The localized expression of the “funny” current If in the SA node and its important role in pacemaker activity provide an attractive therapeutic target for heart rate control. Ivabradine is a selective blocker of If. It slows pacemaker activity by decreasing diastolic depolarization of sinus node cells. It is an open channel blocker that shows use-dependent block. Unlike other heart rate-lowering agents such as β blockers, it reduces heart rate without affecting myocardial contractility, ventricular repolarization, or intracardiac conduction. At therapeutic concentrations, block of If is not complete. As a result, autonomic control of the sinus node pacemaker rate is retained.
Elevated heart rate is an important determinant of the ischemic threshold in patients with coronary artery disease and a prognostic indicator in patients with congestive heart failure. Antianginal and anti-ischemic effects of ivabradine have been demonstrated in patients with coronary artery disease and chronic stable angina. In controlled clinical trials, ivabradine proved as effective as β blockers in the control of angina. In patients with left ventricular dysfunction and heart rates greater than 70 bpm, ivabradine reduced mean heart rate and the composite end points of cardiovascular mortality and hospitalization.
Inappropriate sinus tachycardia is an uncommon disorder characterized by multiple symptoms, including palpitations, dizziness, orthostatic intolerance, and elevated heart rates. Conventional treatment includes β blockers and nondihydropyridine calcium channel blockers. Recent case reports and one clinical trial have shown that ivabradine provides an effective alternative to slow the heart rate in patients with inappropriate sinus tachycardia. The drug is administered in doses of 5–10 mg as needed. Visual disturbances attributable to the block of the If channels in the retina have been described. This side effect is limited by the low permeability of ivabradine in the blood-brain barrier. Ivabradine is in use elsewhere but is currently approved only for use in heart failure in the USA.
Ranolazine was originally developed as an antianginal agent. Subsequent studies have demonstrated antiarrhythmic properties that are dependent on the blockade of multiple ion channels. The drug blocks the early INa and the late component of the Na+ current, INaL, the latter having a tenfold higher sensitivity to the drug. The block of both components of the sodium current is frequencyand voltage-dependent. Ranolazine also blocks the rapid component of the delayed rectifier K+ current IKr. The blockade of both INaL and IKr results in opposing effects on the APD; the net effect depends on the relative contribution of INaL and IKr to the APD. In normal ventricular myocytes, the net effect is prolongation of the APD and the QT interval. In myocytes isolated from mice bearing long QT-associated mutations, the net effect is APD shortening. In normal atrial myocytes, the net effect is prolongation of the APD. At rapid rates, eg, during tachycardia, the atrial action potential arises from the incompletely repolarized membrane and results in voltage-dependent reduction of INa. Ranolazine has relatively little effect on ICa and the remaining K+ currents at therapeutic concentrations.
Ranolazine had been shown to have antiarrhythmic properties in both atrial and ventricular arrhythmias. It prevents the induction of and may terminate atrial fibrillation. It is currently undergoing clinical trials in combination with dronedarone for the suppression of atrial fibrillation. Ranolazine has been shown to suppress ventricular tachycardia in ischemic models and in a major clinical trial of its effects in coronary artery disease. The drug has not yet received FDA approval as an antiarrhythmic drug.