eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Monoamine Oxidase Inhibitor

Author: Steven Marcus, MD, Professor, Department of Preventive Medicine and Community Health, Associate Professor, Department of Pediatrics, New Jersey Medical School, University of Medicine and Dentistry of New Jersey; Executive and Medical Director, New Jersey Poison Information and Education System; Consulting Staff, Departments of Pediatrics and Internal Medicine, University Hospital, University of Medicine and Dentistry of New Jersey; Consulting Staff, Department of Pediatrics, Newark Beth Israel Medical Center
Contributor Information and Disclosures

Updated: Jan 8, 2008

Introduction

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 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-A present in the liver is involved in the elimination of ingested monoamines such as dietary tyramine. Circulating monoamines, such as epinephrine, norepinephrine, and dopamine, are inactivated when they pass through a liver rich in MAO-A. MAO-B, on the other hand, is found primarily in the brain and in platelets.

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 MAOI-A or MAOI-B. However, the selectivity is primarily dose related. Additionally, the older MAOIs bind irreversibly to the enzyme, while the newer products are bound reversibly in a competitive equilibrium.

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

The widely prescribed MAOIs are rather unique in the fact that they bind irreversibly (moclobemide 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-A in the gut acts as a barrier to the absorption of tyramine, and thus ingestion of substances containing tyramine 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.^2,3

MAOI poisoning is classified into the following 3 subtypes:

• Actual poisoning from an overdose (uncommon)
• Drug-food interaction
• 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.

Remembering that symptomatology of intentional overdose may be delayed for 6-12 hours post ingestion is extremely important. These patients require prolonged close monitoring to prevent morbidity.

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.⁴ 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.^5,6,7

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.⁴

In 2005, the same database reported 275 exposures with 2 deaths. Thus, the rate of exposures seems to be steady.⁸

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.

Clinical

History

The MAOI agents currently available in the United States include phenelzine sulfate (Nardil), tranylcypromine sulfate (Parnate), isocarboxazid (Marplan), and selegiline (specific for the MAO-B enzyme), all of which irreversibly bind to MAO. Reversible inhibitors of MAO are available in Europe (eg, brofaromine, cimoxatone, clorgyline, lazabemide, moclobemide). Substances, such as St. John's wort, that may have MAOI-like activity are frequently used for self-treatment of depression.

According to recent reviews of the experience with one of the newer selective MAOIs, moclobemide, little is expected in the way of symptoms and signs from a simple overdose, except in the circumstance of the co-ingestion of another serotonin-active substance.

For food and drug interactions, the history must include a careful search for potential offending agents, including over-the-counter preparations.

• Ingestion of an MAOI can induce a complex array of hypermetabolic signs that include the following:
  • Fever
  • Tachycardia
  • Generalized muscle rigidity
  • Tachypnea
  • Metabolic acidosis
  • Hypoxemia
  • Hypercapnia
• Acute overdose usually does not produce a hypertensive crisis unless the patient provokes the interaction.
• Early mild symptoms
  • Irritability
  • Anxiety
  • Flushing
  • Sweating
• Moderate symptoms
  • Anxiousness
  • Restlessness
  • Fever
• Severe symptoms
  • Severe fever
  • Seizures
  • Sleepiness

Physical

MAOI overdoses or interactions present with excessive catecholamine stimulation toxidromes. Late in the course, the patient may become hypotensive and comatose. Symptoms can be classified into mild, moderate, and severe.

• Mild symptoms
  • Agitation
  • Confusion
  • Flushing
  • Diaphoresis
• Moderate symptoms
  • Altered mental status
  • Fever
  • Diplopia
  • Hypertension
  • Tachycardia
  • Tachypnea
• Severe symptoms
  • Severe hyperpyrexia
  • Seizures
  • CNS depression
  • Coma
  • Cardiorespiratory depression
  • Malignant hyperthermia
  • Muscle rigidity

Causes

MAOIs may have drug interactions with serotonin reuptake inhibitors, several analgesics (particularly meperidine), and tyramine-containing foods. Any drug that releases catecholamines may precipitate life-threatening events in individuals also using MAOIs.

• Tyramine-containing foods
  • Aged cheeses
  • Aged, pickled, or smoked meats (eg, salami)
  • Yeast extracts
  • Beer (dark more than light, on tap more than in bottles because tyramine is adsorbed to glass)
  • Red wine more than white wine
  • Avocado
  • Sauerkraut
• Potential drug interactions
  • Meperidine
  • Dextromethorphan
  • Selective serotonin reuptake inhibitors (SSRIs) – Fluoxetine, paroxetine
  • Sertraline
  • Sumatriptan
  • All serotonergic agents
  • Linezolid, an antibiotic used to treat certain drug-resistant organisms such as MRSA, has been determined to be a reversible, nonselective MAOI and has been implicated in acute serotonin syndrome, so it may be a risk.⁹

• Search for CME/CE on This Topic »

• Toxicity, Monoamine Oxidase Inhibitor (Pediatrics: Cardiac Disease and Critical Care Medicine)
• Toxicity, Lidocaine (Emergency Medicine)
• Chloroquine/Hydroxychloroquine Toxicity (Ophthalmology)
• Toxicity, Lead (Emergency Medicine)

• Genetically Diverse Mouse Panel Predicts Individual Variability in Drug Toxicity
• EGFR Plus Radiation Raises Risk of Dermatologic Toxicity
• AANS 2009: Novel Delivery for Topotecan Shows Promise for Gliomas

• Impact of Tobacco Smoking and Smoking Cessation on Cardiovascular Risk and Disease
• Pharmacotherapy for Post-traumatic Stress Disorder
• EGFR-Targeted Therapies in Lung Cancer: Predictors of Response and Toxicity

• Iron Toxicity InfoSite