Ranolazine is approved for chronic stable angina refractory to other agents. Unlike conventional anti-anginals, it does not reduce heart rate or blood pressure at therapeutic doses. What is its unique anti-ischemic mechanism?

• A Ranolazine is a partial fatty acid oxidation (pFAO) inhibitor that shifts myocardial metabolism from fatty acid to glucose oxidation, improving metabolic efficiency per oxygen consumed
• B Ranolazine directly activates cardiac ATP-sensitive K+ channels, inducing hyperpolarization and reducing ventricular excitability
• C Ranolazine inhibits the 'late inward sodium current' (late I-Na) in ischemic cardiomyocytes, preventing Na-driven Ca2+ overload and reducing myocardial oxygen demand ✓
• D Ranolazine inhibits adenosine deaminase, preserving adenosine-mediated coronary vasodilation during ischemia

Explanation

During myocardial ischemia, abnormal persistent (late) activation of voltage-gated sodium channels (NaV1.5) occurs, generating a late inward sodium current (late I-Na). This excess intracellular Na+ is exchanged for Ca2+ via the Na+/Ca2+ exchanger (NCX) in reverse mode, causing intracellular Ca2+ overload, which increases wall tension, impairs relaxation, and worsens ischemia. Ranolazine selectively blocks this late I-Na, preventing the Na+-driven Ca2+ overload cascade. This reduces diastolic wall tension and myocardial oxygen demand without affecting basal cardiac function. Although ranolazine was initially thought to work via fatty acid oxidation inhibition, the late I-Na inhibition is now recognized as its primary anti-ischemic mechanism.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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