DRUG INTERACTIONS
Drug Interactions
Concomitant use of dilatrate®-SR with phosphodiesterase inhibitors in any form is contraindicated (see CONTRAINDICATIONS).
Concomitant use of dilatrate®-SR with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see CONTRAINDICATIONS).
The vasodilating effects of isosorbide dinitrate may be
additive with those of other vasodilators. Alcohol, in
particular, has been found to exhibit additive effects of this
variety.
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OVERDOSAGE
Hemodynamic Effects
The ill effects of isosorbide dinitrate overdose are
generally the results of isosorbide dinitrate's capacity to
induce vasodilatation, venous pooling, reduced cardiac output,
and hypotension. These hemodynamic changes may have protean
manifestations, including increased intracranial pressure, with
any or all of persistent throbbing headache, confusion, and
moderate fever; vertigo; palpitations; visual disturbances;
nausea and vomiting (possibly with colic and even bloody
diarrhea); syncope (especially in the upright posture); air
hunger and dyspnea, later followed by reduced ventilatory
effort; diaphoresis, with the skin either flushed or cold and
clammy; heart block and bradycardia; paralysis; coma; seizures
and death.
Laboratory determinations of serum levels of isosorbide
dinitrate and its metabolites are not widely available, and such
determinations have, in any event, no established role in the
management of isosorbide dinitrate overdose.
There are no data suggesting what dose of isosorbide
dinitrate is likely to be life-threatening in humans. In rats,
the median acute lethal dose (LD50) was found to be
1100 mg/kg.
No data are available to suggest physiological maneuvers
(e.g., maneuvers to change the pH of the urine) that might
accelerate elimination of isosorbide dinitrate and its active
metabolites. Similarly, it is not known which, if any, of these
substances can usefully be removed from the body by
hemodialysis.
No specific antagonist to the vasodilator effects of
isosorbide dinitrate is known, and no intervention has been
subject to controlled study as a therapy of isosorbide dinitrate
overdose. Because the hypotension associated with isosorbide
dinitrate overdose is the result of venodilatation and arterial
hypovolemia, prudent therapy in this situation should be
directed toward an increase in central fluid volume. Passive
elevation of the patient's legs may be sufficient, but
intravenous infusion of normal saline or similar fluid may also
be necessary. The use of epinephrine or other arterial
vasoconstrictors in this setting is likely to do more harm than
good.
In patients with renal disease or congestive heart
failure, therapy resulting in central volume expansion is not
without hazard. Treatment of isosorbide dinitrate overdose in
these patients may be subtle and difficult, and invasive
monitoring may be required.
Methemoglobinemia
Nitrate ions liberated during metabolism of isosorbide
dinitrate can oxidize hemoglobin into methemoglobin. Even in
patients totally without cytochrome b5 reductase
activity, however, and even assuming that the nitrate moieties
of isosorbide dinitrate are quantitatively applied to oxidation
of hemoglobin, about 1 mg/kg of isosorbide dinitrate should be
required before any of these patients manifests clinically
significant (≥ 10%) methemoglobinemia. In patients with normal
reductase function, significant production of methemoglobin
should require even larger doses of isosorbide dinitrate. In one
study in which 36 patients received 2-4 weeks of continuous
nitroglycerin therapy at 3.1 to 4.4 mg/hr (equivalent, in total
administered dose of nitrate ions, to 4.8-6.9 mg of bioavailable
isosorbide dinitrate per hour), the average methemoglobin level
measured was 0.2%; this was comparable to that observed in
parallel patients who received placebo. Notwithstanding these
observations, there are case reports of significant
methemoglobinemia in association with moderate overdoses of
organic nitrates. None of the affected patients had been thought
to be unusually susceptible. Methemoglobin levels are available
from most clinical laboratories. The diagnosis should be
suspected in patients who exhibit signs of impaired oxygen
delivery despite adequate cardiac output and adequate arterial
p02. Classically, methemoglobinemic blood is
described as chocolate brown, without color change on exposure
to air.
When methemoglobinemia is diagnosed, the treatment of
choice is methylene blue, 1-2 mg/kg intravenously.
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CONTRAINDICATIONS
Isosorbide dinitrate is contraindicated in patients who are allergic to it.
Do not use dilatrate®-SR in patients who are taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), such as sildenafil, tadalafil, vardenafil, or avanafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia.
Do not use dilatrate®-SR in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.
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