Monoamine Oxidase Inhibitor Toxicity in Emergency Medicine 

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, newer selective serotonin reuptake inhibitors) or interfere with the breakdown of the reabsorbed monoamines within the nerve terminal (monoamine oxidase inhibitors [MAOIs]).^[1]

The 2 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]

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. MAOIs are said to be specific for the two types, but such specificity seems to be somewhat dose dependent.

The widely prescribed monoamine oxidase inhibitors (MAOIs) are rather unique in the fact 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 be effective in the CNS, their location of clinically significant effect, they 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 "prevent" their absorption. The inhibition of gut MAO by these medications coupled with ingestion of substances containing tyramine (see causes below) may produce significant toxicity.

Recently, a transdermal preparation of a "selective" MAO-B drug, selegiline, has appeared on the market, which by by-passing 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]} Lowest effective dose at 6 mg/day 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 3 subtypes:

• Actual poisoning from an overdose is uncommon. 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 is 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 3 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.

Frequency

United States

In 2003, the American Association of Poison Control Centers' Toxic Exposure Surveillance System (AAPCC-TESS) reported 285 MAOI exposures in the United States.^[7] This is compared with 463 MAOI exposures in 1997, which was an increase from the 451 exposures reported in 1996 but a significant drop compared with the 618 cases reported in 1990.^{[8, 9, 10]}

Of the toxic exposures reported in 2003, 32 occurred in children younger than 6 years and 244 occurred in those older than 19 years. The data from 2003 also showed that 157 of the toxic exposures were unintentional and 74 were intentional. In 2003, of those who ingested MAOIs, 2 died and 20 had severe clinical manifestations.^[7]

In 2005, the same database reported 275 exposures with 2 deaths. Thus, the rate of exposures seems to be steady.^[11]

In 2007, 302 exposures were reported to the AAPCC's new National Poison Data System.^[12]

In 2008, AAPCC reported 139 MAOI exposures; 14 occurred in children younger than 6 years and 98 occurred in those older than 19 years. Seventy-five cases were treated in healthcare facilities, and 31 cases had moderate-to-severe clinical manifestations.^[13]

Mortality/Morbidity

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

Race

No scientific data have found that outcomes of toxic MAOI exposure are dependent on race.

Sex

No scientific data have found that outcomes of toxic MAOI exposure are dependent on sex.