Mechanism of Action of Ranolazine

Primary Electrophysiologic Mechanism

Ranolazine inhibits the late sodium current (INa) in cardiac myocytes, preventing intracellular calcium overload during ischemia, which reduces left‑ventricular wall tension without altering heart rate or blood pressure. 1, 2
The inhibition of the late sodium current is concentration‑dependent, voltage‑dependent, and frequency‑dependent. 1, 3, 4
By blocking late sodium influx, Ranolazine prevents the cascade of intracellular sodium accumulation that would otherwise lead to calcium overload via the sodium‑calcium exchanger. 1, 2
Prevention of calcium overload lowers left‑ventricular wall tension and myocardial oxygen demand, providing the most plausible explanation for Ranolazine’s anti‑anginal effects. 1, 3, 5
Unlike traditional anti‑anginal agents (e.g., beta‑blockers, calcium‑channel blockers), Ranolazine does not reduce heart rate or blood pressure, preserving hemodynamic stability. 2, 6

Ranolazine promotes glucose oxidation and improves anaerobic metabolism under ischemic conditions, a metabolic shift similar to that produced by trimetazidine. 1, 3, 4
The therapeutic concentration required to reduce calcium overload is comparable to the concentration that enhances glucose oxidation, suggesting synergistic anti‑ischemic mechanisms. 1, 5

The neutral hemodynamic profile makes Ranolazine especially useful for patients with bradycardia, hypotension, or heart failure who cannot tolerate traditional anti‑anginal drugs. 1, 7, 8
Ranolazine may be more effective in patients with left‑ventricular hypertrophy because its actions on sodium current and calcium homeostasis address the pathophysiology of hypertrophied myocardium. 1, 5, 7