Despite undeniable benefit in relieving acute angina, the clinical use of organic nitrates is complicated by the development of tolerance to their pharmacologic effects.
Nitrate tolerance is characterized by:
2-higher and higher doses are needed to obtain the same physiologic effect.
3-Tolerance to intravenous, topical, and transdermal nitrates can develop in as little as 24 hours.
4- The use of the long-acting oral nitrates, isosorbide dinitrate and isosorbide mononitrate, also results in clinically significant nitrate tolerance in as little as 1 week, depending on the dosing schedule used.[1]
In clinical research, tolerance to nitrates typically manifests as:
a significantly decreased time to angina symptoms in treadmill testing after repeated dosing as compared with initial dosing.[1]
Potential mechanisms of nitrate tolerance include:
1- the production of free radicals, which reduces the biotransformation of organic nitrates to nitric oxide (NO), and
2- depletion of sulfhydryl groups involved in the conversion of nitrates to NO.
3- In addition, counterregulatory mechanisms including volume expansion via sodium and water retention may also be involved.[2-4]
Nitrate-Free Intervals to Avoid Nitrate Tolerance
Intermittent dosing of organic nitrates to provide a nitrate-free interval has been the preferred approach to nitrate tolerance for 2 decades.[4,5] While intermittent dosing may preserve the hemodynamic effects of organic nitrates, it has many disadvantages.
Disadvantages of Intermittent dosing of organic nitrates
1-potentially confusing dosing schedules and
2- inconvenience to the patient,
3-the nitrate-free periods may be associated with worsening endothelial dysfunction and rebound ischemia, with increased frequency and intensity of ischemic events
