CLINICAL PHARMACOLOGY
The principal pharmacological action of isosorbide dinitrate is
relaxation of vascular smooth muscle and consequent dilatation of
peripheral arteries and veins, especially the latter. Dilatation of the
veins promotes peripheral pooling of blood and decreases venous return
to the heart, thereby reducing left ventricular end-diastolic pressure
and pulmonary capillary wedge pressure (preload). Arteriolar relaxation
reduces systemic vascular resistance, systolic arterial pressure, and
mean arterial pressure (afterload). Dilatation of the coronary arteries
also occurs. The relative importance of preload reduction, afterload
reduction, and coronary dilatation remains undefined.
Dosing regimens for most chronically used drugs are designed to
provide plasma concentrations that are continuously greater than a
minimally effective concentration. This strategy is inappropriate for
organic nitrates. Several well-controlled clinical trials have used
exercise testing to assess the antianginal efficacy of
continuously-delivered nitrates. In the large majority of these trials,
active agents were no more effective than placebo after 24 hours (or
less) of continuous therapy. Attempts to overcome nitrate tolerance by
dose escalation, even to doses far in excess of those used acutely, have
consistently failed. Only after nitrates have been absent from the body
for several hours has their antianginal efficacy been
restored.
Pharmacokinetics
The kinetics of absorption of isosorbide dinitrate from
dilatrate®-SR sustained release capsules have not been well
studied. Studies of immediate-release formulations of ISDN have
found highly variable bioavailability (10 to 90%), with
extensive first-pass metabolism in the liver. Most such studies
have observed progressive increases in bioavailability during
chronic therapy; it is not known whether similar increases in
bioavailability appear during the course of chronic therapy with
dilatrate®-SR sustained release capsules.
Once absorbed, the distribution volume of isosorbide
dinitrate is 2-4 L/kg and this volume is cleared at the rate of
2-4 L/min, so ISDN's half-life in serum is about an hour. Since
the clearance exceeds hepatic blood flow, considerable
extrahepatic metabolism must also occur. Clearance is affected
primarily by denitration to the 2-mononitrate (15 to 25%) and
the 5-mononitrate (75 to 85%).
Both metabolites have biological activity, especially the
5-mononitrate. With an overall half-life of about 5 hours, the
5-mononitrate is cleared from the serum by denitration to
isosorbide; glucuronidation to the 5-mononitrate glucuronide;
and denitration/hydration to sorbitol. The 2-mononitrate has
been less well studied, but it appears to participate in the
same metabolic pathways with a half-life of about 2 hours.
The interdosing interval sufficient to avoid tolerance to
ISDN has not been well defined. Studies of nitroglycerin (an
organic nitrate with a very short half-life) have shown that
dosing intervals of 10-12 hours are usually sufficient to
prevent or attenuate tolerance. Dosing intervals that have
succeeded in avoiding tolerance during trials of moderate doses
(e.g., 30 mg) of immediate release ISDN have generally been
somewhat longer (at least 14 hours), but this is consistent with
the longer half-lives of ISDN and its active metabolites.
An interdosing interval sufficient to avoid tolerance
with dilatrate®-SR has not been demonstrated. In an eccentric
dosing study, 40 mg capsules of dilatrate®-SR were administered
daily at 0800 and 1400 hours. After two weeks of this regimen,
dilatrate®-SR was statistically indistinguishable from placebo.
Thus, the necessary interdosing interval sufficient to avoid
tolerance remains unknown, but it must be greater than 18 hours.
Few well-controlled clinical trials of organic nitrates
have been designed to detect rebound or withdrawal effects. In
one such trial, however, subjects receiving nitroglycerin had
less exercise tolerance at the end of the daily interdosing
interval than the parallel group receiving placebo. The
incidence, magnitude, and clinical significance of similar
phenomena in patients receiving ISDN have not been
studied.
Clinical Trials
In clinical trials, extended-release oral isosorbide
dinitrate has been administered in a variety of regimens, with
total daily doses ranging from 40 to 160 mg. A controlled trial
using a single 40 mg sustained-release oral dose of isosorbide
dinitrate (dilatrate®-SR) has demonstrated effective reductions
in exercise-related angina for up to 8 hours. Antianginal
activity is present about 1 hour after dosing.
Adequate multiple-dose trials of dilatrate®-SR sustained
release capsules have not been reported.
Most controlled trials of multiple-dose immediate-release
oral ISDN taken every 12 hours (or more frequently) for several
weeks have shown statistically significant antianginal efficacy
for only 2 hours after dosing. Once-daily regimens, and regimens
with one daily interdosing interval of at least 14 hours (e.g.,
a regimen providing doses at 0800, 1400 and 1800 hours), have
shown efficacy after the first dose of each day that was similar
to that shown in the single dose studies cited above. The
efficacy of subsequent doses has not been demonstrated. From
large, well-controlled studies of other nitrates, it is
reasonable to believe that the maximal achievable daily duration
of antianginal effect from isosorbide dinitrate is about 12
hours. No dosing regimen for dilatrate®-SR sustained release
capsules has actually been shown to achieve this duration of
effect.
|
