Are Nitrate-Free Intervals Really Needed?

Devin N. Holden, PharmD


October 11, 2013

In This Article


Is a nitrate-free interval always required when using organic nitrates, and are there any alternative approaches to a nitrate-free interval?

Response from Devin N. Holden, PharmD
PGY-1 Pharmacy Practice Resident, Albany Medical Center, Albany, New York

Despite undeniable benefit in relieving acute angina, the clinical use of organic nitrates is complicated by the development of tolerance to their pharmacologic effects. Nitrate tolerance is characterized by loss of hemodynamic and antianginal effects after repeated dosing; higher and higher doses are needed to obtain the same physiologic effect. Tolerance to intravenous, topical, and transdermal nitrates can develop in as little as 24 hours. The use of the long-acting oral nitrates, isosorbide dinitrate and isosorbide mononitrate, also results in clinically significant nitrate tolerance in as little as 1 week, depending on the dosing schedule used.[1]

In clinical research, tolerance to nitrates typically manifests as a significantly decreased time to angina symptoms in treadmill testing after repeated dosing as compared with initial dosing.[1] Potential mechanisms of nitrate tolerance include the production of free radicals, which reduces the biotransformation of organic nitrates to nitric oxide (NO), and depletion of sulfhydryl groups involved in the conversion of nitrates to NO. In addition, counterregulatory mechanisms including volume expansion via sodium and water retention may also be involved.[2,3,4]

Nitrate-Free Intervals to Avoid Nitrate Tolerance

Intermittent dosing of organic nitrates to provide a nitrate-free interval has been the preferred approach to nitrate tolerance for 2 decades.[4,5] While intermittent dosing may preserve the hemodynamic effects of organic nitrates, it has many disadvantages. Besides potentially confusing dosing schedules and inconvenience to the patient, the nitrate-free periods may be associated with worsening endothelial dysfunction and rebound ischemia, with increased frequency and intensity of ischemic events.[3]


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