Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

Specific Substances

A)

1) Isocarboxazida
2) Isocarboxazide
3) Isocarboxazidum
4) CAS 59-63-2

1) Nialamid
2) Nialamida
3) Nialamidi
4) Nialamidum
5) CAS 51-12-7

1) Fenelzina, sulfato de
2) Phenelzine sulfate
3) CAS 51-71-8 (phenelzine)
4) CAS 156-51-4 (phenelzine sulfate)

1) SKF-385
2) Transamine sulphate
3) Tranylcypromine sulfate
4) CAS 155-09-9 (Tranylcypromine)
5) CAS 13492-01-8 (Tranylcypromine sulfate)

1) MAOI
2) MAOIs
3) MAO INHIBITORS

Available Forms Sources

A)

1) ISOCARBOXAZID: Available in the United States as 10 mg oral tablets (Prod Info MARPLAN(R) oral tablets, 2007).
2) NIALAMIDE: Not available in the United States.
3) PHENELZINE: Available in the United States as 15 mg oral tablets (Prod Info NARDIL(R) oral tablets, 2007).
4) TRANYLCYPROMINE: Available in the United States as 10 mg oral tablets (Prod Info PARNATE(R) oral tablets, 2008).

B)

1) Monoamine Oxidase Inhibitors (MAOIs) are primarily used for the treatment of depression (Prod Info MARPLAN(R) oral tablets, 2007; Prod Info NARDIL(R) oral tablets, 2007; Prod Info PARNATE(R) oral tablets, 2008).
2) This management discusses non-selective MAOIs (eg, isocarboxazid, phenelzine, and tranylcypromine). Drugs that are selective inhibitors of MAO-B (eg, selegiline) and those that are selective inhibitors of MAO-A (eg, moclobemide) are discussed in separate managements. These agents appear to have less toxicity than irreversible non-selective MAOIs. For further information, please refer to "Reversible MAO-A Inhibitors" and "MAO-B Inhibitors" documents.

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Monoamine Oxidase Inhibitors (MAOIs) are primarily used for the treatment of depression. This management discusses non-selective MAOIs (eg, isocarboxazid, phenelzine, and tranylcypromine). Drugs that are selective inhibitors of MAO-B (eg, selegiline) and those that are selective inhibitors of MAO-A (eg, moclobemide) are discussed in separate managements. These agents appear to have less toxicity than irreversible non-selective MAOIs. For further information, please refer to "Reversible MAO-A Inhibitors" and "MAO-B Inhibitors" documents.
B) PHARMACOLOGY: First generation MAOIs non-selectively inhibit monoamine oxidase enzymes, increasing serotonin, epinephrine, norepinephrine, phenylethylamine, and dopamine. Monoamine oxidase (MAO) may be inhibited in the gastrointestinal tract where it limits metabolism of tyramine and decreases the concentration of tyramine in the systemic circulation. Inhibition of MAO by these drugs is irreversible; effects persist for days to weeks after drug discontinuation.
C) TOXICOLOGY: Toxicology is an extension of the pharmacology of MAOIs. Patients have a catecholamine excess which leads to a hyperadrenergic state/sympathetic hyperactivity. Toxicity generally occurs after an overdose or when MAOIs are combined with certain drugs (other drugs with MAO or serotonergic activity) or certain foods (tyramine reactions). While tyramine reactions are serious, they are generally self-limited. Overdose is life-threatening.
D) EPIDEMIOLOGY: First generation MAOIs are rarely used and overdose is rare, but can be life-threatening.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: The following adverse effects have been reported following MAOIs therapy: Dizziness, headache, drowsiness, sleep disturbances, fatigue, weakness, tremors, twitching, muscle spasm, myoclonic movements, hyperreflexia, nausea, diarrhea, constipation, tachycardia, hypertension, postural hypotension, sensorimotor peripheral neuropathy (a dose-related side effect of phenelzine); RARE: anemia, agranulocytosis, leukopenia , thrombocytopenia. Worsening of depression or suicidal ideation may occur during the therapeutic use of these agents.
2) DRUG INTERACTIONS: The concurrent use of MAOIs and drugs that may augment catecholamine release (eg, pseudoephedrine and phenylephrine) may cause or exacerbate toxicity. Serotonin syndrome may develop in patients taking MAOIs with other serotonergic agents such as illicit drugs (eg, ecstacy/MDMA), medications (eg, dextromethorphan, SSRIs, meperidine), and herbal supplements (eg, St John's Wort). Drugs that are not typically considered MAOIs but have MAO inhibition properties, include the antibiotic linezolid, the herbal supplement St John’s Wort, and the chemotherapeutic agent procarbazine. When combined with other medications with MAOI activity, these may cause toxicity.
3) FOOD INTERACTIONS: Foods containing high concentrations of tyramine may interact with MAOIs and cause serious reactions. These foods include chocolate, certain aged cheeses, Chianti and other aged red wines, vermouth, avocado, pickled fish, broad beans, beers, liver, smoked or pickled meats, snails, and yeast extracts.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Tachycardia, mild hypertension, anxiety, flushing, and headache are common in mild to moderate toxicity. Because MAO inhibition by these drugs is irreversible, drug or food interactions symptoms may develop days to weeks after discontinuation of therapy.
2) SEVERE TOXICITY: Hyperadrenergic symptoms, such as severe tachycardia and hypertension, diaphoresis, delirium, seizures, dysrhythmias and possibly cardiovascular collapse and coma, may occur. Hypertensive crisis can lead to intracranial hemorrhage, renal damage, and myocardial infarction. Serotonin syndrome is a triad of autonomic instability (ie, hyperthermia, hypertension or hypotension), neuromuscular excitability (ie, clonus and rigidity), and altered mental status that may be thought of as a spectrum of symptoms. Multiorgan failure and death may result from any of these complications.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Severe hyperthermia has been reported in overdose.

0.2.5)

A) WITH THERAPEUTIC USE

1) Severe hypertensive crisis may be noted with the combined use of MAO inhibitors and oral sympathomimetic amines at therapeutic doses.

B) WITH POISONING/EXPOSURE

1) Mild overdose or the early phase of severe toxicity may manifest hypertension, tachycardia, flushing and palpitations. Profound hypotension, bradycardia, cardiovascular collapse and asystolic arrest may be noted following overdose of MAO inhibitors alone.

0.2.6)

A) WITH POISONING/EXPOSURE

1) Tachypnea, pulmonary edema, and respiratory depression may be noted.

0.2.7)

A) WITH POISONING/EXPOSURE

1) MILD TO MODERATE INTOXICATION is associated with drowsiness, followed by dizziness, restlessness, irritability, headache, hallucinations, myoclonus and tremors.
2) SEVERE INTOXICATION - Symptoms can occur within hours. Initial manifestation is faintness, followed by intense headache, agitation, hyperreflexia, opisthotonus, seizures and coma.

0.2.8)

A) WITH THERAPEUTIC USE

1) Nausea, diarrhea and constipation have been reported with therapeutic use.

0.2.10)

A) WITH THERAPEUTIC USE

1) Urinary retention and sexual disturbances may occur with therapeutic use of these agents.

B) WITH POISONING/EXPOSURE

1) Renal failure may develop in severe cases.

0.2.11)

A) WITH POISONING/EXPOSURE

1) Metabolic or respiratory acidosis may develop in severe cases.

0.2.13)

A) WITH THERAPEUTIC USE

1) Coagulopathy, hemolysis and thrombocytopenia have been reported.

B) WITH POISONING/EXPOSURE

1) Coagulopathy, hemolysis and thrombocytopenia may develop with MAOI overdose.

0.2.15)

A) WITH THERAPEUTIC USE

1) Muscle hyperactivity and rigidity can develop with therapeutic use, as well as rhabdomyolysis.

B) WITH POISONING/EXPOSURE

1) Muscle hyperactivity and rigidity are common in overdose. Rhabdomyolysis may develop.

0.2.20)

A) Phenelzine and tranylcypromine are both FDA Pregnancy Category C.

Laboratory Monitoring

A)

B)

C)

D)

E)

F)

G)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treat anxiety, agitation, and tachycardia with benzodiazepines. Monitor the patient carefully for progression of symptoms. Symptoms and the potential for drug/food interactions may persist for several weeks due to the irreversibility of MAO inhibition. The offending agents should be discontinued and patient education involving drug and food interactions should be provided to all symptomatic patients.

B) MANAGEMENT OF SEVERE TOXICITY

1) Careful attention to the ABCs (airway, breathing and circulation) should guide symptomatic and supportive treatment, which is the mainstay of management of MAOI toxicity. Orotracheal intubation for airway protection should be performed early in cases of coma or severe toxicity, especially for patients that are agitated with hyperthermia. Recognition and aggressive treatment of agitation, hyperthermia, hypertension, seizures, end-organ damage and muscular rigidity is paramount. There is no antidote for MAOI toxicity. Please see below for treatment of specific signs and symptoms.

C) DECONTAMINATION

1) PREHOSPITAL: MAOI overdoses are life-threatening. Induction of emesis is not recommended. Activated charcoal should be considered early in the course after a significant oral ingestion in patients that are protecting their airways and have not yet manifested signs of toxicity. If a patient is displaying signs of toxicity, the risk of aspiration likely outweighs the potential benefit of charcoal.
2) HOSPITAL: Activated charcoal should be administered in asymptomatic or minimally symptomatic patients who present within a few hours of ingestion, or in symptomatic patients who have a secure airway. Gastric lavage may be considered for large overdoses who present within 1 hour of ingestion, though airway protection should be considered prior to the procedure.

D) AIRWAY MANAGEMENT

1) Perform early in patients with severe intoxication (coma, respiratory depression, severe agitation).

E) ANTIDOTE

1) None.

F) PSYCHOMOTOR AGITATION

1) Liberal use of benzodiazepines is recommended until patient is mildly sedated.

G) HYPERTENSION

1) If hypertension persists after agitation is controlled with benzodiazepines, rapidly-acting, easily titrated vasodilators like nitroglycerin and nitroprusside should be used as these patients often cycle between hyper and hypotension.

H) TACHYCARDIA

1) Tachycardia may occur from a combination of agitation and catecholamine release. Treat with benzodiazepines. Pure beta blockade is generally avoided in these patients as it may exacerbate hypertension.

I) SEROTONIN SYNDROME

1) Treat the patient aggressively with benzodiazapines and cooling if needed. Cyproheptadine may be considered (seek guidance from a toxicologist prior to administering).

J) HYPERTHERMIA

1) Hyperthermia can result from psychomotor agitation, increased neuromuscular activity or persistent seizures. Sedate the patient with benzodiazepines (large doses may be required). Other cooling measures can include cool mist and fans, cool packs in axilla and groin, or more aggressive cooling measures, such as ice baths, for severe hyperthermia. Neuromuscular paralysis of the patient may be necessary.

K) DYSRHYTHMIAS

1) Follow ACLS protocols.

L) SEIZURES

1) Treat seizures with intravenous benzodiazepines; add propofol and/or barbiturates if necessary. If seizures persist, intubate and paralyze the patient and institute barbiturate coma with continuous EEG monitoring. Obtain a CT scan of head to rule out intracranial hemorrhage.

M) HYPOTENSION

1) Mild orthostatic hypotension is common with therapeutic use. Severe hypotension is rare but may occur as a late and ominous finding as a result of cardiovascular collapse. Hypotension should be treated with an initial bolus of NS, if patient can tolerate a fluid load, then adrenergic vasopressors can be used to raise mean arterial pressure. Direct agents (norepinephrine) are preferred to indirect agents (dopamine) because indirect pressors rely on catecholamine release from sympathetic neurons.

N) ENHANCED ELIMINATION

1) Hemodialysis and hemoperfusion are not of value.

O) PATIENT DISPOSITION

1) HOME CRITERIA: Home management is not recommended. Children should be evaluated in the hospital and observed. Adults should be evaluated by a health care professional if they have received a higher than therapeutic dose, or if they are symptomatic.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions or children with inadvertent ingestions should be sent to a health care facility for observation for development of toxicity. After an overdose, clinical effects may be delayed up to 32 hours but are usually apparent within 24 hours.
3) ADMISSION CRITERIA: Any patient with presumed overdose should be observed with cardiac monitoring for 24 hours due to the possibility of delayed toxicity. Patients with significant persistent hypertension, hyperthermia, seizures, dysrhythmias, delirium, tachycardia or central nervous depression should be admitted to the ICU.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

P) PITFALLS

1) Failure to not recognize or to misdiagnose MAOI toxicity. Note that effects extend for many weeks and failure to wait for a "washout period" after discontinuing an MAOI and starting another substance that may interact with an MAOI can result in toxicity. Other causes of altered mental status, such as hypoxia or hypoglycemia, must be ruled out.

Q) PHARMACOKINETICS

1) In general, MAOIs are well absorbed when taken orally. Metabolism is primarily hepatic and metabolites are excreted in the urine. Half lives: tranylcypromine, 1.5 to 2.5 hours; phenelzine, 11.6 hours. The therapeutic and toxic effects of MAOIs often lag behind their metabolism and excretion.

R) DIFFERENTIAL DIAGNOSIS

1) CNS infection, intracranial hemorrhage, manic or psychotic episode due to psychiatric illness, sympathomimetic intoxication (eg, cocaine, methamphetamine), ethanol/benzodiazepine/barbiturate, antipsychotic or clonidine withdrawal, hypoglycemia, hypoxia, serotonin syndrome from other agents.

Range Of Toxicity

A)

B)

C)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) ADVERSE EFFECTS: The following adverse effects have been reported following MAOIs therapy: Dizziness, headache, drowsiness, sleep disturbances, fatigue, weakness, tremors, twitching, muscle spasm, myoclonic movements, hyperreflexia, nausea, diarrhea, constipation, tachycardia, hypertension, postural hypotension, sensorimotor peripheral neuropathy (a dose-related side effect of phenelzine); RARE: anemia, agranulocytosis, leukopenia , thrombocytopenia. Worsening of depression or suicidal ideation may occur during the therapeutic use of these agents.
2) DRUG INTERACTIONS: The concurrent use of MAOIs and drugs that may augment catecholamine release (eg, pseudoephedrine and phenylephrine) may cause or exacerbate toxicity. Serotonin syndrome may develop in patients taking MAOIs with other serotonergic agents such as illicit drugs (eg, ecstacy/MDMA), medications (eg, dextromethorphan, SSRIs, meperidine), and herbal supplements (eg, St John's Wort). Drugs that are not typically considered MAOIs but have MAO inhibition properties, include the antibiotic linezolid, the herbal supplement St John’s Wort, and the chemotherapeutic agent procarbazine. When combined with other medications with MAOI activity, these may cause toxicity.
3) FOOD INTERACTIONS: Foods containing high concentrations of tyramine may interact with MAOIs and cause serious reactions. These foods include chocolate, certain aged cheeses, Chianti and other aged red wines, vermouth, avocado, pickled fish, broad beans, beers, liver, smoked or pickled meats, snails, and yeast extracts.

F)

1) MILD TO MODERATE TOXICITY: Tachycardia, mild hypertension, anxiety, flushing, and headache are common in mild to moderate toxicity. Because MAO inhibition by these drugs is irreversible, drug or food interactions symptoms may develop days to weeks after discontinuation of therapy.
2) SEVERE TOXICITY: Hyperadrenergic symptoms, such as severe tachycardia and hypertension, diaphoresis, delirium, seizures, dysrhythmias and possibly cardiovascular collapse and coma, may occur. Hypertensive crisis can lead to intracranial hemorrhage, renal damage, and myocardial infarction. Serotonin syndrome is a triad of autonomic instability (ie, hyperthermia, hypertension or hypotension), neuromuscular excitability (ie, clonus and rigidity), and altered mental status that may be thought of as a spectrum of symptoms. Multiorgan failure and death may result from any of these complications.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Severe hyperthermia has been reported in overdose.

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPERTHERMIA: Severe hyperthermia has been commonly reported following overdose (van Riel et al, 2002; Prueter et al, 2001; Kaplan et al, 1986; Verrilli et al, 1987; Erich et al, 1995; Pennings et al, 1997).

a) INCIDENCE: Elevated temperature was described in 50% of published cases in a review of 12 overdose reports (Meredith & Vale, 1985).
b) Hyperthermia is also common in patients with serotonin syndrome related to MAOI use (Miller et al, 1991; Rossiter & Souney, 1993; Ooi, 1991) and has been reported with the newer monoamine oxidase A agents (See Monoamine Oxidase A (MAO-A) .

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS: Pupils may be enlarged and minimally reactive to light after MAOI overdose or MAOI-induced serotonin syndrome (Mallampalli et al, 1987; Verrili et al, 1987; (Miller et al, 1991; Erich et al, 1995).

a) INCIDENCE: Mydriasis was reported in 58% of MAOI overdoses in a review of 12 published cases (Meredith & Vale, 1985).

2) NYSTAGMUS has been reported following overdoses.

a) INCIDENCE: Nystagmus was reported in 33% of MAOI overdoses in a review of 12 published cases (Meredith & Vale, 1985).
b) Nystagmus has also been reported with MAOI-meperidine interactions (Rossiter & Souney, 1993).

3) PING PONG GAZE has been reported following overdoses.

a) CASE REPORT: A 55-year-old unconscious man had spontaneously open eyes which exhibited periodic alternating gaze (cycle lasting 3 to 4 seconds) following an ingestion of 500 mg tranylcypromine several hours prior to admission. The movements persisted continuously for approximately 12 hours. He recovered completely without residual neurologic impairment (Watkins & Ellis, 1989).
b) Ping pong gaze has been described in three other patients following MAOI overdose (Prueter et al, 2001; Erich et al, 1995).

Cardiovascular

3.5.1)

A) WITH THERAPEUTIC USE

1) Severe hypertensive crisis may be noted with the combined use of MAO inhibitors and oral sympathomimetic amines at therapeutic doses.

B) WITH POISONING/EXPOSURE

1) Mild overdose or the early phase of severe toxicity may manifest hypertension, tachycardia, flushing and palpitations. Profound hypotension, bradycardia, cardiovascular collapse and asystolic arrest may be noted following overdose of MAO inhibitors alone.

3.5.2)

A) TACHYARRHYTHMIA

1) WITH THERAPEUTIC USE

a) Tachycardia can occur with therapeutic use (Prod Info PARNATE(R) oral tablets, 2007).

2) WITH POISONING/EXPOSURE

a) Tachycardia is common in patients with MAOI overdose, serotonin syndrome or other drug interactions (Waring & Wallace, 2007; van Riel et al, 2002; Verrilli et al, 1987; Miller et al, 1991; Erich et al, 1995; Pennings et al, 1997).
b) INCIDENCE - In a series of 12 patients with MAOI overdose 67% developed tachycardia (Meredith & Vale, 1985).
c) Mild overdose or the early phase of severe toxicity may manifest hypertension, tachycardia, flushing, and palpitations.
d) CASE REPORT: After taking tranylcypromine (twenty 10 mg tablets) and possibly 10 tablets of 50 mg chlorthalidone, a 50-year-old woman developed hyperthermia, shock, tachycardia (150 BPM), seizures, renal failure, disseminated intravascular coagulation and rhabdomyolysis. She recovered following symptomatic treatment (van Riel et al, 2002).
e) CASE REPORT: A 56-year-old woman developed a neurotoxic syndrome with hyperthermia, muscular rigidity, myoclonic jerks, tachycardia (140 BPM), rhabdomyolysis, and coma, similar to neuroleptic malignant syndrome, following intoxication with 80 tablets of tranylcypromine (800 mg), 24 tablets of thioridazine (720 mg), and 6 tablets of clomipramine (450 mg). In addition, she experienced rhythmic and pendular conjugate horizontal eye movements (ping-pong gaze) for 3 days. She recovered with supportive care (Prueter et al, 2001).

B) HYPERTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Hypertension has also been reported after therapeutic doses of MAOI or when switching a patient from one MAOI to another (Waring & Wallace, 2007; Prod Info PARNATE(R) oral tablets, 2007; Safferman & Masiar, 1992; Lavin et al, 1993).

1) SYMPTOMS: The effect is characterized by either some or all of the following: occipital headache (radiating to frontal area), palpitations, neck stiffness or soreness, nausea or vomiting, sweating and photophobia. Either tachycardia or bradycardia may be present which can be accompanied by chest pain and dilated pupils (Prod Info PARNATE(R) oral tablets, 2007).
2) DOSE-EFFECT RELATIONSHIP: In a study of 13 patients receiving tranylcypromine, an increase in supine systolic blood pressure was significantly correlated with dose; systolic pressure increased by 30 mmHg or more in 31% of the subjects (Keck et al, 1991).

a) This effect was not apparent for standing blood pressure, possibly due to negation by the orthostatic hypotensive effect. In one patient a dose of 50 milligrams produced symptomatic hypertension requiring treatment with nifedipine (Keck et al, 1991).
b) Hypertension occurs as part of the serotonin syndrome when MAOIs are ingested with serotonin reuptake inhibitors or meperidine (Rossiter & Souney, 1993; Montastruc et al, 1993).
c) Hypertensive crisis may develop when the MAOIs and indirect acting sympathomimetic drugs (Lefebvre et al, 1993) or tyramine (found in cheese, beer, wine, pickled herring, etc) are combined. A rapid and irregular pulse has also been noted.

1) The reversible, selective monoamine oxidase inhibitors have been suggested to interact less with tyramine than traditional MAOIs and thus may have less potential to cause hypertensive crisis when tyramine-containing foods are ingested (Livingston & Livingston, 1996; Anderson et al, 1993). This is likely due to selectivity for MAO type A, leaving MAO type B available to deaminate tyramine (Freeman, 1993).
2) In a review of tyramine interactions with monoamine oxidase inhibitors, the newer selective reversible inhibitors of monoamine oxidase (RIMAs) required an approximate 10-fold higher dose of tyramine to elicit an increase in blood pressure compared to irreversible MAOIs (Berlin & Lecrubier, 1996). For further information see: Monamine Oxidase A (MAO-A) management.

2) WITH POISONING/EXPOSURE

a) Mild to moderate hypertension is common in MAOI overdose (Erich et al, 1995).

1) INCIDENCE: Hypertension was reported in 17% (2 of 12) of published overdose cases with MAOIs (Meredith & Vale, 1985).

C) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Postural hypotension is a common side effect following therapeutic use with these agents (Prod Info NARDIL(R) oral tablets, 2007; Prod Info PARNATE(R) oral tablets, 2007).
b) Hypotension has also been reported in severe MAOI-meperidine interactions (Rossiter & Souney, 1993).

2) WITH POISONING/EXPOSURE

a) Hypotension occurs in patients with severe MAOI overdose (Waring & Wallace, 2007; van Riel et al, 2002; Verrilli et al, 1987) .

1) INCIDENCE: In a review of 12 acute overdoses with MAOIs, hypotension was noted in 17% (2 of 12) (Meredith & Vale, 1985).

D) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Severe toxicity following overdose causes profound hypotension, bradycardia, cardiovascular collapse, and asystolic arrest. Peaked T-waves, even in the absence of hyperkalemia, have been reported (Quill, 1981).

E) MYOCARDITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 23-year-old woman presented with sweating, tachycardia (resting pulse, 96 bpm), hypertension (BP 172/100 mmHg), and acidosis 45 minutes after ingesting phenelzine 2760 mg, olanzapine 50 mg, two glasses of beer and a glass of wine. She became agitated and drowsy with cool and clammy peripheries. Her acidosis worsened and lactate concentration increased over the next 15 hours. At this time, she experienced severe tachycardia (140 bpm) and hypotension (64/47 mmHg). An ECG revealed broadened QRS complexes and transthoracic echocardiogram showed impaired left ventricular function. Serum troponin I and creatine kinase activity were 2.94 mcg/L (reference range 0 to 0.2 mcg/L) and 777 Units/L (reference range, 30 to 135 Units/L), respectively. She died 3 days later after experiencing refractory seizures. Post-mortem examination revealed a high serum phenelzine concentration of 4.1 mg/L and histopathological features (an inflammatory infiltrate within the myocardium composed of lymphocytes, macrophages, neutrophils and scattered eosinophils, and focal areas of necrosis) that were consistent with drug-induced acute myocarditis (Waring & Wallace, 2007).

F) MYOCARDIAL INFARCTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: MYOCARDIAL INFARCTION: One hour after eating an unknown type and amount of cheese, a 34-year-old woman taking phenelzine for depression developed chest-heaviness, hyperventilation, severe anxiety, headache, hypertension (peak systolic 200 mmHg ) and ST depression on ECG. An initial troponin level was normal, however a repeat level 6 hours after the initial draw was 4.89 ug/L (reference range less than 0.05 ug/L). She was treated with morphine, aspirin, and IV nitroprusside. Her chest pain was relieved by the morphine and the ST depression reversed. After administration of the next scheduled therapeutic dose of phenelzine she developed hypotension (65/30 mmHg) and was treated with IV fluids. Nine hours after admission, a third troponin level was 1.89 ug/L. A Sestamibi scan showed no evidence of coronary artery disease. She was discharged on day 3 with a blood pressure of 99/60 mmHg.(Ngo et al, 2010).

Respiratory

3.6.1)

A) WITH POISONING/EXPOSURE

1) Tachypnea, pulmonary edema, and respiratory depression may be noted.

3.6.2)

A) HYPERVENTILATION

1) WITH POISONING/EXPOSURE

a) Tachypnea may occur with overdose or with MAOI-induced serotonin syndrome (Brodribb et al, 1994; Erich et al, 1995).
b) INCIDENCE: Reported in 17% (2 of 12) of patients in one series of 12 overdose cases (Meredith & Vale, 1985).

B) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH THERAPEUTIC USE

a) There have been rare reports of edema of the glottis with phenelzine use (Prod Info NARDIL(R) oral tablets, 2007)

2) WITH POISONING/EXPOSURE

a) Respiratory depression develops in severe overdose cases (Erich et al, 1995; Pennings et al, 1997) and severe cases of MAOI-meperidine interaction (Rossiter & Souney, 1993).

C) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Pulmonary edema and respiratory depression may occur in severe cases (Robertson, 1972; Breheny et al, 1986; Coulter et al, 1971).

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

1) MILD TO MODERATE INTOXICATION is associated with drowsiness, followed by dizziness, restlessness, irritability, headache, hallucinations, myoclonus and tremors.
2) SEVERE INTOXICATION - Symptoms can occur within hours. Initial manifestation is faintness, followed by intense headache, agitation, hyperreflexia, opisthotonus, seizures and coma.

3.7.2)

A) CENTRAL STIMULANT ADVERSE REACTION

1) WITH THERAPEUTIC USE

a) Commonly reported central nervous system effects reported with therapy include: dizziness, headache, drowsiness, sleep disturbances, fatigue, and weakness (Prod Info PARNATE(R) oral tablets, 2007; Prod Info NARDIL(R) oral tablets, 2007).
b) Anxiety, agitation, and manic symptoms are signs of overstimulation which are likely due to excessive therapeutic action (Prod Info PARNATE(R) oral tablets, 2007).

2) WITH POISONING/EXPOSURE

a) Agitation, delirium, confusion, hypomania and restlessness may develop after overdose or with drug-induced serotonin syndrome (Waring & Wallace, 2007; Verrilli et al, 1987; Feighner et al, 1990; Thorp et al, 1997).

B) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH POISONING/EXPOSURE

a) CNS depression and coma develop with more severe overdose and in severe cases of MAOI-induced serotonin syndrome (Prueter et al, 2001; Ooi, 1991; Erich et al, 1995; Pennings et al, 1997).

C) SEIZURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 31-year-old woman with a history of insulin-dependent diabetes mellitus and depression developed two seizures shortly after starting phenelzine therapy. Although blood glucose was not tested in the first episode, it was normal in the second episode (Albareda et al, 1999).

2) WITH POISONING/EXPOSURE

a) Seizures may develop in severe overdose (van Riel et al, 2002; Thorp et al, 1997) .
b) Refractory seizures developed in a 23-year-old woman after ingesting phenelzine 2760 mg, olanzapine 50 mg, two glasses of beer and a glass of wine. She died 3 days after presentation. Post-mortem examination showed histopathological features consistent with drug-induced acute myocarditis (Waring & Wallace, 2007).

D) INCREASED MUSCLE TONE

1) WITH THERAPEUTIC USE

a) Tremors, twitching, muscle spasm, myoclonic movements, and hyperreflexia are commonly reported with therapeutic use (Prod Info NARDIL(R) oral tablets, 2007; Prod Info PARNATE(R) oral tablets, 2007).

2) WITH POISONING/EXPOSURE

a) Myoclonus and diffuse muscle rigidity are common findings in patients with overdose (Verrilli et al, 1987; Ooi, 1991; Miller et al, 1991; Erich et al, 1995; Feighner et al, 1990) .

E) SECONDARY PERIPHERAL NEUROPATHY

1) WITH THERAPEUTIC USE

a) Sensorimotor peripheral neuropathy is a dose-related side effect of phenelzine therapy (Goodheart et al, 1991).

F) HEADACHE

1) WITH POISONING/EXPOSURE

a) Severe headache is common in patients with overdose and/or MAOI-tyramine interaction (Safferman & Masiar, 1992; Lavin et al, 1993; Mills, 1993).
b) Because these patients may develop severe hypertension the possibility of a CNS bleed should always be considered.

G) HYPERREFLEXIA

1) WITH THERAPEUTIC USE

a) Hyperreflexia and clonus are common (Prod Info NARDIL(R) oral tablets, 2007; Miller et al, 1991; Verrilli et al, 1987).

H) DRUG WITHDRAWAL

1) WITH THERAPEUTIC USE

a) Drug withdrawal may be associated with nausea, vomiting and malaise (Prod Info NARDIL(R) oral tablets, 2007).
b) CASE REPORT: A 34-year-old man developed delirium, disorientation, visual hallucinations, paranoia, agitation and violent behavior 30 hours after discontinuing tranylcypromine. He had been taking an average of 500 to 600 milligrams/day for the preceding 6 weeks (Davids et al, 2000). The patient had an extensive history of prescription drug abuse. Withdrawal from other agents may have contributed to these effects.

Gastrointestinal

3.8.1)

A) WITH THERAPEUTIC USE

1) Nausea, diarrhea and constipation have been reported with therapeutic use.

3.8.2)

A) GASTROINTESTINAL TRACT FINDING

1) WITH THERAPEUTIC USE

a) Common gastrointestinal effects may include: nausea, diarrhea, abdominal pain, constipation, dry mouth and other gastrointestinal disturbances (Prod Info PARNATE(R) oral tablets, 2007; Prod Info NARDIL(R) oral tablets, 2007).

B) DIARRHEA

1) WITH THERAPEUTIC USE

a) Diarrhea may develop with mild MAOI-induced serotonin syndrome (Feighner et al, 1990).

C) VASCULAR INSUFFICIENCY OF INTESTINE

1) WITH THERAPEUTIC USE

a) CASE REPORT: Intestinal infarction developed in a 72-year-old woman who developed severe hypertension, peripheral vasoconstriction and seizures after products containing phenylephrine and terbutaline were added to a drug regimen that included thyroid hormones, furosemide, prazosin, bezafibrate, dipyridamole and toloxatone (Lefebvre et al, 1993).

Hepatic

3.9.2)

A) LIVER DAMAGE

1) WITH THERAPEUTIC USE

a) Hepatotoxicity may be noted, usually with chronic use. Hepatotoxicity of MAOI is thought to be a hypersensitivity reaction and not related to the dose or duration of therapy.
b) Rare reports of hepatitis have occurred with tranylcypromine use (Prod Info PARNATE(R) oral tablets, 2007).

B) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) Mild elevations in liver enzymes have been reported in patients who developed hyperthermia and rhabdomyolysis after MAOI overdose and MAOI-induced serotonin syndrome (Miller et al, 1991; Erich et al, 1995).

Genitourinary

3.10.1)

A) WITH THERAPEUTIC USE

1) Urinary retention and sexual disturbances may occur with therapeutic use of these agents.

B) WITH POISONING/EXPOSURE

1) Renal failure may develop in severe cases.

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Overdose complicated by rhabdomyolysis or hypotension may lead to myoglobinuria, acute tubular necrosis and renal failure (van Riel et al, 2002; Robertson, 1972; Linden et al, 1984; Miller et al, 1991).

B) RETENTION OF URINE

1) WITH THERAPEUTIC USE

a) Urinary retention may occur with therapeutic use of these agents (Prod Info PARNATE(R) oral tablets, 2007; Prod Info NARDIL(R) oral tablets, 2007).

C) ABNORMAL SEXUAL FUNCTION

1) WITH THERAPEUTIC USE

a) Sexual disturbances including anorgasmia, impotence and ejaculatory disturbances are common events with these agents (Prod Info PARNATE(R) oral tablets, 2007; Prod Info NARDIL(R) oral tablets, 2007).

Acid-Base

3.11.1)

A) WITH POISONING/EXPOSURE

1) Metabolic or respiratory acidosis may develop in severe cases.

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis may develop in patients with severe muscle rigidity, hyperthermia or hypotension. It has been reported with phenelzine overdose (Waring & Wallace, 2007; Kaplan et al, 1986; Verrilli et al, 1987), tranylcypromine overdose (King et al, 1979), and MAOI-associated serotonin syndrome (Miller et al, 1991).

B) RESPIRATORY ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Respiratory acidosis develops if muscle rigidity or CNS depression interfere with ventilation (Erich et al, 1995).

Hematologic

3.13.1)

A) WITH THERAPEUTIC USE

1) Coagulopathy, hemolysis and thrombocytopenia have been reported.

B) WITH POISONING/EXPOSURE

1) Coagulopathy, hemolysis and thrombocytopenia may develop with MAOI overdose.

3.13.2)

A) DISSEMINATED INTRAVASCULAR COAGULATION

1) WITH THERAPEUTIC USE

a) CASE REPORT: Thrombocytopenia, hemolysis, elevated PT and PTT, decreased fibrinogen and increased fibrin degradation products developed in a woman with severe hyperthermia and rhabdomyolysis from MAOI-associated serotonin syndrome (Miller et al, 1991).

2) WITH POISONING/EXPOSURE

a) Coagulopathy, hemolysis and thrombocytopenia may develop with MAOI overdose (van Riel et al, 2002; Linden et al, 1984).

B) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) Leukopenia has been reported rarely with phenelzine use (Prod Info NARDIL(R) oral tablets, 2007; Tipermas et al, 1984). It has also been reported with tranylcypromine use (Prod Info PARNATE(R) oral tablets, 2007).

C) HEMATOLOGY FINDING

1) WITH THERAPEUTIC USE

a) Anemia and agranulocytosis have been reported with therapeutic use of tranylcypromine (Prod Info PARNATE(R) oral tablets, 2007).

D) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) Thrombocytopenia has been reported with therapeutic use (Prod Info PARNATE(R) oral tablets, 2007).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 41-year-old man developed thrombocytopenia after overdose with 400 x 10 milligrams tranylcypromine (Pennings et al, 1997). The lowest platelet count occurred on the seventh day after ingestion.
b) CASE REPORT: A 34-year-old man developed severe thrombocytopenia (nadir 6 x 10(9)/L) after taking tranylcypromine 500 to 600 milligrams/day for the preceding 6 weeks (Davids et al, 2000).

Musculoskeletal

3.15.1)

A) WITH THERAPEUTIC USE

1) Muscle hyperactivity and rigidity can develop with therapeutic use, as well as rhabdomyolysis.

B) WITH POISONING/EXPOSURE

1) Muscle hyperactivity and rigidity are common in overdose. Rhabdomyolysis may develop.

3.15.2)

A) INCREASED MUSCLE TONE

1) WITH THERAPEUTIC USE

a) THERAPEUTIC DOSES: Myoclonus at sleep onset has been reported to occur in 10% to 15% of patients taking phenelzine. Neuromuscular side effects are dose-related and usually develop after 10 to 14 days of therapy (Lieberman et al, 1985).

1) CLINICAL FEATURES: Involuntary twitching or jerking movements most commonly involve the upper and lower extremities, are frequently associated with muscle or joint pain, and predominate during rest or sleep (Lieberman et al, 1985).
2) MECHANISM - A serotonergic mechanism is suggested, based on the observation that neuromuscular symptoms are aggravated by serotonin agonists such as tryptophan, and alleviated by serotonin antagonists, such as cyproheptadine (Lieberman et al, 1985).

2) WITH POISONING/EXPOSURE

a) OVERDOSE: Muscular hyperactivity is a common manifestation of MAOI overdose. Muscle fasciculations, myoclonus, tremors, trismus, and muscle or joint pain and stiffness have been described (Prueter et al, 2001; Matter et al, 1965; Robertson, 1972; Kaplan et al, 1986).

B) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Rhabdomyolysis is common in patients who develop muscle rigidity and hyperthermia after MAOI overdose or MAOI-induced serotonin syndrome (van Riel et al, 2002; Prueter et al, 2001; Verrilli et al, 1987; Miller et al, 1991; Erich et al, 1995; Brodribb et al, 1994).

Reproductive

3.20.1)

A) Phenelzine and tranylcypromine are both FDA Pregnancy Category C.

3.20.2)

A) PREGNANCY CATEGORY

1) Phenelzine - Pregnancy C (Prod Info PARNATE(R) oral tablets, 2007)
2) Tranycyrpomine - Pregnancy C(Prod Info NARDIL(R) oral tablets, 2007)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs (especially blood pressure and temperature) and mental status.
B) Institute continuous cardiac and pulse oximetry monitoring and obtain an ECG.
C) MAOI plasma levels are not clinically useful or readily available.
D) Screening urine toxicology immunoassays will not detect MAOIs.
E) Helpful laboratory tests include basic chemistry profile, lactate, CPK, troponin, and coagulation panel.
F) Consider a head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection if the patient has altered mental status.
G) Monitor liver enzymes, renal function, and serum electrolytes.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Blood concentrations of tranylcypromine do not correlate well with toxicity or fatality (Boniface, 1991).

Methods

A)

1) Assay procedures and toxic levels of MAOI have not been well-defined and the diagnosis must ultimately be made clinically. MAOI activity in man can be measured indirectly by measuring MAO substrates and their metabolites, such as plasma serotonin, norepinephrine, methoxy-4-hydroxymandelic acid (VMA), and urinary 5-hydroxyindoleacetic acid (5-HIAA).
2) TRANYLCYPROMINE: Extraction of tranylcypromine from buffered blood and analysis by gas chromatography with nitrogen-phosphorus selective detection is described by Boniface (1991). The limit of quantitation is about 0.2 mg/L with linearity in blood over the range of 0.5 to 20 mg/L.

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Any patient with presumed overdose should be observed with cardiac monitoring for 24 hours due to the possibility of delayed toxicity. Patients with significant persistent hypertension, hyperthermia, seizures, dysrhythmias, delirium, tachycardia or central nervous depression should be admitted to the ICU.

6.3.1.2) HOME CRITERIA/ORAL

A) Home management is not recommended. Children should be evaluated in the hospital and observed. Adults should be evaluated by a health care professional if they have received a higher than therapeutic dose, or if they are symptomatic.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions or children with inadvertent ingestions should be sent to a health care facility for observation for development of toxicity. After an overdose, clinical effects may be delayed up to 32 hours but are usually apparent within 24 hours.

Monitoring

A)

B)

C)

D)

E)

F)

G)

Oral Exposure

6.5.1)

A) PREHOSPITAL: MAOI overdoses are life-threatening. Induction of emesis is not recommended. Activated charcoal should be considered early in the course after a significant oral ingestion in patients that are protecting their airways and have not yet manifested signs of toxicity. If a patient is displaying signs of toxicity, the risk of aspiration likely outweighs the potential benefit of charcoal.
B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) SUMMARY: Activated charcoal should be administered in asymptomatic or minimally symptomatic patients who present within a few hours of ingestion, or in symptomatic patients who have a secure airway. Gastric lavage may be considered for large overdoses who present within 1 hour of ingestion, though airway protection should be considered prior to the procedure.
B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

C) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs (especially blood pressure and temperature) and mental status.
2) Institute continuous cardiac and pulse oximetry monitoring and obtain an ECG.
3) MAOI plasma levels are not clinically useful or readily available.
4) Screening urine toxicology immunoassays will not detect MAOIs.
5) Helpful laboratory tests include basic chemistry profile, lactate, CPK, troponin, and coagulation panel.
6) Consider a head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection if the patient has altered mental status.
7) Monitor liver enzymes, renal function, and serum electrolytes.

B) PSYCHOMOTOR AGITATION

1) INDICATION

a) If patient is severely agitated, sedate with IV benzodiazepines.

2) DIAZEPAM DOSE

a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

3) LORAZEPAM DOSE

a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

4) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
5) If unresponsive, amobarbital has been recommended (Linden et al, 1984). Sedative hypnotic agents should be used with caution due to possible potentiation of CNS depression due to MAOI overdose. Phenothiazines should be avoided due to possible hypotension.

C) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

D) HYPOTENSIVE EPISODE

1) Administer intravenous fluids and keep the patient supine. If the patient is unresponsive to these measures, administer norepinephrine or dopamine cautiously, monitoring for possible exaggerated response.

a) The direct-acting alpha-adrenergic agonist norepinephrine (levarterenol) may be preferable since it does not require release of intracellular amines (Linden et al, 1984).

2) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

3) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

E) HYPERTENSIVE EPISODE

1) Symptomatic hypertension is best treated with the rapid, short-acting parenteral alpha-adrenergic blocker phentolamine, or by the direct vasodilator sodium nitroprusside (Guzzardi, 1983). Methyldopa and guanethidine are contraindicated as they may potentiate hypertensive crises.
2) IV NITROPRUSSIDE (ADULT and CHILD: Initially 1 microgram/kilogram/minute by intravenous infusion; titrate up to 10 micrograms/kilogram/minute as needed to achieve desired effect) or PHENTOLAMINE (ADULT: 2.5 to 5 milligrams every 5 minutes until hypertension is controlled then every 2 to 4 hours as needed; CHILD: 0.05 to 0.1 milligram/kilogram/dose every 5 minutes until hypertension is controlled then every 1 to 4 hours as needed).
3) LABETALOL: Has been used to treat successfully one case of accelerated hypertension due to a tranylcypromine-tyramine interaction (Abrams et al, 1985).
4) NIFEDIPINE: Two patients developed hypertension (BP 194/120, 182/112) following consumption of food containing cheese. Both patients were treated by biting a nifedipine capsule and placing it under the tongue.

a) Within 7 to 10 minutes the headache had subsided and the blood pressure dropped to 166/96 mmHg and 132/84, respectively. Both patients remained normotensive over 8 hours and symptoms did not recur (Clary & Schweizer, 1987).

F) BODY TEMPERATURE ABOVE REFERENCE RANGE

1) SUMMARY: Hyperthermia can result from psychomotor agitation, increased neuromuscular activity or persistent seizures. Sedate the patient with benzodiazepines (large doses may be required). Other cooling measures can include cool mist and fans, cool packs in axilla and groin, or more aggressive cooling measures, such as ice baths, for severe hyperthermia. Neuromuscular paralysis of the patient may be necessary.
2) Avoid phenothiazines since they can precipitate irreversible shock (Robertson, 1972). Acetaminophen may also be useful. Early neuromuscular paralysis, intubation and ventilation in patients with a core temperature of greater than 39 degrees C has been advocated by some authors (Henry, 1994).

G) DANTROLENE

1) OVERDOSE - Kaplan et al (1986) described the effective treatment of phenelzine overdose in a 33-year-old male with dantrolene sodium. The patient developed a fulminant hypermetabolic reaction to phenelzine which was similar to malignant hyperthermia and the neuroleptic malignant syndrome.

a) Administration of dantrolene 2.5 milligrams/kilogram intravenously resulted in resolution of muscle rigidity, trismus, tachycardia, hyperthermia, and metabolic acidosis. Continuation of dantrolene 2.5 milligrams/kilogram intravenously every 6 hours for 42 hours resulted in continued improvement.

2) THERAPEUTIC DOSE - Dantrolene has also been successfully used to treat phenelzine toxicity from therapeutic doses (Verrilli et al, 1987). The dose of dantrolene in this case was 2.5 milligrams/kilogram/day in divided doses and the creatine kinase was followed to document a beneficial effect.

H) CYPROHEPTADINE

1) Some of the manifestations of MAOI overdose, such as muscle hyperactivity, appear to be related to a "serotonin syndrome". Both animal and human data have suggested that administration of serotonin antagonists might antagonize this effect.

a) There are no reports of the efficacy of this intervention in the setting of acute MAOI overdose. Benzodiazepines more effectively treat the centrally-induced serotonergic and sympathomimetic toxicity.

2) Animal studies have shown attenuation of the fluoxetine-phenelzine interaction by cyproheptadine (Marley & Wozniak, 1984).

a) In anecdotal reports, human patients experiencing neuromuscular effects from therapeutic doses of either phenelzine alone or from a phenelzine-tryptophan interaction, had prompt antagonism following administration of cyproheptadine or methysergide (Lieberman et al, 1985).

I) RHABDOMYOLYSIS

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

J) SEROTONIN SYNDROME

1) SUMMARY

a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).

2) HYPERTHERMIA

a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
c) Non-depolarizing paralytics may be used in severe cases.

3) CYPROHEPTADINE

a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).

4) HYPERTENSION

a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.

5) HYPOTENSION

a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
c) NOREPINEPHRINE

1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
2) INITIAL DOSE

a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.

3) MAINTENANCE DOSE

a) 0.5 to 1 mL (2 to 4 mcg)/minute.

6) SEIZURES

a) DIAZEPAM

1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.

b) LORAZEPAM

1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).

c) RECURRING SEIZURES

1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.

d) PHENOBARBITAL

1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.

7) CHLORPROMAZINE

a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.

8) NOT RECOMMENDED

a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

Enhanced Elimination

A)

1) Although MAO inhibitor excretion is enhanced by forced acid diuresis, there is no evidence that it is effective in reducing the severity of an overdose. In fact, such a procedure may be dangerous in this situation because of the instability of the cardiovascular system (Crome, 1982).
2) While acid diuresis has been shown to enhance the elimination of tranylcypromine following therapeutic doses, the maximal urinary recovery was only 8 percent of the ingested dose.

a) It is therefore unlikely that such therapy will have any impact on the course of MAO inhibitor overdose. In addition, urinary acidification may result in myoglobin precipitation in kidney tubules, with subsequent renal failure if rhabdomyolysis is present (Linden et al, 1984).

B)

1) There is little evidence documenting the efficacy of dialysis in reducing MAO inhibitor toxicity (Linden et al, 1984).

C)

1) Charcoal hemoperfusion has been used to treat phenelzine overdose. Although the patient's serum level dropped from 19.5 nanograms/milliliter to 6.5 nanograms/milliliter, there was no improvement in clinical status (Kaplan et al, 1986).

Abstracts

Case Reports

A)

1) SPECIFIC AGENT

a) TRANYLCYPROMINE

1) Matter et al (1965) describe the successful treatment of a tranylcypromine overdose in a 15-year-old adolescent who ingested 350 mg in a suicide attempt. Patient had general muscular hyperactivity, facial grimaces, limb thrashing, was semicomatose, had hypotension, and was irrational. After hemodialysis, there was an uneventful recovery.
2) A 27-year-old woman ingested 0.5 g of tranylcypromine in a single dose as a deliberate overdose. Patient was also receiving imipramine. On admission blood pressure was 150/100, pulse 160, temperature 102 degrees. Patient was restless, drowsy, sweating and had muscle contractions resembling rigor. She had 5 cardiac arrests with blood pressure of 60/0 and ventricular tachycardia. Temperature rose to 106 degrees.

a) The patient received 100 mg chlorpromazine IM followed by hydrocortisone, glucagon, lidocaine, and isoproterenol with 5% dextrose. Twenty-four hours following patient's overdose the general condition much improved (Robertson, 1972).

3) After taking tranylcypromine (twenty 10 mg tablets) and possibly 10 tablets of 50 mg chlorthalidone, a 50-year-old woman developed hyperthermia (43.1 degrees C), shock (systolic BP 60 mmHg), tachycardia (150 BPM), seizures, renal failure (creatinine 188 micromole/L), disseminated intravascular coagulation and rhabdomyolysis (CK 18039 units/L). She recovered following symptomatic treatment (van Riel et al, 2002).
4) A 56-year-old woman developed a neurotoxic syndrome with hyperthermia (41 degrees C), muscular rigidity, myoclonic jerks, tachycardia (140 BPM), rhabdomyolysis (CK 5000 IU/L), and coma, similar to neuroleptic malignant syndrome, following intoxication with 80 tablets of tranylcypromine (800 mg), 24 tablets of thioridazine (720 mg), and 6 tablets of clomipramine (450 mg). In addition, she experienced rhythmic and pendular conjugate horizontal eye movements (ping-pong gaze) for 3 days. She recovered following treatment with dantrolene (Prueter et al, 2001).

Range Of Toxicity

Summary

A)

B)

C)

Therapeutic Dose

7.2.1)

A) ISOCARBOXAZID: The recommended initial dose for isocarboxazid is 10 mg orally twice daily; may be increased to 60 mg daily in 2 to 4 divided doses (Prod Info MARPLAN(R) oral tablets, 2007).
B) PHENELZINE: The recommended initial dose for phenelzine is 15 mg orally three times daily; may be increased to 90 mg daily in divided doses (Prod Info NARDIL(R) oral tablets, 2007).
C) TRANYLCYPROMINE: The recommended dose for tranylcypromine is 30 to 60 mg/day orally in divided doses (Prod Info PARNATE(R) oral tablets, 2008).

7.2.2)

A) The safety and efficacy of isocarboxazid, phenelzine, and tranylcypromine have not been established in pediatric patients (Prod Info PARNATE(R) oral tablets, 2008; Prod Info MARPLAN(R) oral tablets, 2007; Prod Info NARDIL(R) oral tablets, 2007).

Minimum Lethal Exposure

A)

1) An acute overdose of 4 to 6 milligrams/kilogram or greater of an MAOI is consistent with reported fatal cases (Linden et al, 1984).

B)

1) TRANYLCYPROMINE: MAOI have a low toxic to therapeutic ratio. Death has been reported from as little as 170 milligrams of tranylcypromine in an adult (Bell & Scaff, 1963).
2) PHENELZINE: In a review of MAOI toxicity, phenelzine was reported to result in death with doses ranging from 375 mg to 1,500 mg (Mills, 1993).

a) CASE REPORT: A 23-year-old woman developed acute myocarditis after ingesting phenelzine 2760 mg, olanzapine 50 mg, two glasses of beer and a glass of wine. She died 3 days later after experiencing refractory seizures. Post-mortem serum phenelzine concentration was 4.1 mg/L (Waring & Wallace, 2007)

3) PHENELZINE: Ingestion of 4 to 6 milligrams/kilogram of phenelzine was fatal (Linden et al, 1984).
4) NIALAMIDE: 5 grams was fatal in an adult (Matell & Thorstrand, 1967).

Maximum Tolerated Exposure

A)

1) SUMMARY: The ingestion of 2 to 3 milligrams/kilogram or greater of an MAOI should be considered potentially life-threatening, with mild toxicity anticipated with lesser amounts (Linden et al, 1984).

B)

1) PHENELZINE: A 2-year-old child recovered fully after ingesting 150 to 225 milligrams of phenelzine (Greenblatt et al, 1976). Adults have survived after ingestion of 2,250 milligrams (Kaplan et al, 1986) and 900 milligrams (Breheny et al, 1986).
2) TRANYLCYPROMINE

a) CASE REPORT: An adult who ingested tranylcypromine 250 milligrams survived (Quill, 1981).
b) CASE REPORT: After taking tranylcypromine (twenty 10 mg tablets) and possibly 10 tablets of 50 mg chlorthalidone, a 50-year-old female developed hyperthermia (43.1 degrees C), shock (systolic BP 60 mmHg), tachycardia (150 bpm), seizures, renal failure (creatinine 188 micromole/L), disseminated intravascular coagulation and rhabdomyolysis (CK 18039 U/L). She recovered following symptomatic treatment (van Riel et al, 2002).
c) CASE REPORT: A 56-year-old female developed a neurotoxic syndrome with hyperthermia (41 degrees C), muscular rigidity, myoclonic jerks, tachycardia (140 bpm), rhabdomyolysis (CK 5000 IU/L), and coma, similar to neuroleptic malignant syndrome, following intoxication with 80 tablets of tranylcypromine (800 mg), 24 tablets of thioridazine (720 mg), and 6 tablets of clomipramine (450 mg). In addition, she experienced rhythmic and pendular conjugate horizontal eye movements (ping-pong gaze) for 3 days. She recovered following treatment with dantrolene (Prueter et al, 2001).

3) PARGYLINE: 150 to 175 milligrams was ingested with survival in a 2.5-year-old boy (Lipkin & Kushnick, 1967).
4) ISOCARBOXAZID: Survival was reported in a 48-year-old woman who ingested 300 milligrams (Vlahakis, 1964).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) TRANYLCYPROMINE - Therapeutic blood concentration of tranylcypromine is 0.1 milligram/liter (Stead & Moffat, 1983).

a) Postmortem blood concentrations range from 0.25 to 9.1 milligrams/liter in fatalities due to tranylcypromine overdose (Boniface, 1991; Griffiths, 1973; Baselt et al, 1979; Mackell et al, 1979).

2) PHENELZINE - A 23-year-old woman developed acute myocarditis after ingesting phenelzine 2760 mg, olanzapine 50 mg, two glasses of beer and a glass of wine. She died 3 days later after experiencing refractory seizures. Post-mortem serum phenelzine concentration was 4.1 mg/L (Waring & Wallace, 2007).

Pharmacology Toxicology

Pharmacologic Mechanism

A)

B)

C)

1) Monoamine oxidase inhibitors may inhibit the activity of monoamine oxidase reversibly or irreversibly. In patients taking irreversible inhibitors complete regeneration of the monoamine oxidase enzyme is required for activity to be restored. This requires a drug free interval of at least two weeks.

a) Reversible monoamine oxidase inhibitors include moclobemide. For further information SEE: Monoamine Oxidase A (MAO-A).
b) Irreversible MAOIs include clorgyline, selegiline, phenelzine, isocarboxazid, and tranylcypromine.

D)

1) Some MAOIs are selective for the monoamine oxidase A enzyme, located primarily in the placenta, intestines and liver. Others are selective for the monoamine oxidase enzyme B, located primarily in the platelets, brain and liver. Others are non selective. Selectivity is lost in overdose.

a) Moclobemide is a reversible, selective MAO-A inhibitor. For further information SEE: Reversible MAO-A Inhibitors management.
b) Rasagiline and selegiline are selective MAO-B inhibitors. For further information SEE: MAO-B Inhibitors management.
c) Phenelzine, tranylcypromine and isocarboxazid are non-selective MAOIs.

Toxicologic Mechanism

A)

1) They do not inhibit MAO production. Recovery from the effect of MAOI thus depends upon enzyme regeneration which can take several weeks.

B)

C)

D)

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MONOAMINE OXIDASE INHIBITORS (MAO)

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

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Treatment Overview

Range Of Toxicity

Summary Of Exposure

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Acid-Base

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Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

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Serum Plasma Blood Concentrations

Pharmacologic Mechanism

Toxicologic Mechanism

General Bibliography