tricyclic antidepressant
Summary
Tricyclic antidepressants (TCAs) are older antidepressants that block reuptake of serotonin and norepinephrine at presynaptic terminals. They are used for depression, neuropathic pain, migraine prophylaxis, and enuresis, but their use is limited by anticholinergic, antihistaminergic, and cardiotoxic side effects. Overdose is particularly dangerous due to cardiac arrhythmias.
Detail
Mechanism: TCAs (e.g., amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, doxepin) inhibit presynaptic reuptake of serotonin (5-HT) and norepinephrine (NE), increasing their synaptic concentration. They also block muscarinic (M1), histaminergic (H1), and alpha-1 adrenergic receptors, accounting for their side-effect profile.
Clinical uses: Major depressive disorder (especially atypical or treatment-resistant cases), chronic neuropathic pain (e.g., diabetic neuropathy, postherpetic neuralgia), migraine prophylaxis, fibromyalgia, nocturnal enuresis in children (imipramine), and OCD (clomipramine).
Side effects: Anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, confusion - 'can't see, can't pee, can't spit, can't shit'), antihistaminergic (sedation, weight gain), alpha-1 blockade (orthostatic hypotension), and cardiotoxicity (quinidine-like effect causing QT prolongation, QRS widening, and arrhythmias).
Toxicity/Overdose: Classic triad is coma, seizures, and cardiotoxicity (arrhythmias from Na+ channel blockade). ECG shows widened QRS. Treatment involves sodium bicarbonate to reverse cardiotoxicity (by increasing extracellular Na+ gradient and alkalinizing serum to reduce drug binding to Na+ channels). TCAs are a common cause of fatal overdose due to narrow therapeutic index.
Contraindications: Recent MI (due to arrhythmogenic potential), concurrent MAOI use (risk of serotonin syndrome), and caution in elderly (anticholinergic burden, fall risk from orthostatic hypotension).
Pharmacokinetics: Highly protein-bound, hepatically metabolized via CYP450, long half-lives allowing once-daily dosing.
Secondary vs tertiary amines: Tertiary amines (amitriptyline, imipramine, clomipramine) have more anticholinergic/antihistaminergic effects; secondary amines (nortriptyline, desipramine) have relatively more NE selectivity and fewer side effects, often preferred in elderly patients.
Sources
- First Aid for the USMLE Step 1
- Katzung's Basic and Clinical Pharmacology
- Goodman & Gilman's The Pharmacological Basis of Therapeutics
- UpToDate: Tricyclic antidepressant poisoning
Reviewed by AnkiBoss editorial — medical student review. Information here is for study reference only and is not medical advice. Spotted an error? Let us know.