MAO

**Physiology** - Located on the outer mitochondrial membrane in neurons, liver, gut, and platelets (MAO-B in platelets). - Catalyzes oxidative deamination of monoamines, producing aldehyde + H2O2 + NH3 (FAD-dependent). - Two isoforms: - MAO-A: substrates are serotonin, norepinephrine, epinephrine, and tyramine (also dopamine). Found in gut, liver, and placenta. Selectively inhibited by clorgyline and moclobemide. - MAO-B: substrates are dopamine, phenylethylamine, and benzylamine. Found in the brain (glia/serotonergic neurons) and platelets. Selectively inhibited by selegiline and rasagiline. - MAO works with COMT in catecholamine metabolism. End products include HVA (dopamine), VMA (NE/epi), and 5-HIAA (serotonin). - Gut and liver MAO-A degrades dietary tyramine (aged cheese, cured meats, red wine, fava beans, sauerkraut) and protects against its pressor effects.

**MAO inhibitors (MAOIs)** - Nonselective, irreversible: phenelzine, tranylcypromine, isocarboxazid. Selective MAO-B: selegiline (transdermal form for depression), rasagiline, safinamide (reversible). - Uses: atypical depression (hypersomnia, hyperphagia, leaden paralysis, rejection sensitivity), treatment-resistant depression, panic disorder, and social anxiety. Selegiline and rasagiline are used for Parkinson disease because they reduce dopamine breakdown. - Mechanism: Increased presynaptic stores of NE, serotonin, and dopamine.

**Adverse effects and interactions (high-yield)** - Hypertensive crisis ("cheese reaction"): Tyramine is not metabolized in the gut, so it displaces stored NE from nerve terminals, causing a massive NE surge. Treat with phentolamine (alpha-blocker) or other rapid-acting antihypertensives. Sympathomimetics such as pseudoephedrine and amphetamines can also trigger it. - Serotonin syndrome: seen with SSRIs, SNRIs, TCAs, meperidine, tramadol, dextromethorphan, linezolid (a weak MAOI), and St. John's wort. Presents with hyperthermia, clonus, hyperreflexia, autonomic instability, and agitation. Treat with cyproheptadine and benzodiazepines, and stop the offending agents. - Other adverse effects: orthostatic hypotension, weight gain, sexual dysfunction, insomnia. - Washout: wait at least 2 weeks after stopping an irreversible MAOI before starting a serotonergic drug (5 weeks after fluoxetine before starting an MAOI). - Methylene blue is also a MAO-A inhibitor and can precipitate serotonin syndrome.

**Other associations** - MAO-A deficiency (Brunner syndrome): X-linked, associated with impulsive aggression and intellectual disability. - The MAO-B-mediated conversion of MPTP to MPP+ causes parkinsonism (a classic Step 1 association). - Selegiline is selective for MAO-B at low doses and loses selectivity at high doses, so dietary restrictions apply at high doses or with the transdermal antidepressant form at higher strengths.

**Do not confuse with** "MAO" meaning "Mean Arterial Output" (not a standard term; mean arterial pressure is MAP), or "MAOI" (the drug class) versus the enzyme itself.