Farmacología clínica de la ranolazina, un nuevo fármaco en el tratamiento de la angina crónica estable
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.
- SourceAvailable from: pcommed.com[Show abstract] [Hide abstract]
ABSTRACT: The anti-anginal efficacy and safety of ranolazine in diabetic and non-diabetic patients included in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial (JAMA 2004;291:309) were studied. Glycaemic control was also assessed in CARISA and its long-term open-label extension study. Patients with chronic angina enrolled in CARISA (189 with diabetes, 634 without diabetes) on background atenolol, diltiazem, or amlodipine therapy were randomized to placebo, ranolazine 750 or 1000 mg twice daily for 12 weeks, during which exercise tolerance, angina frequency, nitroglycerin usage, glucose, HbA(1c), and lipids were measured. Patients completing the randomized study could enroll in an ongoing open-label extension study and were evaluated every 3 months. Ranolazine produced similar improvements in exercise parameters, nitroglycerin use, and angina frequency in diabetic and non-diabetic patients. Adverse events were similar between groups. Fasting glucose and lipids remained unaltered in diabetic patients after 12 weeks of therapy. In a post hoc analysis, ranolazine 750 and 1000 mg reduced HbA(1c) vs. placebo by 0.48+/-0.18% (P=0.008) and 0.70+/-0.18% (P=0.0002), respectively; the HbA(1c) levels appeared to remain unchanged over time during long-term therapy. Anti-anginal efficacy and safety of ranolazine for angina were similar between diabetic and non-diabetic patients. Ranolazine significantly improved glycaemic control in diabetic patients.European Heart Journal 02/2006; 27(1):42-8. DOI:10.1093/eurheartj/ehi495 · 14.72 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Ranolazine is a novel anti-ischemic drug that prolongs the QT interval. To evaluate the potential mechanisms and consequences, we studied: (i) Ranolazine's effects on HERG and IsK currents in Xenopus oocytes with two-electrode voltage clamp; (ii) effects of ranolazine, compared to d-sotalol, on effective refractory period (ERP), QT interval and ventricular rhythm in a dog model of acquired long QT syndrome; and (iii) effects on selected native currents in canine atrial myocytes with whole-cell patch-clamp technique. Ranolazine inhibited HERG and IsK currents with different potencies. HERG was inhibited with an IC(50) of 106 micromol l(-1), whereas the IC(50) for IsK was 1.7 mmol l(-1). d-Sotalol caused reverse use-dependent ERP and QT interval prolongation, whereas ranolazine produced modest, nonsignificant increases that plateaued at submaximal doses. Neither drug affected QRS duration. d-Sotalol had clear proarrhythmic effects, with all d-sotalol-treated dogs developing torsades de pointes (TdP) ventricular tachyarrhythmias, of which they ultimately died. In contrast, ranolazine did not generate TdP. Effects on I(Kr) and I(Ks) were similar to those on HERG and IsK. Ranolazine blocked I(Ca) with an IC(50) of approximately 300 micromol l(-1). I(Na) was unaffected. We conclude that ranolazine inhibits I(Kr) by blocking HERG currents, inhibits I(Ca) at slightly larger concentrations, and has modest and self-limited effects on the QT interval. Unlike d-sotalol, ranolazine does not cause TdP in a dog model. The greater safety of ranolazine may be due to its ability to inhibit I(Ca) at concentrations only slightly larger than those that inhibit I(Kr), thus producing offsetting effects on repolarization.
- [Show abstract] [Hide abstract]
ABSTRACT: Angina affects approximately 6.4 million Americans with stable coronary disease (CAD) (1). Currently available antianginal agents in the U.S. include beta-blockers, calcium-channel blockers, and long-acting nitrates (LANs) (2 and 3). Despite treatment with conventional agents and/or revascularization, many patients remain symptomatic. One year after coronary artery bypass grafting or percutaneous coronary intervention, 25% to 60% of patients continue to have angina and require antianginal medication (4 and 5). Conventional pharmacologic therapies exert an anti-ischemic effect by lowering determinants of myocardial O2 demand (heart rate, myocardial contractility, or wall stress). Although combination regimens of conventional antianginal therapies may provide incremental efficacy (6, 7, 8 and 9), such combination regimens may lead to excessive side effects (10, 11 and 12) or to a decrease in anti-ischemic efficacy (13).Journal of the American College of Cardiology 08/2006; 48(3):566-75. DOI:10.1016/j.jacc.2006.05.044 · 15.34 Impact Factor