Nitrate Tolerance in Angina Therapy: How to Avoid It

Tolerance is the attenuation, or loss, of one or several of the effects of organic nitrates after long term administration. All organic nitrate regimens using frequent doses of long-acting nitrates (3 or more times daily), continuous delivery systems [transdermal nitroglycerin (glyceryl trinitrate) patches or continuous intravenous infusions of nitroglycerin] or long-acting (sustained release) preparations will result in partial or complete nitrate tolerance. There are several proposed mechanisms which may contribute to the development of tolerance including activation of neurohormonal mechanisms, plasma volume expansion and depletion of intracellular sulfhydryl cofactors. To avoid tolerance to long term nitrate therapy, regimens should be tailored to provide a 10- to 12-hour nitrate-free interval when possible. This means that antianginal prophylaxis can only be provided by nitrate therapy for some portion of each day, and that some patients will develop an increase in angina in the nitrate-free intervals which will necessitate short term therapy with sublingual nitroglycerin or a similar preparation.