Ranolazine's mechanism is unlike any other antianginal drug class covered so far. It does not reduce heart rate, blood pressure, or contractility at therapeutic doses, which is precisely what makes it useful as an add-on agent when those hemodynamic levers have already been maximized.
During normal heart function, sodium briefly enters cardiac muscle cells during each heartbeat and is quickly cleared. During myocardial ischemia, an abnormal "late" sodium current persists well beyond its normal brief window, allowing excess sodium to build up inside the cell. This sodium overload secondarily drives calcium into the cell as well, since the cell's normal mechanism for clearing calcium depends on a favorable sodium gradient that ischemia disrupts.
The resulting calcium overload impairs the heart muscle's ability to relax between beats, raises pressure inside the ventricle, and worsens the very ischemia that triggered the problem in the first place, a self-reinforcing cycle. Ranolazine selectively blocks this abnormal late sodium current, interrupting the cycle, improving diastolic relaxation, and reducing oxygen consumption without measurably affecting heart rate, blood pressure, or contractility.
Ranolazine is approved only as add-on therapy for patients with chronic stable angina who remain symptomatic despite adequate doses of a beta-blocker, calcium channel blocker, or nitrate. It is not used for acute angina relief, since the only available formulation is extended-release and acts too slowly. Because it has no hemodynamic effect, it is particularly useful in patients who cannot tolerate an additional heart-rate-lowering or blood-pressure-lowering agent.
Ranolazine produces mild prolongation of the corrected QT interval through weak blockade of a cardiac potassium channel, and this is the primary clinically significant adverse effect. Baseline electrocardiogram and corrected QT interval measurement are required before starting, and ranolazine is contraindicated in patients with significant baseline corrected QT interval prolongation.
