ANTIARRHYTHMIC DRUGS

IBUTILIDE

Ibutilide is an antiarrhythmic drug that was recently marketed for the rapid conversion of atrial fibrillation and atrial flutter.

After intravenous administration, Ibutilide is moderately effective in acheaving prompt conversion to sinus rhythm with greater efficacy in patients who have atrial flutter.

Like other drugs that prolong ventricular repolarization, Ibutilide administration carries a risk of excessive QT prolongation, or the aquired long-QT syndrome, with associated polymorphic ventricular tachycardia (torsade de pointes) necessitating careful patient selection and clinical monitoring during drug administration.

Pharmacology

Ibutilide prolongs action potential duration by activating a slow inward current, largely carried by sodium ions.

In addition, Ibutilide blocks the rapidly activating component of the delayed rectifier potassium current (IKr).

Action potential prolongation by Ibutilide leads to an increase in atrial and ventricular refractoriness in vivo.

No significant effect on heart rate, PR interval, or QRS interval was seen in healthy volunteers.

Ibutilide administration is associated with minimal hemodynamic effects both in animal models of ischemic left ventricular dysfunction and in patients.

There has been no clinically significant effect of Ibutilide to lower blood pressure or worsen congestive heart failure in published clinical trials.

Pharmacokinetics

Ibutilide is not available for long term oral use because of extensive first pass metabolism when administered by this route.

t1/2b (h): 2 - 12 (mean: 6.0 - 8.8).

Linear Kinetics: No

Route of elimination: hepatic with 8 metabolites excreted.

Activity of metabolites vs parent drug: less than parent drug

Drug interaction

Although the metabolic pathways for Ibutilide have not been completely determined, they do not appear to involve the cytochrome P450 isoenzymes CYP3A4 or CYP2D6, suggesting that previously described drug interaction with other agents are unlikely.

Coadministration of Digoxin, calcium channel blockers or beta-adrenergic receptor blockers with Ibutilide has not apparent effect on the pharmacokinetics, safety or the efficacy of the drug in clinical trials.

Indications

Rapid conversion of atrial fibrillation and atrial flutter. It is considered by Pharmacia & Upjohn to be an effective alternative to electrical cardioversion for this indication.

Contraindications

QTc interval exceeding 440ms

Bradycardia

Electrolite disturbances

Other QT-prolonging drugs

Adverse effects

Noncardiovascular adverse effects were rare, while cardiovascular ones were more frequent.

Polymorfic ventricular tachycardia (TdP) (5.1%);

Premature ventricular complexes (5.1%)

Monomorfic ventricular tachycardia (2.7%)

Hypotension (2%);

Bundle branch block (1.9%);

Atrioventricular block (1.5%)

Hypertension (1.2%);

Palpitations (1%);

Bradycardia (1.2);

Nausea (1.9%);

Headache (3.6%).

Dosage and Administration

Ibutilide is available in 10 mL vials containing 0.1 mg/mL (1 mg total).

For intravenous administration, the recommended dose of Ibutilide is 1mg over a 10 minute period in patients weighing ³ 60 kg.

Ten minutes after the end of the initial infusion, a second 10 minute infusion of equal strenght can be given if the arrhythmia has not terminated.

For patients weighing < 60 kg, the recommended dose is 0.01 mg/kg initially, with a second dose of the same strenght 10 minutes later if necessary.

Clinical Use

Ibutilide is indicated for rapid conversion of atrial fibrillation or flutter of recent onset.

Yet, largely due to the risk of proarrhythmia, the role of Ibutilide in this clinical circumstance is not well defined at the present time.

When considering administration of Ibutilide, it is essential that patients at low risk for proarrhythmia be chosen.

Arrhythmias of recent onset, particularly atrial flutter, are more likely to be successfully terminated.

Ibutilide might be especially useful in patients with an initial episode of atrial fibrillation or flutter.

Given the need for careful observation during drug administration, Ibutilide may also find increasing use to terminate arrhythmias in patients who are already in a monitored environment, such as the surgical intensive care units, the cardiac catheterization laboratory and the electrophysiological laboratory under selected circumstances.

Undoubtedly, the clinical use of Ibutilide will become more widespread if therapeutic maneuvers can be identified (eg, prophylactic magnesium administration) that lower the proarrhythmic risk of drug administration.

References:

- K.T. Murray: Ibutilide
Circulation. 1998; 97:493-97

- Scrip 1996; Jan 19; 2095:20

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