indication

Indicated for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm.

pharmacology

Ibutilide prolongs the action potential duration and increases both atrial and ventricular refractoriness in vivo, i.e., class III electrophysiologic effects. Voltage clamp studies indicate that ibutilide, at nanomolar concentrations, delays repolarization by activation of a slow, inward current (predominantly sodium), rather than by blocking outward potassium currents, which is the mechanism by which most other class III antiarrhythmics act.

mechanism of action

Ibutilide is a 'pure' class III antiarrhythmic drug, used intravenously against atrial flutter and fibrillation. At a cellular level it exerts two main actions: induction of a persistent Na+ current sensitive to dihydropyridine Ca²⁺ channel blockers and potent inhibition of the cardiac rapid delayed rectifier K⁺ current, by binding within potassium channel pores. In other words, Ibutilide binds to and alters the activity of hERG potassium channels, delayed inward rectifier potassium (IKr) channels and L-type (dihydropyridine sensitive) calcium channels

toxicity

Acute overdose in animals results in CNS toxicity; notably, CNS depression, rapid gasping breathing, and convulsions. The intravenous median lethal dose in the rat was more than 50 mg/kg which is, on a mg/m² basis, at least 250 times the maximum recommended human dose.

biotransformation

Primarily hepatic. Eight metabolites of ibutilide were detected in metabolic profiling of urine. These metabolites are thought to be formed primarily by o-oxidation followed by sequential b-oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the o-hydroxy metabolite possesses class III electrophysiologic properties similar to that of ibutilide in an in vitro isolated rabbit myocardium model.

absorption

Rapid after intravenous injection

half life

6 hours (ranges from 2-12 hours)

route of elimination

In healthy male volunteers, about 82% of a 0.01 mg/kg dose of [14C] ibutilide fumarate was excreted in the urine (about 7% of the dose as unchanged ibutilide) and the remainder (about 19%) was recovered in the feces.

drug interactions

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Ranolazine: Possible additive effect on QT prolongation

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Trimipramine: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Voriconazole: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).