Tolerance to organic nitrates in ischemic heart disease

The development of tolerance to organic nitrates in patients with ischemic heart disease is reviewed, with particular interest in alterations to both the hemodynamic and antiischemic effects over time. The article primarily focuses on how tolerance is defined, what biochemical mechanisms are involved when this condition occurs, which agents have been associated with the development of tolerance, and what can be done to prevent or reverse the condition in patients taking nitrates for ischemic heart disease. From a historical perspective, tolerance to organic nitrates has been a recognized phenomenon since the last century. The role that blood-level determinations and nitroglycerin pharmacokinetics have in the development of tolerance is discussed, and an extensive overview of currently marketed organic nitrate preparations and a few others available only through approved investigational protocols is presented. The role of cross-tolerance is discussed as is the role that nitrate-free intervals play in partially or completely reversing the effects of tolerance during chronic nitrate therapy. Additionally, a discussion of which specific nitrate formulation are least likely to have tolerance associated with their use is included, such as short-acting nitrate formulations with the exception of the intravenous dosage form. Finally, buccal nitroglycerin is presented as another new formulation that appears to be associated with minimal tolerance in studies already completed.