Ranolazine

Ranolazine, sold under the trade name Ranexa™ by CV Therapeutics, is an antianginal medication. On January 31, 2006, ranolazine was approved for use in the United States by the FDA for the treatment of chronic angina.^[1]

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Mechanism of action

Ranolazine is believed to have its effects via altering the trans-cellular late sodium current. It is by altering the intracellular sodium level that ranolazine affects the sodium-dependent calcium channels during myocardial ischemia.^[2] Thus, ranolazine indirectly prevents the calcium overload that causes cardiac ischemia.^[3]

Indications for use

Ranolazine is indicated for use in the treatment of chronic stable angina in individuals with angina which is refractory to more standard anti-anginal medications. It has been shown to decrease angina episodes in individuals with coronary artery disease on maximal doses of amlodipine.^[4] In addition, it has been shown to both decrease angina episodes and increase exercise tolerance in individuals taking concomitant atenolol, amlodipine, or diltiazem.^[5]

Unlike other antianginal medications such as nitrates and beta blockers, ranolazine does not significantly alter either the heart rate or blood pressure. For this reason, it is of particular use in individuals with angina that is refractory to maximal tolerated doses of other anti-anginal medications.

While it would seem from the mechanism of action that ranolazine may be of benefit in individuals with non-ST-elevation acute coronary syndromes and acute myocardial infarction (heart attack), the recently completed Merlin/TIMI-36 trial showed no benefit in this population.^[6]

Contraindications

Ranolazine is known to increase the QT interval on the electrocardiogram. While the mean increase in the QTc is approximately 6 msec, about 5 percent of individuals may have QTc prologations of 15 msec or longer.^[7]

Because of this, caution should be used when ranolazine is used in combination with other medications that increase the QT interval. In addition, because the effect of ranolazine on the QT interval is increased in the setting of liver dysfunction, it is contraindicated in the setting of mild, moderate, or severe liver disease.^[1]

Metabolism

Ranolazine is metabolized in the liver, particularly by one of the cytochrome CYP3A enzymes, a member of the cytochrome P450 system.^[8]

Drug interactions

While ranolazine is not significantly metabolized by cytochrome CYP2D6, it does inhibit this enzyme.^[8] Because of this, the doses of medications metabolized by cytochrome CYP2D6 may need to be reduced to prevent toxicity.

Drugs that may interact with ranolazine include:^[9]

• Digoxin
• Simvastatin (Zocor)
• Cyclosporine (Gengraf, Neoral, Restasis, Sandimmune)
• various antidepressant medicines
• Inhibitors of cytochrome CYP3A, including:
  • Diltiazem
  • Verapamil
  • Ketoconazole and other azole antifungals
  • Macrolide antibiotics
  • Ritonavir (Norvir)
  • Grapefruit products or grapefruit juice
• QTc prolonging drugs, including:
  • Class Ia antiarrhythmic agents (eg, quinidine)
  • Class III antiarrhythmic agents (eg, dofetilide, sotalol)
  • Certain antipsychotics (eg, thioridazine, ziprasidone)

While caution should be used when administrating ranolazine in combination with any of the above medications, some combinations may be considered relatively safe. For instance, in the CARISA trial, ranolazine was used in individuals taking diltiazem without any adverse events attributable to the combination.^[5]

References