Sertraline transporters

Selective serotonine reuptake inhibitor (SSRI) is an abbreviation for the class of antidepressants known as the Selective Serotonin Reuptake Inhibitors. Examples of SSRIs include fluoxetine, paroxetine, citalopram, and sertraline. These drugs selectively inhibit the serotonin transporter thus prolonging the synaptic lifespan of the neurotransmitter serotonin. 

Ng, C. H., Easteal, S., Tan, S. et al. (2006b). Serotonin transporter polymorphisms and clinical response to sertraline across ethnicities. Progress in Neuropsychopharmacology and Biological... 

Durham, L. K., Webb, S. M., Milos, P. M., Clary, C. M. Seymour, A. B. (2004). The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology, 174, 525-9. 

Despite their common ability to enhance serotonergic function in vivo, the SSRIs differ both in terms of their pharmacological profiles and their pharmacokinetics. Thus in addition to their direct inhibitory action on the serotonin transporter, they also affect other neurotransmitter systems which may have some clinical relevance. Citalopram has a modest antihistamine action which might account for its slightly sedative action. Sertraline has a... 

These drugs increase synaptic serotonin by selectively blocking the serotonin reuptake transporter. In preclinical and human studies acute doses tend to be anxiogenic (Bell and Nutt 1998) but chronic administration has anxiolytic effects, possibly due to downregulation of presynaptic autoreceptors (Blier et al. 1990). There are five SSRIs widely available citalopram, fluoxetine, fluvoxam-ine, paroxetine and sertraline. Escitalopram, the S-enantiomer of citalopram. 

The selective serotonin reuptake inhibitors (SSRIs) represent a chemically diverse class of agents that have as their primary action the inhibition of the serotonin transporter (SERT) (Figure 30-3). Fluoxetine was introduced in the United States in 1988 and quickly became one of the most commonly prescribed medications in medical practice. The development of fluoxetine emerged out of the search for chemicals that had high affinity for monoamine receptors but lacked the affinity for histamine, acetylcholine, and adrenoceptors that is seen with the tricyclic antidepressants (TCAs). There are currently six available SSRIs, and they are the most common antidepressants in clinical use. In addition to their use in major depression, SSRIs have indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia. Fluoxetine, sertraline, and citalopram exist as isomers and are formulated in the racemic forms, whereas paroxetine and fluvoxamine are not optically active. Escitalopram is the S enantiomer of citalopram. As with all antidepressants,... 

Several drugs (for example amiodarone, androgens, glucocorticoids, phenytoin, and salicylates) interfere with the transport or metabolism of thyroid hormones and thereby alter thyroid function tests. These have been reviewed (90). In patients taking levothyroxine serum TSH rises after treatment with sertraline (91) and antimalarial prophylaxis with chloroquine and proguanil... 

The primary metabolite of sertraline (Zoloft, 8.62), an antidepressant, arises from oxidative dealkylation of the amine group by CYP enyzmes in the liver (Figure 8.1). The metabolite, /V-desmethylsertraline (8.63), is essentially inactive and is readily eliminated by the kidneys. Other metabolites of sertraline include 8.64 and 8.65, both of which involve modification of the amine. Neither is an effective inhibitor of the serotonin transporter, the target of sertraline.10... 

Sertraline also has some ability to block dopamine reuptake pump (dopamine transporter), which could increase dopamine neurotransmission and contribute to its therapeutic actions... 

SLC6A4 Serotonin transporter 5 -HTTLPR VNTR Alcohol Ondansetron, sertraline... 

Kranzler HR, Armeli S, Tennen H, Covault J, Feinn R, Arias AJ, Pettinati H, Oncken C (2011) A double-blind, randomized trial of sertraline for alcohol dependence moderation by age of onset [corrected] and 5-hydroxytryptamine transporter-linked promoter region genotype. J Clin Psychopharmacol 31 22-30... 

Sertraline 22 Serotonin transporter protein or SERT (inhibitor) Alternative to fluoxetine Targeted compound library Overcame drug-drug interactions Antidepressan t GI tract... 

HT transporter Inhibitor Fluoxetine, sertraline Depression panic, obsessive-compulsive, and posttraumatic stress disorders social phobia... 

The affinity data for the SSRIs show that the SSRIs, as a group, are very potent and selective inhibitors for SERT compared with their affinity for NE and dopamine reuptake transporters (Fig. 21.6) and are more potent inhibitors of 5-HT reuptake than are the tertiary amine TCAs, with the exoeption of clomipramine. None of the SSRIs has substantial effeot on the NET or dopamine transporter. Of the SSRIs, sertraline exhibits the most potent inhibition of dopamine reuptake transporter, although it is still 100 times less potent in terms of inhibiting the dopamine versus the SERT. Therefore, the plasma oonoentration of sertraline would have to be increased by as much as 100 times to inhibit the dopamine reuptake transporter. When drugs are this selective for the reuptake transporters, differences in potency become olinioally irrelevant, because the plasma concentration oan be dose-adjusted to achieve inhibition of the desired transporter without affecting the other transporters. Clomipramine displays less affinity for SERT than oitalopram, fluvoxamine, paroxetine, or sertraline does and is more potent than fluoxetine. In terms of the ability to inhibit the NET, the SSRIs are two to three times less potent than the SNRI TCA, desipramine. 

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. 

Sertraline is a potent and selective inhibitor of the neuronai reuptake 5-HT transporter, in vitro binding studies suggest that sertraiine has a substantiaiiy higher seiectivity for inhibiting 5-HT reuptake than other SSRis or TCAs, inciuding ciomipramine (Fig. 21.6). it has oniy weak effects on neuronai uptake of NE and dopamine, its mechanism of action is common to the SSRis. Sertraiine is very seiective, iacking affinity for other neuroreceptors at therapeutic concentrations. 

Nomifensine is a substituted phenyipiperidine (an aminophenyitetrahydroisoquinoline) structurally related to sertraline that was marketed as a stimulatory antidepressant in the mid-1970s but later withdrawn because of a high incidence of hemolytic anemia. Nomifensine inhibits the NE and dopamine reuptake transporters. It displays high affinity for NET (human pK, = 7.8), moderate affinity for dopamine transporter (pK, = 6.6), and a low affinity for SERT (5-HT NE ratio, 65). 

Biological target Sertraline is an aryl-substituted tetrahydronaphthalene derivative which selectively inhibits the plasma membrane serotonin transporter (SERT) and thereby blocks serotonin re-uptake from the neuronal synapse. 

Nervous system The addition of serfraline to ziprasidone in a 30-year-old female resulted in tixe development of a serotonin syndrome [282 ]. Ziprasidone is bofh a 5-HTlA agonist and inhibitor of serotonin transporters sertraline was discontinued and the patient was maintained on ziprasidone. 

---