What are the pharmacodynamics of Ranolazine?

Pharmacodynamics of Ranolazine

Primary Mechanism of Action

Ranolazine exerts its antianginal effects primarily through inhibition of the late inward sodium current (late INa), which prevents intracellular sodium and calcium overload during myocardial ischemia, thereby reducing left ventricular diastolic tension and oxygen consumption. 1, 2, 3

• The drug works through concentration-dependent, voltage-dependent, and frequency-dependent inhibition of late INa, though the precise relationship between this inhibition and angina symptom relief remains uncertain 2, 3
• Ranolazine reduces sodium-dependent intracellular calcium accumulation during ischemia, leading to decreased oxygen demand and left ventricular wall tension 2
• The mechanism also includes metabolic effects such as promoting glucose oxidation and improving anaerobic metabolism under ischemic conditions 2

Hemodynamic Effects

Ranolazine produces minimal hemodynamic changes, with mean heart rate changes less than 2 bpm and systolic blood pressure changes less than 3 mm Hg, making it particularly useful in patients with bradycardia or hypotension. 2, 3

• The antianginal effects do not depend on reductions in heart rate or blood pressure 1, 3
• Ranolazine does not affect the rate-pressure product (a measure of myocardial work) at maximal exercise 3
• Similar minimal hemodynamic effects were observed in subgroups with CHF NYHA Class I or II, diabetes, reactive airway disease, and elderly patients 3

Electrocardiographic Effects

Ranolazine causes dose-related QTc prolongation through inhibition of the rapid delayed rectifier potassium current (IKr), which prolongs the ventricular action potential. 2, 3

• The relationship between QTc change and ranolazine plasma concentrations is linear, with a slope of approximately 2.6 msec per 1000 ng/mL 3
• At Tmax following 1000 mg twice daily dosing, the mean QTc change is about 6 msec, but in the 5% of patients with highest plasma concentrations, QTc prolongation reaches at least 15 msec 3
• In cirrhotic patients with mild or moderate hepatic impairment, the QTc-concentration relationship is much steeper, making ranolazine absolutely contraindicated in hepatic impairment or liver cirrhosis 2, 4, 3
• Despite QTc prolongation, torsades de pointes has not been observed at therapeutic doses 2

Antiarrhythmic Effects

Ranolazine demonstrates antiarrhythmic properties, with significantly lower incidence of ventricular tachycardia, supraventricular tachycardia, and new-onset atrial fibrillation compared to placebo. 5

• In 6351 patients with continuous ECG monitoring, ranolazine reduced ventricular tachycardia ≥8 beats (5.3% vs 8.3%, P<0.001), supraventricular tachycardia (44.7% vs 55.0%, P<0.001), and new-onset atrial fibrillation (1.7% vs 2.4%, P=0.08) 5
• Pauses ≥3 seconds were less frequent with ranolazine (3.1% vs 4.3%, P=0.01) 5
• However, these reductions in arrhythmias did not translate to reductions in mortality, arrhythmia hospitalization, or arrhythmia symptoms 3

Metabolic Effects

Ranolazine produces small reductions in HbA1c in patients with diabetes, though it should not be considered a treatment for diabetes. 2, 3

• The clinical significance of HbA1c reduction is unknown 3
• No dose adjustment is required in patients with diabetes 3

Critical Clinical Limitations

Despite symptom improvement, ranolazine does not improve hard cardiovascular outcomes including cardiovascular death, myocardial infarction, or mortality in patients with chronic stable angina or acute coronary syndrome. 2, 4

• The MERLIN-TIMI 36 trial in 6560 patients with NSTE-ACS showed ranolazine provided symptom relief but did not significantly reduce the composite of cardiovascular death, MI, or recurrent ischemia 1, 2
• All post hoc analyses showing benefit should be interpreted with caution since the primary endpoint was not met 1