American Journal of Cardiovascular Drugs

, Volume 14, Issue 4, pp 287–301 | Cite as

Challenges with Nitrate Therapy and Nitrate Tolerance: Prevalence, Prevention, and Clinical Relevance

Review Article


Nitrate therapy has been an effective treatment for ischemic heart disease for over 100 years. The anti-ischemic and exercise-promoting benefits of sublingually administered nitrates are well established. Nitroglycerin is indicated for the relief of an established attack of angina and for prophylactic use, but its effects are short lived. In an effort to increase the duration of beneficial effects, long-acting orally administered and topical applications of nitrates have been developed; however, following their continued or frequent daily use, patients soon develop tolerance to these long-acting nitrate preparations. Once tolerance develops, patients begin losing the protective effects of the long-acting nitrate therapy. By providing a nitrate-free interval, or declining nitrate levels at night, one can overcome or reduce the development of tolerance, but cannot provide 24-h anti-anginal and anti-ischemic protection. In addition, patients may be vulnerable to occurrence of rebound angina and myocardial ischemia during periods of absent nitrate levels at night and early hours of the morning, and worsening of exercise capacity prior to the morning dose of the medication. This has been a concern with nitroglycerin patches but not with oral formulations of isosorbide-5 mononitrates, and has not been adequately studied with isosorbide dinitrate. This paper describes problems associated with nitrate tolerance, reviews mechanisms by which nitrate tolerance and loss of efficacy develop, and presents strategies to avoid nitrate tolerance and maintain efficacy when using long-acting nitrate formulations.



Latoya M. Mitchell, PhD, Luana Atherly, PhD, and Mary Hines of inScience Communications, Springer Healthcare provided medical writing support funded by Gilead Sciences, Inc.

Funding Sources

The development of this review was supported by Gilead Sciences, Inc.


Dr. Thadani has consulted for several pharmaceutical companies in the past and at present and is currently serving as a consultant for Servier, Gilead Sciences, and Arbor Pharmaceuticals. He serves on the speaker’s bureau for Gilead Sciences and conducts clinical trials for several pharmaceutical companies for which he acts as local Principal Investigator for which the University of Oklahoma Health Science Center and VA Medical Center, Oklahoma City, receives funding to conduct the study without any funds going to Dr. Thadani.


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Emeritus Professor of Medicine, University of Oklahoma Health Sciences Center, Consultant Cardiologist, Oklahoma University Medical Center and VA Medical CenterOklahoma CityUSA

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