[Long-term therapy with nitrates. Relation between dosage and tolerance effect]

In 56 patients with angiographically-documented coronary artery disease, the longterm effects of isosorbide dinitrate (ISDN) and isosorbide 5-mononitrate (5-ISMN) on exercise hemodynamics and exercise capacity were assessed. The hemodynamic and antianginal acute and longterm effects of the respective agents were objectively analyzed on the basis of the tested parameters of mean pulmonary artery pressure and work capacity (watts X minutes). These parameters are unaffected by placebo and show reproducible changes at rest and during exercise after drug administration. After the standard 20 mg dose of ISDN or 5-ISMN, both at rest and during exercise, there was a marked decrease in pulmonary artery pressure as well as an increase in exercise capacity. The acute effects of 60 mg ISDN or 50 mg 5-ISMN were not substantially more marked than those of the 20 mg doses. During longterm treatment with 20 mg ISDN or 5-ISMN three times daily there was no attenuation of the hemodynamic effects, that is, no tolerance development; the increase in exercise capacity was maintained. In contrast, at the end of the four-week treatment period with 60 mg ISDN or 50 mg 5-ISMN three times daily there was a marked attenuation of the hemodynamic effects as well as the associated exercise capacity. The results of this study do not enable delineation of the mechanism responsible for the attenuated effect during high-dose treatment. Most probably, it is due to a complex process, in which, in addition to pharmacokinetics and pharmacodynamics, alterations in various reflex and adaptive mechanisms also play a role.