Tolerance development nitrates

Tolerance to nitrates is defined as the reduction in hemodynamic effect or the requirement for higher doses to achieve a persistent effect with continuous use in the face of constant plasma concentrations [15]. Nitrate tolerance was first described for nitroglycerin in 1888 [36] it occurs with all organic nitrates, albeit to different extents. For reasons that are not understood, PETN appears to be the least susceptible to the development of tolerance. No, or much less, tolerance is observed with nitrite esters, such as amyl nitrite [37], molsidomine, and sodium nitroprusside. Earlier investigations suggested that a depletion of intracellular thiols is involved in tolerance development [17], but this has not been substantiated in later studies [38, 39]. As with organic nitrate bioactivation, the precise mechanism(s) involved in nitrate tolerance remain(s) unknown, but it is likely to be complex and multifactorial. Two principal... 

For sustained daytime angina prophylaxis, nitrates are of limited value because "nitrate pauses of about 12 h are appropriate if nitrate tolerance is to be avoided. If attacks occur during the day, ISDN, or its metabolite isosorbide mononitrate, may be given in the morning and at noon (e.g ISDN 40 mg in extended-release capsules). Because of hepatic presystemic elimination, NTG is not suitable for oral administratioa Continuous delivery via a transdermal patch would also not seem advisable because of the potential development of tolerance. With molsidomine, there is less risk of a nitrate tolerance however, due to its potential carcinogenicity, its clinical use is restricted. 

Since depletion of tissue stores of sulfhydryl groups has been proposed to play an important role in nitrate tolerance, some investigators have administered sulfhydryl-containing compounds in an attempt to reverse or prevent the development of tolerance. The most commonly used agent is A-acetylcysteine (NAC), which is hydrolyzed in vivo to cysteine. Although some... 

L. Cloarec-Blanchard, C. Funck-Brentano, A. Carayon, and P. Jaillon. Rapid development of nitrate tolerance in healthy volunteers assessment using spectral analysis of short-term blood pressure and heart rate variability. J. Cardiovasc. Pharmacol. 24 266-273, 1994. 

The mechanisms by which tolerance develops are not completely understood. As noted above, diminished release of nitric oxide may be partly responsible for tolerance to nitroglycerin. Systemic compensation also plays a role in tolerance in the intact human. Initially, significant sympathetic discharge occurs and after one or more days of therapy with long-acting nitrates, retention of salt and water may reverse the favorable hemodynamic changes normally caused by nitroglycerin. 

Pathophysiology Hydralazine and isosorbide dinitrate are effective vasodilators which may interfere with the biochemical and molecular mechanisms responsible for the progression of HF Combined use may interfere with the development of nitrate tolerance (62). 

Molsidomine itself is inactive. After oral intake, it is slowly converted into an active metabolite, linsidomine. The differential effectiveness in arterial vs. venous beds is less evident compared to the drugs mentioned above. Moreover, development of nitrate tolerance is of less concern. These differences i n activi ty profi le appear to reflect a different mechanism of NO release. The same applies to the following sodium nitroprusside. 

Needleman P, Johnson EM Jr. Mechanism of tolerance development to organic nitrates. J Pharmacol Exp Ther 1973 184(3) 709-15. 

M. Hill, H. Takano, X.-L. Tang, E. Kodani, G. Shirk, R. Bolli, Nitroglycerin induces late preconditioning against myocardial infarction in conscious rabbits despite development of nitrate tolerance, Circulation 104, 694-699 (2001). 

Pizzulli L, Hagendorff A, Zirbes M, et al. Influence of captopril on nitroglycerin-mediated vasodilation and development of nitrate tolerance in arterial and venous circulation. Am Heart J 1996 131 342-349. 

Monday disease Industrial disease caused by weekly exposure to vasodilating concentrations of organic nitrates in the workplace characterized by headache, dizziness, and tachycardia on Mondays, with tolerance developing during the week... 

Tolerance, usually in the form of shortened duration of action, is commonly observed with chronic nitrate use. The clinical importance of this tolerance is, however, a matter of controversy. Because tolerance to nitrates has not been reported to lead to a total loss of activity, some physicians feel that it is not olinioally relevant. In addition, an adjustment in dosage oan compensate for the reduced response (26). It also has been reported that intermittent use of long-acting and sustained-release preparations may limit the extent of tolerance development. 

B. Workers or patients regularly exposed to nitrates may develop tolerance and may suffer angina or myocardial infarction owing to rebound coronary vasoconstriction upon sudden withdrawal of the drug. 

Because of die risk of tolerance to oral nitrates developing, die primary care provider may prescribe die short-acting preparations 2 to 3 times daily, witii die last dose no later than 7 pm and die sustained release preparations once daily or twice daily at 8 AM and 2 PM. 

The major limitation of nitrate therapy is the development of tolerance with continuous use. The loss of anti-anginal effects may occur within the first 24 hours of continuous nitrate therapy. While the cause of tolerance is unclear, several mechanisms have been proposed. These include depletion of the sulfhydryl groups necessary for the conversion of nitrates to nitric oxide, activation of neurohormonal systems, increased intravascular volume, and generation of free radicals that degrade nitric oxide. The most effective method to avoid tolerance and maintain the anti-anginal efficacy of nitrates is to allow a daily nitrate-free interval of at least 8 to 12 hours. Nitrates do not provide protection from ischemia during the nitrate-free period. Therefore, the nitrate-free... 

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