What is the pathophysiology of tricyclic antidepressant (TCA) toxicity in pediatric patients?

Updated: Mar 18, 2020
  • Author: Derrick Lung, MD, MPH; Chief Editor: Stephen L Thornton, MD  more...
  • Print

Cyclic antidepressants are named for their three-ring or four-ring aromatic (heterocyclic) structure. They are rapidly absorbed in the GI tract and undergo first-pass metabolism in the liver. Conjugates are then renally eliminated.

Cyclic antidepressants are very lipophilic and highly protein-bound, leading to large volumes of distribution. They have long elimination half-lives that often exceed 24 hours (>31-46 h for amitriptyline). In an overdose, altered pharmacokinetics may prolong elimination and increase toxic effects. Cyclic antidepressants have significant antimuscarinic effects that can delay gastric emptying. Additionally, the acidosis that results from respiratory depression and hypotension reduces protein binding, resulting in higher serum levels of active free drug.

Although the exact therapeutic mechanism of cyclic antidepressants is not known, it is most likely related to decreased central norepinephrine and serotonin reuptake, resulting in increased levels of these biogenic amines in the brain. The toxic effects of cyclic antidepressants are related to the following four pharmacologic effects:

  • Antimuscarinic effects
  • Direct alpha-adrenergic blockade
  • Inhibition of norepinephrine and serotonin reuptake
  • Blockade of fast sodium channels in myocardial cells, resulting in quinidinelike membrane-stabilizing effects

The most serious adverse effects of cyclic antidepressant toxicity are due to CNS effects and cardiovascular instability. Depressed mental status is generally caused by the antihistamine and antimuscarinic properties of cyclic antidepressants, whereas seizures are thought to be due to increased CNS levels of biogenic amines. Life-threatening cardiovascular complications are due to impaired conduction from fast sodium channel blockade. This decreases the slope of phase zero depolarization, widens the QRS complex, and prolongs the PR and QT intervals. Impaired cardiac conduction may lead to heart block and unstable ventricular dysrhythmias or asystole.  Fast sodium channel blockade may also contribute to development of seizures.

Cyclic antidepressants have also been shown to directly depress myocardial contractility. However, the profound hypotension seen in serious cyclic antidepressant poisoning is primarily due to vasodilatation from direct alpha-adrenergic blockade.

Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!