Isosorbide 5-nitrate

N. Mizuno, C. Shimizu, E. Morita, D. Shinkuma, Y. Yamanaka, Determination of Isosorbide Nitrates by HPLC and Their Stability in Aqueous Solution , J. Chromatogr. 1983, 264, 159-163. 

Nitroglycerin (also isosorbide nitrate) relaxes isolated strips of human corpus cavernosum. Its mechanism involves the stimulation of guanylate cyclase. Clinically, nitroglycerin has been of limited use in the treatment of ED. 

Isosorbide 2- and 5-nitrates substituted at the second hydroxyl group by a number of aliphatic, aromatic, and cinnamic acids (78, R = various acyl groups) have been claimed to be useful in vasodilating therapy.111 However, it was confirmed by the authors that there seems to be no direct correlation between lipophilicity and therapeutic activity, and that structure-activity relationships in the isosorbide nitrate area are more complex than that. 

Yes. Isosorbide nitrates relax all types of smooth muscle including bronchial, biliary, gastrointestinal (GI), ureteral, and uterine. 

Explain how tolerance to isosorbide nitrates might be minimized. 

The nitrates, such as isosorbide (Isordil) and nitroglycerin, have a direct relaxing effect on die smooth muscle layer of blood vessels. The result of diis effect is an increase in the lumen of die artery or arteriole and an increase in the amount of blood flowing through diese vessels. An increased blood flow results in an increase in die oxygen supply to surrounding tissues. 

CgHi20s 65940-93-4) see Isosorbide mononitrate isosorbide 2-acetate-5-nitrate (C(,H]iN07 39813-48-4) see Isosorbide mononitrate l-isothiucyanato-2-nitrobenzene... 

The nitrate-hydralazine combination was first shown to improve survival compared to placebo.27 Subsequently, the combination of isosorbide dinitrate 40 mg and hydralazine 75 mg, both given four times daily, was compared to the ACE inhibitor enalapril.28 Enalapril produced a 28% greater decrease in mortality. Therefore, the combination is considered a third-line vasodilatory option for patients truly intolerant of ACE inhibitors and ARBs. 

The frequent dosing of isosorbide dinitrate (e.g. 3-4 times daily) is not conducive to patient adherence therefore, a once-daily isosorbide mononitrate is commonly substituted for isosorbide dinitrate to simplify the dosing regimen. A nitrate-free interval is still required when using nitrates for HE... 

Isosorbide dinitrate slow-release capsules Isosorbide mononitrate tablets Isosorbide mononitrate 40 mg 1-2 times daily, with a daily nitrate-free interval of at least 18 hours 20 mg 2 times daily, with doses 7 hours apart 30-120 mg once daily... 

Nitrates have been suggested in patients who do not achieve therapeutic goals (heart rate reduction) with P-blocker therapy alone. Trials to evaluate the effects of nitrates (e.g., isosorbide mononitrate) on portal pressure, both alone and in combination with P-blockers, show enhanced reduction of portal pressure however, there is an increase in mortality when nitrates are used alone. Adverse effects are significantly higher in patients treated with the combination of non-selective P-blockers and nitrates as opposed to P-blocker monotherapy.42,43 Unfortunately,... 

Fig. 2.1 Commonly used organic nitrates and nitrites. GTN, glyceryl trinitrate ISDN, isosorbide dinitrate IAN, isoamyl nitrite IBN isobutyl nitrite.

A number of organic nitrates are potent vasodilators and have been used clinically for over lOOyears, particularly for the relief of the symptoms of angina (Fig. 8.6). The most widely used is glyceryl trinitrate (GTN) but the group includes pentaerythrityl tetranitrate (PETN), isosorbide mononitrate (ISMO) andisosorbide dinitrate (ISDN). 

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]. 

The above mechanism of intramolecularly catalyzed cleavage is possible only for compounds with a N02 group close to the departing NO group. In other words, it can be postulated to follow nitro reduction in erythritol tetra-nitrate (9.8), mannitol hexanitrate (9.9), pentaerythritol tetranitrate (9.10), and perhaps trolnitrate (9.14), but not in isosorbide dinitrate (9.11). 

Isordil is a proprietary (trade name) preparation of isosorbide dinitrate, a nitrate. Sildenafil, the active ingredient of Viagra, interacts with nitrates and the two active ingredients should not be administered concurrently, as a significant hypotensive effect may occur. 

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. 

The main drngs nsed for myocardial ischema therapy and for relieving pain in angina pectoris are nitrates and nitrites (nitroglycerin, isosorbide dinitrate, and pentaerythritol tetranitrate) snbstances that snppress adrenergic systems of the heart—j3-adrenoblockers (atenolol, methoprolol, propranolol, and nadolol), and Ca + channel blockers (verapamil, diltiazem, nifedipine, and nicardipine) as well as a few older drugs, in particular papaverine and dipyridamole. 

---