Chemistry and Pharmacodynamics
Chemical structure
The monoamine oxidase inhibitors (MAOIs) have variable chemical structures.
- Some are derivatives of hydralazine:
- Isocarboxazid
- Phenelzine
- Other agents (or their metabolites) resemble amphetamine → provide some CNS-stimulating properties:
- Tranylcypromine
- Active metabolites of selegiline
Chemical structure of phenelzine, a derivative of hydralazine
Image: “Phenelzine” by Edgar181. License: Public Domain
Chemical structure of tranylcypromine
Image: “Tranylcypromine” by Mykhal. License: Public Domain
Chemical structure of amphetamine:
Note the similarity between this structure and that of tranylcypromine.
Image: “Amphetamine” by C.Löser. License: Public Domain
Mechanism of action
Monoamine oxidase (MAO):
- Mitochondrial enzyme
- Metabolizes monoamine neurotransmitters:
- Serotonin (5-hydroxytryptamine (5-HT))
- Norepinephrine (NE)
- Dopamine
- 2 isomers:
- MAO-A metabolizes 5-HT, NE, and dopamine.
- MAO-B metabolizes dopamine.
- Note: MAO also metabolizes tyramine (sympathomimetic amino acid).
MAOIs:
- 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
Mechanisms of antidepressants:
The basic mechanisms of action of commonly prescribed antidepressants are listed. These medications include monoamine oxidase (MAO) inhibitors, the α-2 antagonist mirtazapine, the selective serotonin reuptake inhibitor fluoxetine, the serotonin antagonist and reuptake inhibitor trazodone, the tricyclic antidepressant desipramine, and the tetracyclic drug maprotiline.
Classification
MAOIs are classified based on their selectivity for MAO-A and MAO-B.
- Nonselective (inhibits both MAO-A and MAO-B):
- Isocarboxazid
- Phenelzine
- Tranylcypromine
- MAO-A selective: moclobemide (not approved in the United States)
- MAO-B selective:
- Selegiline
- Rasagiline
Pharmacokinetics
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)
Indications
- Depression:
- 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
Adverse effects
- Cardiovascular:
- Bradycardia
- Orthostatic hypotension
- Hypertensive crisis
- GI:
- Xerostomia
- Nausea
- Diarrhea or constipation
- ↑ Transaminases
- Metabolic: weight gain
- Neurologic/psychiatric:
- Headache
- Insomnia
- Sedation
- Paresthesias
- Sexual dysfunction
Contraindications
- Tyramine-containing foods:
- Triggers release of NE → vasoconstriction → ↑ risk of hypertensive crisis
- Includes (list is not exhaustive):
- Aged cheese
- Aged/smoked meats
- Beer
- Red wine
- Sauerkraut
- Soybeans
- Soy sauce
- Tofu
- Any drugs that potentially ↑ monoamines
- Severe renal or hepatic impairment
- Not recommended in pregnancy
Drug interactions
- Drugs that ↑ serotonin syndrome risk:
- Selective serotonin reuptake inhibitors (SSRIs)
- Serotonin/norepinphrine reuptake inhibitors (SNRIs)
- Tricyclic antidepressants (TCAs)
- Trazodone, nefazodone
- Ergotamines
- Triptans
- Serotonergic opioids (e.g., fentanyl, meperidine, methadone, tramadol)
- Carbamazepine
- Dextromethorphan
- Linezolid
- Drugs with ↑ hypertensive crisis risk:
- Amphetamines, methylphenidate
- Decongestants (e.g., oxymetazoline, pseudoephedrine)
- Phentermine
- Bupropion
Overdose
Clinical presentation
- Several hours may pass before an overdose becomes clinically apparent.
- Signs and symptoms can include:
- Agitation
- Mydriasis
- Vomiting
- Diaphoresis
- Tachycardia and dysrhythmias
- Hypertension or hypotension
- Myoclonus and hyperreflexia
- Muscle rigidity
- Hyperthermia
- Altered mental status
- CNS depression
- Seizure
- Respiratory depression
Management
- 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)
References
- 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/
