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1204 SECTION 15: Toxicology of muscle clonus alone or at least one or two of the other common features.40-44 TREATMENT The cornerstone of treating serotonin syndrome is discontinuing all serotonergic drugs and providing appropriate supportive care (Table 178-12). 40-44,50-52 All patients with serotonin syndrome should be admitted to the hospital until their symptoms have completely resolved. Severely ill patients require admission to an intensive care unit. Approximately 25% of patients require endotracheal intubation and ventilatory support. Most patients show dramatic improvement within 24 hours of symptom onset. Mortality varies according to the severity of the syn drome and aggressiveness of care. 41-44 The most common cause of death is severe hyperthermia. Benzodiazepines are nonspecific serotonin antagonists and can be used to decrease patient discomfort and promote muscle relaxation. 52 Patients with severe serotonin syndrome should be sedated, undergo neuromuscular blockade with a nondepolarizing agent, have an endo tracheal tube placed, be started on mechanical ventilation, and be admitted to the intensive care unit. Cyproheptadine, is an antihistamine and serotonin antagonist with anticholinergic effects. 41-44 It can be used (off-label) for serotonin syndrome, but is only available in PO form. The initial dose is 12 milligrams, with repeat doses of 2 milligrams every 2 hours until clinical improvement is seen. However, benefits of, and indications for, cyproheptadine are not known due to lack of supportive clinical evidence. Chlorpromazine is an antagonist of 5-HT 2A receptors and there are reports of successful treatment of serotonin syndrome. 41,43 The advantage of chlorpromazine is that it is available in a parenteral form, but a potential disadvantage is that it can cause hypotension. It also blocks dopamine receptors, which can promote muscle rigidity, lower seizure threshold, and exacerbate neuroleptic malignant syndrome. 50 The use of dopamine agonists (e.g., bromocriptine) has no accepted role in treating patients with serotonin syndrome. 42 Dantrolene is a nonspecific muscle relaxant that is used occasionally in the management of serotonin syn drome, but clinical benefit is unproven.42 Patients with muscle rigidity, seizures, or hyperthermia should be monitored closely for rhabdomyolysis and/or metabolic acidosis. Clinical features of the serotonin syndrome usually resolve within 24 hours after the inciting drug is stopped, with an exception being fluoxetine due to its long half-life and that of the active metabolite. Once a patient recovers from serotonin syndrome, avoid future exposure to serotonergic drugs (Table 178-4), although the risk of recurrence is unknown. REFERENCES The complete reference list is available online at www.TintinalliEM.com.

eption being fluoxetine due to its long half-life and that of the active metabolite. Once a patient recovers from serotonin syndrome, avoid future exposure to serotonergic drugs (Table 178-4), although the risk of recurrence is unknown. REFERENCES The complete reference list is available online at www.TintinalliEM.com. TABLE 178-12 Treatment of Serotonin Syndrome •   Stop all serotonergic therapy •   Initiate cardiopulmonary monitoring, establish peripheral IV access, and obtain ECG •   IV fluid rehydration; evaluate for rhabdomyolysis •   External cooling measures for hyperthermia •   Benzodiazepines for agitation •   Use short-acting IV antihypertensives (nitroprusside or esmolol) for severe hypertension •   Use direct-acting IV vasopressors (norepinephrine, epinephrine, or phenylephrine) for hypotension resistant to IV fluid resuscitation •   Cyproheptadine  has been suggested  in the past,  but clinical  evidence  of benefit is lacking Monoamine Oxidase Inhibitors Frank LoVecchio INTRODUCTION Monoamine oxidase inhibitors (MAOIs) were the first class of antide pressants, but current use of these agents is primarily limited to treating atypical and refractory cases of depression ( Table 179-1).1 Newer antidepressants have a more favorable side effect profile, less overdose toxicity, and no dietary restrictions. The declining popularity of oral MAOIs for the treatment of depression is partially offset by their increasing use for the treatment of Parkinson’s disease. 2 In addition, a transdermal method of selegiline administration, approved for use in major depres sion, appears to avoid some of the worrisome aspects associated with traditional oral therapy. 3-5 Safety and effectiveness of MAOIs in children have not been estab lished, and the four agents used for treatment of depression have the identical U.S. Food and Drug Administration–mandated black box warning stating that patients <24 years old may have increased suicidal thinking and behavior while taking any type of antidepressant medication. MAOIs are associated with tyramine reactions, serotonin syndrome, and medication incompatibilities that are unique to this class of antidepressants. Overdoses of MAOIs are considered life-threatening emergencies, and even one pill could potentially kill a toddler . The onset of clinical toxicity is often delayed to between 6 and 24 hours after ingestion, which can lead to misdiagnosis and mismanagement. MAOI antidepressants with improved safety and tolerability, such as moclobemide, are available in Canada, Australia, and Europe, but not the United States. St. John’s wort (Hypericum perforatum) contains many active ingredients, some of which have the ability to inhibit monoamine oxidase (MAO) and block serotonin reuptake. 6 St. John’s wort is considered generally safe when taken at recommended dosages, but even modest MAO inhibition may become clinically significant in overdose, contribute to serotonin syndrome, or participate in a drug–drug interaction. Medications with MAO inhibition as a pharmacologic action unre lated to their clinical indication (e.g., linezolid, procarbazine, fura zolidone, and methylene blue) can precipitate serotonin syndrome when combined with other serotonergic agents. 7,8 PHARMACOLOGY MAO is an intracellular enzyme bound to the outer mitochondrial membrane. 9,10 It has been identified in most human cells except eryth rocytes (which do not contain mitochondria). MAO removes amine groups from both endogenous and exogenous biogenic amines. This oxidative deamination process is the primary mechanism by which endogenous biogenic amines, such as norepinephrine, dopamine, and serotonin, become inactivated.

in most human cells except eryth rocytes (which do not contain mitochondria). MAO removes amine groups from both endogenous and exogenous biogenic amines. This oxidative deamination process is the primary mechanism by which endogenous biogenic amines, such as norepinephrine, dopamine, and serotonin, become inactivated. A second important function of MAO is to decrease the systemic availability of absorbed dietary biogenic amines (e.g., tyramine) via hepatic and intestinal metabolism. Thus, inhibition of MAO leads to the accumulation of neurotransmitters in presynaptic nerve terminals (both centrally and peripherally) and increased systemic availability of dietary amines. MAO has a negligible role in metabolizing circulating catecholamines, either secreted endogenously (e.g., by the adrenal gland) or administered parenterally (e.g., epinephrine). Circulating catecholamines are metabolized by the enzyme catechol-O-methyl transferase that is located extraneuronally and is not affected by MAOIs. MAO exists as two different isoenzymes, designated monoamine oxidase isoenzyme A (MAO-A) and monoamine oxidase isoenzyme B (MAO-B). Each isoenzyme has its own relative preference for differ ent neurotransmitters, dietary amines, and inhibitory drugs. 9 During normal physiology, MAO-A is primarily responsible for the breakdown of serotonin and norepinephrine, whereas MAO-B preferentially metabolizes phenylethylamine; MAO-A and MAO-B have equal ability to metabolize dopamine or tyramine. These preferences are entirely dose CHAPTER Tintinalli_Sec15_p1187-1332.indd 1204 8/2/19 8:39 PM

physiology, MAO-A is primarily responsible for the breakdown of serotonin and norepinephrine, whereas MAO-B preferentially metabolizes phenylethylamine; MAO-A and MAO-B have equal ability to metabolize dopamine or tyramine. These preferences are entirely dose CHAPTER Tintinalli_Sec15_p1187-1332.indd 1204 8/2/19 8:39 PM CHAPTER 179: Monoamine Oxidase Inhibitors 1205 dependent and can be overcome at higher substrate concentrations or inhibitor doses (e.g., selegiline). Overall, the human brain contains more MAO-B, and this predomi nance increases with advancing age. Dopaminergic neurons lack MAO-B activity and have limited MAO-A activity, 2 but significant MAO-B activity is present in surrounding astrocytes and glial cells. Thus, dopamine inactivation depends on astrocyte and glial cell metabolism. Serotonergic neurons exclusively contain MAO-B, which allows more serotonin to be recycled intact while metabolizing other nonserotonin neurotransmit ters. Intestinal MAO activity is mostly due to MAO-A, whereas approximately equal proportions of both isoenzymes are found in the liver, affording the body protection against ingested exogenous amines that can cause toxicity (e.g., tyramine reaction). Blockade of MAO-A in the GI tract is responsible for a severe hypertensive crisis that can occur after patients on MAOIs ingest foods containing the sympathomimetic tyramine, and the use of transdermal formulations may avert these side effects. Tyramine is usually metabo lized in the GI tract, but the blockade of MAO-A allows it to flow into the general circulation. Although the accepted “MAOI diet” has been liberalized in recent years, 11 there are still several dietary restrictions to which patients on these medications must adhere. MAOIs share structural similarities with endogenous amines that allow them to act as potential substrates for the enzyme. The antidepressant activity of phenelzine, tranylcypromine, isocarboxazid, and trans dermal selegiline has been primarily attributed to their ability to increase norepinephrine and serotonin neurotransmission by increasing presynaptic concentrations of both amines. Their antidepressant effect cor relates with >80% MAO-A inhibition. Additional mechanisms by which they exert their therapeutic effects are probably related to delayed post synaptic receptor modifications (e.g., downregulation), indirect release of neurotransmitters, and inhibition of neurotransmitter reuptake. The therapeutic benefit of selective MAO-B inhibitors in Parkinson’s disease is related to increased striatal dopamine neurotransmission and protection against neuronal damage from oxidative stress. 2 MAO-B inhibition of >80% correlates with the observed therapeutic effect of selegiline and rasagiline in Parkinson’s disease. At therapeutic doses, there is limited inhibition of MAO-A with modest effects on norepinephrine and serotonin metabolism. 2 However, at large doses (e.g., selegiline >20 milligrams/d), increasing MAO-A inhibition increases presynaptic norepinephrine and serotonin concentrations and thus has the potential to produce drug-related toxicity similar to that of the nonselective agents (phenelzine, tranylcypromine, and isocarboxazid). Traditional MAOIs, such as isocarboxazid, phenelzine, tranylcypro mine, rasagiline, and selegiline, form irreversible covalent bonds with the enzyme, rendering it permanently inactive. Once an irreversible inhibitor drug has been discontinued, it takes approximately 2 weeks before new enzyme synthesis restores activity to 50% of normal and up to 40 days to regain 100% activity. 10 Reversible inhibitors, on the other hand, competitively inhibit enzyme activity. After the reversible TABLE 179-1 U.S.

e. Once an irreversible inhibitor drug has been discontinued, it takes approximately 2 weeks before new enzyme synthesis restores activity to 50% of normal and up to 40 days to regain 100% activity. 10 Reversible inhibitors, on the other hand, competitively inhibit enzyme activity. After the reversible TABLE 179-1 U.S. Food and Drug Administration Approved Monoamine Oxidase Inhibitors Agent Indication Formulation Average Daily Therapeutic Dose Maximum Daily Therapeutic Dose Selectivity Isocarboxazid Major depression 10-milligram tablet 10–40 milligrams 60 milligrams Nonselective Phenelzine Major depression 15-milligram tablet 45–75 milligrams 90 milligrams Nonselective Tranylcypromine Major depression 10-milligram tablet 20–40 milligrams 60 milligrams Nonselective Selegiline Major depression 6 milligrams, 9 milligrams, and 12 milligrams per 24-h patch 6 milligrams per 24-h patch 12 milligrams per 24-h patch Nonselective (as a skin-patch formulation) Rasagiline Parkinson’s disease 0.5- and 1.0-milligram tablets 0.5–1.0 milligram 1 milligram MAO-B Selegiline Parkinson’s disease 5-milligram tablet 10 milligrams 10 milligrams MAO-B (as an oral formulation) 1.25-milligram oral disintegrating tablet 1.25 milligrams 2.5 milligrams MAO-B (as an oral formulation) Moclobemide * Major depression, social anxiety 150- and 300-milligram tablets 300 milligrams 600 milligrams MAO-A Abbreviations: MAO-A = monoamine oxidase isoenzyme A; MAO-B = monoamine oxidase isoenzyme B. *Not available in the United States. inhibitor drug is stopped, MAO function recovers over a period of hours as the drug–enzyme complex spontaneously dissociates. Moclobemide and toloxatone are reversible MAOIs available in most of the world, but not in the United States.  PHARMACOKINETICS MAOI tablets are absorbed rapidly and completely from the GI tract but have relatively low bioavailability because of a large first-pass effect of hepatic metabolism. 10 The skin patch form of selegiline allows for more parent drug to bypass first-pass liver metabolism; this results in elevated blood levels with nonselective MAO inhibition and antidepressant activity. 4 The oral form of selegiline has lower blood levels second ary to first-pass effects, retains its MAO-B selectivity, and does not have antidepressant qualities. Metabolism by hepatic cytochrome P450 predisposes MAOIs to potential interactions with other drugs requiring similar hepatic enzyme pathways. Peak drug levels usually occur within 1 to 3 hours of ingestion. These drugs are highly protein bound and have relatively large volumes of distribution. Elimination half-life is relatively short, and an important feature of clinical toxicity is that it is usually delayed until well after most of the drug has already been metabo lized. Hence, blood levels do not correlate with clinical toxicity. Selegiline has many active metabolites, including desmethylselegiline, amphetamine, and methamphetamine. 5,12 Tranylcypromine does not produce amphetamine metabolites at normal therapeutic doses, but amphetamine has been noted in the serum following tranylcypromine overdose. Phenelzine metabolism results in multiple active metabolites such as β-phenylethylamine, which is metabolized by MAO-B. Rasagiline does not have any active metabolites. 2 Transdermal selegiline offers the advantage of continuous absorption over a 24-hour period without any peak effects. However, its absorption can be drastically increased by external heat application (e.g., sauna, heating pad). 4,5 The pharmacokinetic profile of most MAOIs indicates that attempts at extracorporeal removal (e.g., hemodialysis) or administration of repeat doses of activated charcoal would be unsuccessful in significantly reducing plasma drug levels.

drastically increased by external heat application (e.g., sauna, heating pad). 4,5 The pharmacokinetic profile of most MAOIs indicates that attempts at extracorporeal removal (e.g., hemodialysis) or administration of repeat doses of activated charcoal would be unsuccessful in significantly reducing plasma drug levels.  DRUG INTERACTIONS Long-term MAOI therapy predisposes to many potentially significant drug–drug interactions; some have been well established, whereas others are based on single case reports or solely on theoretical considerations. Controlled human studies are impossible due to the life-threatening nature of these reactions, and animal studies often have limited appli cability to human toxicity. Therefore, emergency physicians should never administer new medications to patients taking MAOIs unless absolutely necessary. Compatibility should always be confirmed before a new drug is administered, and the lowest effective dose should be used. Drug–drug interactions involving MAOIs can be grouped into two categories: pharmacodynamic or pharmacokinetic. The most common Tintinalli_Sec15_p1187-1332.indd 1205 8/2/19 8:39 PM

olutely necessary. Compatibility should always be confirmed before a new drug is administered, and the lowest effective dose should be used. Drug–drug interactions involving MAOIs can be grouped into two categories: pharmacodynamic or pharmacokinetic. The most common Tintinalli_Sec15_p1187-1332.indd 1205 8/2/19 8:39 PM 1206 SECTION 15: Toxicology pharmacodynamic reaction involves indirect-acting sympathomimetics. They have the potential to produce a hyperadrenergic condition similar to the tyramine reaction and can be found in over-the-counter preparations, drugs of abuse, and some prescription products. Pharmacokinetic interactions have been noted between certain drugs and MAOIs because these drugs are metabolized through the cytochrome oxidase enzyme system and thus can inhibit the metabolism of each other. A notable example of this type of drug interaction is the ability of ciprofloxacin and cimetidine to inhibit the metabolism of rasagiline, which can double its serum concentration. 2 Tranylcypromine and phenelzine have been shown to increase insulin release and predispose to hypoglycemia, especially in patients taking oral sulfonylurea agents.  SEROTONIN SYNDROME Serotonin syndrome (see Chapter 178, “ Atypical and Serotonergic Antidepressants”) is a potentially life-threatening, often iatrogenic reaction. With MAOIs, serotonin syndrome most commonly occurs when combined with other serotonergic agents. The important principle for emergency physicians is not to use meperidine, dextromethorphan, tramadol, linezolid, propoxyphene, a selective serotonin reuptake inhibitor, or a selective serotonin-norepinephrine reuptake inhibi tor in a patient on MAOI therapy. Patients should be warned about concomitant use of illicit drugs in general but especially cocaine, 3,4-methylenedioxymethamphetamine (MDMA; popularly known as ecstasy), and methamphetamine. Even after a patient discontinues MAOI therapy, 2 weeks are required before 50% of MAO enzyme activity returns. In general, selective serotonin reuptake inhibitors and serotoninnorepinephrine reuptake inhibitors should be discontinued for 2 weeks prior to using an MAOI with the exception of fluoxetine, which should be stopped 4 weeks before using an MAOI. Consequently, there should be at least a 2-week abstinence period between the time an MAOI is discontinued and when any contraindicated drug is started; this rec ommendation is particularly important to prevent the development of serotonin syndrome. Awareness of which medications are generally considered safe for patients taking MAOIs is useful (Table 179-2). Aspirin, acetaminophen, ibuprofen, morphine, and most antibiotics have been used in combination with MAOIs without complications. CLINICAL FEATURES MAOIs have a low ratio of toxic to therapeutic dose. This character istic predisposes patients to significant drug toxicity with ingestions just slightly larger than normal therapeutic doses. For isocarboxazid, phenelzine, or tranylcypromine, acute ingestions of 1 to 2 milligrams/kg may produce mild to moderate toxicity, ingestions of more than 2 to 3 milligrams/kg can be life threatening, and the lethal dose is estimated to be between 4 and 6 milligrams/kg. 13 Selegiline overdose experience is extremely limited, but because selectivity is lost after a 30-milligram ingestion, it should be assumed to produce toxicity similar to that of the traditional nonselective MAOIs. 12 Rasagiline is a far more selective MAO-B inhibitor than selegiline. It was given to healthy volunteers at doses 20 times the normal therapeutic dose without any significant toxicity. However, as of this writing, there are no published cases of rasagiline overdose, so prudence dictates that it should be subject to the same precautions as other agents in this class.

itor than selegiline. It was given to healthy volunteers at doses 20 times the normal therapeutic dose without any significant toxicity. However, as of this writing, there are no published cases of rasagiline overdose, so prudence dictates that it should be subject to the same precautions as other agents in this class. Toxicity from moclobemide overdose alone is usually mild, even with large ingestions. But when combined with a serotonergic agent, serotonin syndrome is common and can be severe. An important clinical aspect of MAOI overdose is that the appearance of toxic symptoms is characteristically delayed to between 6 and 12 hours after ingestion, and the delay can be as long as 24 hours. The delayed onset of toxicity is attributed to the gradual accumulation of norepinephrine and serotonin in the brain and peripheral sympa thetic neurons. Symptoms of MAOI overdose are most consistent with a hyperadrenergic state secondary to excessive stimulation of α-adrenergic and β-adrenergic receptors, but symptoms related to excessive serotonin receptor activity are also seen. Patients receiving long-term therapy may show earlier signs of toxicity due to preexisting enzyme inhibition. In severe cases, the hyperadrenergic state can be followed rapidly by hypotension and CNS depression resembling a sympatholytic condition. Toxicity usually persists for 1 to 4 days after ingestion. Published descriptions of MAOI toxicity indicate tremendous variation in presentation: there is no “typical” presentation of MAOI toxicity and no orderly progression of symptoms. 12,13,15,16 The initial symptoms of overdose are reported to include headache, agitation, irri tability, nausea, palpitations, and tremor. The earliest signs of 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 described as “ping-pong gaze” has been observed in some cases of MAOI toxicity and refers to bilateral wandering hori zontal eye movements. 17 The cause for this gaze disorder is unknown, and it resolves gradually as the patient improves. Severe toxicity is accompanied by coma, seizures, bradycardia, hypotension, hypoxia, and worsening hyperthermia. Hypotension is an ominous finding and is commonly resistant to therapy. Fetal death, intracranial hemorrhage, and cerebral or pulmonary edema have been reported in association with MAOI overdoses. The most common ECG abnormality seen with toxicity is sinus tachycardia, but T-wave abnor malities are occasionally seen. Moclobemide overdose may produce QT-interval prolongation but without associated dysrhythmias. 18 Death is usually secondary to multiorgan failure. DIAGNOSIS MAOI overdose is a clinical diagnosis based solely on history. Plasma drug levels do not correlate with clinical toxicity, nor are such tests routinely available in most hospital laboratories. Routine urine drug screens do not detect drugs of this class. Selegiline is likely to produce amphetamine metabolites, which can be detected on most urine drug screens. Tranylcypromine has the potential to produce amphetamine metabolites in overdose, but these are rarely detected. Laboratory tests can assist in the differential diagnosis and identify possible complications, including hypoxia, rhabdomyolysis, renal failure, hyperkalemia, metabolic acido sis, hemolysis, and disseminated intravascular coagulation. Leukocyto sis and thrombocytopenia are seen commonly with toxicity.

rarely detected. Laboratory tests can assist in the differential diagnosis and identify possible complications, including hypoxia, rhabdomyolysis, renal failure, hyperkalemia, metabolic acido sis, hemolysis, and disseminated intravascular coagulation. Leukocyto sis and thrombocytopenia are seen commonly with toxicity. The differential diagnosis includes drugs and medical conditions capable of producing a hyperadrenergic state, altered mental status, and/ or muscle rigidity (Table 179-3). In addition, toxicity can be associated with a sympatholytic presentation. As noted, MAOI toxicity is difficult to diagnose without a history of exposure to the drug. TABLE 179-2 Medications Considered Safe in Combination With Monoamine Oxidase Inhibitors* Direct-Acting Sympathomimetics Miscellaneous Drugs Albuterol aerosol Acetaminophen Dobutamine Antibiotics (except linezolid and furazolidone) Epinephrine Barbiturates Isoproterenol Benzodiazepines Methoxamine Calcium channel blockers Norepinephrine Corticosteroids Terbutaline Lidocaine Vasopressin Morphine Nitroglycerin Nitroprusside NSAIDs Phentolamine Procainamide *Always use the lowest effective dosage. Tintinalli_Sec15_p1187-1332.indd 1206 8/2/19 8:39 PM

Epinephrine Barbiturates Isoproterenol Benzodiazepines Methoxamine Calcium channel blockers Norepinephrine Corticosteroids Terbutaline Lidocaine Vasopressin Morphine Nitroglycerin Nitroprusside NSAIDs Phentolamine Procainamide *Always use the lowest effective dosage. Tintinalli_Sec15_p1187-1332.indd 1206 8/2/19 8:39 PM CHAPTER 179: Monoamine Oxidase Inhibitors 1207 An elevated blood pressure in a patient receiving long-term MAOI therapy presents a dilemma. At therapeutic doses, hypertension can result from tyramine reactions, spontaneous hypertensive crisis, or serotonin syndrome. 9 Tyramine reactions are likely to occur in close relation to ingestion of food or drugs containing indirect sympathomimetics. Spontaneous hypertensive crisis is a rare condition, usually occurring in relation to recent drug dosing. 9 Serotonin syndrome most commonly occurs shortly after exposure to other serotonergic agents and usually is associated with significant cognitive-behavioral and neuromuscular abnormalities. TREATMENT  GENERAL CARE There are no known antidotes for MAOI toxicity. ED management is therefore directed toward supportive care and early treatment of complications. Place at least one (preferably large-bore) peripheral IV line and a cardiac monitor. Obtain laboratory studies, especially to identify hyperkalemia, metabolic acidosis, and rhabdomyolysis. Onset of toxicity is usually gradual and delayed, sometimes up to 24 hours after ingestion. However, the abrupt development of seizures, coma, respiratory insufficiency, hyperadrenergic storm, and cardiovascular collapse is possible. For any given dose of inhibitor, toxicity is predicted to be greater for children, the elderly, and patients with co-ingestants or significant underlying medical problems. There is no accepted need or best method for GI decontamina tion in an MAOI overdose. 19 Ipecac syrup is contraindicated.20 Gastric lavage is generally not recommended. 19,21 MAOIs are absorbed rapidly, so delayed gastric lavage or whole-bowel irrigation is unlikely to be of clinical benefit. 22 If presentation is within 1 hour, consider activated charcoal administered as a single dose ; however, multidose adminis tration is not expected to be useful.23 Hemodialysis, hemoperfusion, and peritoneal dialysis have no established role in the treatment of MAOI poisoning. Urinary acidification is not recommended because it is inef fective in enhancing MAOI elimination and predisposes to acute renal failure secondary to myoglobin precipitation within renal tubules.  HYPERTENSION Treat hypertension only with short-acting IV antihypertensive agents because of the potential for development of precipitous hypotension. In many cases, an intra-arterial catheter is required for accurate blood pressure monitoring. The recommended antihypertensive agents are phen tolamine and nitroprusside. Phentolamine is a nonspecific α-adrenergic receptor blocker usually administered in 2.5- to 5.0-milligram IV boluses every 10 to 15 minutes until the blood pressure is controlled. It also can be given as a continuous infusion (0.2 to 0.5 milligram/min) for maintenance therapy. Phentolamine use is commonly associated with reflex tachycardia. Nitroprusside is as effective as phentolamine. It is given as a continuous IV infusion starting at a rate of 1 microgram/kg per minute and is then titrated according to blood pressure response. Prolonged administration of high doses of nitroprusside can predispose to cyanide toxicity, but this potential complication is not relevant to initial treatment. Nitroglycerin is indicated for the relief of anginal chest pain and in patients with signs of myocardial ischemia. β-Blockers pose a theoretical risk of increasing blood pressure (through unopposed vasoconstriction) and are relatively contraindicated.

ut this potential complication is not relevant to initial treatment. Nitroglycerin is indicated for the relief of anginal chest pain and in patients with signs of myocardial ischemia. β-Blockers pose a theoretical risk of increasing blood pressure (through unopposed vasoconstriction) and are relatively contraindicated.  HYPOTENSION Hypotension indicates a poor prognosis after MAOI overdose. Give IV normal saline fluid boluses initially. When vasopressors are required, a direct-acting agent such as norepinephrine is preferred, and all indirect-acting agents such as dopamine should be avoided. Patients receiving long-term MAOI therapy usually demonstrate an increased sensitivity to vasopressors, so use low initial dosages.  DYSRHYTHMIAS Sinus tachycardia rarely calls for specific drug therapy unless it is producing cardiac ischemia. Lidocaine and procainamide are the most effective antiarrhythmics for treating the ventricular dysrhythmias seen with toxicity. Bradycardia may degrade quickly into asystole in the later stages of toxicity and requires pacemaker placement. Pharmacologic treatment of bradycardia includes atropine, isoproterenol, and dobutamine.  SEIZURES Benzodiazepines such as lorazepam and diazepam are the anticon vulsants of choice in treating MAOI-induced seizures. Barbiturates such as phenobarbital are as effective as benzodiazepines but may cause hypotension, especially at higher dosages. Phenytoin is gener ally ineffective in stopping drug-induced seizures. General anesthesia and muscle paralysis may be necessary in cases of status epilepticus to prevent the metabolic acidosis, hyperthermia, and rhabdomyolysis that commonly accompany persistent seizure activity. Muscle paralysis is best accomplished using nondepolarizing neuromuscular blocking agents, because the action of succinylcholine may be enhanced by these MAOIs. Vecuronium is preferred to pancuronium because of the latter’s propensity to produce elevations in heart rate and blood pressure. Electroencephalographic monitoring is required when muscle paralysis is used to control the peripheral manifestations of seizure activity.  HYPERTHERMIA Antipyretics are not effective in lowering drug-induced fever. Benzodi azepines such as lorazepam or diazepam are useful first-line agents to reduce muscle hyperactivity and thus decrease secondary heat production. Increasing evaporative and conductive heat loss is essential for the successful treatment of drug-induced hyperthermia. This is best accomplished by using cool mist sprays and evaporative fans or cooling blankets. Hyperthermia is often resistant to treatment as long as there is persistent muscle rigidity. Muscle paralysis (using nondepolarizing agents) should be considered when diffuse rigidity is refractory to ben zodiazepine therapy. Anecdotally, dantrolene is an effective relaxant in resistant cases of muscle rigidity, given at a dose of 0.5 to 2.5 milligrams/kg IV every 6 hours, but should only be used when other measures have failed to relieve muscle rigidity. 24,25 DISPOSITION AND FOLLOW-UP All patients with intentional MAOI overdoses or accidental ingestions of isocarboxazid, phenelzine, or tranylcypromine >1 milligram/kg require admission to an intensive care unit or equivalent. Patients with accidental exposures of <1 milligram/kg still require hospital admission but, because they are less likely to develop life-threatening complications, can be admitted to a bed with less frequent monitoring. Consultation with a medical toxicologist and regional poison control center is strongly recommended. Asymptomatic patients should be monitored for at least 24 hours before discharge.

sion but, because they are less likely to develop life-threatening complications, can be admitted to a bed with less frequent monitoring. Consultation with a medical toxicologist and regional poison control center is strongly recommended. Asymptomatic patients should be monitored for at least 24 hours before discharge. Dietary and medication restrictions should be TABLE 179-3 Differential Diagnosis of Monoamine Oxidase Inhibitor Overdose Intoxications Medical conditions Adverse drug reactions Amphetamines Heatstroke Dystonic reactions Antimuscarinics Hypoglycemia Malignant hyperthermia Cathinone Hyperthyroidism Serotonin syndrome Cocaine Pheochromocytoma Tyramine reaction Methylphenidate Withdrawal states Spontaneous hypertensive crisis MDMA (3,4-methylenedioxymethamphetamine) Ethanol (delirium tremens) Neuroleptic malignant syndrome Sedative-hypnotics Malignant catatonia Phencyclidine Clonidine Infectious diseases Phenylpropanolamine β-Blockers Encephalitis Strychnine Meningitis Theophylline Rabies Tricyclic antidepressants (early) Sepsis Tetanus Tintinalli_Sec15_p1187-1332.indd 1207 8/2/19 8:39 PM