Nitrate tolerance in angina pectoris

Abstract

Tolerance to the hemodynamic and antianginal effects of the organic nitrates develops rapidly during therapy. This has been documented with a variety of nitrate preparations and with different routes of administration. Dosing strategies designed to provide therapeutic plasma nitrate concentrations throughout the 24 hours of the day are regularly associated with the development of tolerance. Recent information indicates that dosing schedules providing a nitrate-free period will permit continued efficacy of the organic nitrates without tolerance development. This can be accomplished in several ways. With oral preparations of isosorbide dinitrate, medication can be given 3 times daily, omitting the evening dose. Buccal nitroglycerin is usually given 3 times daily after meals, and this has been shown not to be associated with tolerance. Likewise, preliminary studies suggest that removal of the nitroglycerin patches for a period of several hours each day will prevent the development of tolerance. Much needs to be learned about the nitrate-free period. With oral isosorbide dinitrate, it appears that 12 hours is required, but this could be substantially less with nitroglycerin preparations. It is also possible that several short periods with low nitrate levels each day would suffice. Thus, simply increasing the interval between dosing of oral preparations may provide an adequate, low, nitrate-free period.