Isosorbide‐5‐mononitrate

Abstract

In 1967 Dietz ( 19) reported that isosorbide dinitrate (ISDN), a long-acting antianginal drug, was rapidly metabolized to isosorbide-5-mononitrate (IS-5-MN, Fig. 1 ), isosorbide-2-mononitrate (IS-2-MN), and isosorbide. Studies from the early 1970s established that although ISDN and IS-5-MN were radically different in terms of drug disposition (68), they were remarkably similar in their pharmacological effects (90). Unlike ISDN, IS-5-MN was not subject to first-pass degradation, and thus the mononitrate persisted in plasma for many hours after ISDN had disappeared (68). Most importantly, IS-5-MN and ISDN are similar in that both are effective dilators of the coronary and systemic vasculature (90). It is now widely appreciated that IS-5-MN is the molecule responsible for the sustained antianginal actions of ISDN. This monograph is a review of the studies that have led to this understanding and to the subsequent development of IS-5-MN as a clinically important antianginal compound. CHEMISTRYThe chemical structure of IS-5-MN is shown in Fig. 1. Chemically, it is 1,4:3,6-dianhydro-D-glucitol 5-nitrate. The nitrate ester in the 5-position of IS-5-MN exists in the endo-configuration. This provides a degree of steric protection from denitration. The chemically similar drug ISDN has nitrate ester groups in both the 2-and 5-positions. Because the nitrate ester in the 2-position is in the exo-configuration, it is not stencally protected. Therefore, it is more susceptible to metabolic attack than the nitrate ester group in the 5-position. The steric hindrance protecting the 5-nitrate is responsible for the long half-life of IS-5-MN.IS-5-MN is an odorless, white, fine, crystalline powder with a slightly sweet taste; it is freely soluble in water, methanol, acetone, and ethanol. Its molecular weight is 19 I . 14, and its melting point range is 87"-90°C. Because of the potentially explosive nature of pure IS-5-MN, it is supplied as a tnturation with lactose. PRECLINICAL PHARMACOLOGY Effects in Experimental Models of Myocardial IschemiaExperimental production of canine ischemia by coronary artery occlusion and treadmill exercise closely simulates exercise-induced angina pectoris. The severity of