Norepinephrine-dopamine reuptake inhibitors

Different types of antidepressants are supposed to work by different means. SSRIs (selective serotonin reuptake inhibitors) are supposed to increase serotonin levels. NDRIs (norepinephrine dopamine reuptake inhibitors) are supposed to increase norepinephrine and dopamine, rather than serotonin. These two types of antidepressants are supposed to be selective , affecting the... 

Listing of antidepressants grouped by principal mechanism of action in the synapse. Abbreviations MAOI—irreversible = irreversible monoamine oxidase inhibitor MAOI—reversible = reversible monoamine oxidase inhibitor NDRl = norepinephrine/ dopamine reuptake inhibitor NRI = norepinephrine reuptake inhibitor NSRl = norepinephrine/serotonin reuptake inhibitor NSSA = norepinephrine/specific serotonin agonist SRI = serotonin reuptake inhibitor SRl/serotonin-2 blocker = serotonin reuptake inhibitor and serotonin-2 receptor antagonist. 

Figure 7.3. Structural formulae of the noradrenaline (norepinephrine)/dopamine reuptake inhibitor amfebutamone (bupropion) and some nonselective noradrenaline and serotonin (5-hydroxytr3 tamine 5-HT) reuptake inhibitors (venlafaxine, and...

NDRi (norepinephrine dopamine reuptake inhibitor) antidepressant smoking cessation treatment... 

First, the extracts of the roots of Ruscus aculeatus at higher concentrations caused their contractions of canine cutaneous veins in part because the extracts could reveal an indirect sympathomimetic effect for the inhibition to the neuronal uptake such as cocaine (40) (Figure 11) of a serotonin-norepinephrine-dopamine reuptake inhibitor [31]. Here, a selective ai-adrenergic blocker prazosin (41) and a selective a2-adrenergic blocker rauwolscine (a-yohimbine. 42) (Figure 11) are present in the canine saphenous vein [32, 33] might greatly contribute to their contractile response to the extracts of the roots of Ruscus aculeatus. 

MAOI, monoamine oxidase inhibitor NaSSA, noradrenergic and specific serotonergic antidepressant NDRI, norepinephrine and dopamine reuptake inhibitor SARI, serotonin antagonist and reuptake inhibitor SNRI, serotonin and norepinephrine reuptake inhibitor SSRI, selective serotonin reuptake inhibitor TCA, tricyclic antidepressant. 

Bupropion belongs to the chemical class of aminoketones. It is an atypical antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor, and nicotinic antagonist. Initially developed and marketed as an antidepressant, bupropion was subsequently found to be effective as a smoking cessation aid. If given to lactating women it can trigger convulsions in the newborn. 

Bupropion and also varenicline are mentioned in Chapter 21, Section I.c.4. Bupropion is a norepinephrine and dopamine reuptake inhibitor de-veoped as an antidepressant. It is now used on a large scale as a smoking cessation aid. Varenicline is the first nicotinic receptor partial agonist approved to treat smoking addiction. 

Reboxetine is a norepinephrine selective reuptake inhibitor (NSRI). Based on in vitro studies, reboxetine does not block the reuptake of either dopamine or serotonin. 

FIGURE 6-48. Shown here is the icon of a norepinephrine and dopamine reuptake inhibitor (NDRI). In this case, four of the five pharmacological properties of the tricyclic antidepressants (TCAs) (Fig. 6—27) were removed. Only the norepinephrine reuptake inhibitor (NRI) portion remains to this is added a dopamine reuptake inhibitor action (ORI). 

FIGURE 6—49- In this diagram, the norepinephrine reuptake inhibitor (NRI) and the dopamine reuptake inhibitor (DRI) portions of the NDRI molecule are shown inserted in the norepinephrine and the dopamine reuptake pumps, respectively, blocking them and causing an antidepressant effect. 

In addition, several new PDE5 inhibitors are in various phases of clinical development. The closest to marketing are ICOS/Eli Lilly s IC-351 (Cialis) and Bayer s vardenafil. Both drugs are expected to be approved by the FDA in 2002. Other novel compounds include didesmethylsibutramine (by Sepracor), which is a single isomer of an active metabolite of sibutramine—a norepinephrine and dopamine reuptake inhibitor--and nitric oxide NMI-870 (NitroMed), which is a nitric oxide-enhanced compound of yohimbine for specific delivery of NO to target tissue. 

Reuptake inhibitors, which include the tricyclic and tetracyclic antidepressants (TCAs and TeCAs),the SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), the serotonin and norepinephrine reuptake inhibitors (SNRIs duloxetine, milnacipran, and venlafaxine), and the norepinephrine and dopamine reuptake inhibitor (bupropion). 

DA = dopamine reuptake inhibitor NE = norepinephrine hibitor alpha-2 = alpha-2-adrehergic receptor blocker. 

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. 

Monoamine reuptake inhibitors elevate extracellular levels of serotonin (5-HT), norepinephrine (NE) and/or dopamine (DA) in the brain by binding to one or more of the transporters responsible for reuptake, namely the serotonin transporter (SERT), the norepinephrine transporter (NET) and the dopamine transporter (DAT), thereby blocking the reuptake of the neurotransmitter(s) from the synaptic cleft [1], Monoamine reuptake inhibitors are an established drug class that has proven utility for the treatment of a number of CNS disorders, especially major depressive disorder (MDD). 

After more than a decade of use, bupropion (24) is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant and has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of action of bupropion is still uncertain but may be related to inhibition of dopamine and norepinephrine reuptake transporters as a result of active metabolites [71,72]. In a recently reported clinical trial, bupropion extended release (XL) had a sexual tolerability profile significantly better than that of escitalopram with similar re-... 

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