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Nitrate tolerance in angina pectoris
1Department of Medicine, Queen's University, Kingston, Ontario, Canada.
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.
Insights
Tolerance to organic nitrates can be overcome by incorporating nitrate-free periods into dosing schedules. This strategy ensures continued efficacy of organic nitrates, preventing tolerance development during therapy.
Area of Science:
- Cardiovascular Pharmacology
- Pharmacology
- Drug Efficacy
Background:
- Organic nitrates are crucial for managing angina but rapidly lose efficacy due to tolerance.
- Continuous dosing strategies aiming for 24-hour therapeutic plasma nitrate levels are linked to tolerance development.
- Tolerance impacts hemodynamic and antianginal effects of organic nitrates.
Purpose of the Study:
- To investigate dosing strategies that prevent tolerance to organic nitrates.
- To determine if nitrate-free intervals can maintain the efficacy of organic nitrates.
- To explore methods for overcoming nitrate tolerance.
Main Methods:
- Review of existing literature on nitrate tolerance and dosing.
- Analysis of different nitrate preparations (oral, buccal, transdermal).
- Examination of various dosing schedules and their impact on nitrate levels and efficacy.
Main Results:
- Dosing schedules with a nitrate-free period prevent tolerance development.
- Oral isosorbide dinitrate requires approximately a 12-hour nitrate-free interval.
- Buccal nitroglycerin and daily patch removal show potential for preventing tolerance.
- Intermittent dosing may be sufficient to maintain therapeutic effects without tolerance.
Conclusions:
- Incorporating nitrate-free periods is a viable strategy to maintain organic nitrate efficacy.
- Optimizing dosing intervals can prevent tolerance and ensure sustained antianginal benefits.
- Further research is needed to define optimal nitrate-free periods for different preparations.