Nitrate tolerance.

The nitrate group of drugs is one of the most commonly used therapeutic modalities. The application of the nitrates is generally directed at ameliorating the symptoms of occlusive coronary artery disease (angina) and/or congestive heart failure. Although studies are available that attempt to refute the concept of nitrate-induced tolerance in angina pectoris, well-designed and well-controlled reports are appearing that convincingly establish the occurrence of one or more expressions of tolerance (e.g., shorter duration of action, loss of intensity of effect) with long-term dosing in this clinical setting. The type and degree of tolerance to nitrate therapy in angina pectoris depend on a number of pharmaceutic-pharmacokinetic considerations, including route of administration, dose strength, dosing frequency, and magnitude and duration of drug delivery. Reports concerning the development of tolerance to nitrates in congestive heart failure are also somewhat conflicting. However, one form and dose of nitrate therapy has been studied rather extensively: isosorbide dinitrate at 40 mg orally every 6 hours. The administration of this preparation over 3 months to a population with heart failure resulted in the development of tolerance to the systemic arterial-arteriolar effects, whereas the pulmonary vascular and venous dilative effects were maintained throughout the long-term dosing period. Exercise tolerance improved for the long-term isosorbide dinitrate group compared to the group receiving long-term placebo therapy. The mechanism(s) of tolerance to the nitrates is not known; altered disposition of reduced sulfhydryl groups at receptor and intracellular sites is the leading hypothesis.