Isosorbide mononitrate tolerance

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. 

Throbbing headache as a result of dilatation of cerebral vessels (36,37) is common, although it often abates as tolerance develops. The once-a-day modified-release formulations of oral isosorbide mononitrate are particularly likely to cause headache on first exposure and have accounted for premature withdrawal in about 1% of cases in some trials (38,39). 

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. 

Does tolerance develop to antianginal therapy with isosorbide mononitrate ... 

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]. 

A long-acting nitrate, isosorbide dinitrate or mononitrate use so as to avoid tolerance (p. 463). 

Variceal bleeding is a frequent and serious event in cirrhosis, and carries an increased risk of death (SEDA-22, 218). Therapy to prevent bleeding is therefore essential in these patients. Propranolol alone has been compared with propranolol plus isosorbide-5-mononitrate in a randomized, double-blind study in 95 patients (21). The combined treatment reduced the incidence of variceal bleeding compared with propranolol alone, but without any improvement in survival Isosorbide-5-mononitrate added to propranolol appeared to be less well tolerated than propranolol alone, since seven patients had to be withdrawn from treatment because of adverse effects (four with feehngs of faintness, two with headache, one with angina-like chest pain), compared with one with atrioventricular block taking propranolol alone. 

Manabe, T., Yamamoto, A., Satoh, K., and Ichihara, K. (2001). Tolerance to nitroglycerin induced by isosorbide-5-mononitrate infusion in vivo. Biol. Pharm. BuU. 24,1370-1372. 

Stauch, M., Grossmann, G., Wanjura, D., and Adam, WE. (1990). Lack of tolerance after chronic administration of controlled-release isosorbide-5-mononitrate. Eur. J. Clin. Pharmacol. 38, 31-34. 

Thadani, U., Maranda, C.R., Amsterdam, E., Spaccavento, L., Friedman, R.G., Chemoff, R., Zellner, S., Gorwit, J., and Hinderaker, RH. (1994). Lack of pharmacologic tolerance and rebound angina pectoris during twice-daily therapy with isosorbide-5-mononitrate. Ann. Intern. Med. 120, 353-359. 

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