Why Use Isosorbide Dinitrate vs Isosorbide Mononitrate?

Laura S. Lehman, PharmD

Disclosures

August 23, 2010

Question:

What is the difference or advantage of using isosorbide dinitrate over isosorbide mononitrate?

Response from Laura S. Lehman, PharmD
Pharmacist, Carroll Hospital Center, Westminster, Maryland

Isosorbide is a nitrate vasodilator available in various oral forms, which include inexpensive generic versions. Isosorbide dinitrate (ISDN) is an intermediate-acting nitrate approved for prevention of angina pectoris.[1] It is also used in conjunction with hydralazine in treating congestive heart failure, particularly in African Americans who have inadequate response to optimal medical therapy.[2] The US Food and Drug Administration (FDA)-approved formulation for heart failure is the fixed combination of ISDN/hydralazine tablet (BiDil®). Isosorbide dinitrate is also available in immediate-release (eg, Isordil®) and extended-release (eg, Dilatrate-SR®) forms. The bioavailability of ISDN varies widely, and it undergoes significant first-pass metabolism. The half-life of ISDN is about 1 hour. When ISDN is administered in 3 to 4 doses daily, nitrate tolerance can develop, rendering the agent less efficacious.[1]

Isosorbide mononitrate (ISMN) is the active metabolite of ISDN and is primarily used in the management of chronic stable angina. It is not FDA-approved for treating heart failure. It has high bioavailability and a longer half-life (4-6 hours) than ISDN. The immediate-release form (eg, ISMO® and Monoket®) is typically given in 2 doses daily 7 hours apart to minimize tolerance, whereas the sustained-release form (Imdur®) can be given once daily.[3]

Development of nitrate tolerance and clinical rebound should be considered with long-term nitrate use. Nitrate tolerance may develop within 1 to 2 days, resulting in decreased angina control. It is induced by nitrate regimens that produce continuous therapeutic levels. Dose adjustments allowing a low-nitrate period have been devised to reduce development of nitrate tolerance. Unfortunately, breakthrough angina, or clinical rebound, can occur during the nitrate-free intervals used in some dosing strategies.

According to Thadani,[4] ISMN given on awakening and 7 hours later each day has been shown to prevent development of tolerance without inducing clinical rebound in a well-designed clinical trial. Isosorbide dinitrate lacks a large randomized study to delineate the ideal drug-free interval. For immediate-release forms of ISDN, a 14-hour drug-free interval has been recommended, and for sustained-release forms, a greater than 18-hour drug-free period is recommended.[1]

Another consideration in the selection of an isosorbide regimen is patient adherence. The COMPASS (Compliance with Oral Mononitrates in Angina Pectoris Study) demonstrated that once-daily dosing of ISMN resulted in better patient adherence (fewer missed doses) and a greater decrease in chest pain episodes than did ISMN given twice daily at 8 AM and 2 PM.[5]

  • For management of angina pectoris, ISMN may be preferred because of its ease of administration as a once-daily formulation. Better adherence can lead to a decrease in chest pain episodes. Although the pharmacokinetic parameters of ISDN extended-release are not well defined, it also has been given in a single daily dose for prevention of angina.

  • For heart failure, ISDN has been more extensively studied than ISMN and is recognized in the American College of Cardiology/American Heart Association guidelines for treatment of heart failure.[2] The ISDN/hydralazine combination form may be preferred, because it ensures the appropriate ratio of each drug and may enhance adherence. In some cases, giving ISDN and hydralazine separately, instead of the fixed combination product, may be preferable so that each agent can be individually titrated to response. This is also a less expensive option than the combination ISDN/hydralazine product.

  • If adherence is a concern, off-label ISMN could be considered in place of ISDN in management of heart failure.

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