Nitrates tolerance with

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... 

In their studies of the flavoprotein inhibitor, DPI, Bennett and colleagues [91, 120] found that DPI inhibited GTN-induced accumulation of cGMP to the same extent in aortae from naive and from GTN-tolerant animals. They argued that, if inactivation of flavoproteins is a major cause of tolerance, then there should be less scope for further, DPI-induced inactivation in tolerant animals, compared with naive ones. Their conclusion, accordingly, was that, while flavoproteins may participate in biotransformation of organic nitrates and associated vasodilation, their alteration cannot be the basis for nitrate tolerance. 

Finally, in this context, it should be noted that Laursen et al. [121] dispute the whole concept that nitrate tolerance is associated with reduced bioconversion of GTN to NO. 

M. E., Meister, A., Nitrate tolerance in vivo is not associated with depletion of arteria. or venous thiol levels. Circ. 

Laursen, J. B., Mulsch, S., Boesgaard, S., Mordvintcev, P., Trautner S., Gruhn, N., Nielsen-Kudsk, J. E., Busse, R., Alsershvile, J., In vivo nitrate tolerance is not associated with reduced bioconversion of nitroglycerin to nitric oxide. Circulation 94 (1996), p.2241-2247... 

The other factor affecting the use of organic nitrates is nitrate tolerance, the mechanism of which is unclear. An early explanation of tolerance was thiol depletion [68] but that now seems unlikely as their is an abundance of thiol in most tissue [69]. A more likely explanation is down regulation of the enzymes involved in the biotransformation but few details are available. An interesting suggestion is that GTN induces increased production of superoxide from the vascular wall and tolerance is caused by reaction of NO, produced enzymatically from GTN, with superoxide to give peroxynitrite and then nitrate [70] (Eq. (16)). 

Some new organic nitrates are of interest. Sininitrodil [76] (Fig. 8.7), SPM-4744 and SM P-5185 [77] selectively dilate large microvessels and SPM-5185 is resistant to cross-tolerance with GTN in human blood vessels in vitro. 

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... 

Uses. Organic nitrates are used chiefly in angina pectoris (p. 308, 310), less frequently in severe forms of chronic and acute congestive heart failure. Continuous intake of higher doses with maintenance of steady plasma levels leads to loss of efficacy, inasmuch as the organism becomes refractory (tachy-phylactic). This nitrate tolerance can be avoided if a daily nitrate-free interval is maintained, e.g., overnight. 

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. 

To help avoid nitrate tolerance, clinicians should employ the smallest effective dose and administer the compound infrequently. A daily nitrate-free period is also recommended, particularly with use of the transdermal patches or ointment. A better understanding of the pharmacokinetic profile achieved with these sustained-release formulations should result in more effective dosing regimens. 

Several isovalent ions form solid solutions with KTP (Table II), showing that this structure is relatively tolerant, with respect to isovalent impurities, as are the traditional nonlinear optical oxide crystal structures. But due to the relatively limited range of nonstoichiometry in KTP, aliovalent impurities, such as divalent Ba, Sr and Ca introduced through ion exchange in nitrate melts, which substitute on the K site, are incorporated at concentrations less than one mole percent.(36) Typical impurity concentrations present in flux and hydrothermally grown KTP are shown in Table ID. 

As described below, tolerance is an important consideration in the use of nitrates. While tolerance may be caused in part by a decrease in tissue sulfhydryl groups, it can be only partially prevented or reversed with a sulfhydryl-regenerating agent. The site of this cellular tolerance may be in the unknown reaction responsible for the release of nitric oxide from the nitrate, since other agents, eg, acetylcholine, that cause vasodilation via release of nitric oxide from endogenous substrates do not show cross tolerance with the nitrates. 

Hirai N, Kawano H, Yasue H, et al. Attenuation of nitrate tolerance and oxidative stress by an angiotensin II receptor blocker in patients with coronary spastic angina. Circulation 2003 108 1446-1450. 

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). 

In an assessment of how nitrate tolerance might be avoided, the efficacy of thrice-daily buccal glyceryl trinitrate and that of four times a day oral isosorbide dinitrate were compared (71) over 2 weeks, prolonged antianginal efficacy was maintained only with thrice-daily buccal administration. Nevertheless, in another study, transdermal glyceryl trinitrate seemed to offer a prolonged effect, sufficient to wean patients with unstable angina from intravenous nitrate therapy (71). 

Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y. Randomized, double-blind, placebo-controUed study of carvedilol on the prevention of nitrate tolerance in patients with chronic heart failure. J Am CoU Cardiol 1998 32(5) 1194-200. 

When using long-acting nitrates, it is important to schedule a 10- to 12-hour nitrate-free interval to minimize tolerance. With continuous exposure to nitrates, tolerance or the loss of antianginal and hemodynamic effects occurs. When exposure is discontinued, symptoms of withdrawal (severe headache, chest pain, or sudden cardiac death) can occur. Short-acting nitrates are not likely to lead to tolerance due to their rapid onset of action and short duration. 

Tolerance limits the clinical use of organic nitrite and nitrate esters it is associated with increased angiotensin II (ANGII)-dependent vascular production of superoxide radical from NAD(P)H oxidase and endothelial NOS (eNOS) (25,26). The superoxide radical generated by these enzymes reacts with NO derived from the NO-donor to form peroxynitrite, as indicated by the finding of increased urinary 3-nitrotyrosine in nitrate-tolerant patients (27). Importantly, nitrate tolerance is also associated with cross-tolerance to endothelium-derived NO (28), both by... 

Like dinretics, therapy should be initiated at low doses in order to avoid hypotension. Isosorbide dinitrate 10 mg three or fonr times daily, isosorbide mononitrate (Imdur) 30 mg/day, nitroglycerin paste 1 /2 to 1 inch every 4 to 6 honrs, and nitroglycerin patch 0.1 to 0.2 mg/h applied each day are common initial doses. Doses can be increased during long-term therapy and titrated against symptoms. Nitrate tolerance has not been studied in this patient population but probably occurs. Similar to diuretics, nitrates can cause hypotension and a low-output syndrome. Headaches are common but may be less frequent with continued use. 

Tolerance can limit the long-term effectiveness of nitrates in the treatment of CHF. Blood levels of these drugs should be permitted to fall to negligible levels for at least 6-8 hours each day, which can be adjusted to the patient s symptoms. Patients with recurrent orthopnea or paroxysmal nocturnal dyspnea, for example, would likely benefit most by using nitrates at night. N-acetylcysteine (mucomyst) may diminish tolerance to the hemodynamic effects of nitrates in heart failure. Likewise, hydralazine may decrease nitrate tolerance by an antioxidant effect that attenuates superoxide formation, thereby increasing NO bioavailability. 

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