[Avoidance of tolerance development to long term therapy with nitrates through correct dosage]

Tolerance development to organic nitrates, with respect to blood pressure reduction and precipitation of headache, had been assumed for almost a century but it was not until 1980 that the anti-ischemic effect was proven to be subject to this phenomenon, in a placebo-controlled, double-blind study carried out by our group exemplarily employing long-term treatment with isosorbide dinitrate (ISDN) in sustained-release form. Subsequent studies showed that tolerance development was also incurred during administration of ISDN, nonsustained-release form, 40 mg q.i.d. and on application of transdermal nitroglycerin patch systems. Both changes in the pharmacokinetics and activation of counter-regulatory mechanisms can be excluded as meaningful etiologic factors for the development of nitrate tolerance. It must be assumed that intracellular changes in the target organ which are associated with a diminished responsiveness for guanylate cyclase activation are at the basis of tolerance development. Prerequisite, according to laboratory experiments and clinical observations, are high concentrations of nitrates. After development of tolerance, on allowing a nitrate-free interval to intervene, the attenuated effects rapidly resume. Consequently, we investigated the hypothesis that tolerance could be avoided by an intermittent administration of nitrates which prevented accumulation of high serum concentrations. This was confirmed in two placebo-controlled, double-blind studies. Both during treatment with 20 mg ISDN in the morning and at midday as well as with the once-daily administration of 120 mg ISDN sustained-release form in the morning, there was an unequivocal anti-ischemic effect without tolerance development together with a significant reduction in the rate of anginal attacks and nitrate consumption.(ABSTRACT TRUNCATED AT 250 WORDS)