Nitroglycerin tolerance

Hasegawa, K., Taniguchi.T., Takakura, K., Goto, Y., Muramatsu, I., Possible involvement of nitroglycerin converting step in nitroglycerin tolerance. Life Sci. 64 (1999), p. 2199-2206... 

Axelsson, K. I., and Karlsson, J.-O. G. (1984). Nitroglycerin tolerance in vitro Effect on cGMP turnover in vascular smooth muscle. Acta Pharmacol. Toxicol. 55, 203-210. 

Bauer, J., Balthasar, J., and Fung, H., Application of pharmacodynamic modeling for designing time-variant dosing regimens to overcome nitroglycerin tolerance in experimental heart failure, Pharmaceutical Research, Vol. 14, No. 9, 1997, pp. 1140-1145. 

Ghio, S., de Servi, S, Perotti, R, Eleuteri, E, Montemartini, C, and Specchia, G. 1992. Different susceptibility to the development of nitroglycerin tolerance in the arterial and venous circulation in humans. Effects of N-acetylcysteine administration. Circulation 86 798-802. 

Munzel T, Kurz S, Rajagopalan S, Tho-enes M, Berrington WR, et al. 1996. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase a new action for an old drug. J. Clin. Invest. 98 1465-70... 

K. Sydow, A. Daiber, M. Oelze, Z. Chen, M. August, M. Wendt, V. Ullrich, A. Mnelsch, E. Schulz, J. F. Keaney Jr., J. S. Stamler and T. Muenzel. Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance. J. Clin. Invest. 113, 2004,482—489. 

Each of the transdermal nitroglycerin systems is effective in treating angina pectoris when worn for 12—16 h followed by an off period. The FDA recommends the period without dmg (8—12 h) to mitigate the possibiUty of the patient acquiring a tolerance to the antianginal effects of nitrate therapy. Thus, a noncontinuous dosing schedule of nitrates is recommended even with the transdermal deflvery system (81). 

Nitroglycerin 5-1 00 mcg/kg/minute as IV infusion 2-5 minutes 5-1 0 minutes Headache, vomiting, methemoglobinemia, tolerance with prolonged use Coronary ischemia... 

Continuous infusions of nitroglycerin should be initiated at a dose of 5 to 10 mcg/minute and increased every 5 to 10 minutes until symptomatic or hemodynamic improvement. Effective doses range from 35 to 200 mcg/minute. The most common adverse events reported are headache, dose-related hypotension, and tachycardia. A limitation to nitroglycerin s use is the development of tachyphylaxis, or tolerance to its effects,... 

Duke University Office of News Communications. 130-year-old mysteries solved How nitroglycerin works why patients develop tolerance, Duke University Web site. Available online. URL http //www.dukenews.duke.edu/2002/06/nitro0602.html. Accessed on March 11, 2008. 

Nitroglycerin should be initiated at 5 to 10 mcg/min (0.1 mcg/kg/min) and increased every 5 to 10 minutes as necessary and tolerated. Maintenance doses usually range from 35 to 200 mcg/min (0.5 to 3 mcg/kg/min). Hypotension and an excessive decrease in PAOP are important dose-limiting side effects. Some tolerance develops in most patients over 12 to 72 hours of continuous administration. 

Chong, S., Fung, H-L., Biochemical and pharmacological interactions between nitroglycerin and thiols. Effects of thiol structure on nitric oxide generation and tolerance reversal. Biochem. Pharmacol. 42 (1993), p. 1433-1439... 

Axelsson, K. L., Anderson, R. G. G., Tolerance towards nitroglycerin, induced in vivo, is correlated to a reduced cGMP response and an... 

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... 

In other work, C87-3754has been compared with SIN-1, the equivalent metabolite from molsidomine, and from the organic nitrate class, isosorbide-5-mononitrate (IS-5-MN) [146]. In this latter study, which involved long term oral administration in a dog model, IS-5-MN showed tolerance whilst the sydnonimines showed no self- or cross-tolerance. Elsewhere, tolerance studies in dogs by oral or continuous infusion of C87-3754 have shown benefits in the treatment of a failing heart, without tolerance [147] and with better results than those observed by nitroglycerin [148]. 

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... 

Tolerance Use only the smallest dose required for effective relief of the acute anginal attack. Excessive use of sublingual nitroglycerin may lead to the development of tolerance. 

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