Vernakalant: A Novel Agent for the Termination of Atrial Fibrillation

Miki Finnin

Disclosures

Am J Health Syst Pharm. 2010;67(14):1157-1164. 

In This Article

Pharmacology

Vernakalant blocks sodium channels, and this action varies with heart rate and membrane potential. At low heart rates and negative membrane resting potentials, vernakalant is a weak blocker of the activated sodium channel (INa).[13] As the heart rate increases, the affinity of vernakalant for INa also increases and leads to greater INa blockade and a fast onset of drug action. In addition, vernakalant demonstrates a quick offset of binding, which is very attractive in an antiarrhythmic drug once the heart rate slows and the INa blockade is no longer required.[13,31] Regarding membrane potentials, normal atria have a resting membrane potential of approximately – 70 to – 80 mV, which is about 10 mV more positive than that of the ventricles. In AF, as the atria fail to fully repolarize, the difference in resting membrane potential between the atria and ventricles increases. This accentuated difference in membrane potential is thought to play a part in vernakalant's selectivity in blocking sodium channels in the atria and diseased tissue as opposed to the normal ventricles.[13]

Much more prominent in vernakalant's mechanism of action is its ability to block certain potassium channels. Specifically, it blocks the atrial-selective potassium current, IKur, which is involved in atrial repolarization. In addition, at low concentrations, vernakalant blocks the other atrial-selective potassium current, IKACh, resulting in a lengthening of the action potential duration and prolongation of the atrial action potential plateau.[13,16] Finally, vernakalant also blocks the channel Ito, which is involved more with atrial than ventricular refractoriness, and—as occurs with sodium channel blockade—this blockade increases as the heart rate increases.[13] This particular mechanism renders vernakalant unique as compared with most other antiarrhythmic agents, which exhibit reverse use dependence (i.e., they prolong the action potential at normal heart rates but lose effectiveness as the heart rate increases). Vernakalant also partially blocks the hERG channel (an underlying current of IKr), an action that prolongs the Q-T interval and may produce ventricular tachyarrhythmias. However, this blockade is at a minimal level, and there is no conclusive electrophysiological or clinical evidence that this occurs at target vernakalant concentrations.[31]

The electrophysiological effects of intravenous vernakalant were studied in a Phase I clinical trial involving 10 healthy subjects.[32] Vernakalant hydrochloride was given at a dose of 2 mg/kg i.v. over 10 minutes, followed by a 35-minute infusion of 0.5 mg/kg/hr. The drug prolonged the atrial refractory period and atrioventricular (AV) nodal conduction but had no effect on ventricular cells or AV nodal refractoriness. In a Phase II trial, 19 patients being evaluated or treated for cardiac arrhythmias were enrolled for a dose-comparison electrophysiological study.[33] The effects seen with a dose of 2 mg/kg over 10 minutes followed by an infusion of 0.5 mg/kg/hr over 35 minutes were compared with the effects of a dose of 4 mg/kg over 10 minutes followed by an infusion of 1 mg/kg/hr over 35 minutes. Like the aforementioned Phase I trial, this trial resulted in a dose-dependent prolongation of the atrial effective refractory period and had no effect on ventricular effective refractoriness. Unlike the Phase I trial, however, this study showed a small but significant prolongation in AV nodal refractoriness. Although vernakalant slightly prolonged conduction through the atria, AV node, and His–Purkinje system, these effects were seen only at the higher dosage and were not statistically significant. The Q-T interval and the ventricular effective refractory period were not significantly prolonged by vernakalant administration, which led to the conclusion that vernakalant is relatively atrial selective.

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