Ranolazine – antianginal agent

Ranolazine – antianginal agent

Ranolazine, an antianginal agent, is a piperazine derivative, which has been approved in US for treatment of chronic stable angina pectoris as combination therapy when angina is not adequately controlled with conventional drugs. An extended release preparation has been developed to facilitate twice-daily administration. Therapy is initiated with 500 mg twice daily and can be increased to 1000 mg twice daily if needed.

Mechanism of action of ranolazine

The main action of ranolazine is that it blocks late sodium currents in ischemic conditions and prevents excess calcium entry into the myocardial cells. This is because the blockage of late sodium current reduces the amount of sodium available for the functioning of sodium-calcium exchanger which facilitates the entry of calcium into the cell.
In addition, ranolazine is also a partial fatty acid oxidation inhibitor, inhibiting the beta oxidation of fatty acids. This causes a shift of myocardial energy substrate from fatty acids to glucose. Anaerobic glycolysis needs less number of oxygen for production of ATP molecules. Hence shift of myocardial metabolism towards glucose utilisation is beneficial to the ischemic myocardium.

Ranolazine is hemodynamically neutral and does not produce any significant alteration in heart rate or blood pressure.

Pharmacokinetics of ranolazine

Pharmacokinetics of ranolazine is altered in mild, moderate and severe renal impairment. But mild hepatic impairment has no significant effects on pharmacokinetics of ranolazine. Moderate and severe hepatic impairment alters Cmax and AUC (area under the curve) of ranolazine. Gender, heart failure and diabetes has no effect on pharmacokinetics of ranolazine.

Effect of ranolazine on QT interval

Minor increases in QTc interval with ranolazine has been reported in MARISA and CARISA trials. Increases in QTc ranged from 6.1 to 9.2 ms. But no discontinuation of drug was required because of QTc prolongation. No cases of torsades de pointes were reported with ranolazine. The cellular electrophysiology underlying the QTc effect of ranolazine appears to be different from that of drugs known to cause torsade de pointes. Even though ranolazine does prolong action potential duration and QT interval, it has not been shown to induce early afterdepolarizations like other QT prolonging drugs. Ranolazine does not increase dispersion of ventricular repolarization. Still, it is prudent to exercise caution while using ranolazine along with other drugs which are likely to prolong the QT interval.