Tricyclic antidepressants pharmacological properties

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

FIGURE 6-33. Shown here is the icon of a selective serotonin reuptake inhibitor (SSRI). In this case, four of the five pharmacological properties of the tricyclic antidepressants (TCAs) (Fig. 6-27) were removed. Only the serotonin reuptake inhibitor (SRI) portion remains thus the SRI action is selective, which is why these agents are called selective SRIs. 

Thus, reboxetine is the logical pharmacological complement to the SSRIs—since it provides selective noradrenergic reuptake inhibition greater than serotonin reuptake inhibition but without the undesirable binding properties of the tricyclic antidepressants. The discovery of reboxetine has given rise to the questions What is the... 

Tricyclic antidepressants—so called because of the characteristic three-ring nucleus—have been used clinically for four decades (Figure 30-1). They closely resemble the phenothiazines chemically and, to a lesser extent, pharmacologically. Like the latter drugs, they were first thought to be useful as antihistamines with sedative properties and later as antipsychotics. The discovery of their antidepressant properties was a fortuitous clinical observation. Imipramine and amitriptyline are the prototypical drugs of the class as mixed norepinephrine and serotonin uptake inhibitors though they also have several other properties. 

So overall it is difficult to know what sort of drugs the tricyclic antidepressants are. They combine many different types of pharmacological action. They show some similarities to neuroleptics, to whom they are closely related structurally and there is some evidence that they too block the effects of dopamine. However there is not enough data currently to determine whether they share the neuroleptics most characteristic property of psychomotor deactivation. Most of them are powerful sedatives but it is not clear that they have any advantages over the use of safer sedatives like benzodiazepines. 

Phenothiazines are tricyclic compounds tliat have chemical and pharmacological properties in common with the tricyclic antidepressant drugs (Figure 34-13 see also previous section on Tricyclic Antidepressants). They are primarily used for their neuroleptic (behavior modifying) properties in the treatment of severe psychiatric iUness (psychoses and mania). In addition, phenothiazines are administered to control nausea and vomiting, for sedation, and for potentiation of analgesia and general anesthesia. ... 

Obviously, this spectrum of pharmacologic activities has been derived post facto from the properties of the tricyclic antidepressants and it will be interesting to see whether it will be useful in predicting clinical antidepressant activity of totally unrelated structures. 

Doxepin [1668-19-5] (38), unlike other commercially available tricyclics, has an oxygen atom in the bridge between the two aromatic rings. It is marketed as a cis—trans mixture (1 5) of isomers, both of which are active. This close relative of amitriptyline (33) has both sedative and anxiolytic properties associated with its antidepressant profile. Maprotiline [10262-69-8] (39) and amoxapine [14028-44-5] (40) are pharmacologically, although not chemically, similar to the tricyclic secondary amines. Clomipramine [303-49-1] (41) has similar pharmacological and antidepressant efficacy. However, clomipramine is approved by the U.S. FDA only for the treatment of obsessive—compulsive disorder. Representative brands of tricyclic antidepressants marketed in the United States are Us ted in Table 2. 

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