Vernakalant is a multi-ion channel blocker, placing it in several classes of antiarrhythmic action. It causes frequencyand voltage-dependent block of the early and late components of the sodium current. The muscarinic potassium current IKACh, which is constitutively activated in atrial fibrillation, is blocked by vernakalant. The early-activating potassium channels Ito and Ikur are also blocked by the drug. These potassium channel currents play a more prominent role in atrial than ventricular repolarization. As a result, vernakalant produces only mild QT-interval prolongation. It does not produce torsades de pointes. Though not yet approved by the FDA, vernakalant can be administered intravenously for the rapid termination of atrial fibrillation in patients with no or minimal structural heart disease. In a direct comparison trial, vernakalant proved more effective than placebo or amiodarone in terminating atrial fibrillation in a 90-minute period. This relatively rapid action decreases the required observation period for untoward side effects following drug administration. Sinus bradycardia and hypotension are the only noticeable cardiovascular adverse effects.
Originally used for patients with digitalis-induced arrhythmias who were hypomagnesemic, magnesium infusion has been found to have antiarrhythmic effects in some patients with normal serum magnesium levels. The mechanisms of these effects are not known, but magnesium is recognized to influence Na+/ K+-ATPase, sodium channels, certain potassium channels, and calcium channels. Magnesium therapy appears to be indicated in patients with digitalis-induced arrhythmias if hypomagnesemia is present; it is also indicated in some patients with torsades de pointes even if serum magnesium is normal. The usual dosage is 1 g (as sulfate) given intravenously over 20 minutes and repeated once if necessary. A full understanding of the action and indications for the use of magnesium as an antiarrhythmic drug awaits further investigation.
The significance of the potassium ion concentrations inside and outside the cardiac cell membrane was discussed earlier in this chapter. The effects of increasing serum K+ can be summarized as (1) a resting potential depolarizing action and (2) a membrane potential stabilizing action, the latter caused by increased potassium permeability. Hypokalemia results in an increased risk of early and delayed afterdepolarizations, and ectopic pacemaker activity, especially in the presence of digitalis. Hyperkalemia depresses ectopic pacemakers (severe hyperkalemia is required to suppress the SA node) and slows conduction. Because both insufficient and excess potassium are potentially arrhythmogenic, potassium therapy is directed toward normalizing potassium gradients and pools in the body.
Several types of chloride channels have been identified. At present, no drugs acting on chloride channels are in clinical use for cardiac indications. However, the chloride channels involved in cystic fibrosis and other conditions are of great clinical importance and have been the subject of intensive research (see Box: A Cystic Fibrosis Link in the Heart?).
The margin between efficacy and toxicity is particularly narrow for antiarrhythmic drugs. Risks and benefits must be carefully considered (see Box: Antiarrhythmic Drug-Use Principles Applied to Atrial Fibrillation).
Several important steps must be taken before initiation of any antiarrhythmic therapy: 1.
Eliminate the cause. Precipitating factors must be recognized and eliminated if possible. These include not only abnormalities of internal homeostasis, such as hypoxia or electrolyte abnormalities (especially hypokalemia or hypomagnesemia), but also drug therapy and underlying disease states such as hyperthyroidism or cardiac disease. It is important to separate this abnormal substrate from triggering factors, such as myocardial ischemia or acute cardiac dilation, which may be treatable and reversible by different means.
2.