Tranylcypromine

1. Drug Name

• Generic Name: Tranylcypromine

• Brand Names: Parnate

2. Drug Classification

• Class: Antidepressant

• Subclass: Monoamine Oxidase Inhibitor (MAOI)

3. Mechanism of Action

• Tranylcypromine is a monoamine oxidase inhibitor (MAOI) that works by inhibiting the activity of the monoamine oxidase (MAO) enzymes, particularly MAO-A and MAO-B.

  • MAO-A deaminates neurotransmitters like serotonin, norepinephrine, and dopamine.

  • MAO-B primarily breaks down dopamine.

• By inhibiting these enzymes, tranylcypromine increases the levels of these neurotransmitters in the brain, leading to improvement in mood, decreased anxiety, and reversal of depressive symptoms.

• It is non-selective in its action and inhibits both MAO-A and MAO-B, which contributes to its effectiveness in treating depression, especially when other treatments have failed.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Tranylcypromine has a moderate bioavailability of approximately 50–60% after oral administration.

  • Peak Plasma Concentration (Tmax): Peak plasma levels occur within 1–2 hours after oral ingestion.

• Distribution:

  • Volume of Distribution (Vd): Tranylcypromine is widely distributed in the body, including the central nervous system (CNS), where it exerts its therapeutic effects.

  • Protein Binding: It has moderate protein binding, approximately 50%, which can influence its pharmacokinetic profile.

• Metabolism:

  • Tranylcypromine is metabolized primarily in the liver, with CYP450 enzymes playing a role in its metabolism, although the exact enzyme responsible for its primary metabolism is not completely characterized.

  • The metabolic pathway includes the formation of active metabolites which contribute to its effects.

• Excretion:

  • Half-life (t½): The half-life of tranylcypromine is 2–3 hours. However, the clinical effects may last much longer due to its irreversible binding to the MAO enzyme.

  • Excretion: The drug is primarily excreted in the urine, with a small amount eliminated via the feces. Most of the drug is eliminated as metabolites.

• Special Considerations:

  • Hepatic Impairment: Caution is advised in patients with hepatic dysfunction, as the drug is metabolized by the liver, and impaired hepatic function may affect drug clearance.

  • Renal Impairment: Dosage adjustments are usually not necessary in renal impairment unless the impairment is severe.

5. Indications

• Primary Indications:

  • Major Depressive Disorder (MDD): Tranylcypromine is used for treatment-resistant depression or when other antidepressants, such as SSRIs or tricyclics, have not been effective.

  • Atypical Depression: It is often effective for atypical depression, which is characterized by mood reactivity, increased sleep and appetite, and feelings of heaviness in the limbs.

  • Generalized Anxiety Disorder (GAD): May be used in the treatment of anxiety, particularly in patients with comorbid depression.

• Off-label Uses:

  • Parkinson’s Disease: Sometimes used for dopaminergic enhancement in Parkinson’s disease, given its effect on increasing dopamine levels.

  • Social Anxiety Disorder: Off-label use in patients who have not responded to first-line treatments.

6. Dosage and Administration

• Adult Dosing:

  • Major Depressive Disorder: The typical starting dose is 10 mg/day, which is increased gradually to 40–60 mg/day (divided into 2 doses). Some patients may require up to 80 mg/day, but doses above this level are rarely needed.

  • Atypical Depression: Similar dosing as for major depression, but sometimes higher doses may be necessary for response.

• Pediatric Dosing:

  • Tranylcypromine is not generally recommended for use in pediatric patients due to limited safety and efficacy data.

• Renal and Hepatic Impairment:

  • Dose adjustments may be necessary in patients with hepatic impairment to avoid drug accumulation.

  • In cases of severe renal impairment, monitoring is necessary, but dose adjustments are typically not required.

• Elderly Dosing:

  • Elderly patients should begin treatment at the lower end of the dosing range (e.g., 10 mg/day) and be carefully monitored due to the increased risk of adverse effects like hypotension and sedation.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to tranylcypromine or any of its components.

  • Concurrent use with other MAOIs (including linezolid and methylene blue) due to risk of serotonin syndrome and hypertensive crisis.

  • Pheochromocytoma: Tranylcypromine can precipitate a hypertensive crisis due to the excessive release of catecholamines.

  • Concomitant use with serotonergic agents, including SSRIs, SNRIs, TCAs, triptans, and certain opioids (e.g., tramadol, meperidine) because of the risk of serotonin syndrome.

• Relative Contraindications:

  • Cardiovascular Disease: Caution should be exercised in patients with a history of heart disease, arrhythmias, or stroke.

  • Bipolar Disorder: The use of tranylcypromine in patients with bipolar disorder may induce a manic episode in the absence of a mood stabilizer.

8. Warnings and Precautions

• Black Box Warning:

  • Suicidal Thoughts: Like all antidepressants, tranylcypromine carries a black box warning about the increased risk of suicidal thoughts and behavior in children, adolescents, and young adults.

• Other Warnings:

  • Hypertensive Crisis: Patients must avoid foods containing tyramine (e.g., aged cheeses, fermented foods, cured meats) to prevent the dangerous risk of hypertensive crisis.

  • Serotonin Syndrome: Risk increases when tranylcypromine is combined with other serotonergic medications, leading to serotonin syndrome (fever, hyperreflexia, altered mental status, and autonomic instability).

  • Orthostatic Hypotension: Tranylcypromine can cause orthostatic hypotension, especially in the elderly. Monitoring of blood pressure is essential during treatment.

  • Liver Toxicity: Monitor liver function, as hepatotoxicity is a rare but possible side effect.

  • Discontinuation Syndrome: Abrupt discontinuation may cause withdrawal symptoms like dizziness, nausea, and anxiety.

9. Adverse Effects

• Common Adverse Effects:

  • Orthostatic hypotension: Common, especially upon standing, can lead to dizziness or syncope.

  • Drowsiness and Sedation: Especially at higher doses.

  • Weight Gain: Can occur due to increased appetite.

  • Dry Mouth: An anticholinergic side effect.

• Less Common but Clinically Significant:

  • Sexual Dysfunction: Decreased libido, erectile dysfunction, and anorgasmia.

  • Cognitive Impairment: Some patients report issues with concentration or memory.

  • Hypomania or Mania: Especially in patients with bipolar disorder.

• Rare/Serious:

  • Serotonin Syndrome: Symptoms include fever, muscle rigidity, mental status changes, and autonomic dysregulation.

  • Hypertensive Crisis: Severe headache, chest pain, and nausea after consuming tyramine-containing foods.

10. Drug Interactions

• Tyramine: Avoid foods high in tyramine (e.g., aged cheese, red wine, cured meats) to prevent hypertensive crisis.

• Other MAOIs: Do not combine with other monoamine oxidase inhibitors due to the risk of serotonin syndrome and hypertensive crisis.

• Serotonergic Drugs: Combining tranylcypromine with SSRIs, SNRIs, tricyclic antidepressants, or triptans increases the risk of serotonin syndrome.

• Sympathomimetic Drugs: Drugs like ephedrine, pseudoephedrine, and amphetamine can cause a hypertensive crisis.

• Antihypertensives: Can have an enhanced hypotensive effect, requiring dose adjustments.

11. Clinical Pharmacology

• Pharmacodynamics: Tranylcypromine’s primary mechanism of action involves the inhibition of monoamine oxidase, leading to increased levels of serotonin, norepinephrine, and dopamine in the brain.

• It also has sympathomimetic effects, which can contribute to its ability to elevate blood pressure in certain patients.

12. Special Populations

• Pregnancy: Category C. Use during pregnancy only if the potential benefit justifies the potential risk.

• Lactation: Excreted in breast milk; use with caution in nursing mothers.

• Elderly: Higher sensitivity to adverse effects such as hypotension and sedation.

• Renal and Hepatic Impairment: Adjustments in dosing or careful monitoring may be needed in patients with liver dysfunction.

13. Therapeutic Uses

• First-Line: Typically reserved for treatment-resistant depression or atypical depression.

• Combinational Therapy: Often combined with other agents for patients with complex or comorbid conditions.

14. Monitoring and Follow-Up

• Monitor blood pressure regularly to detect hypertensive crisis.

• Liver function tests should be performed periodically, especially if the patient is on long-term treatment.

• Electrocardiogram (ECG) may be indicated in patients with cardiovascular risk factors.

15. Overdose Management

• Symptoms of Overdose: Severe hypotension, tachycardia, seizures, delirium, fever.

• Treatment: Gastric lavage and activated charcoal may be used early on. Supportive measures including IV fluids, benzodiazepines for seizure control, and sodium bicarbonate for arrhythmias may be required.

16. Patient Counseling Information

• Key Points:

  • Avoid consuming tyramine-rich foods to prevent a hypertensive crisis.

  • Gradual discontinuation is essential to avoid withdrawal symptoms.

  • Report any symptoms of serotonin syndrome or hypertensive crisis to a healthcare provider immediately.

• Signs to Watch For:

  • Severe headache, nausea, or vomiting indicating potential hypertensive crisis.

  • Muscle rigidity, fever, and mental status changes, which could indicate serotonin syndrome.