Tolerance to the circulatory effects of oral isosorbide dinitrate. Rate of development and cross-tolerance to glyceryl trinitrate.

The effects of 15, 30, 60 and 120 mg of isosorbide dinitrate (ISDN) on systolic blood pressure (SBP) and heart rate (HR) were compared after acute oral administration and during sustained therapy four times daily with ISDN in six patients. After any given dose, plasma ISDN levels were higher during sustained therapy than during acute therapy. The average peak reduction in standing SBP occurred at 2 hours after 15, 30, 60 and 120 mg of ISDN; the values were 39, 42, 45 and 46 mm Hg, respectively, after acute therapy and 21, 20, 26 and 24 mm Hg, respectively, during sustained therapy (p < 0.01). Compared with placebo, the reduction in SBP was still apparent 6 hours after any given dose of ISDN during acute but not during sustained therapy (p < 0.01). HR increased significantly only after acute therapy. The rapidity of development of tolerance to ISDN and cross-tolerance to glyceryl trinitrate (GTN) was evaluated in eight other patients. The average peak reduction in SBP after the first dose of 15 mg of ISDN was 36 mm Hg, but after therapy with ISDN every 6 hours, the fifth dose of 15 mg of ISDN produced a peak reduction in SBP of only 7 mm Hg (p < 0.001). The first dose of 0.6 mg GTN before therapy with ISDN produced a peak reduction in SBP of 40 mm Hg, but after therapy with ISDN every 6 hours for 5 days, the same dose of GTN produced a maximum reduction in SBP of only 10 mm Hg (p < 0.001). The results show that partial circulatory tolerance to ISDN and cross-tolerance to GTN developed rapidly during regular therapy with ISDN. The plasma ISDN concentrations were higher during sustained than after acute therapy, suggesting that the tolerance (tachyphylaxis) to nitrates in man is due to the diminution of the end organ response and not to the accelerated metabolism of nitrates.