Serotonin and noradrenaline reuptake inhibition

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. 

Antidepressants in this group include duloxetine, milnacipran and venla-faxine. They inhibit both serotonin and noradrenaline reuptake but with differing selectivity. Milnacipran blocks serotonin and noradrenaline reuptake approximately equally, but duloxetine and to a greater extent ven-lafaxine have selectivity for serotonin. Duloxetine and venlafaxine are reported to weakly inhibit dopamine reuptake. They are also reported to have no significant affinity for histaminergic, muscarinic or adrenergic receptors, and, compared with the tricyclics, appear to lack significant sedative and antimuscarinic effects. 

Indirect effects of drugs on catecholamines have ako resulted in takotsubo syndrome. In one case there was transient typical ballooning of the left ventricular apex during systole following the use of cocaine, thought to have been due to inhibition of catecholamine reuptake [22ft]. A 43-year-old woman who took an overdose of venlafaxine, an inhibitor of serotonin and noradrenaline reuptake, developed a takotsubo cardiomyopathy and there was an increase in urinary normetadrenaline (normetanephrine) concentration [23 ]. 

Falls SSRIs and serotonin and noradrenalin reuptake inhibitors (SNRIs) have long been linked with an increased risk of osteopenia/osteoporosis potentiating falls and fractures, especially in tiie elderly. A biological mechanism for these risks associated with SSRIs has been idenhfied. Studies have demonstrated a reduction in osteoblast proliferation and activity following treatment with SSRIs, the magnitude of such effects being linked to affinity to the serotonin transporter. In addition, recent research examining serotonin receptor expression in human osteoblasts and osteoclasts has found that SSRIs differentially inhibit bone cells via apoptosis [10 ]. 

Venlafaxine An atypical antidepressant that inhibits the reuptake of both serotonin and noradrenaline. 

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. 

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... 

Fig. 2. In vitro efficacy of compounds rac-Sa, rac-Sh, rac-6, and rac-1 regarding serotonin, noradrenaline, and dopamine reuptake inhibition. pICso denotes the negative decadic logarithm of the half-maximum effect concentration [M]. The monoamine reuptake inhibition profiles of rac-Sa, rac-5b, rac-6, and rac-1 were genoated via radioligand transporter assays using recombinant human monoamine transporter proteins. The data represent the mean of duplicate analyses.

Tramadol is a synthetic, centrally acting analgesic with multiple mechanisms of action. The drug is a p opioid receptor agonist, with the active metabohte (+)-0-desmethyltramadol [(-i-)-Ml] being the major contributor to its action at p opioid receptors. The enantiomers of tramadol also act synergistically by different mechanisms to inhibit pain transmission the (-i-)-enantiomer inhibits neuronal reuptake of serotonin and the (-)-enantiomer inhibits neuronal reuptake of noradrenaline [1,2]. 

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... 

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. 

The mechanism by which bupropion acts as an aid in smoking cessation is unknown. Bupropion weakly inhibits neuronal reuptake of noradrenaline and serotonin and inhibits the reuptake of... 

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). 

Nefopam is a centrally acting non-opioid analgesic used for mild to moderate pain its mechanism of action is uncertain but may be due to an inhibition of serotonin, noradrenaline and dopamine reuptake. It is considered by some to act on GABA B receptors and is likely to interact with other drugs affecting these neuro transmitters,... 

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). 

Specific serotonin reuptake inhibitors, as the class name implies, act predominantly by preventing serotonin reuptake and have more limited effects on noradrenaline reuptake. Tricyclic antidepressants in general inhibit noradrenaline reuptake, but effects on serotonin reuptake vary widely desipra-mine and protriptyline have minimal potential for raising serotonin concentrations, whereas clomipramine possesses a greater propensity for blocking serotonin reuptake than for noradrenaline. The... 

SSRb are the most recent class, named after the drugs mechanisms of action (Selective Serotonin Reuptake Inhibitors), of which fluoxetine is the archytype. Other examples include danopramine, dtalopram, fluvoxamine, mirtazapine and paroxetine. Later members, such as venlafaxine, differ in being serotonin (re) UPTAKE INHIBITORS that also inhibit noradrenaline reuptake (but are weaker against dopamine uptake). The SSRIs show less side-effects, particularly less sedative actions, than the other classes. 

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