Treatment of Atrial Fibrillation and Flutter: Focus on Oral Dofetilide, a New Selective Class III Antiarrhythmic Agent

Abstract

Atrial fibrillation and atrial flutter, the most common forms of supraventricular tachyarrhythmias, are associated with a high risk of embolic complications, tachycardia-induced ventricular dysfunction, and disabling symptoms. Pharmacological therapy is used to restore or maintain sinus rhythm, prevent recurrences, or control ventricular response rate. The selection of an antiarrhythmic drug for maintenance of sinus rhythm following termination of persistent atrial fibrillation or flutter should balance clinical effectiveness against the potential for adverse events. The risk of drug-induced proarrhythmias is a pertinent safety concern, particularly in patients with underlying structural heart disease. One specific proarrhythmia, polymorphic ventricular tachycardia, commonly known as torsade de pointes, is associated with QT interval prolongation as a result of sodium and potassium channel blockade, observed with the use of class IA and III drugs, respectively. Dofetilide is a new class III antiarrhythmic drug that works by selective potassium channel blockade. As an extension of its pharmacological action, it may exhibit dose-dependent QT prolongation and torsade de pointes. This review focuses on treatment of atrial fibrillation and atrial flutter emphasizing the drug profile of oral dofetilide, its use in clinical studies, and its role in treatment of these arrhythmias.

Discovery of ((S)-5-(Methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone As a Potent and Selective IKur Inhibitor

“…Compound 5d was isolated as a white solid (38 mg, 61% yield). 1 (6). To a solution of tert-butyl 3oxobutanoate (1.2 g, 7.7 mmol) in toluene (10 mL) was added 1-(4-fluorophenyl)piperazine (1.4 g, 7.7 mmol).…”

“…The termination of AF and restoring of normal sinus rhythm (rhythm control) is typically achieved with antiarrhythmic drugs . Currently available antiarrhythmic drugs target ion channels which are expressed in the human atrium and ventricle, for example, amiodarone/dronedarone, dofetilide, flecainide, and sotalol . Inhibition of ventricular ion channels can lead to prolongation of ventricular effective refractory period and the potentially life threatening arrhythmia torsades de pointe .…”