Ranolazine

Ranolazine is a medication used to treat chest pain associated with the heart.

Use and indications

Ranolazine is used for the treatment of chronic angina. It may be used alone or in combination with nitrates, beta-blockers, angiotensin receptor blockers, antiplatelet agents, calcium channel blockers, lipid-lowering agents, and ACE inhibitors. However, it is most commonly used as an add-on therapy when previous therapy is inadequate.

Ranolazine has also been used off-label for the treatment of certain cardiac arrhythmias, including ventricular tachycardia. However, there is insufficient scientific evidence to support this use. Ranolazine has also been studied for the treatment of acute coronary syndrome, microvascular coronary dysfunction, arrhythmias, and glycemic control, although these indications have not been approved.

Ranolazine is administered as extended-release tablets and is available in 375 mg, 500 mg and 750 mg doses. Initially, 375 mg is usually given 2 times daily. This dose may then be slowly increased. In patients: with hepatic or renal impairment, this increase should be particularly slow.

Ranolazine is available by prescription and is approved in the U.S., EU and Switzerland.

History

Ranolazine was developed in the 1980s by the Mexican company Syntex, which was acquired by Roche in 1994. Ranolazine was first approved in the U.S. in 2006 and in the EU in 2008. It was finally approved in Switzerland in 2010.

Pharmacology and mechanism of action

Myocardial ischemia, which is decreased blood flow to the heart muscle, can affect the way energy is produced and used in the heart. This can result in less energy available for the heart muscle to contract and relax properly. To maintain normal heart function, a balance of the electrolytes sodium and potassium is essential. An imbalance of these electrolytes can lead to excessive accumulation of sodium and calcium, which impairs oxygen delivery to the heart muscle. This can eventually lead to angina symptoms such as chest pain or pressure, nausea and dizziness.

Ranolazine has both antianginal and ischemic effects, regardless of the reduction in heart rate or blood pressure. Ranolazine exerts its therapeutic effects without negative chronotropic, dromotropic, or inotropic effects on the heart, either at rest or during exercise.

The mechanism of action of ranolazine is not fully understood. At therapeutic concentrations, ranolazine may inhibit cardiac late sodium current (INa), which may affect electrolyte balance in the myocardium and relieve angina symptoms. The clinical significance of this inhibition for the treatment of angina symptoms has not yet been confirmed.

Ranolazine is also known to inhibit potassium ion channels and to have a mild effect at L-type calcium channels. It is not certain whether these are the founders behind effect of ranolazine.

Pharmacokinetics

Ranolazine is administered in the form of sustained-release tablets and therefore has a delayed release. Therefore, absorption is also delayed. The time to reach maximum serum concentration is in the range of 2-6 hours. The volume of distribution is approximately 53 L. Ranolazine is rapidly and extensively metabolized in the liver by the activity of the enzyme CYP3A4, with CYP2D6 also metabolizing ranolazine to a minor extent. More than 100 different metabolites of this drug have been discovered. It is not known whether these are also pharmacologically active. Approximately 3/4 of the dose is excreted in the urine and ¼ of the dose is excreted in the feces. The half-life of the substance is approximately 7 hours.

Drug Interactions

Ranolazine has a significant potential for drug interactions. This is mainly because it is metabolized by both CYP3A4 and CYP2D6 enzymes and also inhibits CYP3A4 itself. The use of drugs that inhibit this enzyme can lead to a significant increase in plasma levels and thus an increased risk of side effects.

The most common CYP3A4 inhibitors include:

• Systemic azole antifungals (ketoconazole, fluconazole, itraconazole, etc.)
• HIV protease inhibitors (ritonavir, nelfinavir, etc.)
• Clarithromycin
• Nefazodone
• Grapefruit juice

CYP inducers such as carbamazepine, rifampicin and phenytoin can significantly decrease the plasma level of ranolazine. Therefore, it should not be combined with these agents either.

Ranolazine is also a substrate of the transporter protein p-gp. If it is taken together with p-gp inhibitors (ciclosporin or verapamil), the dose must be adjusted.

Contraindications

Ranolazine is contraindicated in case of severe renal impairment or moderate hepatic impairment.

Side effects

Possible side effects of ranolazine:

• Asthenia
• Headache
• Fatigue
• constipation
• QT prolongation
• Dizziness
• Feeling of weakness
• Nausea
• Vomiting

Pregnancy and breastfeeding

Ranolazine should not be used during pregnancy and breastfeeding.