Ibutilide

Abstract

Ibutilide is the first ‘pure’ class III antiarrhythmic drug to become available. Its predominant action is prolongation of the myocardial action potential duration. This appears to be achieved by a unique ionic mechanism of action that involves activation of a late inward sodium current and possibly blockade of the rapidly activating component of the cardiac delayed rectifier potassium current. Intravenous ibutilide 0.01 to 0.025 mg/kg or 1 to 2mg successfully converted atrial flutter or fibrillation to sinus rhythm in 33 to 49% of patients in 2 placebo-controlled trials involving 439 patients with sustained arrhythmia. In a third trial in 300 patients who developed atrial flutter or fibrillation after cardiac surgery, ibutilide 2mg successfully converted the arrhythmia in 57% of patients. The mean times to conversion were ≤30 minutes in these trials. In 3 comparative trials, ibutilide was significantly more effective than racemic sotalol or procainamide in terminating atrial flutter or fibrillation. The pretreatment duration of the arrhythmia is an important predictor of the success of ibutilide treatment; the greatest conversion rates are achieved when the arrhythmia is of recent onset (i.e. ≤ 30 days’ duration). Ibutilide is more effective in terminating atrial flutter than atrial fibrillation. Adverse events associated with ibutilide are predominantly cardiovascular. Sustained polymorphic ventricular tachycardia developed in 1.7%, and non-sustained polymorphic ventricular tachycardia in 2.7%, of 586 patients treated with ibutilide in clinical trials. However, no proarrhythmia-related deaths have been reported with the use of ibutilide. The drug has minimal haemodynamic effects and is associated with few noncardiovascular adverse events. Thus, ibutilide is a useful agent for the pharmacological cardioversion of recent-onset atrial fibrillation or flutter, provided that adequate steps are taken to monitor for proarrhythmic events. The drug causes few noncardiovascular adverse events and has minimal haemodynamic effects. Furthermore, it appears to be more effective than procainamide (especially in patients with atrial flutter) and racemic sotalol. Ibutilide is a pure class III antiarrhythmic agent that acts predominantly by prolonging myocardial action potential duration. However, the exact ionic mechanisms by which this is achieved remain controversial. In isolated guinea-pig ventricular cells, prolongation of action potential duration by ibutilide 10⁻⁸mol/L is associated with activation of a slow inward sodium current, which is not seen with other class III agents. Ibutilide also blocks the rapidly activating component of the cardiac delayed rectifier potassium current in vitro, but it is not yet clear how much this contributes to the antiarrhythmic activity of the drug. At concentrations of more than 10⁻⁷ mol/L, ibutilide has been reported to increase an outward potassium current. In vitro and in vivo studies have demonstrated that ibutilide significantly prolongs the action potential duration and effective refractory period in the atria and ventricles, whereas conduction velocity is only modestly affected. Ibutilide does not affect myocardial contractility. No reverse use-dependence was observed in studies in isolated rabbit myocardium or in dogs. In electrocardiographic studies involving healthy volunteers and patients with atrial fibrillation or flutter, ibutilide dose-dependently prolonged the rate-corrected QT (QT_C) interval, indicating prolongation of repolarisation of the ventricles. Ibutilide did not significantly affect the PR or QRS intervals. Conversion of atrial flutter to sinus rhythm in patients treated with ibutilide was associated with an increase in beat-to-beat atrial flutter cycle length variability. Pharmacokinetic data from studies in healthy volunteers indicate that intravenous ibutilide has a large volume of distribution and a clearance value that approximates hepatic blood flow. The mean elimination half-life was 5.7 to 8.8 hours after administration of intravenous ibutilide 0.01 or 0.03 mg/kg as a 10-minute infusion, or 0.01 to 0.1 mg/kg as an 8-hour infusion, to 42 healthy volunteers. Approximately 40% of ibutilide is protein bound in plasma. The drug undergoes extensive first-pass metabolism. Consequently the oral bioavailability of ibutilide is very low. Only 1 of 8 identified metabolites has been shown to have class III electrophysiological activity, but it is not present in sufficient concentrations to contribute significantly to the clinical effects of ibutilide. Ibutilide is mainly excreted in the urine, predominantly as metabolites. In patients with atrial fibrillation or flutter, the pharmacokinetics of ibutilide are not significantly altered by the type of arrhythmia or patient age or gender. The clearance of ibutilide appears to be independent of creatinine clearance and left ventricular ejection fraction in such patients. Sustained atrial fibrillation or flutter was successfully converted to sinus rhythm in 33 to 49% of patients who were treated with intravenous ibutilide 0.01 to 0.025 mg/kg or 1 to 2mg in 2 placebo-controlled trials involving a total of 439 patients. Administration of intravenous ibutilide 0.005 mg/kg was no more effective than placebo. In a third 300-patient trial that specifically involved patients who developed atrial flutter or fibrillation after cardiac surgery, the arrhythmia was converted in 57% of patients treated with ibutilide 2mg. The mean times to arrhythmia termination in ibutilide recipients in these studies were 30 minutes or less. In a large comparative trial involving 319 patients, intravenous ibutilide (1 to 2mg) was significantly more effective than racemic sotalol (1.5 mg/kg) in terminating atrial fibrillation or flutter. In 2 smaller studies, intravenous ibutilide (0.005 to 0.025 mg/kg or 2mg) was superior to procainamide...