Ranolazine  

The Drug Ranolazine is a novel antianginal and anti-ischemic agent. Most other angina medications work by decreasing heart rate, lowering blood pressure, or dilating coronary arteries, but ranolazine works via myocardial metabolic actions to reduce oxygen consumption, resulting in angina relief, making it a useful and novel treatment for chronic stable angina.

Mechanism of Action (MoA)

Inhibition of the Late Sodium Current (late INa):

In ischemic myocardial tissue, the late sodium current is pathologically upregulated, resulting in excess sodium influx into cardiac myocytes. This causes calcium overload because of sodium–calcium exchange. Increased intracellular calcium results in:

On diastole impaired relaxation.

Anything that increases tension in the myocardial wall.

Higher oxygen demand. Ranolazine blockage of this late sodium current restores ionic equilibrium and reduces myocardial oxygen demand without affecting heart rate or blood pressure.

Impact on Myocardial Efficiency:

By shifting energy production away from fatty acid oxidation into the less oxygen-consuming glucose oxidation, ranolazine may also improve myocardial energy efficiency.

Indications

Ranolazine is approved by the FDA for:

Chronic Stable Angina:

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Used as monotherapy or in combination with conventional anti-anginal drugs (e.g., beta-blockers, calcium channel antagonists, nitrates).

Off-Label Uses

Microvascular Angina:

Class III. May relieve symptoms in patients with angina without significant obstruction of coronary arteries.

Heart Failure with Preserved Ejection Fraction (HFpEF).

Use in Diastolic Function (Investigational).

Long QT Syndrome (LQT3):

May block arrhythmias in some genetic subtypes.

Atrial Fibrosis After Cardiac Surgery:

Examined for possible rhythm-stabilizing impacts.

Dosage and Administration

Available Forms

Extended-Release Tablets:

500 mg and 1000 mg tablets.

Dosing Recommendations

Initial Dose:

500 mg orally twice daily.

Maintenance Dose:

Adjustable up to 1000 mg bid according to symptom control and tolerability.

Maximum Dose:

1000 mg twice daily.

Administration Instructions

Take with or without food.

Swallow the tablets whole — do not crush, split or chew them — because that would interfere with the extended-release mechanism.

Missed Dose

If a dose is missed, do not take it, and continue to the next dose as normal. Do not double the dose.

Pharmacokinetics

Absorption:

Oral bioavailability: ~35–50%.

Time to maximum plasma concentration: ~2–5 hours.

Distribution:

Protein binding: ~62%.

Volume of distribution: ~ 85 L.

Metabolism:

Heavily metabolized in the liver by CYP3A4 (major route) and CYP2D6.

Generates many active and inactive metabolites.

Excretion:

Approximately 75% is excreted in urine ( <5% unchanged).

~25% in feces.

Half-life:

Approximately 7 hours.

Contraindications

Absolute Contraindications:

Congenital long QT interval.

Hepatic impairment (Child-pugh class C)

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Relative Contraindications:

Moderate to severe renal impairment (eGFR < 30 mL/min/1.73 m²)

Risk factors: Hypokalemia or hypomagnesemia (risk of QT prolongation)

Precautions and Monitoring

QT Prolongation:

Ranolazine-induced dose-dependent QT interval prolongation seen more in high risk populations can lead to torsades de pointes.

In patients with a high baseline risk of arrhythmias, ECG monitoring periodically

Renal Function:

Considerations for useShould not be used in patients with severe renal impairment (eGFR < 30 mL/min) Monitor renal function (particularly in patients with moderate renal impairment) — exposure to ranolazine increases in renal dysfunction.

Electrolytes:

Before starting treatment, correct any hypokalemia or hypomagnesemia.

Drug Interactions:

Do not use strong CYP3A4 inhibitors/inducers.

Be careful with other QT-prolonging agents.

Drug Interactions

Elevate the plasma levels of ranolazine, thereby heightening the potential for toxicity.

Notable examples include ketoconazole, itraconazole, and clarithromycin.

CYP3A4 Inducers:

Diminish the therapeutic efficacy of ranolazine.

Prominent examples are rifampin, phenytoin, carbamazepine, and St. John’s Wort.

CYP2D6 Substrates:

Ranolazine may elevate the plasma concentrations of CYP2D6 substrates, such as metoprolol and certain antidepressants.

QT-Prolonging Drugs:

Present an additive risk for arrhythmias.

Examples include amiodarone, sotalol, and select antipsychotics.

Side Effects

Common Adverse Effects:

– Dizziness

– Nausea

– Constipation

– Headache

Less Common but Serious Effects:

– QT prolongation, which may lead to arrhythmias.

– Syncope (episodes of fainting).

– Acute kidney injury, particularly in cases of severe renal dysfunction.

Use in Special Populations

Pregnancy:

Categorized as C. Human data is limited; should be utilized only when the benefits

significantly outweigh the risks.

Lactation:

It remains uncertain whether ranolazine is excreted in breast milk; caution is advised.

Pediatrics:

The safety and efficacy of ranolazine have not been established in this population.

Geriatrics:

No adjustment in dosage is necessary; however, close monitoring is essential due to an increased risk of QT prolongation.

Clinical Advantages

Ranolazine serves as a distinguished second-line treatment for chronic angina, particularly when first-line options such as beta–blockers and calcium channel blockers prove inadequate or are not suitable for the patient. It offers remarkable symptomatic relief while maintaining hemodynamic stability, ensuring minimal impact on heart rate and blood pressure, thus catering to a diverse patient demographic.

Comparative Analysis with Other Medications

Medication | Mechanism | Impact on BP/HR | Distinctive Feature

Ranolazine | Inhibitor of late sodium current | No notable effect | Enhances metabolic efficiency

Beta–blockers | Reduce heart rate and contractility | Lowers both | Alleviates myocardial workload

Calcium channel blockers | Induce vasodilation and lower heart rate | Lowers both | Eases coronary spasm

Nitrates | Promote vasodilation | Lowers BP (with reflex increase in HR) | Provides swift relief from angina