Tricyclic antidepressants

TCAs were introduced in the 1950s and became the gold standard treatment for depression before the launch of the first SSRI, fluoxetine, in 1987.42 All current antidepressants rely upon the principle of enhancing monoamine neurotransmission interfering with the presynaptic transporter that reimports the neurotransmitter from the synaptic cleft once released from presynaptic nerve terminals. The classic tricyclic compounds were much less specific, representing a shotgun approach to several neurotransmitter receptors and transporters. Now they are increasingly used as a third-line therapy as the side-effect profile of second-generation SSRI antidepressants is far superior. The leading TCAs are imipramine (23), clomipramine (24), and amitriptyline (25), along with a number of other marketed products.

The TCAs such as imipramine exert their therapeutic actions by inhibition of both 5HT and NE reuptake/ transporter sites (Table 9). Unfortunately, their polypharmic target profiles, which extend to antagonism of a1-adrenoceptors, muscarinic receptors, and histamine receptors, as well as cardiac ion channels, NMDA and SK1, underlies their poor tolerance. Based on their complex pharmacology this class exhibits a variety of adverse side effects (see Table 7). Although some of these side effects are not of great concern, others are life threatening and only have a narrow therapeutic safety index (Table 7). The most serious side effects of the classical tertiary (e.g., imipramine (23), clomipramine (24), amitriptyline (25), doxepin (26), trimipramine (27)) and secondary amine (e.g., amoxapine (28), desipramine (29), maprotiline (30)) tricyclics are attributed to direct quinidine-like actions on the heart, interfering with normal conduction and prolongation of the QRS or QT interval with associated cardiac arrhythmia and arrest. Other toxic effects include respiratory depression, delirium, seizures, shock, and coma. Anticholinergic side effects including dry mouth, blurred vision, urinary retention, and sinus tachycardia are perhaps the most commonly reported (Table 7). The adverse event profile of tricyclics is also associated with a greater risk due to their interaction with cytochrome P450 (CYP) isoenzymes, in particular CYP2D6, which is a highly polymorphic gene. A considerable minority of the population has CYP2D6 polymorphic variations, gene deletion, or gene duplication. CYP2D6 polymorphism results in ultrarapid or ultraslow metabolism, leading to varying degrees of drug bioavailability according to genotype, which can lead to increased bioavailability and severe toxicity in some cases.

All the 'classical' TCAs have a basic three-ring pharmacophore. The therapeutic and commercial success of N-aminoalkylphenothiazines such as promethazine (31), promazine, and chlorpromazine (32) initiated an enormous effort in the molecular modification of the polycyclic phenothiazine ring structure and its N-aminoalkyl side chain. The substitution of the sulfur bridge of the phenothiazine ring of promethazine with an ethylene bridge resulted in imipramine, the first clinically useful TCA. It did not take long for medicinal chemists focusing on the diamine structure to substitute the additional N-CH2 group in imipramine for a C = CH group in amitriptyline. Following earlier dimethylamine work, monomethyl amine derivatives were then synthesized, from which desipramine (29) and nortriptyline (33) evolved.

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