Potential problems with intermittent nitrate therapy.

Abstract

The organic nitrates continue to be widely used in clinical practice. The development of tolerance to these agents is now a well-recognized problem, although the use of a nitrate-free interval or compounds with specialized pharmacokinetic profiles can overcome this difficulty. Despite this success, prospective studies of intermittent transdermal nitroglycerin have suggested that the nitrate-free interval may be associated with two potential problems. The first is the development of crescendo angina during the nitrate-free interval. Such unstable clinical events occurring during the nitrate-free interval have been termed 'rebound angina' and are reminiscent of ischemic events reported in the munitions industry, where workers are exposed to high nitroglycerin concentrations. Intermittent nitroglycerin therapy has also been reported to cause a decrease in treadmill walking time to the onset of angina. This has been suggested from observations made in clinical trials of intermittent transdermal nitroglycerin therapy and was recently confirmed in a study from our laboratory, where the withdrawal of transdermal nitroglycerin was associated with a reduction in tread-mill exercise performance for a period of at least 6 h. Although rebound ischemia has been reported, this has not been a consistent observation in all clinical trials of intermittent nitrate therapy. Furthermore, it is not at all clear that a decrease in exercise tolerance, which would usually be occurring in the evening hours, is of any clinical importance. Nevertheless, these are potentially important observations that warrant further study and may provide further insight into the pathophysiology of nitrate tolerance.