Ranolazine reduces anginal episodes by a mechanism independent of heart rate or blood pressure lowering. It acts by inhibiting:

• A Mitochondrial fatty acid beta-oxidation shifting metabolism toward glucose oxidation
• B L-type calcium channels in ventricular myocytes directly reducing contractility
• C Adenosine A2A receptors mediating coronary vasoconstriction under ischemic conditions
• D Late inward sodium current (late INa) preventing Na+-driven Ca2+ overload via NCX ✓

Explanation

Ranolazine inhibits the late (persistent) inward sodium current (late INa) that is abnormally increased in ischemic myocardium. This late INa causes intracellular Na+ accumulation; elevated intracellular Na+ reverses the Na+/Ca2+ exchanger (NCX) direction, loading the cell with Ca2+ and impairing diastolic relaxation. By blocking late INa, ranolazine reduces Ca2+ overload, improves myocardial relaxation (lusitropy), and reduces ischemia-related stiffness without altering heart rate or blood pressure. This makes it uniquely effective as add-on therapy in patients already on maximal antianginal dosing.

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

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Written and medically reviewed by the StethoPrep medical team.