Clinical pharmacokinetics of tricyclic antidepressant overdose

Tricyclic antidepressants (TCAs) taken in large quantities during suicide attempts have altered pharmacokinetics. Their absorption may be delayed by inhibition of gastric emptying and peristalsis. A significant enterohepatic recirculation delays final elimination of a large fraction of the drug. The enzymes responsible for TCA benzyl-hydroxylation can become saturated and thus reduce TCA elimination to zero-order kinetics. TCA unbound to plasma proteins may also increase because of an acidemia resulting from a respiratory depression after overdose. Other compounds are ingested in suicide attempts which greatly change TCA pharmacokinetics. Metabolism of ethanol generates an excess of reducing equivalents which inhibit TCA oxidative metabolism. Neuroleptics directly inhibit TCA hydroxylation. Fluoxetine significantly prolongs elimination and increases plasma levels of TCA. Toxic hepatic metabolites of acetaminophen would delay TCA elimination. The elderly have slower rates of drug elimination and are particularly susceptible to TCA antidepressants taken in overdose.