Monoamine Oxidase Inhibitor Toxicity

Updated: Feb 09, 2017
  • Author: Steven Marcus, MD; Chief Editor: Asim Tarabar, MD  more...
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Overview

Practice Essentials

Toxicity from drugs in the monoamine oxidase inhibitor (MAOI) class of antidepressants most often results from a drug-food interaction, the so-called tyramine reaction. Uncommonly, MAOI toxicity may result from overdose or drug-drug interactions. (See Pathophysiology.)

All three mechanisms produce quite similar symptoms and signs, which represent the effects of excessive catecholamine neurotransmitters. Clinical manifestations include hypertension, tachycardia, tremors, seizures, and hyperthermia. (See Presentation.)

Because of the potential for severe toxicity and lack of antidotes, aggressive decontamination is very important in patients with MAOI toxicity. Control of hyperthermia and fluid therapy are paramount. (See Treatment.)

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Background

Neurotransmitters are generally monoamines. They are "manufactured," stored in vesicles in the nerve terminals, and then released through the plasma membrane into the synaptic cleft. When released into the synaptic space, neurotransmitters are either reabsorbed into the proximal nerve and metabolized by monoamine oxidase (MAO) or destroyed by catechol-o-methyl transferase (COMT) in the synaptic cleft.

It is hypothesized that clinical depression is related to decreases in concentration of the neurotransmitters. For this reason, pharmaceutical research has produced drugs that can either block the reuptake of neurotransmitters (eg, cyclic antidepressants, selective serotonin reuptake inhibitors [SSRIs]) or interfere with the breakdown of the reabsorbed monoamines within the nerve terminal (monoamine oxidase inhibitors [MAOIs]). [1]

The two types of MAO are MAO-A and MAO-B. MAO-A is found primarily in the liver and gastrointestinal tract with some found in the monoaminergic neurons. MAO-B, on the other hand, is found primarily in the brain and in platelets. Circulating monoamines, such as epinephrine, norepinephrine, and dopamine, are inactivated when they pass through a liver rich in MAO-A. Norepinephrine is primarily metabolized by MAO-A, whereas MAO-A and MAO-B have equal ability to metabolize dopamine and tyramine. [2]

The older MAOIs, such as phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate), are considered nonselective inhibitors, while the newer MAOIs tend to be more specific inhibitors of either MAO-A or MAO-B. However, the selectivity is primarily dose related. Additionally, the older MAOIs bind irreversibly to the enzyme and could have clinical effects up to 2 weeks or until new MAO is synthesized, while the newer products are bound reversibly in a competitive equilibrium. [3]

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Pathophysiology

Monoamine oxidase is responsible for the deactivation of active monoamines such as epinephrine, norepinephrine, dopamine, and serotonin. Such oxidases are present in a wide variety of body tissues. They control the concentration of monoamines in the nerve terminal.

Two categories of MAOs exist: MAO-A and MAO-B. Individual MAOIs are said to be specific for one of the two types, but such specificity seems to be somewhat dose dependent.

The widely prescribed monoamine oxidase inhibitors (MAOIs) are unique in that they bind irreversibly (moclobemide [Aurorix, Manerix] is an exception, since it is a reversible inhibitor) at their sites of action, are eliminated from circulation by such binding and, since they do not recirculate after such binding, their effects are not, strictly speaking, related to their blood levels. Additionally, MAOs are located in many tissues, including the gut wall. MAOIs absorbed through the gastrointestinal tract bind significantly to MAO in the gut mucosa and liver producing significant first pass effect.

To act in the central nervous system, their location of clinically significant effect, MAOIs must be given in high enough concentration to reach plasma levels, and thus brain levels, sufficient to produce binding centrally to MAO. MAO in the gut mucosa essentially breaks down potentially toxic dietary monoamines, such as tyramine, and "prevents" their absorption. The inhibition of gut MAO by these medications coupled with ingestion of substances containing tyramine (see causes below) may produce significant toxicity.

A transdermal preparation of a "selective" MAO-B drug, selegiline, has appeared on the market, which by bypassing the first pass effect of gut and hepatic MAOI effects, appears to produce antidepressant effects with significantly reduced risk for dietary-induced toxicity. [4, 5] At the lowest effective dosage of 6 mg/day, selegiline can be used without dietary modification. [6]

MAOIs are orally absorbed well, and peak plasma concentrations are reached within 2-3 hours. They have a relatively large volume of distribution (1-5 L/kg) and are highly protein bound. They are metabolized by oxidation and acetylation in the liver and are excreted in the urine.

MAOI poisoning is classified into the following three subtypes:

  • Overdose: This occurs uncommonly. Symptoms of intentional overdose may be delayed up to 32 hours post ingestion but generally occur within 24 hours. These patients require prolonged close monitoring to prevent significant morbidity.
  • Drug-food interaction: This is the so-called tyramine reaction or cheese reaction. It is usually rapid in onset, occurring within 15-90 minutes after ingestion. Most symptoms resolve in 6 hours. Fatalities have been reported due to complications from hypertensive emergencies.
  • Drug-drug interaction

The symptoms and signs of all three categories are quite similar and represent the effects of excessive catecholamine neurotransmitters. MAOIs inhibit breakdown of the neurotransmitters norepinephrine, dopamine, and serotonin, resulting in hypertension, tachycardia, tremors, seizures, and hyperthermia.

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Epidemiology

United States

Reported exposures to MAOIs have decreased dramatically over past decades. By year, the American Association of Poison Control Centers has reported the following:

  • 1990: 618 cases [7]
  • 1997: 463 cases [8]
  • 2003: 285 cases [9]  
  • 2008: 139 cases [10]
  • 2012: 97 cases [11]
  • 2015: 90 cases [12]

Of the 90 single exposures reported in 2015, 71 were in adults, and 62 were known to be unintentional. Two cases (both involving tranylcypromine) had major outcomes. No deaths occurred. [12]

The decline in MAOI toxicity cases presumably reflects the preferential use of other classes of antidepressants. However, MAO enzymes have also been found to play a central role in the pathogenesis of Alzheimer disease, and MAOIs are currently being studied as potential neuroprotective agents. [13] If they prove effective for that purpose, their use—and episodes of toxicity—may well increase

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Mortality/Morbidity

Severe toxicity is manifested by hyperthermia, seizures, respiratory depression, and CNS depression. Hypotension, cardiovascular collapse, and death may ensue.

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