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Nitrate therapy in patients with coronary artery disease--preparations and doses with and without development of
W Rudolph1, J Dirschinger, F Kraus
1Department of Cardiology, German Heart Center, Munich.
Abstract:
Rapid tolerance development with respect to hemodynamic, anti-anginal and anti-ischemic effects is a relevant clinical problem associated with any longterm treatment with nitroglycerin, isosorbide dinitrate or isosorbide 5-mononitrate. Tolerance occurs with any dosing regimen that results in nitrate accumulation in the plasma or nearly-constant plasma concentrations, as is the case with multiple daily doses of oral nitrates or continuous application of transdermal patch systems. Nitrate tolerance can be prevented by the interval treatment. This encompasses incorporation of an application-free interval which prevents meaningful nitrate accumulation such that, from a low baseline level, renewed drug administration leads to an increase in the nitrate plasma concentration greater than 2.5-fold. From controlled studies, dosing regimens for interval treatment proven to be effective have been designated for isosorbide dinitrate and isosorbide 5-mononitrate, as well as for transdermal nitroglycerin patch systems. The early attenuation of nitroglycerin, seen within the first 12 h of its use, according to the results of a recently completed study, can be counteracted through continuously increasing plasma concentrations during this period. Interval treatment does not enable 24-h therapeutic protection. Studies with ST-Holter monitoring, however, have shown that adequate coverage can be provided for the period during which the vast majority of ischemic episodes occur. Clinically-relevant rebound phenomena do not occur during interval treatment. Pharmacological approaches to prevent nitrate tolerance, on the basis of the limited and, in part, conflicting data available, do not provide an alternative to interval treatment.
Insights
Nitrate tolerance is a clinical issue with long-term use. Interval treatment, incorporating an application-free period, effectively prevents tolerance to nitrates like nitroglycerin and isosorbide mononitrate.
Area of Science:
- Cardiovascular Pharmacology
- Clinical Therapeutics
- Pharmacokinetics
Background:
- Long-term nitrate therapy (nitroglycerin, isosorbide dinitrate, isosorbide 5-mononitrate) is limited by rapid tolerance development.
- Tolerance affects hemodynamic, anti-anginal, and anti-ischemic effects, particularly with continuous or multiple daily dosing regimens leading to nitrate accumulation.
Purpose of the Study:
- To evaluate the efficacy of interval treatment in preventing nitrate tolerance.
- To identify effective dosing regimens for interval treatment across different nitrate formulations.
Main Methods:
- Review of controlled studies and ST-Holter monitoring data.
- Analysis of dosing regimens designed to prevent nitrate accumulation and maintain therapeutic efficacy.
Main Results:
- Interval treatment, characterized by an application-free interval, prevents nitrate tolerance by avoiding significant plasma accumulation.
- Proven effective dosing regimens exist for interval treatment of isosorbide dinitrate, isosorbide 5-mononitrate, and transdermal nitroglycerin.
- While not providing 24-hour coverage, interval treatment ensures therapeutic protection during peak ischemic episodes and avoids rebound phenomena.
Conclusions:
- Interval treatment is the recommended strategy to prevent nitrate tolerance.
- Pharmacological alternatives are not currently supported by robust evidence and do not replace interval treatment.