From the Guidelines
Ranolazine primarily works by inhibiting the late sodium current (late INa) in cardiac cells, which prevents intracellular sodium and calcium overload, thereby improving diastolic relaxation, decreasing myocardial oxygen consumption, and enhancing myocardial perfusion, particularly in ischemic areas. This mechanism of action is supported by the most recent and highest quality study available, which suggests that ranolazine exerts its antianginal effects without reducing heart rate or blood pressure 1.
The exact mechanism of action of ranolazine is complex and involves multiple pathways, including the promotion of glucose oxidation and the inhibition of the late sodium current, which reduces the deleterious effects of intracellular sodium and calcium overload that accompany myocardial ischemia 1. The therapeutic concentration needed to reduce calcium overload is similar to that at which an increase in glucose oxidation was observed, suggesting a potential link between these two mechanisms 1.
Some studies have suggested that ranolazine may have additional benefits, such as reducing the incidence of recurrent ischemia and improving exercise duration in patients with chronic angina 1. However, the primary mechanism of action of ranolazine remains the inhibition of the late sodium current, which is supported by the most recent and highest quality evidence available 1.
In terms of dosing, the recommended initial dose of ranolazine is 500 mg orally twice daily, which can be escalated as needed to a maximum of 1000 mg twice daily 1. The extended-release formulation is preferred for consistent blood levels, and ranolazine can be safely administered for symptom relief after UA/NSTEMI, although it does not appear to significantly improve the underlying disease substrate 1.
Overall, the mechanism of action of ranolazine is complex and multifaceted, but the inhibition of the late sodium current remains the primary mechanism by which it exerts its antianginal effects. This is supported by the most recent and highest quality evidence available, and ranolazine remains a useful add-on therapy for chronic angina when other medications are insufficient or poorly tolerated.
Key points about ranolazine include:
- Inhibition of the late sodium current (late INa) in cardiac cells
- Prevention of intracellular sodium and calcium overload
- Improvement of diastolic relaxation, decrease of myocardial oxygen consumption, and enhancement of myocardial perfusion
- Antianginal effects without reducing heart rate or blood pressure
- Recommended initial dose of 500 mg orally twice daily, with a maximum dose of 1000 mg twice daily
- Extended-release formulation preferred for consistent blood levels
- Safe administration for symptom relief after UA/NSTEMI, although it does not appear to significantly improve the underlying disease substrate.
From the FDA Drug Label
The mechanism of action of ranolazine’s antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, a measure of myocardial work, at maximal exercise Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (I Na). However, the relationship of this inhibition to angina symptoms is uncertain.
The cellular mechanism of action of Ranolazine is not fully determined, but it is known to have anti-ischemic and antianginal effects that do not depend on reductions in heart rate or blood pressure. Ranolazine inhibits the cardiac late sodium current (I Na) at therapeutic levels, but the relationship of this inhibition to angina symptoms is uncertain 2.
From the Research
Cellular Mechanism of Action of Ranolazine
The cellular mechanism of action of Ranolazine involves the inhibition of the late sodium current, which reduces sodium-dependent intracellular calcium overload during ischemia and reperfusion 3, 4, 5. This mechanism is unique compared to traditional antianginal drugs, which typically decrease heart rate and/or blood pressure levels or the inotropic status of the left ventricle to decrease myocardial oxygen consumption.
Key Effects of Ranolazine
- Reduces ion deregulation and prevents cellular calcium overload 3
- Decreases diastolic tension without impacting heart rate and blood pressure 3
- Improves exercise tolerance and reduces ischemic symptoms in patients with chronic angina 3, 5
- Reduces the frequency of angina attacks and improves quality of life 4, 5
Comparison with Traditional Antianginal Drugs
Ranolazine has a different mechanism of action compared to traditional antianginal drugs, such as beta-blockers and nitrates, which affect blood pressure or heart rates 4, 5. Ranolazine's unique mechanism of action makes it a useful therapeutic option for patients with chronic stable angina who are symptomatic despite optimal anti-ischemic therapy or intolerant to traditional anti-ischemic drugs 3, 5.