Chemistry and Pharmacodynamics
The monoamine oxidase inhibitors (MAOIs) have variable chemical structures.
- Some are derivatives of hydralazine:
- Other agents (or their metabolites) resemble amphetamine → provide some CNS-stimulating properties:
- Active metabolites of selegiline
Mechanism of action
Monoamine oxidase (MAO):
- Mitochondrial enzyme
- Metabolizes monoamine neurotransmitters:
- Serotonin (5-hydroxytryptamine (5-HT))
- Norepinephrine (NE)
- 2 isomers:
- MAO-A metabolizes 5-HT, NE, and dopamine.
- MAO-B metabolizes dopamine.
- Note: MAO also metabolizes tyramine (sympathomimetic amino acid).
- Inhibit (reversibly or irreversibly) MAO in the nerve terminal → prevent degradation of monoamines
- Lead to ↑ neurotransmitter concentration in terminal storage vesicles → more is released into the synaptic cleft
MAOIs are classified based on their selectivity for MAO-A and MAO-B.
- Nonselective (inhibits both MAO-A and MAO-B):
- MAO-A selective: moclobemide (not approved in the United States)
- MAO-B selective:
Absorption and distribution
- Tend to be rapidly and well absorbed orally
- Large volume of distribution
- Highly protein-bound
Metabolism and excretion
- Nonselective MAOIs tend to undergo extensive 1st-pass metabolism in the liver.
- MAO-B inhibitors are metabolized by the cytochrome P450 system.
- Selegiline has active metabolites.
- Excreted primarily in the urine (mostly as metabolites)
- Not 1st-line therapy
- May be considered for:
- Atypical depression
- Persistent depression (unresponsive to other pharmacotherapy)
- Parkinson disease:
- MAO-B inhibitors (selegiline, rasagiline) can be used as monotherapy or adjunctive therapy.
- May be used as initial therapy for early disease with minimal symptoms
- Other conditions for which MAOIs may be helpful:
- Bulimia nervosa
- Panic disorder
- Social anxiety disorder
Adverse Effects and Contraindications
- Orthostatic hypotension
- Hypertensive crisis
- Diarrhea or constipation
- ↑ Transaminases
- Metabolic: weight gain
- Sexual dysfunction
- Tyramine-containing foods:
- Triggers release of NE → vasoconstriction → ↑ risk of hypertensive crisis
- Includes (list is not exhaustive):
- Aged cheese
- Aged/smoked meats
- Red wine
- Soy sauce
- Any drugs that potentially ↑ monoamines
- Severe renal or hepatic impairment
- Not recommended in pregnancy
- Drugs that ↑ serotonin syndrome risk:
- Selective serotonin reuptake inhibitors (SSRIs)
- Serotonin/norepinphrine reuptake inhibitors (SNRIs)
- Tricyclic antidepressants (TCAs)
- Trazodone, nefazodone
- Serotonergic opioids (e.g., fentanyl, meperidine, methadone, tramadol)
- Drugs with ↑ hypertensive crisis risk:
- Amphetamines, methylphenidate
- Decongestants (e.g., oxymetazoline, pseudoephedrine)
- Several hours may pass before an overdose becomes clinically apparent.
- Signs and symptoms can include:
- Tachycardia and dysrhythmias
- Hypertension or hypotension
- Myoclonus and hyperreflexia
- Muscle rigidity
- Altered mental status
- CNS depression
- Respiratory depression
- First, manage airway, breathing, and circulation.
- Activated charcoal for those who present within 1 hour after ingestion (avoid in those with altered mental status or at risk for seizure)
- Management of hyperthermia:
- IV fluids
- Cooling (wet skin, fans)
- Management of severe agitation or seizures: benzodiazepines
- For refractory symptoms: cyproheptadine (a 1st-generation antihistamine)
- Hirsch, M., Birnbaum, R.J. (2020). Monoamine oxidase inhibitors: pharmacology, administration, and side effects. UpToDate. Retrieved August 10, 2021, from https://www.uptodate.com/contents/monoamine-oxidase-inhibitors-maois-pharmacology-administration-safety-and-side-effects
- Goodman, L. S., et al. (Eds.). (2011). Goodman & Gilman’s Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill.
- Trevor, A. J., et al. (Eds.). (2008). Katzung & Trevor’s Pharmacology: Examination & Board Review. McGraw-Hill.
- Doroudgar, S. (2018). Antidepressants. DeckerMed Medicine. Retrieved October 4, 2021, from https://doi.org/10.2310/PSYCH.13064
- Doroudgar, S. (2018). General psychopharmacology. DeckerMed Medicine. Retrieved October 4, 2021, from https://doi.org/10.2310/PSYCH.13063
- Sub Laban, T., Saadabadi, A. (2021). Monoamine oxidase inhibitors (MAOI). StatPearls. Retrieved October 6, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK539848/
- Coryell, W. (2021). Drug treatment of depression. MSD Manual Professional Version. Retrieved October 7, 2021, from https://www.msdmanuals.com/professional/psychiatric-disorders/mood-disorders/drug-treatment-of-depression#v27413109
- Baker, G.B., Urichuk, L.J., McKenna, K.F., Kennedy, S.H. (1999). Metabolism of monoamine oxidase inhibitors. Cellular and Molecular Neurobiology 19:411–426. https://pubmed.ncbi.nlm.nih.gov/10319194/