Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Selective inhibitors of MAO type B can also be used for the treatment of Parkinson disease. Other uses include for bulimia nervosa Bulimia nervosa Bulimia nervosa is an eating disorder marked by recurrent episodes of binge eating accompanied by inappropriate compensatory behaviors (laxatives or diuretics use, self-induced vomiting, fasting, or excessive exercise) to counteract the effects of binge eating and prevent weight gain. Bulimia Nervosa and panic disorder Panic disorder Panic disorder is a condition marked by recurrent and episodic panic attacks that occur abruptly and without a trigger. These episodes are time-limited and present with cardiorespiratory (palpitations, shortness of breath, choking), GI (nausea, abdominal distress), and neurologic (paresthesias, lightheadedness) symptoms. Panic Disorder. The major adverse effects include serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome and hypertensive crisis. Special care should be taken to avoid other serotonergic medications and tyramine-containing foods.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Chemistry and Pharmacodynamics

Chemical structure

The monoamine oxidase inhibitors (MAOIs) have variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 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

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 Sympathomimetic Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids).

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 antidepressants

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 Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications desipramine, and the tetracyclic drug maprotiline.

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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 Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Social anxiety disorder Social anxiety disorder, or social phobia, is a psychiatric illness marked by fear and avoidance of social interactions due to concerns about embarrassment. The disorder usually occurs in more than one social situation for more than 6 months and leads to a significant decline in function. Social Anxiety Disorder 

Adverse Effects and Contraindications

Adverse effects

  • Cardiovascular:
    • Bradycardia
    • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension 
    • Hypertensive crisis 
  • GI:
    • Xerostomia
    • Nausea
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea or constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
    • ↑ Transaminases
  • Metabolic: weight gain
  • Neurologic/psychiatric:
    • Headache
    • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. 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 Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care 

Drug interactions

  • Drugs that ↑ serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome risk:
    • Selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (SSRIs)
    • Serotonin/norepinphrine reuptake inhibitors (SNRIs)
    • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants (TCAs)
    • Trazodone, nefazodone
    • Ergotamines 
    • Triptans Triptans Triptans and ergot alkaloids are agents used mainly for the management of acute migraines. The therapeutic effect is induced by binding to serotonin receptors, which causes reduced vasoactive neuropeptide release, pain conduction, and intracranial vasoconstriction. Triptans and Ergot Alkaloids
    • Serotonergic opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics (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 Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension or hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. 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 IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids
    • Cooling (wet skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, fans) 
  • Management of severe agitation or seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures: benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
  • For refractory symptoms: cyproheptadine (a 1st-generation antihistamine)

References

  1. 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
  2. Goodman, L. S., et al. (Eds.). (2011). Goodman & Gilman’s Pharmacological Basis of Therapeutics. 12th ed. McGraw-Hill.
  3. Trevor, A. J., et al. (Eds.). (2008). Katzung & Trevor’s Pharmacology: Examination & Board Review. McGraw-Hill.
  4. Doroudgar, S. (2018). Antidepressants. DeckerMed Medicine. Retrieved October 4, 2021, from https://doi.org/10.2310/PSYCH.13064
  5. Doroudgar, S. (2018). General psychopharmacology. DeckerMed Medicine. Retrieved October 4, 2021, from https://doi.org/10.2310/PSYCH.13063
  6. Sub Laban, T., Saadabadi, A. (2021). Monoamine oxidase inhibitors (MAOI). StatPearls. Retrieved October 6, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK539848/
  7. 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
  8. 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/

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