Serotonin-norepinephrine agents

Although the SSRIs provided a tremendous advantage over the TCAs in terms of tolerability, an effect on norepinephrine also has some theoretical advantages. For example, some authors have suggested that dual reuptake inhibitors may be more likely to lead to remission (Thase et al. 2001). As the name of the class implies, these agents affect the reuptake of both serotonin and norepinephrine, while having very little effect on muscarinic, histaminic or Hj, or aj-adrenergic receptors. Hence these medications share many of the tolerability and safety benefits of the SSRIs. Currently, two serotonin-norepinephrine reuptake inhibitors (SNRIs) are available in the United States venlafaxine and duloxetine. 

FIGURE 7—1. Shown here is the icon of a dual reuptake inhibitor, which combines the actions of both a serotonin reuptake inhibitor (SRI) and a norepinephrine reuptake inhibitor (NRI). In this case, three of the five pharmacological properties of the tricyclic antidepressants (TCAs) (Fig. 6—27) were removed. Both the SRI portion and the NRI portion of the TCA remain however the alpha, antihistamine, and anticholinergic portions are removed. These serotonin/norepinephrine reuptake inhibitors are called SNRIs or dual inhibitors. A small amount of dopamine reuptake inhibition (DRI) is also present in some of these agents, especially at high doses. 

These agents have many properties in common. Both are sympathomimetic amines that exert their pharmacologic action by interfering in the reuptake of serotonin and norepinephrine into the presynaptic nerve terminal, thereby increasing their brain levels. In the case of phentermine, there is an increased release of dopamine, whereas with sibutramine, the reuptake into the presynaptic nerve terminal of serotonin, norepinephrine, and to a lesser extent dopamine, is hindered. 

Alpha 2 antagonist NaSSA (noradrenaline and specitic serotonergic agent) dual serotonin and norepinephrine agent antidepressant... 

PEA and TYR are substrates for W-acetyltransferase (NAT)-mediated biotransformation process. NATs metabolize agents that contain an aromatic amine or hydrazine group. Addition of an acetyl group leads to a less soluble molecule, altering its pharmacokinetics [37]. Therefore, W-acetylation is used by cells as an inactivation process of excess amines. Substrate specificity of NAT for biogenic amines was investigated in Fasciola Hepatica. TYR and PEA were found to be the best substrates with a relative rate of 98-100 % as compared to serotonin, norepinephrine, and DOP [38]. 

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

Tricyclic antidepressants (TCAs) such as amitriptyline and doxepin have been used with some success in the treatment of IBS-related pain (Table 18-5). They modulate pain principally through their effect on neurotransmitter reuptake, especially norepinephrine and serotonin. Their helpfulness in functional gastrointestinal disorders seems independent of mood-altering effects normally associated with these agents. Low-dose TCAs (e.g., amitriptyline, desipramine, or doxepin 10 to 25 mg daily) may help patients with IBS who predominantly experience diarrhea or pain. 

SSRIs are theorized to reduce the frequency of hot flashes by increasing serotonin in the central nervous system and by decreasing LH. Of the SSRIs, citalopram, paroxetine, and sertraline all have been studied and have demonstrated a reduction in hot flashes while treating other symptomatic complaints such as depression and anxiety.33 Venlafaxine, which blocks the reuptake of serotonin and norepinephrine, has demonstrated a reduction in hot flashes primarily in the oncology population.34 Overall, these antidepressant medications offer a reasonable option for women who are unwilling or cannot take hormonal therapies, particularly those who suffer from depression or anxiety. These agents should be prescribed at the lowest effective dose to treat symptoms and may be titrated based on individual response. 

Which of the following is an antidepressant agent that selectively inhibits serotonin (5-HT) uptake with minimal effect on norepinephrine uptake ... 

Pharmacoiogy Nefazodone is an antidepressant with a chemical structure unrelated to available antidepressant agents. The mechanism of action is unknown. Nefazodone inhibits neuronal uptake of serotonin and norepinephrine. Pharmacokinetics ... 

Pharmacology These agents are potent and selective inhibitors of neuronal serotonin reuptake and they also have a weak effect on norepinephrine and dopamine neuronal reuptake. 

Therapeutic efficacy by selective MAO-A inhibitors (such as clorgyline or moclobemide) in major depressions strongly suggests that MAO inhibition at central serotonin or norepinephrine synapses or both is responsible for the antidepressant properties of these agents. However, since complete MAO-A inhibition is achieved clinically within a few days of treatment, while the antidepressant effects of these drugs are not observed for 2 to 3 weeks, suggests that additional actions must be involved. 

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