Tricyclic Antidepressants
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Direct answer
Tricyclic antidepressants (TCAs), the oldest effective antidepressants, block the reuptake of serotonin and noradrenaline into the presynaptic neuron — imipramine and amitriptyline are tertiary amines with stronger serotonin effect, while nortriptyline and desipramine are secondary amines with noradrenergic dominance and fewer side effects. Their three additional receptor actions explain their toxicity: muscarinic blockade (dry mouth, constipation, urinary retention, blurred vision), alpha-1 blockade (postural hypotension, sedation) and histamine H1 blockade (sedation, weight gain). They are lethal in overdose through quinidine-like cardiac sodium-channel blockade producing wide-complex arrhythmias — the ECG and sodium bicarbonate are central to management.
What you must remember
- Mechanism: inhibition of serotonin and noradrenaline reuptake transporters; clomipramine is the most serotonergic TCA and the classic choice for obsessive-compulsive disorder.
- Tertiary versus secondary amines: imipramine, amitriptyline and clomipramine (tertiary, serotonergic, more side effects) metabolise to desipramine and nortriptyline (secondary, better tolerated); nortriptyline is often preferred in the elderly.
- Anticholinergic burden: dry mouth, blurred vision, constipation, urinary retention, tachycardia and worsening of delirium — "blind as a bat, dry as a bone, mad as a hatter".
- Cardiovascular effects: orthostatic hypotension from alpha-1 blockade (the commonest serious problem in the elderly) plus conduction slowing — avoided after myocardial infarction and in bundle branch block.
- Overdose toxicity: the psychiatric emergency of the class — coma, hyperthermia, seizures and widened QRS with ventricular arrhythmias from sodium-channel blockade; QRS above 100 ms predicts seizures in standard teaching.
- Overdose management: ECG monitoring, sodium bicarbonate for QRS widening, benzodiazepines for seizures and intensive support; avoid class I antiarrhythmics.
- Other clinical facts: antidepressant effect takes two to four weeks; abrupt stoppage causes cholinergic rebound (nausea, diarrhoea, insomnia), so taper; TCAs retain use in neuropathic pain and migraine prophylaxis (amitriptyline), enuresis (imipramine) and OCD (clomipramine).
Common confusion
TCAs versus SSRIs is framed on safety and side-effect profile: TCAs are lethal in overdose (a lethal dose may be a ten-day supply) and anticholinergic-cardiotoxic, while SSRIs are safer with serotonergic and GI effects — hence SSRIs are first line, TCAs reserved. Within the class, amitriptyline (sedating, for pain and insomnia comorbid with depression) versus nortriptyline (less sedating, safer in cardiac disease and the elderly) is a favourite pairing. Students also mix up TCA overdose (wide QRS, sodium bicarbonate) with dopamine-blockade crisis and serotonin syndrome — learn the widened-QRS ECG as the TCA signature.
Exam-focused takeaway
NEET-PG tests TCAs pharmacologically: match side effects to receptor blockades, pick clomipramine for OCD and amitriptyline for neuropathic pain or depression with insomnia, and identify imipramine for enuresis. Overdose stems feature a depressed patient with coma, seizures and a wide QRS — sodium bicarbonate is the answer. Expect one question on why nortriptyline suits the elderly (fewer anticholinergic and hypotensive effects, measurable levels) and one on cholinergic rebound after abrupt withdrawal.
Frequently asked questions
What is the mechanism of action of tricyclic antidepressants?
Serotonin and noradrenaline reuptake blockade, plus muscarinic, alpha-1 and H1 blockade causing most adverse effects.
Which TCA is preferred for obsessive-compulsive disorder?
Clomipramine, the most serotonergic of the class.
Why are TCAs dangerous in overdose?
Sodium-channel blockade produces coma, seizures and wide-complex arrhythmias; QRS above 100 ms warns early.
How is TCA overdose managed?
ECG monitoring, sodium bicarbonate for QRS widening, benzodiazepines for seizures, intensive support.
Which TCA is relatively preferred in elderly patients?
Nortriptyline, with less anticholinergic and orthostatic burden and a defined plasma level.
What happens if a TCA is stopped abruptly?
Cholinergic rebound with nausea, diarrhoea, insomnia and sweating — taper over days to weeks.