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.
