What is the mechanism of action of Ranolazine?

Mechanism of Action of Ranolazine

Ranolazine primarily works through concentration-dependent, voltage-dependent, and frequency-dependent inhibition of the late sodium current (late INa), which prevents intracellular calcium overload during ischemia. 1, 2

Primary Mechanism of Action

Ranolazine has a dual mechanism of action that contributes to its antianginal effects:

1. Inhibition of Late Sodium Current

   • Ranolazine selectively inhibits the persistent or late sodium current (INa) 3
   • By inhibiting late sodium efflux, ranolazine prevents intracellular calcium overload 1
   • This inhibition is:
     • Concentration-dependent
     • Voltage-dependent
     • Frequency-dependent 1, 3

2. Metabolic Effects

   • Promotes glucose oxidation, similar to trimetazidine 1
   • Improves anaerobic metabolism under ischemic conditions 1
   • The therapeutic concentration needed for calcium overload reduction is similar to that required for increased glucose oxidation 1

Physiological Effects

• Reduction in Calcium Overload: By inhibiting late INa, ranolazine decreases sodium-dependent intracellular calcium accumulation during ischemia 4
• Reduced Left Ventricular Wall Tension: Prevention of calcium overload during ischemia leads to reduced oxygen demand 1
• QT Interval Prolongation: Inhibition of IKr prolongs ventricular action potential, resulting in QT prolongation 2

Clinical Effects

• Hemodynamic Profile: Unlike traditional antianginals, ranolazine exerts antianginal effects without significantly affecting:

  • Heart rate (minimal changes <2 bpm)
  • Blood pressure (minimal changes <3 mmHg)
  • Myocardial perfusion 1, 2, 5

• Antiarrhythmic Effects: Ranolazine demonstrates potential antiarrhythmic properties by:

  • Reducing ventricular tachycardia
  • Decreasing supraventricular tachycardia
  • Reducing new-onset atrial fibrillation 6

• Post-Ischemic Recovery: Ranolazine improves recovery of myocardial function after ischemia/reperfusion by reducing calcium overload 7, 4

Important Clinical Considerations

• QT Prolongation: Ranolazine causes dose-related QT interval prolongation, though torsades de pointes has not been observed at therapeutic doses 1, 2

• Contraindications:

  • Hepatic impairment or liver cirrhosis (due to risk of drug accumulation and QT prolongation) 1
  • Concomitant use with strong CYP3A inhibitors 2

• Drug Interactions: Increases digoxin concentration, requiring caution when co-administered 1

• Metabolic Effects: Reduces glycated hemoglobin (HbA1c) levels in diabetic patients, though it is not considered a treatment for diabetes 1, 2