Isosorbide Dinitrate VS Isosorbide Mononitrate

Isosorbide Dinitrate (ISDN) 

• is an intermediate acting nitrate approved for prevention of angina pectoris.
• ISDN is available in immediate release (Ex: Isordil®) and extended release (Ex: DilatrateSR ®) forms. ISDN has an extensive first pass metabolism in the liver, produces two major metabolites (Isosorbide 2 mononitrate & Isosorbide 5 Mononitrate) with half-lives of 2 & 4 hours respectively. 
• Due significant first pass metabolism, ISDN has a half-life of about 1 hour. 
• Normally it is doses in 3 to 4 doses daily. 
• In a study done on patient with TDS dose of ISDN with a 14 hours free interval, the exercise capacity improved after the first dose.

Isosorbide Mononitrate (ISMN)

• active metabolite of ISDN and is primarily used in the management of chronic stable angina. 
• ISMN does not undergo first pass metabolism, hence it has higher bioavailability and a longer half-life (4-6 hours) than ISDN. 
• ISMN is available as an immediate release form (Ex: ISMO® and Monoket®) which is typically given in 2 doses daily 7 hours apart to minimize tolerance and sustained released form (Ex: Imdur®) which can be given once daily. 
• It is primarily used in the management of chronic stable angina. However, it is not approved by the FDA to be used in treating heart failure.

INDICATION

• 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. 
• On the other hand, FDA does not approve the use of ISMN in treating heart failure.

TOLERANCE

• 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. 
• For immediate release form of ISDN, a 14 hours drug free interval has been recommended, and for sustained release forms, a greater than 18 hours drug free period is recommended.
• According to Medscape (2010), for immediate release ISMN, given in 2 doses, 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. 
• Waller (1999), for once daily formulations of ISMN, it delivers high plasma nitrate concentrations that improve exercise tolerance in patients with angina for at least 12 h after dosing. 
• During the remainder of the dosage interval, plasma nitrate concentrations fall but are sufficient to protect against coronary artery spasm overnight. For example, Elantan is a sustained-release capsule formulation of ISMN for once-daily dosing. 
• This capsule contains pellets which release 30% of the dose immediately, while 70% is released slowly to maintain the therapeutic response. 
• The pharmacokinetic profile of this formulation prevents the development of tolerance, while also conferring long-term anti-anginal efficacy.

ADHERENCE/COMPLIANCE

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

References:

1. <www.medscape.com>

2. <http://www.ncbi.nlm.nih.gov/pubmed/10499557>

3. <http://www.drugs.com/monograph/isosorbide-dinitrate-mononitrate.html>

4. Thadani U. Nitrate therapy and the development of tolerance. Arch Fam Med. 1993:2;880885