Venlafaxine transporters

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]. 

Indeed, 5-HT is also a substrate for the 5-HT transporter, itself an important player in the treatment of depression, and more recently for the whole range of anxiety disorders spectrum (GAD, OCD, social and other phobias, panic and post-traumatic stress disorders). It is the target for SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine, paroxetine, fluvoxamine, and citalopram or the more recent dual reuptake inhibitors (for 5-HT and noradrenaline, also known as SNRIs) such as venlafaxine. Currently, there are efforts to develop triple uptake inhibitors (5-HT, NE, and DA). Further combinations are possible, e.g. SB-649915, a combined 5-HTia, 5-HT1b, 5-HT1d inhibitor/selective serotonin reuptake inhibitor (SSRI), is investigated for the treatment of major depressive disorder. 

Milnacipran is also a dual-action antidepressant which, like venlafaxine, has been shown to be more effective than the SSRIs in the treatment of severe, hospitalized and suicidally depressed patients. At lower therapeutic doses, milnacipran blocks the noradrenaline transporters and therefore resembles the NRI antidepressants. Higher doses result in the serotonergic component becoming apparent (i.e. an SSRI-like action). The main problem with milnacipram appears to be its lack of linear kinetics with some evidence that it has a U-shaped dose-response curve (Figure 7.3). 

FIGURE 2.6 Serotonergic synapse. Serotonin binds to at least seven different receptors. The most relevant are the 5-HTi receptors (1), 5-HT2 receptors (2), and 5-HT3 receptors (3). Antagonists of the 5-HT2 receptor include nefazodone and the majority of atypical antipsychotic drugs. The serotonin transporter (4) pumps serotonin back into the serotonergic neuron, which can be blocked by drugs such as venlafaxine, clomipramine, imipramine, and amitriptyline. 

SNRIs are chemically unrelated to each other. Venlafaxine was discovered in the process of evaluating chemicals that inhibit binding of imipramine. Venlafaxine s in vivo effects are similar to those of imipramine but with a more favorable adverse-effect profile. All SNRIs bind the serotonin (SERT) and norepinephrine (NET) transporters, as do the TCAs. However, unlike the TCAs, the SNRIs do not have much affinity for other receptors. Venlafaxine and desvenlafaxine are bicyclic compounds, whereas duloxetine is a three-ring structure unrelated to the TCAs. Milnacipran contains a cyclopropane ring and is provided as a racemic mixture. 

A large number of antidepressants have mixed inhibitory effects on both serotonin and norepinephrine transporters. The newer agents in this class (venlafaxine and duloxetine) are denoted by the acronym SNRIs, whereas the older group (tricyclic antidepressants) are termed TCAs. 

Venlafaxine is a dual reuptake inhibitor of both serotonin and norepinephrine with equal potency for both transporters. 

Venlafaxine is a potent inhibitor of serotonin reuptake and a weaker inhibitor of norepinephrine transport such that at lower therapeutic doses it behaves like an SSRI. At high doses (more than 225 mg/d) it produces mild to moderate increases of heart rate and blood pressure attributable to norepinephrine reuptake inhibition. Doses in the range of 300 mg/d or greater may confer broader therapeutic effects than SSRIs, but a careful titration up to these doses is needed to control adverse effects. 

NE molecules released into the synaptic space are reabsorbed back into the presynaptic neuron by the membrane NE transporter (NET). This process requires ATP. The NET is a target for numerous drugs. Several tricyclic antidepressants (TCA), such as imipramine, non-specifically inhibit both NET and 5-HT (5-HTT) transporters (Corrodi and Fuxe 1968). Other TCAs, called norepinephrine reuptake inhibitors (NRIs), such as desipramine, specifically inhibit the NET (Curet et al., 1992 Lacroix et al., 1991). There are also non-tricyclic selective inhibitors of the NET, called selective norepinephrine reuptake inhibitors (SNeRIs), and dual inhibitors of the NET and 5-HTT (SNRIs). The examples for SneRIs and SNRIs are reboxetine and venlafaxine, respectively (Beique et al., 1998a Beique et al., 1998b Beique et al., 1999 Dawson et al., 1999 Szabo and Blier 2001c). 

Reuptake Norepinephrine transporter Tricyclic antidepressants (imipramine, f) Tricyclic norepinephrine reuptake inhibitors (desipiamine, ) Selective norepinephrine reuptake inhibitors (reboxetine, ) Dual serotonin/ norepinephrine reuptake inhibitors (venlafaxine, J.)... 

St John s wort 1. TCAs (e.g. amitrypty-line, nortryptiline, clomipramine) 2. SSRIs (e.g. fluvoxamine, fluoxetine) 3. Venlafaxine Low blood amitriptyline levels (<20%). May potentially 1 therapeutic effects. Nortriptyline levels may be i by 50%. St John s wort t sedative effects (weakness, lethargy, fatigue, slow movements, incoherence) of SSRIs Due to induction of metabolizing CYP3A4 enzyme and P-gp transport proteins St John s wort inhibits uptake of serotonin and thereby t serotonin levels Avoid concomitant use... 

Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL, Thompson L, Nelson DL, Flemrick-Luecke SK, Wong DT. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology 2001 25(6) 871-80. 

Since dopamine is inactivated by norepinephrine reuptake in frontal cortex, which largely lacks dopamine transporters, venlafaxine can increase dopamine neurotransmission in this part of the brain... 

I Recent evidence that escitalopram may be more effective, or have an earlier onset of action, than citalopram and have equal efficacy to venlafaxine. This is attributed to escitalopram binding to both the re-uptake site and an allosteric site causing conformational change in the 5-HT transporter and enhancing re-uptake blockade. R-enantiomer blocks this effect. This is not seen with other SSRIs. These are mostly company data so claims need independent verification. 

Agents available in slow-release forms that delay absorption but not elimination half-life venlafaxine also inhibits norepinephrine transport at higher doses. 

Milnacipran is a reuptake inhibitor of norepinephrine and serotonin with little effect on dopamine reuptake or other neurotransmitter receptors. Compared with the SSRIs, milnacipran has a higher incidence of headache, dry mouth, and dysuria. Unlike duloxetine and venlafaxine, it is more potent at blocking the noradrenergic transporter (norepinephrine reuptake inhibition) thus, at low therapeutic doses, it is more of a noradrenergic drug. 

Venlafaxine is a potent reuptake inhibitor of serotonin, with a less potent effect on norepinephrine and dopamine, and does not interact with other neurotransmitter receptors. The lower affinity for norepinephrine transport requires dose elevation in order to achieve both serotonin and norepinephrine inhibition. Emerging evidence indicates that higher doses of venlafaxine (200-375 mg/day) may have a faster onset of action, observed as early as 4 days to 1 week following treatment initiation. 

As drugs are usually absorbed by passive diffusion and since enantiomers do not differ in their aqueous and lipid solubilities, absorption is not usually considered to be a stereoselective process. However, stereoselectivity has been described for drugs that are transported by a carrier-mediated process. Typical uptake selectivity is observed for neurotransmitter reuptake inhibitors such as nipecotic acid, oxaprotiline, fluoxetine and venlafaxine. Uptake of drugs by various organs can also be enantioselective, for example the liver/plasma concentration ratios of S(-) and R(-t-)-phenprocoumon in the rat were found to be different (6.9 and 5.2, respectively), indicating a preferential uptake of the more potent isomer. ... 

Their in vitro potenoy for selectively inhibiting the 5-HT transporter more or less mirrors their clinical efficacy as SSRIs (11) paroxetine> sertraline> clomipramine> fluoxetine> citralopram> fluvoxamine> imipramine> amitriptyline> roboxetine> venlafaxine = milnacipran> desipramine. Clinically, however, all the SSRIs are equally effective over time, suggesting that these variations in potency do not affect efficacy or adverse effects. The SSRIs have less affinity for ai, 02, Hi, and musoarinic receptors, which may explain the adverse-effect profile differences between TCAs and SSRIs. 

Venlafaxine and its active metabolite, 0-desmethylvenlafaxine (ODV), have dual mechanisms of action, with preferential affinity for 5-HT reuptake and weak inhibition of NE and dopamine reuptake. Venlafaxine is approximately 30 times more potent as an inhibitor of SERT than of NET (68). Because of the 30 times difference in transporter affinities, increasing the dose of venlafaxine from 75 to 375 mg/day can sequentially inhibit SERT and NERT. Thus, venlafaxine displays an ascending dose-dependent antidepressant response in contrast to the flat dose-antidepressant response curve observed with the SSRIs. This sequential action for venlafaxine also is consistent with its dose-dependent adverse-effect profile. Its mechanism of action is similar to imipramine. 

HT transporter. The potencies and selectivity indices of venlafaxine and its regio isomer (3-MeO) are identical. The regio isomer (3-CFg) of the 4-CF3 compoimd however shows an inversion of selectivity from the 5-HT transporter to the NE transporter. 

Another example of a dual SSRI/NARI is venlafaxine (Fig. 18.27), which one can view as a N,N-dimethylated and para-methoxy-phenylethylamine derivative, substituted with cyclohexanol at the (3-position. It only weakly inhibits dopamine transport and is commonly prescribed for depression but also for general and social anxiety disorder. 

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