Chapter: Modern Pharmacology with Clinical Applications: Pharmacological Management of Chronic Heart Failure

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Ibutilide Fumarate

Ibutilide (Corvert) is a structural analog of sotalol and produces cardiac electrophysiological effects similar to those of the antiarrhythmic agents in class III.

Ibutilide Fumarate

Ibutilide (Corvert) is a structural analog of sotalol and produces cardiac electrophysiological effects similar to those of the antiarrhythmic agents in class III.

Electrophysiological Actions

Ibutilide prolongs action potential in isolated adult car-diac myocytes and increases both atrial and ventricular refractoriness in vivo. An additional action is blockade of outward potassium currents. Thus, ibutilide acts by blocking the rapid component of the delayed rectifier current (IKr) as well as by activation of a slow inward current carried predominantly by sodium.

Sinoatrial Node

Although there is evidence that ibutilide causes a modest slowing of the sinus rate, there is no significant change in heart rate.

Atrium

Ibutilide causes an increase in the atrial refractory period, an effect seen at rapid heart rates.

A-V Node

Ibutilide slows conduction through the A-V node; however, there is no change in the PR interval on ECG.

His-Purkinje System and Ventricular Muscle

Ibutilide increases the ERP of ventricular myocytes and Purkinje fibers but has no clinically significant ef-fect on QRS duration.

Electrocardiographic Changes

There are no changes in the PR or QRS intervals, which reflects a lack of effect on the conduction velocity. Although there is no relationship between the plasma concentration of ibutilide and its antiarrhythmic effect, there is a dose-related prolongation of the QT interval. The maximum effect on the QT interval is a function of both the dose of ibutilide and the rate of infusion.

Hemodynamic Effects

Ibutilide has no significant effects on cardiac output, mean pulmonary arterial pressure, or pulmonary capil-lary wedge pressure in patients with or without com-promised ventricular function.

Pharmacokinetics

The pharmacokinetic characteristics of ibutilide are summarized next. The pharmacokinetics are highly vari-able between patients. Because of extensive first-pass metabolism, ibutilide is not suitable for oral administra-tion.

Oral bioavailability : >90%

Onset of action : Minutes

Peak response : Minutes

Plasma half-life : 3–4 hours (range 2–12 hours)

Primary route of metabolism : Hepatic

Primary route of excretion : Renal

Therapeutic serum concentration : Not applicable

Clinical Uses

Ibutilide is approved for the chemical cardioversion of recent-onset atrial fibrillation and atrial flutter. Ibutilide appears to be more effective in terminating atrial flutter than atrial fibrillation. It can also lower the defibrilla- tion threshold for atrial fibrillation resistant to chemical cardioversion.

Adverse Effects

The major adverse effect associated with the use of ibu-tilide is the risk of torsades de pointes due to QT pro-longation. Other reported adverse cardiovascular events (all 2%) include hypotension and hyperten-sion, bradycardia and tachycardia, and varying degrees of A-V block. The incidence of noncardiac adverse events with the exception of nausea does not differ from that of placebo.

Contraindications

Contraindications to the use of ibutilide include base-line prolongation of the QT interval, use of other QT-prolonging drugs, history of torsades de pointes, hyper-sensitivity to ibutilide, uncorrected hypokalemia or hypomagnesemia, and pregnancy or breast-feeding.

Drug Interactions

Ibutilide has significant drug interactions.

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