Tricyclic Antidepressants

Tricyclic Antidepressants is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles

  • TCAs have fallen out of favor as first-line treatment for major depressive disorder due to their significant toxicity in overdose.
  • TCAs are still prescribed for depression as second-line agents and are also utilized for migraine prophylaxis, neuropathic pain, sleep, and pruritus.
  • A number of other medications are structurally homologous to the TCAs and have similar effects in overdose: diphenhydramine and other first-generation antihistamines, cyclobenzaprine (does not cause cardiac toxicity or seizure in overdose), carbamazepine (cerebellar dysfunction also present in overdose).

Pathophysiology

  • TCAs antagonize a wide variety of receptors, ion channels, and pumps in overdose. Their actions on these molecular targets predict their clinical effects.
    • Serotonin and norepinephrine reuptake pumps: may contribute to the development of serotonin syndrome
    • Cardiac sodium channel: QRS prolongation, ventricular dysrhythmias, cardiogenic shock
    • IKr potassium channel: QT interval prolongation
    • Muscarinic acetylcholine receptor: antimuscarinic toxidrome
    • H1 histamine receptor: somnolence
    • Alpha-1 adrenoceptor: peripheral vasodilation, hypotension, tachycardia
    • GABA-A receptor: seizures

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General Principles

  • TCAs have fallen out of favor as first-line treatment for major depressive disorder due to their significant toxicity in overdose.
  • TCAs are still prescribed for depression as second-line agents and are also utilized for migraine prophylaxis, neuropathic pain, sleep, and pruritus.
  • A number of other medications are structurally homologous to the TCAs and have similar effects in overdose: diphenhydramine and other first-generation antihistamines, cyclobenzaprine (does not cause cardiac toxicity or seizure in overdose), carbamazepine (cerebellar dysfunction also present in overdose).

Pathophysiology

  • TCAs antagonize a wide variety of receptors, ion channels, and pumps in overdose. Their actions on these molecular targets predict their clinical effects.
    • Serotonin and norepinephrine reuptake pumps: may contribute to the development of serotonin syndrome
    • Cardiac sodium channel: QRS prolongation, ventricular dysrhythmias, cardiogenic shock
    • IKr potassium channel: QT interval prolongation
    • Muscarinic acetylcholine receptor: antimuscarinic toxidrome
    • H1 histamine receptor: somnolence
    • Alpha-1 adrenoceptor: peripheral vasodilation, hypotension, tachycardia
    • GABA-A receptor: seizures

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