Tricyclic antidepressants postsynaptic effects

Virtually all types of drug that have been shown to be effective in major depression exert profound effects on the functioning of the serotoninergic or noradrenergic systems, or both. Although some treatments have been shown to decrease the sensitivity of certain postsynaptic 5-HT and NE receptors, it is generally believed that it is an enhancement of neurotransmission in these systems that is responsible for the improvement of the core symptoms of depression. For instance, long-term administration of tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs) decreases the density of (3-adrenoceptors and cortical 5-HT2 receptors (Blier and Abbott 2003). 

Mechanism of Action A tricyclic antidepressant that blocks the reuptake of neu-retransmitters, including norepinephrine and serotonin, at presynaptic membranes, thus increasing their availability at postsynaptic receptor sites. Also has strong anticholinergic activity. Therapeutic Effect Relieves depression. 

Mechanism of Action A tricyclic antidepressant that blocks the reuptake of neu-rotransmitters, such as norepinephrine and serotonin, at presynaptic membranes, in-creasing their concentration at postsynaptic receptor sites. Therapeutic Effect Results in antidepressant effect. Anticholinergic effect controls nocturnal enuresis, Pharmacohinetics Rapidly, completely absorbed after PO administration, and not affected by food. Protein binding 95%, Metabolized in liver (significant first-pass effect), Primarily excreted in urine. Not removed by hemodialysis. Half-life 16-40 hr. 

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. 

Transmitter reuptake after release Cocaine, tricyclic antidepressants Adrenergic nerve terminals Inhibit uptake increase transmitter effect on postsynaptic receptors... 

FIGURE 6-39. Mechanism of action of serotonin selective reuptake inhibitors (SSRIs)—part 5. Finally, once the SSRIs have blocked the reuptake pump (Fig. 6-36), increased somatodendritic serotonin (Fig. 6-36), desensitized somatodendritic serotonin 1A autoreceptors (Fig. 6—37), turned on neuronal impulse flow (Fig. 6-38), and increased release of serotonin from axon terminals (Fig. 6— 38), the final step shown here may be the desensitization of postsynaptic serotonin receptors. This has also been shown in previous figures demonstrating the actions of monoamine oxidase (MAO) inhibitors (Fig. 6-4) and the actions of tricyclic antidepressants (Fig. 6—6). This desensitization may mediate the reduction of side effects of SSRIs as tolerance develops. 

The precise mechanism by which the first-generation tricyclic antidepressants, monoamine oxidase inhibitors, and the newer-generation antidepressants exert their effects is uncertain. However, it is clear that antidepressants exert their effects at both pre- and postsynaptic receptor sites (Figure 43.3 and Figure 43.4). 

Tricyclic antidepressants act on both presynaptic and postsynaptic neurons, as well as on alpha- and beta-adrenoceptors. Because their principal action is to block the re-uptake of noradrenaline at the presynaptic neuron, they potentiate the hypertensive effects of both directly acting and indirectly acting amines (158,159). The hypertensive effects of phenylephrine are increased by a factor of 2-3, and of noradrenaline by a factor of 4-8. Even the administration of local anesthetics containing noradrenaline as a vasoconstrictor has proven fatal. The types of... 

Tricyclic antidepressants block neuronal uptake of norepinephrine and variably serotonin (those with tertiary amine side chains), and the degree of inhibition seems to correlate with antidepressant activity. However, the block in amine uptake occurs shortly after drug administration, whereas the antidepressant effects generally require several weeks to develop. Thus the mechanism of action is incompletely understood and may involve changes in presy-naptic and postsynaptic neurogenic amine receptor response. In addition to their mood-elevating actions, tricyclic antidepressants also have sedative effects that may be... 

With tricyclic antidepressant therapy, postsynaptic adrenergic receptors may be inhibited initially, probably contributing to early hypotensive effects of many tricyclics. Over weeks of treatment, receptors remain available and may even become more sensitive to NE as clinical mood-elevating effects gradually emerge. Therefore, as antidepressant treatment gradually becomes chnically effective, inactivation of transmitter reuptake continues to be blocked, presynaptic production and release of NE returns to or may exceed baseline levels, and a postsynaptic adrenergic mechanism is operative. 

Additional neuropharmacological changes that may contribute to the clinical effects of tricyclic antidepressants include indirect facihtation of 5-HT (and perhaps DA) neurotransmission through excitatory heteroreceptors on other monoaminergic neurons, or desensitized, inhibitory autoreceptors, as well as D autoreceptors. Activated release of 5-HT and DA may, in turn, lead to secondary down-regulation of 5-HTj autoreceptors, postsynaptic S-HT receptors, and perhaps D autoreceptors and postsynaptic Dj receptors. 

Tricyclic antidepressants The acute effect of tricyclic drugs is to inhibit the reuptake mechanisms (transporters) responsible for the termination of the synaptic actions of both NE and 5-HT in the brain. This results in potentiation of their neurotransmitter actions at postsynaptic receptors. 

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