Selective norepinephrine reuptake inhibitors action

Atomoxetine (Strattera) [ADHD/Selective Norepinephrine Reuptake Inhioiter] WARNING Severe liver injury may rarely occur D/C w/ jaundice or TLFT, T frequency of suicidal thoughts Uses ADHD Action Selective norepinephrine reuptake inhibitor Dose Adults Children >70 kg. 40 mg X 3 d, T to 80-100 mg -s- daily-bid Feds <70 kg. 0.5 mg/kg x 3 d, then T 1.2 mg/kg daily or bid (max 1.4 mg/kg or 100 mg) Caution [C, /-] Contra ... 

Unlike other agents approved for ADHD, atomoxetine does not have abuse potential and is not a scheduled substance Despite its name as a selective norepinephrine reuptake inhibitor, atomoxetine enhances both dopamine and norepinephrine in frontal cortex, presumably accounting for its therapeutic actions on attention and concentration... 

Preliminary studies and atomoxetine s known mechanism of action as a selective norepinephrine reuptake inhibitor suggest its efficacy as an antidepressant... 

Mectianism of Action A norepinephrine reuptake inhibitor that enhances noradrenergic function by selective inhibition of fhe presynapfic norepinephrine fransporfer. Therapeutic Effect Improves sympfoms of affenfion-deficif hyperacfivify disorder (ADHD). 

FIGURE 7—40. Adrenergic combo 1 Bupropion plus norepinephrine reuptake inhibitor (NRI). Here the NE actions of bupropion are double-boosted by the NRI (either selective reboxetine or nonselective desipramine, maprotilene, nortriptyline, or protriptyline). Dopamine is single-boosted by bupropion only. 

Fluoxetine (Prozac /Lilly), paroxetine (Paxil /GlaxoSmithKilne), and sertraline (Zoloft /Pfizer) are selective serotonin reuptake inhibitors (SSRIs) and are useful in the treatment of depression. These agents potentiate the pharmacological actions of the neurotransmitter serotonin by preventing its reuptake at presynaptic neuronal membranes. In addition to its SSRI properties, venlafaxine (EfFexor /Wyeth-Ayerst) also appears to be a potent inhibitor of neuronal norepinephrine reuptake and a weak inhibitor of dopamine reuptake thereby enhancing the actions of these neurotransmitters as well. Venlafaxine is indicated for use in anxiety and depression. 

When compared with the selective serotonin reuptake inhibitors (SSRIs), mirtazapine may show an earlier onset of action (although data are currently not well established). Mirtazapine has also been found to be efficacious in the treatment of elderly patients with depression. Mirtazapine has been shown to be effective in the treatment of panic disorder, social phobia, and post-traumatic stress disorder. In one study, mirtazapine combined with citalopram in obsessive-compulsive patients induced an earlier response when compared with citalopram plus placebo. It was suggested that antagonism of presynaptic a2-adrenergic receptors does not enhance serotonin neurotransmission directly, but rather disinhibits the norepinephrine activation of serotonergic neurons and thereby increases serotonergic neurotransmission by a mechanism that may not require a time-dependent desensitization of receptors. 

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Atomoxetine is a selective inhibitor of the norepinephrine reuptake transporter. Its actions, therefore, are mediated by potentiation of norepinephrine levels in noradrenergic synapses. It is used in the treatment of attention deficit disorders (see below). Atomoxetine has surprisingly little cardiovascular effect because it has a clonidine-like effect in the central nervous system to decrease sympathetic outflow while at the same time potentiating the effects of norepinephrine in the periphery. However, it may increase blood pressure in some patients. Norepinephrine reuptake is particularly important in the heart, particularly during sympathetic stimulation, and this... 

Novel use of reboxetine may be for attention deficit disorder, analogous to the actions of another norepinephrine selective reuptake inhibitor, atomoxetine, but few controiied studies... 

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

Most antidepressants in clinical use today act by enhancing the neurotransmission of serotonin [5-hydroxytryptamine (5-HT)], norepinephrine [NE noradrenaline (NA)], or both. They do so either by blocking the reuptake (transport) of neurotransmitter, blocking the metabolism of neurotransmitter [i.e., monoamine oxidase (MAO) inhibitors], or by direct action on a neurotransmitter receptor. Hence, the antidepressants can be classified on the basis of their putative mechanisms of action (Table 8.2 and Figs. 8.1-8.4). Agents that block neurotransmitter reuptake can be further divided into those that are non-selective (e.g., tricyclic antidepressants with mixed action), serotonin-selective reuptake... 

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