The ill effects of isosorbide mononitrate overdose are
generally the results of isosorbide mononitrate'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
mononitrate and its metabolites are not widely available, and such
determinations have, in any event, no established role in the management of
isosorbide mononitrate overdose.
There are no data suggesting what dose of isosorbide
mononitrate is likely to be life-threatening in humans. In rats and mice, there
is significant lethality at oral doses of 1965 mg/kg and 2581 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 mononitrate. Isosorbide mononitrate is significantly
removed from the blood during hemodialysis.
No specific antagonist to the vasodilator effects of
isosorbide mononitrate is known, and no intervention has been subject to
controlled study as a therapy of isosorbide mononitrate overdose. Because the
hypotension associated with isosorbide mononitrate 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 mononitrate overdose in these patients may be subtle
and difficult, and invasive monitoring may be required.
Methemoglobinemia has been reported in patients receiving
other organic nitrates, and it probably could also occur as a side effect of
isosorbide mononitrate. Certainly nitrate ions liberated during metabolism of
isosorbide mononitrate can oxidize hemoglobin into methemoglobin. Even in
patients totally without cytochrome b5 reductase activity, however, and even
assuming that the nitrate moiety of isosorbide mononitrate is quantitatively
applied to oxidation of hemoglobin, about 2 mg/kg of isosorbide mononitrate
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 mononitrate. 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 7.8-11.1 mg of isosorbide
mononitrate 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
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.
Isosorbide mononitrate is contraindicated in patients who
are allergic to it.
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