onse, syncope can result from the decrease in blood pressure that occurs following higher doses of nitrites and nitrates. Although this is not likely to occur with doses of nitrates that do not cause blood pressure reduction, patients should be sitting or lying down during and immediately after administration of isosorbide dinitrate.
Continuous administration of nitrates can lead to the rapid development of tolerance. The mechanisms responsible for nitrate tolerance are not fully understood; however, proposed mechanisms include neurohormonal counterregulatory mechanisms including activation of reflex vasoconstriction, intravascular volume expansion, desensitization of guanylate cyclase, depletion of sulfhydryl groups in vascular smooth muscle, a decrease in nitroglycerin biotransformation, or nitrate-mediated vascular superoxide production. Nitrate tolerance is thought to occur as a result of several of these mechanisms. Using a dosing schedule with a nitrate-free interval is the most reliable and successful strategy in preventing nitrate tolerance during chronic administration.
PHARMACOKINETICS
Isosorbide dinitrate (ISDN) is administered orally. It is about 28% protein bound and the volume of distribution is 2—4 L/kg. Isosorbide distributes throughout the body tissues and is metabolized by denitration to isosorbide-2-mononitrate (15—25%) or isosorbide-5-mononitrate (75—85%), both of which are pharmacologically active and contribute to the efficacy of isosorbide dinitrate, especially isosorbide-5-mononitrate. ISDN is virtually completely metabolized, with minute portions of the parent drug and metabolites excreted renally. The half-life of the parent drug, isosorbide-5-mononitrate, and isosorbide-2-mononitrate in plasma is 1 hour, 5 hours, and 2 hours, respectively.
Oral Route
Orally administered isosorbide dinitrate is absorbed rapidly from the GI tract and undergoes extensive first-pass metabolism resulting in a variable bioavailability of roughly 25% (ranging from 10—90%); most studies have observed increases in bioavailability during chronic therapy. Sublingual administration bypasses the first-pass effect, resulting in a bioavailability of 45—59%. The bioavailability of sustained-release preparations of ISDN approach 75%. The sublingual and chewable preparations of the drug exert their effect within 5—20 minutes, while the onset of action of conventional oral forms of isosorbide begins in 7.5—45 minutes following administration. Extended-release capsules or tablets have an onset of action of 60—90 minutes. The duration of effect of the sublingual and chewable forms of the drug is 45 minutes to 2 hours, while that of the conventional oral forms is 2—6 hours. The duration of effect of the sustained-release oral preparations is 10—14 hours. |
