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
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.
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
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 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