Nortriptyline 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]. 

Reboxetine is the only selective and reasonably potent noradrenaline reuptake inhibitor available clinically at the present time. Reboxetine has a chemical structure not dissimilar from viloxazine, an antidepressant which was of only limited clinical interest in the 1970s because of its weak efficacy and unacceptable side effects (nausea, vomiting and occasionally seizures). Unlike the secondary amine TCA antidepressants, such as maprotiline, desipramine, nortriptyline and protriptyline, reboxetine does not affect any other transporter or receptor system and therefore is largely devoid of TCA and SSRI-like side effects. In clinical trials, reboxetine has been shown to be as effective as the SSRIs in the... 

Kim DL, Lim SW, Lee S, et al (2000) Serotonin transporter gene polymorphism and antidepressant response. Neuroreport ll 215-219Kalow W Kishimoto A, Hollister LE (1984) Nortriptyline kinetics in Japanese and Americans. J Clin Psychopharmacol 4 171-172... 

Norepinephrine is removed from the synapse by means of two mechanisms. In the hrst, catechol-O-methyl-transferase (COMT) degrades intrasynaptic NE. In the second, the norepinephrine transporter (NET), a Na /CH-dependent neurotransmitter transporter, is the primary way of removing NE from the synapse [(4) in Fig. 2.7]. The NET is blocked selectively by desipramine and nortriptyline. Once internalized. 

The TCAs resemble the SNRIs in function, and their antidepressant activity is thought to relate primarily to their inhibition of 5-HT and norepinephrine reuptake. Within the TCAs, there is considerable variability in affinity for SERT versus NET. For example, clomipramine has relatively very little affinity for NET but potently binds SERT. This selectivity for the serotonin transporter contributes to clomipramine s known benefits in the treatment of OCD. On the other hand, the secondary amine TCAs, desipramine and nortriptyline, are relatively more selective for NET. Although the tertiary amine TCA imipramine has more serotonin effects initially, its metabolite, desipramine, then balances this effect with more NET inhibition. 

Treatment with antidepressants will affect a person s ability to drive or operate machinery. Among the tricyclic antidepressants, amitriptyline and doxepin impair skills compared with imipramine and nortriptyline. Fluoxetine and dothiepin also show similar effects, such as affecting ability to work. The United Kingdom s Medical Commission on Accident Prevention has recommended that patients on long-term psychotropic medication are unsuitable drivers of heavy vehicles or public transport services.132,133... 

St John s wort can cause drug interactions by inducing hepatic microsomal drug-metabolizing enzymes or the drug transporter P-glycoprotein, which causes a net efflux of substrates, such as amitriptyline, from intestinal epithelial cells into the gut lumen (SEDA-24,12). In 12 patients (9 women, 3 men) the addition of St John s wort 900 mg/ day to amitriptyline 150 mg/day led to a 20% reduction in plasma amitriptyline concentrations, while nortriptyline concentrations were almost halved (210). 

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... 

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

Nortriptyline Hydrochloride, USP. Pertinent biological and chemical properties for nortriptyline. 3-(IO.II-di-hydro-5//-dibenzu(a.d cyclohepten-S-ylidcne)fV-mcthyl-1 -propanamine hydrochloride. 5-(3-methyl-aminoprupyli-denc)-IO.t l-hydro-S//-dibcnzo a.Metabolic inactivation and elimination are like tho.se of amitriptyline. Nortriptyline is a selective NE transporter (NET) inhibitor. ... 

Amitriptyline is rapidly absorbed from the Gl tract and from parenteral sites. Its pharmacokinetics are shown in Table 21.9. Amitriptyline and its active metabolite, nortriptyline, are distributed into breast milk. Amitriptyline is primarily (65%) metabolized by N-demethylation by CYP2D6 to nortriptyline and hydroxylation to its -10-hydroxy metabolite. Nortriptyline is pharmacologically active as a secondary amine TCA. Amitriptyline shows approximately equal affinity for 5-HT and NE transporters. 

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