Zareba K M. Dronedarone: a new antiarrhythmic agent.  Drugs Today (Barc). 2006;  42 75-86
• 36 European Medicines Agency (EMEA) .Assessment report for Multaq. http://www.ema.europa.eu/humandocs/PDFs/EPAR/multaq/h-1043en6.pdf (Zugriff am 4.3.2010)