Monoamine oxidase is an intracellular enzyme bound to the outer mitochondrial membrane.9,10 It has been identified in most human cells except erythrocytes, which do not contain mitochondria. Monoamine oxidase 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 monoamine oxidase is to decrease the systemic availability of absorbed dietary biogenic amines (e.g., tyramine) via hepatic and intestinal metabolism. Thus, inhibition of monoamine oxidase leads to the accumulation of neurotransmitters in presynaptic nerve terminals (both centrally and peripherally) and increased systemic availability of dietary amines. Monoamine oxidase 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-methyltransferase that is located extraneuronally and is not affected by MAOIs.
Monoamine oxidase 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 different 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 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 predominance 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 while metabolizing more other nonserotonin neurotransmitters. Intestinal monoamine oxidase 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. Tyramine is usually metabolized 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 transdermal selegiline has been primarily attributed to their ability to increase norepinephrine and serotonin neurotransmission by increasing presynaptic concentrations of both amines. Their antidepressant effect correlates with >80% MAO-A inhibition. Additional mechanisms by which they exert their therapeutic effects are probably related to delayed postsynaptic 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, tranylcypromine, 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 inhibitor drug is stopped, monoamine oxidase 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.
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 that have nonselective monoamine oxidase activity, and hence, it works as an antidepressant.4 The oral form of selegiline has lower blood levels secondary to first-pass effects, retains its MAO-B selectivity, and does not have antidepressant qualities. Metabolism by hepatic cytochrome P-450 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 metabolized. 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.
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.11 Controlled human studies are impossible due to the life-threatening nature of these reactions, and animal studies often have limited applicability to human toxicity. Therefore, emergency physicians should never administer 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 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 (see chapter 178, "Atypical and Serotonergic Antidepressants") is a rare, potentially life-threatening, often iatrogenic reaction. It occurs most commonly when MAOIs are 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 inhibitor in a patient on MAOI therapy. Patients should be warned about concomitant use of illicit drugs in general but especially, cocaine, MDMA (3,4-methylenedioxy-methamphetamine popularly known as ecstasy), and methamphetamine. Even after a patient discontinues therapy, 2 weeks are required before 50% of monoamine oxidase enzyme activity returns. 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 recommendation 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. Morphine should be given in decreased dosages due to impairment of morphine metabolism and enhancement of opiate effects. Direct-acting sympathomimetic agents (e.g., norepinephrine) can be given with caution, but use the lowest possible effective dosage. Direct-acting sympathomimetics do not rely on the release of neurotransmitters for their activity, and circulating sympathomimetics do not require monoamine oxidase for deactivation.
TABLE 179-2Medications Considered Safe in Combination with Monoamine Oxidase Inhibitors* ||Download (.pdf) TABLE 179-2 Medications Considered Safe in Combination with Monoamine Oxidase Inhibitors*