Low-dose oral isosorbide in the treatment of coronary artery disease

Background: Isosorbide dinitrate (ISDN) is commonly administered in a dosage of 10 to 20 mg, two to three times daily, as an antianginal agent. The purpose of this study was to investigate the dose-response curve of very low ISDN doses concerning their acute therapeutic effect. Methods: The acute antianginal and peripheral vasodilating effects of a single oral dose of 0.3 mg, 1.25 mg, 5 mg, and 20 mg of isosorbide dinitrate (ISDN) were studied in 30 patients with stable, exercise-induced ST-segment depression and angina pectoris. Mean age was 56 ± 12 years (29 men, 1 woman), and all patients had angiographically documented coronary artery disease. In the randomized, double-blind, placebo-controlled trial, the hemodynamic response to each dose was studied by exercise stress testing and finger-pulse plethysmography. Results: The average 1-hour post-dose increase in serum concentration of the major biologically active metabolite isosorbide-5-mononitrate (IS-5-MN) was below the detection limit (< 5 ng/mL) after 0.3 mg ISDN, and 7 ±16, 45 ± 55, and 127 ±59 ng/mL after 1.25 mg, 5 mg, and 20 mg ISDN, respectively. Compared with placebo, the lowest ISDN dose had no anti-ischemic effect, whereas 1.25 mg of ISDN resulted in a 10% reduction of ST-segment depression (P < 0.05), 5 mg achieved a reduction of 36%, and 20 mg of ISDN, 45%, respectively (P < 0.001). The heart rate at rest decreased 4% after 0.3 mg (P < 0.01) and 3% after 1.25 mg ISDN (P < 0.01), was unchanged after 5 mg, and increased 6% after 20 mg ISDN (P < 0.01). Supine systolic blood pressure decreased 2% after 1.25 mg (NS), 7% after 5 mg (P < 0.01), and 12% after 20 mg ISDN (P < 0.001); corresponding changes for the diastolic blood pressure were 0%, −1 %, −2% (NS). Changes in Wood pressure and heart rate in the upright position were comparable, but augmented with significant decreases in diastolic blood pressure after 5 and 20 mg ISDN, as well (P < 0.001). Peripheral vasodilation, measured by digital pulse plethysmography, occurred with higher ISDN doses: 5 mg ISDN achieved 31 % (P < 0.001); 20 mg, 66% peripheral arterial vasodilation (P < 0.001). Conclusions: These data demonstrate an antianginal efficacy of a very low oral dose of ISDN. The dose-response relationship of the antianginal and hemodynamic effects of ISDN were closely related, both starting at single oral doses of 1.25 mg ISDN.