What is Ranolazine?

What is Ranolazine?

Ranolazine is an antianginal medication that works by inhibiting the late sodium current in cardiac cells, preventing calcium overload during ischemia, and is FDA-approved for treating chronic stable angina either as monotherapy or in combination with other antianginal agents. 1, 2

Mechanism of Action

• Ranolazine primarily inhibits the late sodium current (late INa) in a concentration-dependent, voltage-dependent, and frequency-dependent manner, which prevents intracellular sodium and subsequent calcium overload during myocardial ischemia. 1

• This reduction in intracellular calcium accumulation decreases oxygen demand and left ventricular wall tension without affecting heart rate, blood pressure, or myocardial perfusion. 1

• The drug also has metabolic effects, promoting glucose oxidation and improving anaerobic metabolism under ischemic conditions. 1

• Importantly, ranolazine exerts its antianginal effects without significantly reducing heart rate (<2 bpm change) or blood pressure (<3 mm Hg change), making it particularly useful in patients with bradycardia or hypotension. 1, 3

Chemical and Pharmaceutical Properties

• Ranolazine is chemically described as 1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±)-, with a molecular weight of 427.54 g/mole. 2

• It is available as extended-release tablets in 500 mg and 1000 mg strengths for twice-daily oral administration. 2

• The drug is approximately 62% bound to plasma proteins and has an elimination half-life of approximately 7 hours for the extended-release formulation. 2, 4

Clinical Indications

• The American Heart Association recommends ranolazine at an initial dose of 500 mg orally twice daily, escalating as needed to a maximum of 1000 mg twice daily for chronic angina that has failed to respond to standard antianginal therapy. 1

• The European Society of Cardiology recommends ranolazine as add-on therapy in patients with inadequate control of chronic angina symptoms while on beta-blockers and/or calcium channel blockers (Class IIa, Level B recommendation). 1

• Ranolazine can be used as monotherapy or in combination with amlodipine, beta-blockers, or nitrates. 1

Special Populations and Considerations

• Patients with diabetes and chronic stable angina may particularly benefit from ranolazine, as it reduces glycated hemoglobin (HbA1c) levels, though it is not considered a diabetes treatment. 1, 3

• Patients with left ventricular hypertrophy may experience greater efficacy with ranolazine compared to other antianginal drugs. 1

• The drug's neutral hemodynamic profile makes it especially useful in cases of bradycardia and/or hypotension where traditional antianginal agents may be poorly tolerated. 1, 3

Important Safety Considerations

• Ranolazine causes dose-related QT interval prolongation (approximately 2.6 msec per 1000 ng/mL plasma concentration), though torsades de pointes has not been observed at therapeutic doses. 1, 3

• The drug is absolutely contraindicated in patients with hepatic impairment or liver cirrhosis, as cirrhotic patients show an 80% increase in ranolazine exposure with moderate hepatic impairment and a 3-fold increase in QT prolongation. 1, 2

• Ranolazine is contraindicated with strong CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, indinavir, saquinavir). 2

• Monitor renal function periodically in patients with moderate to severe renal impairment and discontinue if acute renal failure develops, as a pharmacokinetic study was stopped when 2 of 4 subjects with severe renal impairment developed acute renal failure. 2

• Use caution when co-administering with digoxin, as ranolazine increases digoxin concentration by 40-60% through P-glycoprotein inhibition. 1, 4

• Patients should avoid grapefruit and grapefruit juice, which can increase ranolazine blood levels. 2

Clinical Outcomes and Limitations

• Ranolazine effectively reduces angina symptoms and improves exercise tolerance but has not been shown to reduce major cardiovascular events, cardiovascular death, or myocardial infarction. 1

• In patients with non-ST-segment elevation acute coronary syndrome, ranolazine provided symptom relief but did not significantly reduce the composite of cardiovascular death, myocardial infarction, or recurrent ischemia. 1

Common Adverse Effects

• The most common adverse effects include dizziness, headache, constipation, and nausea. 5, 6

• In cases of overdose, hypotension, QT prolongation, bradycardia, myoclonic activity, severe tremor, unsteady gait, dizziness, nausea, vomiting, and hallucinations have been reported. 2