Therapeutic use of ibutilide
- Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA
Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA
- Professor of Medicine
- Director, Center for Women’s Health
- Columbia University Medical Center
Ibutilide is a class III antiarrhythmic drug available only for intravenous use for the termination of atrial arrhythmias. An oral form is not available because of extensive first-pass metabolism .
The physiology and pharmacology of ibutilide use and the side effects that can occur will be reviewed here. The pharmacokinetics of ibutilide, drug interactions, and the various clinical settings in which ibutilide might be used are discussed in detail separately.
MECHANISMS OF ACTION
Cellular mechanisms — Like other class III antiarrhythmic agents (table 1), ibutilide prolongs repolarization in atrial and ventricular myocardium [1,2]. The class III drugs block IKr, the rapid component of the cardiac delayed rectifier potassium current. This results in prolonged repolarization, increased action potential duration, and lengthening of the refractory period . Ibutilide increases the refractoriness of atrial and ventricular myocardium, the atrioventricular node, His-Purkinje system, and accessory pathway . In addition, ibutilide activates a slow, delayed inward sodium current that occurs early during repolarization [1,4]. (See "Myocardial action potential and action of antiarrhythmic drugs" and 'Major side effects' below.)
Effects on the ECG — Ibutilide has two major effects on the electrocardiogram (ECG): it produces mild slowing of the sinus rate and, as with other class III antiarrhythmic drugs, prolongation of the QT interval. There is no effect on the PR interval or QRS duration.
The degree of QT prolongation associated with ibutilide is related to the dose, the rate of infusion, and the serum concentration . Prolongation of the QT interval provides the substrate for torsades de pointes (TdP), a polymorphic ventricular tachycardia. The QT interval returns to baseline within two to four hours after stopping the infusion. (See 'Proarrhythmia' below and 'Discontinuing ibutilide infusion' below.)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Murray KT. Ibutilide. Circulation 1998; 97:493.
- Cimini MG, Brunden MN, Gibson JK. Effects of ibutilide fumarate, a novel antiarrhythmic agent, and its enantiomers on isolated rabbit myocardium. Eur J Pharmacol 1992; 222:93.
- Glatter KA, Dorostkar PC, Yang Y, et al. Electrophysiological effects of ibutilide in patients with accessory pathways. Circulation 2001; 104:1933.
- Lee KS. Ibutilide, a new compound with potent class III antiarrhythmic activity, activates a slow inward Na+ current in guinea pig ventricular cells. J Pharmacol Exp Ther 1992; 262:99.
- Buchanan LV, Kabell G, Brunden MN, Gibson JK. 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.
- Yang T, Snyders DJ, Roden DM. Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (IKr) in AT-1 cells. Concentration-, time-, voltage-, and use-dependent effects. Circulation 1995; 91:1799.
- Yang T, Roden DM. Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence. Circulation 1996; 93:407.
- January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline 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 Heart Rhythm Society. Circulation 2014; 130:e199.
- Vos MA, Golitsyn SR, Stangl K, et al. Superiority of ibutilide (a new class III agent) over DL-sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart 1998; 79:568.
- Ellenbogen KA, Stambler BS, Wood MA, et al. Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study. J Am Coll Cardiol 1996; 28:130.
- Abi-Mansour P, Carberry PA, McCowan RJ, et al. Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and atrial fibrillation. Study Investigators. Am Heart J 1998; 136:632.
- Glatter K, Yang Y, Chatterjee K, et al. Chemical cardioversion of atrial fibrillation or flutter with ibutilide in patients receiving amiodarone therapy. Circulation 2001; 103:253.
- VanderLugt JT, Mattioni T, Denker S, et al. Efficacy and safety of ibutilide fumarate for the conversion of atrial arrhythmias after cardiac surgery. Circulation 1999; 100:369.
- Tallaj JA, Franco V, Rayburn BK, et al. Safety and efficacy of ibutilide in heart transplant recipients. J Heart Lung Transplant 2009; 28:505.
- Gowda RM, Khan IA, Punukollu G, et al. Use of ibutilide for cardioversion of recent-onset atrial fibrillation and flutter in elderly. Am J Ther 2004; 11:95.
- Stambler BS, Wood MA, Ellenbogen KA, et al. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators. Circulation 1996; 94:1613.
- Hoyer AW, Balaji S. The safety and efficacy of ibutilide in children and in patients with congenital heart disease. Pacing Clin Electrophysiol 2007; 30:1003.
- Fragakis N, Bikias A, Delithanasis I, et al. Acute beta-adrenoceptor blockade improves efficacy of ibutilide in conversion of atrial fibrillation with a rapid ventricular rate. Europace 2009; 11:70.
- Korantzopoulos P, Kolettis TM, Papathanasiou A, et al. Propafenone added to ibutilide increases conversion rates of persistent atrial fibrillation. Heart 2006; 92:631.
- Tercius AJ, Kluger J, Coleman CI, White CM. Intravenous magnesium sulfate enhances the ability of intravenous ibutilide to successfully convert atrial fibrillation or flutter. Pacing Clin Electrophysiol 2007; 30:1331.
- Patsilinakos S, Christou A, Kafkas N, et al. Effect of high doses of magnesium on converting ibutilide to a safe and more effective agent. Am J Cardiol 2010; 106:673.
- Gowda RM, Khan IA, Punukollu G, et al. Female preponderance in ibutilide-induced torsade de pointes. Int J Cardiol 2004; 95:219.
- Chiladakis JA, Kalogeropoulos A, Patsouras N, Manolis AS. Ibutilide added to propafenone for the conversion of atrial fibrillation and atrial flutter. J Am Coll Cardiol 2004; 44:859.
- Hongo RH, Themistoclakis S, Raviele A, et al. Use of ibutilide in cardioversion of patients with atrial fibrillation or atrial flutter treated with class IC agents. J Am Coll Cardiol 2004; 44:864.
- Stambler BS, Beckman KJ, Kadish AH, et al. Acute hemodynamic effects of intravenous ibutilide in patients with or without reduced left ventricular function. Am J Cardiol 1997; 80:458.
- MECHANISMS OF ACTION
- Cellular mechanisms
- Effects on the ECG
- Mechanism of proarrhythmic effect
- CLINICAL USES
- Atrial fibrillation
- Atrial flutter
- Ibutilide in children and in patients with congenital heart disease
- Chemical cardioversion of atrial fibrillation or flutter with ibutilide and other antiarrhythmic drugs
- - Patients receiving amiodarone
- - Patients receiving propafenone
- Role of magnesium
- MAJOR SIDE EFFECTS
- Other cardiac toxicities
- Hemodynamic effects
- Discontinuing ibutilide infusion
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS