THERAPY AND PREVENTION PHlARMACOLOGY

The circulatory response and plasma concentions of isosorbide dinitrate (ISDN) were determined in 10 patients with chronic, stable angina after administration of 5 mg of sublingual ISDN during the control stage, after 48 hr of therapy with 15 mg of ISDN orally every 6 hr, and subsequently after a 48 hr period when ISDN was substituted by placebo four times daily. Initially, sublingual ISDN induced major reductions in both supine and standing systolic and diastolic blood pressure, but after 45 hr of therapy with oral ISDN, there was a significantly diminished vasodepressor response in both positions. Subsequently, when placebo was substituted for ISDN, the circulatory response initially seen was restored within 21 hr. Plasma ISDN concentrations after the test sublingual dose were slightly higher after 48 hr of oral ISDN dosing (i.e., the tolerant state) than at the start of the study. This suggests that tolerance is unlikely to be caused by reduced bioavailability or accelerated elimination of ISDN. It is possible that tolerance is related to accumulation of ISDN metabolites. The attenuation of the circulatory response to ISDN may be related to the altered antianginal efficacy commonly seen during sustained therapy with ISDN. Circulation 68, No. 5, 1074-1080, 1983. ISOSORBIDE DINITRATE (ISDN) is widely employed in the management of patients with angina pectoris and is used with increasing frequency for impedance reduction in patients with left ventricular dysfunction. The usefulness of this drug was initially questioned because of extensive first-pass metabolism in the animal liver,1'2 but recent investigations have demonstrated that orally administered ISDN is readily detected in systemic blood,34 induces important hemodynamic effects,4 6 and is effective in the treatment of angina pectoris4' 7-10 and left ventricular dysfunction.5 6 A significant concern in the sustained use of organic nitrates is nitrate tolerance. Studies have shown rapid development of tolerance to the organic nitrates in animals and man and cross tolerance among various nitrates. 11-16 Tolerance in humans was suggested in munitions workers when headaches and postural lightheadedness, which occurred with initial exposure, cleared within a few days of continued exposure. Loss From the Department of Medicine, Queen's University, Kingston, Ontario, and the Department of Pharmaceutics, State University of New York at Buffalo. Supported by grants from the Ontario Heart Foundation and NIH GM-20852. Address for correspondence: J. 0. Parker, M.D., Department of Medicine, Division of Cardiology, Queen's University, Kingston, Ontario, Canada K7L 3N6. Received Nov. 17, 1982; revision accepted July 21, 1983. 1074 of nitrate tolerance in these workers also occurred rapidly, as indicated by the return of the original symptoms after a weekend away from exposure to nitrate, the so-called Monday disease or Monday head.'7 Recent clinical studies have confirmed the early development of partial tolerance to the circulatory effects of ISDN and reduced antianginal efficacy after only 1 week of oral therapy.'5 16 The present investigation was designed to determine the rate of development of tolerance during initiation of therapy with oral ISDN and the rate of tolerance reversal after withdrawal of this drug.