Ranolazine

• ranolazine is an antiischemic agent with novel mechanisms of action to decrease anginal frequency and to improve exercise capacity in patients with chronic stable angina.
  • basis for the improvement in myocardial ischemia appears to be inhibition of the late phase of the inward sodium current (INa) with consequent attenuation of intracellular calcium overload
  • at therapeutic concentrations, ranolazine also affects the delayed rectifier potassium current (IKr), which prolongs ventricular action potential duration (APD)
  • clinically, it has been observed in ambulatory ECG recordings from the MERLIN-TIMI 36 trial that ranolazine exerts significant antiarrhythmic effects, as evidenced by significantly fewer episodes of ventricular tachycardia
  • net effect in patients with chronic stable angina is a dose-related prolongation of the QT interval
    • therefore, for current clinical use, ranolazine is "contraindicated" in patients with preexisting QT prolongation and in combination with other QT-prolonging drugs due to concerns about possible proarrhythmias
    • shortening of action potential duration (and, possibly, antiarrhythmic effect) might be expected under conditions characterized by an abnormal increase in late INa: acute ischemia, some forms of long-QT syndrome type 3 (LQT3), and heart failure

Reference:

• 1. Scirica BM et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non–ST-segment elevation and acute coronary syndrome. Results from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2007;116:1647-1652.
• 2. Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM, Molhoek P, Verheugt FW, Gersh BJ, McCabe CH, Braunwald E: Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: Results from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation 2007;116:1647-1652.