Selective noradrenaline reuptake

Noradrenaline transporters (NAT) are localized in the presynaptic plasma membrane of adrenergic nerve terminals. They belong to a family of proteins with 12 putative transmembrane proteins which are responsible for recycling of released neurotransmitters (noradrena-line/adrenaline, dopamine, serotonin, amino acid transmitters) back into the presynaptic nerve ending. Noradrenaline transporters can be blocked by a number of different antidepressant drags, including tricyclic antidepressants (e.g. desipramine) and selective noradrenaline reuptake inhibitors (e.g. reboxetine). 

Selective noradrenaline reuptake inhibitors (SNRIs) are a group of drugs, which act as antidepressants by the selective inhibition of the reuptake of noradrenaline from the synaptic cleft via the selective blockade of the noradrenaline-specific neurontransmitter transporter (e.g. reboxetine). 

Dostert, P, Benedetti, MS and Poggesi, I (1997) Review of the pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor. Eur. Neuropsychopharmacol. 1 (Suppl. 1) S23-S35. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

These types of antidepressant were introduced around 10 years after the SSRIs. They include the serotonin noradrenaline reuptake inhibitor venlafaxine and the selective noradrenaline reuptake inhibitor reboxetine. Although there are fewer data about these drugs, clinical experience has shown they are well tolerated and, unlike the SSRIs, they are only weak inhibitors of drug metabolism (Kent, 2000). Depression is a common psychiatric disorder seen in the elderly and often remains untreated or inadequately treated (Forsell and Fastbom, 2000). Venlafaxine was shown to improve the mood in a group of 36 older patients without any effect on cognitive function, an important consideration where there is the possibility of the coexistence of mild or undiagnosed dementia (Tsolaki et al., 2000). 

Reboxetine An antidepressant that is a selective noradrenaline reuptake inhibitor. 

Reboxetine was first introduced to the European market in 1997 for the treatment of depression it is not yet available in the United States. Reboxetine represents a novel antidepressant class, the selective noradrenaline reuptake inhibitors (NRIs). 

E.,Versiani, M., Racagni, G. (2002). The role of noradrenaline and selective noradrenaline reuptake inhibition in depression. Eur Neuropsychopharmacol, 12,461-75. 

Clayton AH, Zajecka J, Ferguson JM, Filipiak-Reisner JK, Brown MT, Schwartz GE. Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder. Int Clin Psychopharmacol 2003 18 151-6. 

Reboxetine Morpholine Selective noradrenaline reuptake inhibitor (NRI or NARI)... 

One of the adverse effects of reboxetine is difficulty in passing urine (SEDA-21,13). Eight patients taking reboxetine (4-8 mg/day) had troublesome urinary hesitancy (5). They were successfully treated with tamsulosin (0.4 mg/day), and in two patients tamsulosin was withdrawn after 2 weeks without recurrence of the urinary symptoms. Reboxetine is a selective noradrenaline reuptake inhibitor and may therefore produce urinary symptoms by activating i-adrenoceptors in the bladder, which tamsulosin would be expected to reverse. However, tamsulosin is also effective for urinary symptoms caused by other mechanisms, for example benign prostatic hyperplasia. Whether its apparent effectiveness in reboxetine -induced dysuria represents specific pharmacological antagonism is therefore uncertain. 

One of the adverse effects of clinically used venlafaxine 10 is nausea that may be connected with its mixed serotonin/noradrenaline profile. The selective noradrenaline-reuptake inhibitor sila-velafaxime (R)-ll at oral administration effectively inhibited emetic episodes caused by emetogen (morphine) in the ferret emesis model (06BMCL2555). Intraperitoneally administered sila-venlafaxine (R)-ll was able to reduce cisplatin-induced acute and delayed emesis (08TAP369). 

Kratochvil CJ, Vaughan BS, Harrington MJ, Burke WJ. Atomoxetine a selective noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder. Expert Opin Pharmacother 2003 4(7) 1165-74. 

Scherer D, Hassel D, Bloehs R, Zitron E, von Lowenstem K, Seyler C, Thomas D, Konrad F, Burgers HF, Seemann G, Rottbauer W, Katus HA, Karle CA, Scholz ER Selective noradrenaline reuptake inhibitor atomoxetine directly blocks hERG currents. Br J Pharmacol 2009 156(2) 226-36. 

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