Norepinephrine reuptake with serotonin inhibition

Desipramine [50-47-5] (35) and nortriptyline [72-69-5] (36) are demethylated derivatives and principal metaboHtes of (32) and (33), respectively. Both compounds possess less sedative and stronger psychomotor effects than the tertiary amine counterparts, probably because tricycHcs containing secondary amine groups generally show greater selectivity for inhibiting the reuptake of norepinephrine compared with the reuptake of serotonin. Protriptyline [438-60-8] (37), a stmctural isomer of nortriptyline, is another important secondary amine that displays a similar clinical profile. 

Tricyclic Antidepressants (TCAs). The tricyclic antidepressants are believed to act mainly by increasing norepinephrine and/or serotonin reuptake inhibition. The few studies that have evaluated their use in the treatment of BPD were not promising. Given those disappointing results in conjunction with the prominent side effects and danger in overdose, TCAs are not generally recommended for the treatment of BPD. 

It is believed that trazodone, in therapeutic doses, inhibits the neuronal reuptake of serotonin. It is not a MAO inhibitor or a CNS stimulator. It has a minor influence on the reuptake of norepinephrine and dopamine. In addition, it does not bind with cholinergic or a-adrenergic receptors. Synonyms of this drag are thrombran, pragmarel, desyrel, and others. 

Side effects, mainly due to serotonin reuptake inhibition include G1 upset, nervousness, and sexual dysfunction. SSRls are associated with an increased risk of falls. Hyponatraemia due to SIADH is an uncommon, but important side effect in elderly patients. Selective serotonin and norepinephrine reuptake inhibitors (S SNRls) such as venlafaxine and duloxetine are also useful in older patients. Other heterocyclic antidepressants of importance in older patients because of relative safety include bupro-prion and mirtazepine. They are reserved for patients with resistance to or intolerance of SSRls. Currently, trazodone is used mostly for sleep disturbance in depression in doses of 50-100 mg at bedtime. The monoamine oxidase inhibitors phenelzine. 

The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine s known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effects initially, its metabolite, desipramine, then balances this effect with more NET inhibition. 

The hypericin fraction was initially reported to have MAO-A and -B inhibitor properties. Later studies found that the concentration required for this inhibition was higher than that achieved with recommended dosages. In vitro studies using the commercially formulated hydroalcoholic extract have shown inhibition of nerve terminal reuptake of serotonin, norepinephrine, and dopamine. While the hypericin constituent did not show reuptake inhibition for any of these systems, the hyperforin constituent did. Chronic administration of the commercial extract has also been reported to significantly down-regulate the expression of cortical 13 adrenoceptors and up-regulate the expression of serotonin receptors (5-HT2) in a rodent model. 

Tramadol has about one tenth the pain-relieving ability of morphine.53 There are two enantiomers, and both contribute to pain relief, but via different mechanisms. (+)-Tramadol and the metabolite (+)-0-desmethy 1-tramadol, which is referred to as Ml, are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine re uptake.25 This latter action enhances the inhibitory effects on pain transmission in the spinal cord. Because the actions of the two enantiomers are complementary, they are usually supplied as a racemic mixture. However, because it is a serotonin-reuptake blocker, interaction with other medications can lead to the occurrence of serotonin syndrome.54... 

FIGURE 6-41. Icon of fluoxetine with serotonin 2C agonist action, norepinephrine reuptake inhibition (NRI), and 2D6 and 3A4 inhibition, in addition to serotonin reuptake inhibition (SRI). 

Nefazodone is the prototypical member of the SARI class of antidepressants. It is a powerful serotonin 2A antagonist with secondary actions as a serotonin and norepinephrine reuptake inhibitor (Figs. 7—14 and 7—15). Nefazodone also blocks alpha 1 receptors, but the clinical consequences of this are generally not important, perhaps because its norepinephrine reuptake inhibition reduces this action in vivo. 

MAOIs TCAs-AMITRIPTYLINE CLOMIPRAMINE DESIPRAMINE IMIPRAMINE NORTRIPTYLINE t risk of stroke, hyperpyrexia and convulsions, t plasma concentrations of TCAs, with risk of toxic effects, t risk of serotonin syndrome and of adrenergic syndrome with older MAOIs. Clomipramine may trigger acute confusion in Parkinson s disease when used with selegiline TCAs are believed to also act by inhibiting the reuptake of serotonin and norepinephrine, increasing the risk of serotonin and adrenergic syndromes. The combination of TCAs and antidepressants can t risk of seizures Very hazardous interaction. Avoid concurrent use and consider the use of an alternative antidepressant. Be aware that seizures occur with overdose of TCAs just before cardiac arrest... 

Most of the research regarding the antidepressant action of St. John s wort has focused on the hypericins (Wagner and Bladt, 1994). Research has been done to examine the possibility of monoamine oxidase (MAO) or catechol -O-methyltransferase (COMT) inhibition, and inhibition of serotonin and norepinephrine reuptake (Perovic and Muller, 1995 Raffa, 1998). In one study, the effects of hypericum total extract, hypericum fractions, and hypericin on MAO and COMT activity were examined in vitro (Thiede and Walper, 1994). It was concluded that the in vitro concentrations of these preparations required to inhibit MAO were in excess of that attained through ingestion, and thus MAO inhibition could not be an explanation of the herb s antidepressant activity. In addition, COMT inhibition appeared to be associated with flavonols and xanthones rather than hypericins. Another study (Cott, 1997) showed that pure hypericin did not bind to MAO, and confirmed that concentrations of the crude extract required for MAO inhibition exceeded those attained after oral administration. 

It was initially believed that the antidepressant effectiveness of MAOIs was the direct result of MAO inhibition. This acute effect decreases degradation of monoamines (e.g., norepinephrine, serotonin, or dopamine) stored in presynaptic neurons, thereby resulting in an increased amount of these neurotransmitters available at the synapse. More recent research indicates that this model does not fully explain the mechanism of MAOIs efficacy. For example, the positive (h-) stereoisomer of tranylcypromine is a poor antidepressant despite inhibiting MAO. The main pharmacologic difference between the negative (-) and + isomers of tranylcypromine is that the former has much weaker effects as a norepinephrine reuptake inhibitor in relation to its potency as an MAOI. The other MAOIs may also block the reuptake of selected neurotransmitters. However, like the non-MAOI uptake inhibitors, these acute effects often precede clinical antidepressant effects by weeks. More consistent with the 2- to 4-week lag in therapeutic effect, chronic treatment with a diverse number of MAOIs has been shown to reduce the number of a2- and P-adrenergic and serotonin (5-HT2) postsynaptic binding sites in the brain. 

In addition to oxytocic activity, these drugs act as partial agonists on alpha-adreneigic receptors, as well as receptors for dopamine and serotonin. They also inhibit norepinephrine reuptake. The degree of each effect varies with the individual drug. 

Milnacipran is a reuptake inhibitor of norepinephrine and serotonin with little effect on dopamine reuptake or other neurotransmitter receptors. Compared with the SSRIs, milnacipran has a higher incidence of headache, dry mouth, and dysuria. Unlike duloxetine and venlafaxine, it is more potent at blocking the noradrenergic transporter (norepinephrine reuptake inhibition) thus, at low therapeutic doses, it is more of a noradrenergic drug. 

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