Ranolazine, approved for refractory angina, reduces myocardial ischemia without significantly altering heart rate or blood pressure. Its primary cardioprotective mechanism involves:

• A Shifting myocardial substrate utilisation from fatty acids to glucose (partial fatty acid oxidation inhibitor)
• B Selective mitochondrial ATP-sensitive potassium (mito-KATP) channel opening, causing ischemic preconditioning
• C Inhibiting the Na+/H+ exchanger (NHE-1) in cardiomyocytes, reducing intracellular acidosis
• D Blockade of the persistent late inward sodium current (late INa), reducing intracellular Na+ and downstream Ca2+ overload ✓

Explanation

Ranolazine's primary anti-ischemic mechanism is inhibition of the late (persistent) inward sodium current (late INa) during prolonged depolarisation. During ischaemia, late INa is pathologically enhanced, causing intracellular Na+ to accumulate; the Na+/Ca2+ exchanger (NCX) then works in reverse mode, loading the cell with calcium — causing diastolic dysfunction and increased oxygen demand. By blocking late INa, ranolazine interrupts this cascade without rate/pressure changes. While ranolazine was originally thought to work as a partial fatty acid oxidation inhibitor, this is now considered secondary; late INa blockade is the principal mechanism at therapeutic plasma concentrations.

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

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Written and medically reviewed by the StethoPrep medical team.