ISOSORBIDE DINITRATE

Fetal Risk Summary

Isosorbide is a nitric oxide donor, similar to nitroglycerin, that is used in the management of angina pectoris and of heart failure. It is administered sublingually, chewable tablets, and oral tablets. An oral spray is also available outside of the United States. The molecular weight (about 236) is low enough that passage to the fetus should be expected.

The drug produces dose-related embryotoxicity in rabbits at doses 35 and 150 times the maximum recommended human dose (1). (See also Nitroglycerin or Amyl Nitrite).

Two full reports and one abstract have described the use of isosorbide dinitrate during human pregnancy (2,3 and 4). However, all of the pregnancies in these reports had prescheduled elective terminations for nonmedical reasons shortly after the drug exposure. In a 1996 study (first published as an abstract in 1995), 18 women in the 2nd trimester received a single 5-mg sublingual dose of isosorbide dinitrate (2,3). Statistically significant decreases in the maternal systolic and diastolic blood pressures were observed 6 minutes after the dose. The blood pressures gradually returned to control levels over the ensuing 30 minutes. The mean maternal heart rate significantly increased from about 85 beats/minute to 96 beats/minute at 6 minutes, but declined to near control levels at 8 minutes. The mean systolic-diastolic flow velocity ratios in the umbilical and uterine arteries declined significantly, reaching nadirs at 6 and 10 minutes, respectively, before gradually returning to pre-dose levels. These findings suggested that isosorbide dinitrate may be beneficial in reversing the effects of endothelial cell dysfunction-induced generalized vasoconstriction and increased vascular resistance to flow in the uteroplacental circulation, such as occurs in preeclampsia (2,3).

In a similar investigation by these same researchers, 11 women at a mean gestational age of 10.0 weeks (range 8.2–11.6 weeks) were given a single 5-mg sublingual dose of the drug (4). The results of this study were comparable to the researchers previous work and led them to a similar conclusion that isosorbide dinitrate may be effective in reversing the effects of the endothelial cell dysfunction that is observed in preeclampsia (4).

Breast Feeding Summary

No reports describing the use of isosorbide dinitrate during lactation have been located. The molecular weight (about 236) is low enough that excretion into breast milk should be expected. The effects of this exposure on a nursing infant are unknown.

References

1. Product information. Isordil. Wyeth-Ayerst Laboratories, 1993.
2. Thaler I, Amit A, Itskovitz J. The effect of isosorbide dinitrate, a nitric oxide donor, on human uterine and placental vascular resistance in patients with preeclampsia (abstract). Am J Obstet Gynecol 1995;172:387.
3. Thaler I, Amit A, Jakobi P, Itskovitz-Eldor J. The effect of isosorbide dinitrate on uterine artery and umbilical artery flow velocity waveforms at mid-pregnancy. Obstet Gynecol 1996;88:838–43.
4. Amit A, Thaler I, Paz Y, Itskovity-Eldor J. The effect of a nitric oxide donor on Doppler flow velocity waveforms in the uterine artery during the first trimester of pregnancy. Ultrasound Obstet Gynecol 1998;11:94–8.