Table 1: Cardiovascular response to sustained handgrip

• Inhibits the late sodium channels, not only lowering total inward sodium flux but also the subsequent intracellular calcium overload.

• Reduces the late inward calcium current, the inward Na+/Ca2+ exchange current, and the outward repolarizing, delayed rectifier potassium current. • Peak plasma levels occur 4-6 hours after an oral dose, with 50%-55% bioavailability.

• Cleared by the hepatic enzymes CYP3A4 (70%-85%) and CYP2D6 (10%-15%) and is also a substrate of P-glycoprotein, a widely expressed membrane transporter protein.

Clinical drug interactions of importance

• Ketoconazole significantly raises ranolazine levels up to4.5-fold

• Diltiazem, due to mild CYP3A4 inhibition, may raise ranolazine levels 1.5-fold.

• Paroxetine may raise plasma ranolazine concentrations by a factor of 1.2 because of CYP2D6 inhibition.

• Ranolazine may nearly double levels of simvastatin since it is a mild inhibitor of both CYP3A4 and

• CYP2D6. Simultaneous administration of CYP3A4inhibitors together with some statins remains a clinical concern.

• verapamil may raise ranolazine levels upto 3-fold.

• Digoxin levels may rise 1.4-1.6-fold because ofP- glycoprotein competition by ranolazine.

• Ranolazine may prolong the rate-corrected QT interval, about 6msec at a dose of 2g/d.