Pathophysiology

TCAs have a distinct chemical structure comprised of three aromatic rings: a central seven-member ring, two outer benzene rings, and an aminopropyl side chain connected to the central ring. There are only minor structural differences among the TCAs, usually on the central aromatic ring or aminopropyl side chain. Amoxapine is unique in that it has an aromatic side chain. Maprotiline has an ethylene bridge across a six-member center ring, giving it a tetracyclic chemical structure. It is not surprising that other chemicals that share the same basic tricyclic chemical structure as the TCAs, such as carbamazepine and phenothizaines, would manifest similar toxicity in overdose.

TCAs are nonselective agents that exhibit a multitude of pharmacologic effects (Table 1.5.2-2.) and have considerable variation in potency. There are subtle and potentially clinically significant pharmacologic differences among the TCAs at therapeutic plasma levels. However, these differences become less important at the higher plasma levels typically seen in overdose. Only a few of their pharmacologic actions are believed to have a direct therapeutic effect, such as inhibition of amine reuptake (norepinephrine, serotonin) and antagonism of postsynaptic serotonin receptors (5-HT2). Thus, the remaining pharmacologic actions are essentially without therapeutic benefit but significantly contribute to TCA-related adverse effects and overdose toxicity. Most clinical findings seen in TCA overdose can be explained by the following seven pharmacologic actions, listed in descending order of general potency.

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