Monoamine Oxidase Inhibitor Toxicity


Article Author:
Eddie Garcia


Article Editor:
Cynthia Santos


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
5/5/2019 11:03:31 PM

Introduction

Monoamine oxidase inhibitors (MAOIs) are a class of antidepressants. The use of MAOIs has declined in the past few decades due to the introduction of newer antidepressants [1], making the incidence of toxicity rare. They have the potential to interact with many other medications and certain foods to produce nonspecific symptoms which can range from mild to life-threatening. MAOI toxicity can be difficult to distinguish from much more common clinical entities. Prompt recognition and intervention are vital to treatment.

Etiology

There are three ways in which MAOI toxicity can occur: drug-food interaction, overdose, or drug-drug interactions.

  1. The most common MAOI toxicity involves the interaction with tyramine-containing foods. When MAO found in the gut and liver is inhibited, dietary tyramine indirectly causes an amplification of adrenergic activity. Food rich in tyramine includes aged cheeses, aged/picked/smoked meats, beer, wine, yeast extracts, ginseng, sauerkraut, and avocado. 
  2. MAOIs have a low therapeutic index. Ingestion of 2 mg/kg of a first generation, non-selective MAOI inhibitors such as isocarboxazid, phenelzine, or tranylcypromine has the potential for severe toxicity. MAOI overdose may see a delay in symptoms of several hours or more.
  3. MAOI toxicity can be seen when a MAOI is combined with any drug that increases the synthesis, release, and effect or decreases the metabolism or reuptake of monoamines. These drugs include but are not limited to, dextromethorphan, linezolid, methylene blue, selective serotonin reuptake inhibitors, serotoninergic agents, and tramadol [2] [3] [4] [5].

Epidemiology

There has been a 60% decrease in cases of MAOI exposures in the United States over the last 25 years. In 2015, only 208 cases of MAOI exposures were reported to poison control centers. Single exposures to MAOIs accounted for 90 of the cases. Adults accounted for 71 of these cases, and 28 cases were intentional ingestions. Death due to MAOI exposure is rare, with about one case reported per year over the past decade (including cases with both single and multiple exposures) [6] [7] [8] [5]. The decline in MAOI toxicity cases presumably reflects the preferential use of other classes of antidepressants. However, MAO has been found to play a central role in the pathogenesis of Alzheimer disease. MAOIs are currently being studied as potential neuroprotective agents [9]. If they prove to be an effective treatment and rates of prescribing increase, then the incidence of toxicity has the potential to increase as well.

Pathophysiology

The toxic effects of MAOIs are observed when their inhibitory effects on monoamine oxidase are compounded by drug-food interactions, overdose or drug-drug interactions. Without MAO to break down epinephrine, norepinephrine, dopamine, serotonin, and tyramine, the storage, and release of these monoamines are increased. Increased adrenergic tone produces findings of tachycardia, hyperthermia, myoclonus, hypertension, and agitation (see below for a more comprehensive list of findings). The time course can range from minutes for a drug-food interaction to several hours in a pure MAOI overdose.

Histopathology

There are no clinically relevant histopathologic findings in MAOI toxicity.

Toxicokinetics

MAOIs have high oral bioavailability and plasma concentrations peak within two to three hours. They irreversibly bind monoamine oxidase (except for moclobemide), removing the drug from circulation and making blood concentrations not indicative of effect. It takes two to three weeks to synthesize enough new monoamine oxidase, so clinical effects of MAOIs may last for that amount of time. MAOIs are metabolized in the liver and excreted by the kidneys.

History and Physical

Though many of the symptoms of MAOI toxicity are nonspecific, much of the suspicion for MAOI toxicity will come from the patient history. A complete list of medications, supplements, both current and recently discontinued, should be obtained as there can be significant latency between ingestions and development of symptomatology. Signs of MAOI toxicity are non-specific as well. Mild signs include agitation, diaphoresis, tachycardia and mild temperature elevation. Signs of moderate disease include altered mental status, tachypnea, vomiting, dysrhythmias, hyperthermia, and hypertension. Severe signs include severe hyperthermia, seizures, central nervous system (CNS) depression, coma, cardiorespiratory depression, muscle rigidity and myoclonus. Though similar to other hyperthermic toxidromes, there are a few ways in which MAOI toxicity can be distinguished. MAOI toxicity can present with diaphoresis whereas an anticholinergic syndrome should have dry skin. Additionally, MAOI toxicity is much more likely to present with generalized or ocular clonus than neuroleptic malignant syndrome. A "ping-pong" gaze has also been described in MAOI toxicity [10].

Evaluation

Physicians primarily diagnose patients with a history and physical examination. Frequent measurements of temperature are recommended. Electrolytes and lactic acid should be obtained in patients in which MAOI toxicity is suspected. Salicylate, acetaminophen and alcohol levels should be obtained in any patient in which intentional overdose is suspected as should a pregnancy test in any woman of child bearing age. MAOI levels are not clinically useful. Radiologic tests are not useful for the evaluation of MAOI toxicity.

Treatment / Management

As with any patient with a potentially toxic ingestion, treatment starts with the assessment of the patient’s airway, breathing, and circulation as well as the interventions to maintain a patent airway, adequate ventilation, and circulation. Patients may be significantly dehydrated due to hyperthermia and should be given intravenous fluids. Treat seizures and/or agitation with benzodiazepines.

Cyproheptadine can be considered a third-line treatment after hydration and benzodiazepines. Cyproheptadine is a first-generation antihistamine with anticholinergic and antiserotonergic effects. Its effectiveness has not been proven, but the typical dosing is 12 mg by mouth (or nasogastric/orogastric tube) with additional 2 mg doses every two hours as needed for symptomatic control.

If the time of ingestion was within one hour, activated charcoal could be considered by either emergency medical services during transport or by emergency department providers. The patient’s airway may need to be secured before charcoal administration. Gastric lavage should be considered in a patient with a life-threatening ingestion. There are no antidotes for MAOI toxicity. Hemodialysis is ineffective in removing the drug from the body.

Rapid correction of hyperthermia is vital. Cooling by evaporative heat loss (wetting skin and creating air flow with fans) is an effective treatment. If the patient has signs of severe MAOI toxicity, covering the body with ice or immersing the patient in an ice bath may be necessary. Antipyretics likely will not be adequate treatment.

Patients may present hypertensive, but treatment specifically for hypertension is usually not necessary. If needed, a short-acting agent such as nitroprusside or phentolamine is suggested as beta-blockers may result in unopposed alpha stimulation.

Hospital admission and observation is recommended for any patient with symptoms persisting more than six hours. Consulting the regional poison control center or another medical toxicologist is advised for further recommendations.

Enhancing Healthcare Team Outcomes

Monoamine oxidase inhibitor toxicity is rare but very serious. The toxicity is due to hyperactivity of the sympathetic nervous system and is best managed by a multidisciplinary team that includes a pharmacist, emergency department physician, toxicologist, nurse practitioner, internist and a cardiologist. The key is to prevent and manage the sympathetic overactivity. These patients need close ICU monitoring and aggressive hydration and control of hyperthermia.

The outcomes depend on the severity of the drug overdose, co morbidity, age of patient and prior history of cardiac disorders.


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Monoamine Oxidase Inhibitor Toxicity - Questions

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A 73-year-old woman is being discharged from the hospital after a ten-day admission for pneumonia caused by Staphylococcus aureus with multiple antibiotic resistances. The discharging physician wants to start a short course of oral antibiotics. She has a past medical history of refractory depression and has taking phenylzine for ten years. What antibiotic has the potential to cause a severe reaction with her antidepressant?



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An emergency medicine physician receives a phone call from emergency medical services that they are transporting a 17-year-old male with an intentional ingestion of tranylcypromine, sertraline, tramadol, and diphenhydramine. The time of ingestion and the quantity is unknown. The patient is currently agitated, hyperthermic and displays clonus. Which one of the following treatments is unlikely to help in the treatment of this patient?



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A 43-year-old-female is brought in by friends after collapsing at a church potluck. She is known to have a history of depression and has a bottle of tranylcypromine in her purse. She was her usual self during church and was looking forward to the variety of food that she was going to try. Since her collapse, she has maintained consciousness but is agitated and confused. On exam, she is hot to the touch and diaphoretic. An adrenergic crisis is suspected. Ingestion of what food could have precipitated this event?



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A 22-year-old female is brought in from a "dance party" by paramedics. Her temperature in the field was 40.4C, and external cooling was initiated during transport. She has altered mental status, muscle rigidity, and clonus. What is the most likely etiology of her symptoms?



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A 16-year-old female is brought in by her parents for a witnessed ingestion about 30 minutes ago. Her parents have empty bottles of phenelzine, escitalopram, and diphenhydramine. These medications belong to the patient, and a month’s supply was dispensed one week ago. The patient is currently asymptomatic. What is the best next step in management?



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Monoamine Oxidase Inhibitor Toxicity - References

References

Revisiting monoamine oxidase inhibitors., Krishnan KR,, The Journal of clinical psychiatry, 2007     [PubMed]
Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1-42)-induced toxicity., Caraci F,Pappalardo G,Basile L,Giuffrida A,Copani A,Tosto R,Sinopoli A,Giuffrida ML,Pirrone E,Drago F,Pignatello R,Guccione S,, European journal of pharmacology, 2015 Oct 5     [PubMed]
Methylene blue-associated serotonin syndrome: a 'green' encephalopathy after parathyroidectomy., Rowley M,Riutort K,Shapiro D,Casler J,Festic E,Freeman WD,, Neurocritical care, 2009     [PubMed]
Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction., Ramsay RR,Dunford C,Gillman PK,, British journal of pharmacology, 2007 Nov     [PubMed]
Tramadol: seizures, serotonin syndrome, and coadministered antidepressants., Sansone RA,Sansone LA,, Psychiatry (Edgmont (Pa. : Township)), 2009 Apr     [PubMed]
"Ping-pong" gaze in severe monoamine oxidase inhibitor toxicity., Erich JL,Shih RD,O'Connor RE,, The Journal of emergency medicine, 1995 Sep-Oct     [PubMed]
2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report., Mowry JB,Spyker DA,Brooks DE,McMillan N,Schauben JL,, Clinical toxicology (Philadelphia, Pa.), 2015     [PubMed]
1990 annual report of the American Association of Poison Control Centers National Data Collection System., Litovitz TL,Bailey KM,Schmitz BF,Holm KC,Klein-Schwartz W,, The American journal of emergency medicine, 1991 Sep     [PubMed]
1997 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System., Litovitz TL,Klein-Schwartz W,Dyer KS,Shannon M,Lee S,Powers M,, The American journal of emergency medicine, 1998 Sep     [PubMed]
2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System., Watson WA,Litovitz TL,Klein-Schwartz W,Rodgers GC Jr,Youniss J,Reid N,Rouse WG,Rembert RS,Borys D,, The American journal of emergency medicine, 2004 Sep     [PubMed]

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