Pathophysiology
Clinical meaning
Tricyclic antidepressant (TCA) overdose is a life-threatening toxicological emergency with a narrow toxic-to-therapeutic ratio. The '3 Cs' of TCA toxicity โ Convulsions, Cardiac conduction delays, and Cardiovascular collapse โ result from four distinct pharmacological mechanisms: (1) Sodium channel blockade (quinidine-like effect): TCAs block fast sodium channels in the myocardium (phase 0 depolarization), slowing conduction velocity and causing QRS prolongation. QRS >100 ms predicts seizures; QRS >160 ms predicts ventricular arrhythmias including ventricular tachycardia and fibrillation. This is the most immediately life-threatening mechanism and the primary target of sodium bicarbonate therapy. (2) Anticholinergic effects: blockade of muscarinic receptors produces tachycardia, mydriasis, dry mouth, urinary retention, decreased bowel sounds, hyperthermia, and delirium โ the anticholinergic toxidrome. (3) Alpha-1 adrenergic blockade: peripheral vasodilation causing refractory hypotension. (4) Inhibition of norepinephrine and serotonin reuptake at synaptic cleft: contributes to initial sympathomimetic phase followed by catecholamine depletion. TCAs also block GABA-A receptors, lowering seizure threshold. The temporal progression of TCA toxicity is rapid: patients may deteriorate from alert to seizing and cardiac arrest within 1-2 hours of ingestion. Toxicity typically manifests at doses >10 mg/kg;...