Tricyclic antidepressants available drugs

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

Monoamine oxidase inhibitors (MAOIs) are useful as thymoleptic (antidepressant) drugs, especially since the action of some of these agents is very rapid, as compared to the lag period of days or even weeks shown by tricyclic antidepressants. All MAOIs act by increasing the available concentration of the neurotransmitters NE and 5-HT which, because they are not metabolized, accumulate in the synaptic gap and exert an increased postsynaptic effect. The drugs show hypotensive activity as a side effect, and some MAOIs are used as hypotensive drugs. 

This is the most widely prescribed group of antidepressant drugs, essentially because of their safety in overdose and their relative lack of adverse effects in comparison to the tricyclic antidepressants. They are all inhibitors of reuptake of 5-HT with no significant effect on reuptake of noradrenaline (norepinephrine). The different potencies of the drugs currently available are illustrated in Table 10.5, together with details of other aspects of their pharmacology. 

Original drug classifications in the 1960s emphasized that there were important distinctions between the antidepressants (e.g., tricyclic antidepressants) versus the anxiolytics (e.g., benzodiazepines) available at that time. This reflected the diagnostic notions then prevalent, which tended to dichotomize major depressive disorder and... 

The antidepressants available in the United States are classified by either their chemical structure (e.g., the tricyclics, TCAs) or their actions on neurotransmitters (e.g., SSRIs and MAOIs) or simply as other (e.g., Wellbutrin). In the future, the classification of the antidepressants may become more confusing as new drugs are developed that are neither TCAs, SSRIs, or MAOIs. 

A range of medications is available to treat insomnia, ranging from herbal preparations such as valerian to the recently introduced z compounds, zopiclone, zolpidem and zaleplon. Many drugs used for other primary purposes have sedative and sleep-inducing properties as side effects these include many tricyclic antidepressants and antihistamines. 

It has since been assumed that this is the therapeutic action of tricyclic antidepressants, which are sometimes referred to as monoamine reuptake inhibitors or MARIs. However the exact significance of this reuptake process is unknown, especially as the tricyclic antidepressants have numerous other actions and influence, directly or indirectly, almost all neurotransmitters, many neuropeptides and most hormones (Khan 1999). Further studies of reuptake by heart muscle preparations showed that chlorpromazine was a stronger reuptake inhibitor than imipramine and not all the tricyclic antidepressants had this action (Lahti Maickel 1971). In addition, it has not been possible to demonstrate that reuptake inhibition is actually correlated with increased availability or activity of noradrenalin or serotonin. In fact most evidence suggests that tricyclic drugs reduce levels of noradrenalin (Frazer Mendels 1977 Heydorn, Frazer, Mendels 1980 Schildkraut, Winokur, Applegate 1970). 

Side Effects a.nd Toxicity. Adverse effects to the tricyclic antidepressants, primarily the result of the actions of these compounds on either the autonomic, cardiovascular, or central nervous systems, are summarized in Table 3. The most serious side effects of the tricyclics concern the cardiovascular system. Arrhythmias, which are dose-dependent and rarely occur at therapeutic plasma levels, can be life-threatening. In order to prevent adverse effects, as well as to be certain that the patient has taken enough drug to be effective, the steady-state semm levels of tricyclic antidepressant dmgs are monitored as a matter of good practice. A comprehensive review of structure—activity relationships among the tricyclic antidepressants is available (42). 

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