MAOIs have a dangerously low toxic-to-therapeutic ratio. Ingestions of greater than 2 to 3 mg/kg of body weight can be life-threatening, and doses that are less than 2
mg/kg may still produce mild to moderate toxicity. The lethal dose of irreversible MAOI toxicity is reported to be between 4 and 6 mg/kg. 12 Deaths have been reported in adults with as little as 170 mg of tranylcypromine and 375 mg of phenelzine. Selegiline overdoses have not been reported but should be assumed to produce toxicity similar to that of the traditional MAOI antidepressants until determined otherwise. The average therapeutic dose of tranylcypromine ranges from 20 to 40 mg/day, with a maximum daily dose of 60 mg/day. It is available as a small, round, red 10-mg tablet. Therapeutic doses of phenelzine range between 45 and 75 mg/day, with a maximum of 90 mg/day. The drug comes as a small, round, orange 15-mg tablet. Isocarboxazid is manufactured as a 10-mg peach-colored tablet with therapeutic doses ranging between 10 and 30 mg/day. Selegiline has a standard dose of 10 mg/day and comes as an aqua 5-mg capsule.
An important clinical aspect of MAOI overdoses is that symptoms are characteristically delayed between 6 to 12 h postingestion but can be delayed as long as 24 h. The delayed onset of toxicity is believed to be secondary to the gradual accumulation of NE and 5-HT levels in the brain and in peripheral sympathetic neurons. Symptoms of MAOI overdose are most consistent with a hyperadrenergic state secondary to excessive stimulation of alpha- and beta-adrenergic receptors, but symptoms related to excessive serotonin receptor activity are also seen. Patients on chronic MAOI therapy may show earlier signs of toxicity due to preexisting enzyme inhibition. In severe cases, the hyperadrenergic state can be rapidly followed by hypotension and central nervous system depression resembling a sympatholytic condition. Toxicity usually persists for 1 to 4 days after ingestion.
The signs and symptoms of MAOI toxicity are often nonspecific. Even in its most severe form, it can resemble numerous other conditions (see below). Most clinical overdose information has come from single case reports or case series, with tremendous variation in presentation. Hence, there is no "typical" presentation to MAOI toxicity nor is there an orderly progression of symptoms. The clinician should anticipate the rapid development of life-threatening symptoms in all MAOI overdose patients. The initial symptoms of MAOI overdose are reported to include headache, agitation, irritability, nausea, palpitations, and tremor. The earliest signs of MAOI toxicity include sinus tachycardia, hyperreflexia, hyperactivity, fasciculations, mydriasis, hyperventilation, nystagmus, and generalized flushing. In cases of moderate toxicity, opisthotonus, muscle rigidity, diaphoresis, chest pain, hypertension, diarrhea, hallucinations, combativeness, confusion, marked hyperthermia, and trismus may become evident. A peculiar ocular finding has been observed with some cases of MAOI toxicity and is described as a "ping-pong" gaze because of the bilateral, wandering horizontal eye movements. The mechanism of this gaze disorder is unknown. In all cases, it gradually resolves as the patient improves. Severe toxicity is accomplished by bradycardia, cardiac arrest, hypoxia, papilledema, hypotension, seizures, coma, and worsening hyperthermia. Hypotension is an ominous finding that commonly remains resistant to therapeutic attempts at correction. Fetal demise, cerebral edema, pulmonary edema, and intracranial hemorrhage have all been reported in association with MAOI overdoses. The most common electrocardiographic abnormality seen in MAOI toxicity is sinus tachycardia, but T-wave abnormalities are not uncommon. Deaths are usually secondary to multiple organ failure.
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