Norepinephrine reuptake

Fenfluramine Selective serotonin reuptake Norepinephrine/dopamine... 

Reuptake Norepinephrine transporter Tricyclic antidepressants (imipramine, f) Tricyclic norepinephrine reuptake inhibitors (desipiamine, ) Selective norepinephrine reuptake inhibitors (reboxetine, ) Dual serotonin/ norepinephrine reuptake inhibitors (venlafaxine, J.)... 

Tramadol, however, is thousands of times less potent than morphine as an analgesic agent [18]. It is marketed in the racemic form, and each enantiomer has distinct pharmacological actions. The (+)-isomer is a weak MOP agonist, while the (-)-isomer inhibits neurotransmitter reuptake (norepinephrine and serotonin). The O-demethylated metabolite has improved opioid receptor affinity but is still much less potent (35-fold) than morphine. The ability for this metabolite to ameliorate the analgesic effects of tramadol has not been well studied and remains questionable. The drug has been used for decades in Europe, but was only recently introduced in the United States. It has a greater safety profile than morphine, and produces no respiratory depression or constipation. It is also claimed to be nonaddictive, but remains unscheduled. 

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. 

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. 

The TCAs, such as amitriptyline (Elavil) and dox-epin (Sinequan), inhibit reuptake of norepinephrine or serotonin at the presynaptic neuron. Drug classified as MAOIs inhibit the activity of monoamine oxidase a complex enzyme system that is responsible for breaking down amines. This results in an increase in endogenous epinephrine, norepinephrine and serotonin in the nervous system. An increase in these neurohormones results in stimulation of the CNS. The action of the SSRIs is linked to their inhibition of CNS neuronal uptake of serotonin (a CNS neurotransmitter). The increase in serotonin levels is thought to act as a stimulant to reverse depression. 

The various stimulants have no obvious chemical relationships and do not share primary neurochemical effects, despite their similar behavioral effects. Cocaines chemical strucmre does not resemble that of caffeine, nicotine, or amphetamine. Cocaine binds to the dopamine reuptake transporter in the central nervous system, effectively inhibiting dopamine reuptake. It has similar effects on the transporters that mediate norepinephrine and serotonin reuptake. As discussed later in this chapter in the section on neurochemical actions mediating stimulant reward, dopamine is very important in the reward system of the brain the increase of dopamine associated with use of cocaine probably accounts for the high dependence potential of the drug. 

Based on the modest ability of the (+)-isomers of MDMA and MBDB to inhibit the reuptake of norepinephrine (NE) into hypothalamic synaptosomes (Steele et al. 1987). it seemed possible that noradrenergic pathways might be involved in the eue. In ano er series of drug discrimination experiments designed to test this hypothesis, the specific NE uptake inhibitor (-)-tomoxctine was tested for stimulus transfer in doses up to 10 mg/kg in MDMA-trained rats. At 5 mg/kg, 67 percent of the animals responded on, the drug lever. However, pretreatment with tomoxetine in six rats trained to discriminate MDMA from saline had no effect on the discrimination of a subsequent dose of MDMA. 

The prototype amphetamine enhances release and bloeks reuptake of DA, norepinephrine (ME), and 5-HT and is also a monoamine oxidase inhibitor. As a result of these effeets, drugs in this class are potent indireet agonists at monoaminergie reeeptors. In experimental animals, amphetamine... 

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. 

FIGURE 30-2. Pain algorithm. AED, antiepileptic drug APAP, acetaminophen NSAID, non-steroidal antiinflammatory drug SNRI, serotonin-norepinephrine reuptake inhibitor SSRI, selective serotonin reuptake inhibitor TCA, tricyclic antidepressant. 

Monoamine oxidase inhibition Serotonin reuptake inhibition Norepinephrine reuptake inhibition Dopamine reuptake inhibition a2-Adrenergic receptor blockade Serotonin-2A receptor blockade Serotonin-2C receptor blockade Serotonin-3 receptor blockade op-Adrenergic receptor blockade Histamine-1 receptor blockade Muscarinic cholinergic receptor blockade... 

SSRIs, selective serotonin reuptake inhibitors SNRIs, serotonin and norepinephrine reuptake inhibitors TCAs, tricyclic antidepressant... 

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), alleviates anxiety in GAD patients with and without... 

FIGURE 38-1. Primary assessment and initial treatment for complaint of excessive daytime sleepiness. RLS, restless-legs syndrome NPSG, nocturnal polysomnography OSA, obstructive sleep apnea DA, dopamine agonist MSLT, multiple sleep latency test BZDRA, benzodiazepine receptor agonist SNRI, serotonin and norepinephrine reuptake inhibitor TCA, tricyclic antidepressant CPAP, continuous positive airway pressure. 

BiPAP bi-level positive airway pressure SNRI serotonin norepinephrine reuptake inhibitor SSRI selective serotonin reuptake inhibitor... 

Stimulants theoretically exert their effect by blocking the reuptake of dopamine and norepinephrine, thus improving academic performance and decreasing motor activity in ADHD patients. Stimulants have been shown to decrease fidgeting and finger tapping, increase on-task classroom behavior and positive interactions at home and in social environments, and ameliorate conduct and anxiety disorders.14... 

Bupropion is a monocyclic antidepressant that inhibits the reuptake of norepinephrine and dopamine. Bupropion is effective for relieving symptoms of ADHD in children but is... 

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. 

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