Oral isosorbide dinitrate in the treatment of angina pectoris. Dose-response relationship and duration of action during acute therapy

The duration of effects of single oral doses of 15, 30 and 60 mg of isosorbide dinitrate (ISDN) were studied in 12 patients with stable, exercise-induced angina pectoris. The effects of a 120-mg dose were also studied in seven of these 12 patients. The average peak values for plasma ISDN concentration were 6.8, 14.3, 17.5 and 26.0 ng/ml after 15, 30, 60 and 120 mg of ISDN, respectively, and there was a 5-, 12-, 6-, and 5-fold interindividual variation in peak plasma concentration at these doses. At rest, both the systolic and diastolic blood pressures decreased after each dose of ISDN in both the supine (p<0.05) and standing (p<0.01) positions. The reduction in systolic blood pressure was more marked in the standing position. This effect occurred at 1 hour and persisted for 6 hours after 15 mg of ISDN and for 8 hours after other doses of ISDN. Exercise duration to the onset of angina and to the development of moderate angina increased by a similar degree after each dose of ISDN compared with placebo values (p<0.001). This was apparent by 1 hour and the effects persisted for 8 hours. The maximum increase in walking time to angina occurred after 15 mg in six patients, after 30 mg in two patients, and after 60 mg in three patients. One patient did not improve after any of the doses. The heart rate (p<0.01) and rate-pressure product (p<0.05) at the onset of angina after any dose of ISDN increased compared with placebo values. However, ST-segment depression at the onset of angina was similar after ISDN and placebo. At the onset of moderate angina, the values for rate-pressure product after ISDN were similar to those after placebo, but ST-segment depression was less after ISDN (p<0.05). These data show that administration of single doses of ISDN from 15-120 mg increased exercise tolerance to angina for 8 hours, but for the whole group, higher doses did not have a quantitative greater effect on exercise tolerance than the lower doses.