Farmacología clínica de la ranolazina, un nuevo fármaco en el tratamiento de la angina crónica estable

Departamento de Farmacología. Facultad de Medicina. Universidad Complutense. Madrid. España.
World Pumps 06/2010; 10. DOI: 10.1016/S1131-3587(10)70014-5

ABSTRACT Ranolazine is a piperazine derivative that has a novel mechanism of action and which has been approved as add-on therapy for patients with chronic stable angina. Myocardial ischemia increases the late inward sodium ion (Na +) current in cardiac cells (INaL) and raises the intracellular sodium concentration (Na+i), which in turn activates the reverse mode of the sodium-calcium (Na+Ca2 +) exchanger and increases the intracellular calcium concentration (Ca2 + i). This increase in Na+i and Ca2 + i leads to mechanical dysfunction (i.e. diastolic pressure increases, and contractility and myocardial oxygen supply decrease), electrical dysfunction (i.e. the induction of arrhythmias) and mitochondrial dysfunction (i.e. myocardial oxygen demand increases and the rate of ATP formation decreases). Ranolazine selectively inhibits the increase in INaL, reduces intracellular Na+accumulation and the subsequent Ca2+ accumulation induced by Na+, and decreases mechanical, electrical and metabolic dysfunction in the ischemic or failing myocardium. Controlled clinical trials have shown that ranolazine has both antianginal and anti-ischemic effects in patients with chronic stable angina, and an antiarrhythmic effect in patients with acute coronary syndrome. Moreover, ranolazine reduces the glycosylated hemoglobin level in diabetic patients with coronary heart disease and improves ventricular function in patients with ischemic heart disease or chronic heart failure. Ranolazine is well tolerated, with the most common adverse effects being nausea, dizziness, asthenia and constipation. For these reasons, ranolazine is a safe and effective option for patients with chronic stable angina whose symptoms are not under control or who can not tolerate conventional anti-anginal drugs.

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    ABSTRACT: We investigated whether ranolazine therapy improves exercise-induced angina pectoris and myocardial ischemia compared with placebo or with standard doses of atenolol in patients who had chronic angina and evaluated the effects on hemodynamics at rest and during exercise. In this trial, 158 patients who had symptom-limited exercise discontinued beta-blocker therapy and were randomized into a double-blind, 3-period, crossover study of 400 mg of immediate-release ranolazine 3 times daily, 100 mg/day of atenolol, or placebo, each administered for 1 week. Exercise tests were administered at the end of each treatment period. Therapy with ranolazine or atenolol produced statistically significant improvement in all 3 exercise end points compared with placebo. Compared with atenolol therapy, ranolazine therapy resulted in significantly longer total exercise duration and was statistically indistinguishable from atenolol for time to onset of angina and ST-segment depression. Except for a modest increase in systolic blood pressure at peak exercise during ranolazine therapy, hemodynamic measurements did not differ significantly during ranolazine and placebo therapies. In contrast, atenolol significantly decreased blood pressure, heart rate, and rate-pressure product at rest and during exercise compared with placebo or ranolazine. In conclusion, ranolazine therapy prolonged exercise duration and decreased exercise-induced ischemia and angina with quantitative effects equal to or greater than those with atenolol. Unlike atenolol, the anti-ischemic and antianginal effects of ranolazine occurred without decreases in blood pressure, heart rate, or rate-pressure product.
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