Noradrenaline reuptake inhibition

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

Other agents are also used for the treatment of manic-depressive disorders based on preliminary clinical results (177). The antiepileptic carbamazepine [298-46-4] has been reported in some clinical studies to be therapeutically beneficial in mild-to-moderate manic depression. Carbamazepine treatment is used especially in bipolar patients intolerant to lithium or nonresponders. A majority of Hthium-resistant, rapidly cycling manic-depressive patients were reported in one study to improve on carbamazepine (178). Carbamazepine blocks noradrenaline reuptake and inhibits noradrenaline exocytosis. The main adverse events are those found commonly with antiepileptics, ie, vigilance problems, nystagmus, ataxia, and anemia, in addition to nausea, diarrhea, or constipation. Carbamazepine can be used in combination with lithium. Several clinical studies report that the calcium channel blocker verapamil [52-53-9] registered for angina pectoris and supraventricular arrhythmias, may also be effective in the treatment of acute mania. Its use as a mood stabilizer may be unrelated to its calcium-blocking properties. Verapamil also decreases the activity of several neurotransmitters. Severe manic depression is often treated with antipsychotics or benzodiazepine anxiolytics. 

Future Outlook for Antidepressants. Third-generation antidepressants are expected to combine superior efficacy and improved safety, but are unlikely to reduce the onset of therapeutic action in depressed patients (179). Many dmgs in clinical development as antidepressive agents focus on estabhshed properties such as inhibition of serotonin, dopamine, and/or noradrenaline reuptake, agonistic or antagonistic action at various serotonin receptor subtypes, presynaptic tt2-adrenoceptor antagonism, or specific monoamine—oxidase type A inhibition. Examples include buspirone (3) (only... 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

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). 

NART Inhibition of noradrenaline reuptake Maprotiline Viloxazine Reboxetine Hp and oti-antagonism... 

Paroxetine is the most potent inhibitor of 5-HT reuptake but, in terms of distinguishing one compound from another, their preferential selectivity for inhibition of 5-HT rather than noradrenaline reuptake is the key criterion. Citalopram is by far the most selective in vitro (1500-3000-fold) and fluoxetine, the most frequently prescribed SSRI in the UK, is the least selective of all these agents (see Stanford 1999). In fact, it is worth questioning whether fluoxetine is a true SSRI at all. 

One of these compounds, venlafaxine (licensed in the UK in 1996), is regarded as an inhibitor of both 5-HT and noradrenaline reuptake but this is based on its actions in vitro. At low doses in vivo, it is a more potent inhibitor of 5-HT (Ki 39 nM) than noradrenaline reuptake (K 210 nM). Moreover, its active metabolite, O-demethylven-lafaxine, is a weaker inhibitor of NA reuptake, and has a longer half-life, than its parent compound. However, at high doses, venlafaxine inhibits reuptake of both these monoamines but has negligible activity at muscarinic, Hi-receptors or ai-adrenoceptors and... 

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. 

In neurochemical terms, amphetamine and cocaine boost monoamine activity. Amphetamine has a threefold mode of action first, it causes dopamine and noradrenaline to leak into the synaptic cleft second, it boosts the amount of transmitter released during an action potential and third, it inhibits the reuptake of neurotransmitter back into presynaptic vesicles. These three modes all result in more neurotransmitter being available at the synapse, thus generating an increase in postsynaptic stimulation. Cocaine exerts a similar overall effect, but mainly by reuptake inhibition. The main neurotransmitters affected are dopamine and noradrenaline, although serotonin is boosted to a lesser extent. These modes of action are outlined in Chapter 3, and the neurochemical rationale for drug tolerance is covered more fully in Chapter 10. The main differences between amphetamine and cocaine are their administration routes (summarised above) and the more rapid onset and shorter duration of action for cocaine. 

Desipramine An active metabolite of imipramine that is more selective for inhibiting noradrenaline reuptake into the presynaptic neuron. 

This group includes compounds with actions on a range of neurotransmitter systems. Their antidepressant efficacy is mediated by reuptake inhibition of serotonin and noradrenaline, although side-effects such as sedation may also be useful. Their use in anxiety disorders is supported by a long history of clinical experience and a reasonable evidence base from controlled trials. Studies support the use of clomipramine (a potent serotonin reuptake inhibitor) in panic disorder and OCD (Lecrubier et al. 1997 Clomipramine Collaborative Study Group 1991), of imipramine in panic disorder and GAD (Cross-National Collaborative Panic Study 1992 Rickels et al. 1993), and of amitriptyline in PTSD (Davidson et al. 1993a). No controlled studies support the use of TCAs in social anxiety disorder. 

Milnadpran is a rather newer SNRI licensed as an antidepressant in France. It is associated with clear-cut efficacy judged on the placebo-controlled studies [Lecrubier et al. 1996 Macher et al. 1989]. Milnacipran inhibits the reuptake of both noradrenaline and serotonin (Moret et al. 1985]. It has a relatively short half-life and is given optimally in a dose of 50 mg twice daily. The proportion of reuptake inhibition between serotonin and noradrenaline is approximately equal with this antidepressant, and so one would expect that milnacipran would be more effective than SSRIs, assuming the theory is correct that two actions are better than one. 

Another approach to correct neurotransmission is to inhibit the reuptake of the neurotransmitters into their presvnaptic endings. If the presynaptic reuptake mechanism of a neurotransmitter is blocked then more of the neurotransmitter will stay in the synaptic cleft and be functionally available. Many antidepressant drugs, called reuptake inhibitors , are thought to act via this mechanism. If selective for serotonin they are called selective serotonin reuptake inhibitors (SSRIs, Chapter 1), but if selective for both serotonin and noradrenaline they are called serotonin noradrenaline reuptake inhibitors (SNRIs). Most older antidepressants, such as the tricyclic compounds amitriptyline, imipramine and clomipramine, have little specificity for any of the neurotransmitters fluoxetine, paroxetine, citalopram and a few others are specific for serotonin venlafaxine is a representative of the SNRIs. A more recent mixed-uptake inhibitor is mirtazepine, and some similar compounds are about to be launched. 

Dopexamine is a synthetic catecholamine with direct and indirect sympathomimetic activity. The indirect effect is caused by potent inhibition of neuronal noradrenaline reuptake. It is a potent 32-adrenoceptor agonist with much less (31- than 32-receptor activity. It also has significant dopaminergic DAl-receptor activity, with only minimal activity at DA2 receptors and no o-adrenergic activity. 

The suggested mechanism of this interaction was that finasteride inhibited the hepatic metabolism of sibutramine, which then displaced finasteride from its plasma protein binding sites inhibition of 5HT (serotonin) and noradrenaline reuptake by sibutramine then triggering the psychotic event. 

It has since been assumed that this is the therapeutic action of tricyclic antidepressants, which are sometimes referred to as monoamine reuptake inhibitors or MARIs. However the exact significance of this reuptake process is unknown, especially as the tricyclic antidepressants have numerous other actions and influence, directly or indirectly, almost all neurotransmitters, many neuropeptides and most hormones (Khan 1999). Further studies of reuptake by heart muscle preparations showed that chlorpromazine was a stronger reuptake inhibitor than imipramine and not all the tricyclic antidepressants had this action (Lahti Maickel 1971). In addition, it has not been possible to demonstrate that reuptake inhibition is actually correlated with increased availability or activity of noradrenalin or serotonin. In fact most evidence suggests that tricyclic drugs reduce levels of noradrenalin (Frazer Mendels 1977 Heydorn, Frazer, Mendels 1980 Schildkraut, Winokur, Applegate 1970). 

Citalopram is a racemic bicyclic phthalane derivative and is a highly selective serotonin re-uptake inhibitor with minimal effects on noradrenaline and dopamine neuronal reuptake. Inhibition of 5-HT re-uptake by citalopram is primarily due to escitalopram, the active S-enantiomer of citalopram (1). One would expect escitalopram to be twice as potent as citalopram but otherwise not to differ significantly from the racemic mixture. However, escitalopram is marketed as being more efficacious than citalopram because, it is argued, the inactive R-isomer present in the racemate actually inhibits binding of the S-enantiomer to its site of action, the serotonin transporter. In some, but not all, clinical trials escitalopram has been statistically superior to citalopram in terms of speed of onset of therapeutic action and improvement on depression rating scales. The clinical significance of these differences is debatable (2). 

Rflc-venlafaxine 10 and its sila analogue rac-11 have similar physicochemical properties (pi Ca = 9.7, log P = 3.1 in n-octanol/water, log P = 0.9 at pH 7.4) indicating that venlafaxine and sila-venlafaxine could have a similar brain penetration profile. The in vitro pharmacological studies of venlafaxine, sila-venlafaxine and their enantiomers (used as hydrochlorides) for their efficacy in monoamine reuptake inhibition demonstrated differences in activity and also in inhibition profile (06JOM(691)3589, 06OM1188). With respect to serotonin, noradrenaline and dopamine reuptake inhibition potency these... 

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