Although the venous effects predominate, nitrates produce dilation of both arterial and venous beds. The decrease in ventricular volume reduces intramyocardial tension and lessens myocardial oxygen demand. Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Prolonged administration of nitrate drugs according to traditionally recommended dosage regimens has been shown to produce tolerance.
Tolerance results in a loss of efficacy.
Several well-controlled clinical trials have used exercise testing to assess the antianginal efficacy of continuously delivered nitrates. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their antianginal efficacy been restored. Drug-free intervals sufficient to avoid tolerance to isosorbide dinitrate have not been completely defined. In the only regimen of twice-daily Cedocard SR, the 2 doses are given 6 hours apart.