Phenelzine
1. Drug Name
Generic Name: Phenelzine
Brand Names: Nardil
2. Drug Classification
Class: Antidepressant
Subclass: Monoamine Oxidase Inhibitor (MAOI)
3. Mechanism of Action
Phenelzine is a monoamine oxidase inhibitor (MAOI) that works by inhibiting the activity of monoamine oxidase (MAO) enzymes, specifically MAO-A and MAO-B.
MAO-A primarily deaminates serotonin, norepinephrine, and dopamine, while MAO-B primarily deaminates dopamine.
By inhibiting these enzymes, phenelzine increases the levels of serotonin, norepinephrine, and dopamine in the synaptic cleft, thus improving mood and alleviating symptoms of depression.
The increase in serotonin and norepinephrine also has antianxiety and mood-stabilizing effects, which can be beneficial in treating various mood disorders.
4. Pharmacokinetics
Absorption:
Bioavailability: Phenelzine has variable oral bioavailability (~50%) due to its metabolism in the liver before reaching systemic circulation.
Peak Plasma Concentration (Tmax): Peak levels are typically achieved within 2–3 hours after oral administration.
Distribution:
Volume of Distribution (Vd): Phenelzine has a wide distribution throughout the body, including the brain, reflecting its ability to affect neurotransmitter levels.
Protein Binding: Phenelzine has low protein binding, making it more available in the bloodstream for distribution.
Metabolism:
Metabolized primarily in the liver via oxidation by monoamine oxidase (MAO) and other CYP450 enzymes.
The metabolic products include phenylacetic acid, which is excreted in the urine.
Excretion:
Half-life (t½): Approximately 11–16 hours, which allows for once-daily dosing.
Excretion: Primarily excreted in the urine as metabolites.
Special Considerations:
Hepatic Impairment: Reduced hepatic function can decrease phenelzine metabolism, requiring careful monitoring and potential dose adjustments.
Renal Impairment: Renal dysfunction may affect the elimination of phenelzine metabolites, but dose adjustments are usually not necessary unless renal function is severely impaired.
5. Indications
Primary Indications:
Major Depressive Disorder (MDD): Phenelzine is primarily used in the treatment of depression, especially in patients who have not responded to other classes of antidepressants such as SSRIs or TCAs.
Anxiety Disorders: Useful in treating generalized anxiety disorder (GAD), panic disorder, and social anxiety disorder.
Atypical Depression: Often used for atypical depression, characterized by mood reactivity, increased sleep and appetite, and leaden paralysis.
Treatment-resistant Depression: It is especially beneficial for patients who have not responded to other antidepressants.
Off-label Uses:
Parkinson’s Disease: Sometimes used to increase dopamine levels in Parkinson’s disease, as MAO-B inhibition can enhance dopaminergic activity.
Phobic Disorders: Occasionally used for the treatment of phobias when other treatments fail.
6. Dosage and Administration
Adult Dosing:
Major Depressive Disorder: The typical starting dose is 15 mg/day, increasing gradually to 45–90 mg/day, divided into 2–3 doses daily. Some patients may require higher doses up to 120 mg/day depending on response and tolerance.
Anxiety Disorders: The dose may start at 15 mg/day, titrating to 30–60 mg/day based on clinical response.
Maintenance: The maintenance dose typically ranges between 30–90 mg/day, depending on the individual's response.
Pediatric Dosing:
Phenelzine is not commonly used in pediatric populations, but when necessary, dosing should be carefully adjusted by a healthcare professional.
Renal and Hepatic Impairment:
Reduced doses are recommended in patients with severe hepatic impairment due to slower metabolism of phenelzine.
Dose adjustments may be required in patients with renal impairment, particularly those with end-stage renal disease.
Elderly Dosing:
Start with a lower dose (e.g., 7.5–15 mg/day) and titrate carefully in elderly patients, who may be more susceptible to adverse effects such as orthostatic hypotension.
7. Contraindications
Absolute Contraindications:
Hypersensitivity to phenelzine or any component of the formulation.
Concurrent use with other MAO inhibitors, including linezolid or methylene blue, due to the risk of serotonin syndrome.
Pheochromocytoma: Due to the risk of hypertensive crisis caused by excessive catecholamine release.
Severe liver disease due to impaired drug metabolism.
Relative Contraindications:
Cardiovascular disease: Caution should be exercised in patients with a history of cardiac arrhythmias or stroke.
Bipolar disorder: Risk of triggering manic episodes, particularly in the absence of a mood stabilizer.
Tyramine-rich foods: Patients must avoid foods high in tyramine (e.g., cheese, fermented foods, wine), as tyramine-induced hypertensive crisis can occur.
8. Warnings and Precautions
Black Box Warning:
Suicidal Thoughts: Like other antidepressants, phenelzine carries a black box warning regarding the increased risk of suicidal thoughts and behavior in children, adolescents, and young adults.
Other Warnings:
Hypertensive Crisis: There is a risk of hypertensive crisis when phenelzine is taken in combination with tyramine-containing foods or certain sympathomimetic drugs.
Serotonin Syndrome: Risk increases when combined with other serotonergic drugs (e.g., SSRIs, SNRIs, tricyclic antidepressants, or triptans).
Orthostatic Hypotension: Due to the alpha-1 adrenergic blockade, phenelzine can cause significant orthostatic hypotension; patients should be monitored closely, especially at the initiation of treatment.
Liver Toxicity: Rare cases of liver toxicity have been reported, so liver function should be monitored periodically.
Discontinuation Syndrome: Abrupt discontinuation of phenelzine can cause withdrawal symptoms including headache, nausea, dizziness, and insomnia.
9. Adverse Effects
Common Adverse Effects:
Orthostatic hypotension: Especially in the elderly, caused by the drug’s alpha-blocking properties.
Sedation and drowsiness: Due to the central nervous system (CNS) effects of phenelzine.
Weight gain: Patients may experience weight gain due to increased appetite.
Dry mouth: Due to anticholinergic effects.
Less Common but Clinically Significant:
Sexual dysfunction: Decreased libido and erectile dysfunction may occur.
Hypomania/mania: Particularly in patients with bipolar disorder.
Cognitive impairment: Some patients report difficulty with concentration and memory.
Rare/Serious:
Serotonin Syndrome: Symptoms include fever, rigidity, altered mental status, and autonomic instability.
Hypertensive Crisis: Severe headache, chest pain, nausea, and vomiting in the event of a hypertensive crisis, often caused by the consumption of tyramine-rich foods.
Hepatotoxicity: Although rare, phenelzine has been associated with liver enzyme elevations and hepatitis.
10. Drug Interactions
Tyramine: Phenelzine inhibits MAO-A, and tyramine (found in aged cheese, cured meats, etc.) can cause hypertensive crisis. Tyramine-induced hypertensive crisis can be life-threatening and requires immediate medical attention.
Other MAOIs: Monoamine oxidase inhibitors should never be used in combination with each other, as it increases the risk of serotonin syndrome.
Serotonergic Drugs: Combination with SSRIs, SNRIs, tricyclic antidepressants, or triptans increases the risk of serotonin syndrome.
Sympathomimetics: Drugs like pseudoephedrine, ephedrine, and amphetamines may increase the risk of hypertensive crisis due to increased norepinephrine levels.
Antihypertensives: Phenelzine may enhance the effects of antihypertensive drugs (e.g., alpha-2 agonists, beta-blockers), leading to an increased risk of hypotension.
11. Clinical Pharmacology
Pharmacodynamics:
The antidepressant effects of phenelzine are attributed to the increased availability of serotonin, norepinephrine, and dopamine in the brain, improving mood and emotional stability.
It may also exert some anxiolytic effects, beneficial in patients with comorbid anxiety disorders.
12. Special Populations
Pregnancy Category: Category C. Phenelzine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: Phenelzine is excreted into breast milk; therefore, caution is required when used in nursing mothers.
Geriatrics: Elderly patients may be more sensitive to the hypotensive and sedative effects of phenelzine. Initiate treatment at lower doses.
Renal and Hepatic Impairment: Caution is advised in patients with renal or hepatic dysfunction as dose adjustments may be necessary.
13. Therapeutic Uses
Depression: Phenelzine is particularly useful in treating atypical depression and treatment-resistant depression, where other antidepressants have failed.
Anxiety: It is effective in treating generalized anxiety disorder (GAD), panic disorder, and social anxiety disorder.
14. Monitoring and Follow-Up
Before Starting Treatment: Baseline blood pressure, cardiac evaluation, and liver function tests are essential.
During Treatment: Monitor for signs of serotonin syndrome, blood pressure, and cardiac function (especially if taking with sympathomimetics).
Long-term Monitoring: Periodic liver function tests and electrocardiograms for patients on long-term phenelzine therapy.
15. Overdose Management
Symptoms: Severe hypotension, tachycardia, seizures, delirium, and respiratory depression.
Treatment: Immediate supportive care including gastric lavage (if ingested recently), activated charcoal for early ingestion, and IV fluids to correct hypotension. Seizure control may require benzodiazepines. Sodium bicarbonate may be used for cardiac arrhythmias.
16. Patient Counseling Information
Key Points:
Avoid foods containing tyramine (aged cheeses, fermented foods) to prevent hypertensive crisis.
Notify the healthcare provider about any new medications or supplements being taken, as many drugs can interact with phenelzine.
Gradually taper the medication to avoid withdrawal symptoms.
Signs to Watch For:
Severe headache, neck stiffness, or nausea, as these may indicate a hypertensive crisis.
Mental status changes or muscle rigidity, which could be signs of serotonin syndrome.