Noradrenaline re-uptake

Venlafaxine is a serotonin and noradrenaline re-uptake inhibitor indicated in depression and may be used in generalised anxiety disorder. Venlafaxine can cause diarrhoea and headache as side-effects. It does not cause blurred vision. 

While the inhibition of noradrenaline re-uptake exerts predominantly an a-adrenergic effect, a selective jS-adrenergic effect can not be obtained by such an indirect mechanism. All selective /3-sympathomi-metics activate the receptors, P -, P2- or both sub-types, directly. The first pure jS-sympathomimetic in clinical use was isoproterenol which is structurally identical to adrenaline except the methyl-moiety at the N-position in the side-chain is replaced by an isopropyl-group. All effects produced by isoproterenol are due to either P -or 62-adrenoceptor stimulation tachycardia, increased stroke volume, decreased vascular resistance, broncho dilatation and, in pregnancy, uterus relaxation. The metabolic effects of isoproterenol are less pronounced than those of adrenaline. 

Due to the frequent unwanted effects and, in case of tranylcypromine, the numerous and dangerous interactions MAO-inhibitors are more and more replaced by the much less problematic SSRIs. Compounds belonging to this group are citalopram, escitalopram, fluoxetine, paroxetine and sertraline. They are used clinically in the therapy of depression, bulimia and obsessive-compulsive disorders. All SSRIs show a slow onset of action (1-2 weeks). They may induce insomnia and weight loss. The antidepressant ven-lafaxine inhibits both, serotonin and noradrenaline re-uptake and might therefore additionally induce hypertension. 

Dopexamine reduces afterload via 32 and DAI activation and consequent renal and splanchnic vasodilatation. The 31 activity and inhibition of noradrenaline re-uptake are responsible for its positive inotropic and chronotropic effects. It also promotes naturesis (DAI). 

The noradrenaline re-uptake inhibitor, reboxetine, does not cause weight gain during routine clinical use and indeed has been advocated as an adjunctive treatment in the management of olanzapine-induced weight gain. 

Amitriptyline hydrochloride a tricyclic anti-depressant drug which inhibits serotonin and noradrenaline re-uptake. 

These data suggest that antidepressant-induced sexual dysfunction is more likely to be associated with agents that greatly potentiate 5HT neurotransmission. This notion is supported by the results of a 6-week doubleblind study of 24 men with premature ejaculation, in which paroxetine (20 mg/day) increased latency to ejaculation six-fold while mirtazapine (30 mg/day) had minimal effect (4). In a randomized, 8-week, double-blind, placebo-controlled study in 450 patients with major depression, fluoxetine (20 -0 mg/day) significantly impaired sexual function, while the noradrenaline re-uptake inhibitor reboxetine had no effect (5). 

Hyponatremia with SSRIs is well described (SEDA-27, 12) but has also been reported with other antidepressants, including the selective noradrenaline re-uptake inhibitor reboxetine. 

Duloxetine has recently been marketed as an antidepressant in Europe. It inhibits the re-uptake of serotonin and noradrenaline, with minimal effects on other neurotransmitter mechanisms. It is therefore classified as a serotonin and noradrenaline re-uptake inhibitor (SNRI) and is grouped with venlafaxine. The adverse effect profile of duloxetine appears to be similar to that of the SSRIs and venlafaxine. In placebo-controlled trials the most common adverse effects were nausea (37%), dry mouth (32%), dizziness (22%), somnolence (20%), insomnia (20%), and diarrhea (14%). Sexual dysfunction has also been reported. Current data suggest that, unlike venlafaxine, duloxetine does not increase the blood pressure, but further post-marketing surveillance studies will be needed to confirm this (1). 

Reboxetine is a selective noradrenaline re-uptake inhibitor with low affinity for a-adrenoceptors and muscarinic receptors. In controlled trials the following adverse events occurred significantly more often with reboxetine than with placebo dry mouth (27%), constipation (17%), increased sweating (14%), insomnia (14%), urinary... 

A 72-year-old woman taking venlafaxine 150 mg/day for depression was abruptly switched to the noradrenaline re-uptake inhibitor maprotiline 75 mg/day 1 day later she developed agitation, sweating, nausea, vomiting, tinnitus, and insomnia (27). These symptoms continued for another week, but disappeared on the second day of sertraline treatment 50 mg/day. 

Zinner NR. Duloxetine a serotonin-noradrenaline re-uptake inhibitor for the treatment of stress urinary incontinence. Expert Opin Investig Drugs 2003 ... 

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 (3). 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 re-uptake inhibitor and may therefore produce urinary symptoms by activating ai-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. 

The symptoms experienced by this patient were tjrpical of venlafaxine and SSRI withdrawal (although they could also be experienced after sudden withdrawal of tricyclic antidepressants). The fact that they were relieved by a serotonin but not a noradrenaline re-uptake inhibitor suggests that venlafaxine-induced withdrawal symptoms are mediated by serotonergic mechanisms. 

Tramake Tramal Zydol ) is a phenylcyclohexanol derivative, a (p) OPIOID RECEPTOR agonist with partial OPIOID ANALGESIC activity. It is also a monoamine (serotonin and noradrenaline) re-UPTAKE inhibitor, and this mechanism is thought independently to contribute a component to analgesic activity. 

Prescriptions for two substances are counted toward the totals for each substance. APAP = acetaminophen SSRI = selective serotonin reuptake inhibitor SNRI = serotonin and noradrenaline re-uptake inhibtor HCTZ = hydrochlorothiazide NSAID = non-steroid anti-inflammatory drug. Source Author s estimates based on Verispan VONA, www.drugtopics.com/drugtopics/data/articlestandard/drugtopics/092007/407652/article.pdf. ... 

Both COMT inhibitors and drugs with noradrenaline re-uptake inhibitory activity can impair the inactivation of catecholamines, so in theory the effects of catecholamines may be increased by concurrent use. However, this did not appear to occur in the above studies. 

Investigations along these lines are then confronted with another problem, namely that the relative activity, in comparison with a standard compound such as imipramine (1), may differ essentially in the various animal models aimed at detecting one and the same property, such as noradrenaline re-uptake. Additional pharmacological properties of the studied compound may affect the various test models in different manners. Also basic properties of the test systems, e.g. the turnover rate of the biogenic amine involved in various strains of animals, may determine the results critically. These latter circumstances may be the cause of different results being obtained in different laboratories. For that reason, a short critical appraisal of the most commonly used methods seems appropriate. 

In an in vitro system that generated HO from FeS04-H202, bromocriptine dose-dependently (IC50 = 11.25 0.89x 10" M) quenched HO radicals, but did not inhibit their formation (Ogawa et al. 1994). Pre-treatment with bromocriptine (5mg/kg, i.p., 7 days) completely protected against the decrease in mouse striatal dopamine and its metabolites induced by intraventricular injection of 6-hydroxy-dopamine (40 pg) after intraperitoneal administration of desipramine (25 mg/kg, administered i.p. 30 min after the final injection to block noradrenaline re-uptake sites), but similar pre-treatment with L-DOPA/carbidopa (75/7.5 mg/kg, i.p, 7 days) showed only partial protective effect. 

Serotonin and Noradrenaline Re uptake Inhibitors (SNRIs) Side effects similar to SSRIs, especially GI (constipation, dry mouth, nausea), sedation/insomnia. Added risk of hypertension... 

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