Ranolazine reduces anginal episodes by a mechanism largely independent of heart rate or blood pressure reduction. Its anti-ischemic effect is primarily attributed to:

• A Inhibition of late sodium current (late INa), reducing intracellular calcium overload ✓
• B Selective inhibition of mitochondrial fatty acid oxidation, shifting metabolism to glucose
• C Allosteric activation of adenosine A1 receptors causing metabolic preconditioning
• D Blockade of voltage-gated T-type calcium channels in coronary smooth muscle

Explanation

Ranolazine's primary anti-ischemic mechanism is inhibition of the late (persistent) inward sodium current (late INa). During ischemia, late INa becomes pathologically upregulated, leading to intracellular Na+ accumulation; this reverses the Na+/Ca2+ exchanger, causing calcium overload, impaired relaxation, increased wall tension, and worsened ischemia. Ranolazine by blocking late INa breaks this cycle, improving diastolic relaxation and microvascular flow without haemodynamic effects. Although ranolazine also inhibits fatty acid oxidation at higher concentrations (earlier hypothesis), the late INa mechanism is now confirmed as the primary mechanism. T-type calcium channel blockade and adenosine receptor effects are not ranolazine's mechanism.

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

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Written and medically reviewed by the StethoPrep medical team.