Clomipramine 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]. 

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. 

Whale, R., Quested, D.J., Laver, D., Harrison, P.J., and Cowen, P.J. (2000). Serotonin transporter (5-HTT) promoter genotype may influence the prolactin response to clomipramine. Psychopharmacology (Berl) 150 120—122. 

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. 

Takano A, Suhara T, Yasuno F, Ichimiya T, Inoue M, Sudo Y, Suzuki K. Characteristics of clomipramine and fluvoxamine on serotonin transporter evaluated by PET. Int Clin Psychopharmacol 2002 17(Suppl 2) S84—5. 

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, clomipramine can increase dopamine neurotransmission in this part of the brain... 

Serotonin transporter (5-HTT) Antidepressants (e.g., clomipramine, fluoxetine, paroxetine, fluvoxamine) Clozapine effects, 5-HT neurottansmission, antidepressant response... 

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. 

Because doxepin is administered as an 85 15 mixture of geometric isomers, its mechanism of action and antidepressant properties refiects this ratio. Therefore, dioxepin s seiectivity for inhibiting presynaptic NE reuptake is most iikeiy caused by the 85% presence of the E-isomer in the geometric mixture. Its antidepressant activity is similar to amitriptyline. Data suggest NE reuptake inhibitory potency comparable to imipramine and clomipramine the fact that doxepin is an 85 15 mixture of - and Z-geometric isomers clouds its true efficacy for SERT or NET. The formation of N-desmethyIdoxepin results in inhibition of NE reuptake with enhanced noradrenergic activity. As a result of these mixed effects on the 5-HT and NE transporters, doxepin shares the pharmacological and adverse-effect profile of the other TCAs. 

Clomipramine is considered to be the most powerful antidepressant ever made. This dihydrodibenzazepine TCA, with actions on both the NE and 5-HT transporters, was the last of the major TCAs to come to market. Initially, the U.S. FDA regarded it as another me-too drug, and accordingly, they did not license it. Subsequently, however, it was licensed for the treatment of obsessive-compulsive disorders. Clomipramine differs from imipramine only by the addition of a 3-chloro group (Fig. 21.15). 

Clomipramine is different from the other TCAs, exhibiting preferential selectivity for inhibiting the reuptake of 5-HT at the presynaptic neuronal membrane. Its antidepressant mechanism of action as an inhibitor of the 5-HT transporter is reduced in vivo, however, because of the formation of its active metabolite, N-desmethylclomipramine, which inhibits the reuptake of NE. As a result of its common structure with the other TCAs, clomipramine shares the pharmacological and adverse-effect profile of the other TCAs. 

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