Tricyclic antidepressants receptor specificity

Older tricyclic antidepressants are set in italics. The specificity of action of tricyclic antidepressants (in particular of amitritpyline, imipmmine, doxepine, noitriptyline, maprotiline) is limited because at therapeutic levels ihese drugs also block receptors (H t-histamine, a,-adrenergic, muscarinic). 

Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic tachycardia as a side effect. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking 04 receptors, but the mechanism remains unclear. 

The i.c.v. injection of apamin or charybdotoxin, specific blockers of the SK and BK type of Ca2+-activated K+ channels, respectively, prevented the antinociception mediated by tricyclic antidepressants and H1 histamine receptor antagonists whereas 0C2 adrenoceptor-mediated supraspinal analgesia did not depend on the activation of these K+ channels (Table 1). 

In terms of the therapeutic actions of tricyclic antidepressants, they essentially work as allosteric modulators of the neurotransmitter reuptake process. Specifically, they are negative allosteric modulators. After the neurotransmitter norepinephrine or serotonin binds to its own selective receptor site, it is normally transported back into the presynaptic neuron as discussed in Chapter 5 (Fig. 5-16). However, when certain antidepressants bind to an allosteric site close to the neurotransmitter transporter, this causes the neurotransmitter to no longer be able to bind there, thus blocking synaptic reuptake of the neurotransmitter (Figs. 6-28 and 6—29). Therefore, norepinephrine and serotonin cannot be shuttled back into the presynaptic neuron. 

The selective serotonin-reuptake inhibitors (SSRI) are a new group of chemically unique antidepressant drugs that specifically inhibit serotonin reuptake (see Figure 12.3). This contrasts with the tricyclic antidepressants that nonselectively inhibit the uptake of norepinephrine, and serotonin, and block muscarinic, H histaminic and a -adrenergic receptors. Compared with tricyclic antidepressants, the SSRIs cause fewer anticholinergic effects and lower cardiotoxicity. However, the newer serotonin reuptake inhibitors should be used cautiously until their long-term effects have been evaluated. 

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