Vernakalant

VERNAKALANT

The limited success of highly specific drugs that target single ion channels and the efficacy of multi-ion channel blockers such as amiodarone have shifted the emphasis in antiarrhythmic drug development to the latter class of drugs. Vernakalant is a multi-ion channel blocker that was developed for the treatment of atrial fibrillation.

Vernakalant prolongs the atrial effective refractory period and slows conduction over the AV node. Ventricular effective refrac-tory period is unchanged. In the maximal clinical dose of 1800 mg/day, vernakalant does not change the QT interval on the ECG. Vernakalant blocks I_Kur, I_ACh, and I_to. These currents play key roles in atrial repolarization and their block accounts for the prolongation of the atrial effective refractory period. The drug is a less potent blocker of I_Kr and, as a result, produces less APD pro-longation in the ventricle; that is, the APD-prolonging effect is relatively atrium specific. Vernakalant also produces use-dependent block of the sodium channel. Recovery from block is fast, such that significant blockade is observed only at fast rates or at low membrane potentials. In the therapeutic concentration range, vernakalant has no effect on heart rate.

Toxicity

Adverse effects of vernakalant include dysgeusia (disturbance of taste), sneezing, paresthesia, cough, and hypotension.

Pharmacokinetics & Therapeutic Uses

Pharmacokinetic data for vernakalant are limited. After IV admin-istration, the drug is metabolized in the liver by CYP2D6 with a half-life of 2 hours. However, on an oral regimen of 900 mg twice daily, a sustained blood concentration was observed over a 12-hour interval. Clinical trials with the oral drug have used a twice-daily dosing regimen.

Intravenous vernakalant is effective in converting recent-onset atrial fibrillation to normal sinus rhythm in 50% of patients. Final approval for this purpose is pending. The drug is undergoing clinical trials for maintenance of normal sinus rhythm in patients with paroxysmal or persistent atrial fibrillation.