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Imipramine 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]. [Pg.77]

The tricyclic antidepressants (TCAs), such as imipramine, can alleviate symptoms of ADHD. Like bupropion, TCAs likely will improve symptoms associated with comorbid anxiety and depression. The mechanism of action of TCAs is in blocking norepinephrine transporters, thus increasing norepinephrine concentrations in the synapse the increase in norepinephrine is believed to alleviate the symptoms of ADHD. TCAs have been demonstrated to be an effective non-stimulant option for ADHD but less effective than stimulants. However, their use in ADHD has declined owing to case reports of sudden death and anticholinergic side effects6,13 (Table 39-3). Further, TCAs may lower seizure threshold and increase the risk of car-diotoxicity, (e.g., arrythmias). Patients starting on TCAs should have a baseline and routine electrocardiograms. [Pg.641]

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. [Pg.34]

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. [Pg.174]

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. [Pg.28]

Rickels K, Schweizer E, Clary C, et al Nefazodone and imipramine in major depression a placebo-controlled trial. Br J Psychiatry 164 802-805, 1994 Riddell EG Studies on Li" transport using 7Li and 61i nuclear magnetic resonance, in Lithium and the Cell. Edited by Birch NJ. San Diego, CA, Academic Press, 1991, pp 85-98... [Pg.732]

Many inhibitors of the amine transporters for norepinephrine, dopamine, and serotonin are used clinically. Although specificity is not absolute, some are highly selective for one of the transporters. Many antidepressants, particularly the older tricyclic antidepressants can inhibit norepinephrine and serotonin reuptake to different degrees. This may lead to orthostatic tachycardia as a side effect. Some antidepressants of this class, particularly imipramine, can induce orthostatic hypotension presumably by their clonidine-like effect or by blocking 04 receptors, but the mechanism remains unclear. [Pg.188]

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. [Pg.653]

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. [Pg.661]

The action of norepinephrine is terminated by reuptake mechanisms, two of which have been identified. Biogenic amine Uptake 1 is located in the presynaptic membrane, requires energy for the transport, is sodium and temperature dependent, and is inhibited by ouabain (a cardiac glycoside), cocaine (a local anesthetic), and imipramine (an antidepressant). Biogenic amine Uptake 2 is located extraneuronally in various smooth muscles and glands, requires energy, and is temperature dependent. Approximately 20% of the amine is either taken up by the Uptake 2 mechanism or is metabolized. [Pg.519]

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). [Pg.363]

Reuptake Norepinephrine transporter Tricyclic antidepressants (imipramine, f) Tricyclic norepinephrine reuptake inhibitors (desipiamine, ) Selective norepinephrine reuptake inhibitors (reboxetine, ) Dual serotonin/ norepinephrine reuptake inhibitors (venlafaxine, J.)... [Pg.365]

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... [Pg.351]

Apparsundaram S, Schroeter S, Giovanetti E, Blakely RD (1998b) Acute regulation of norepinephrine transport II. PKC-modulated surface expression of human norepinephrine transporter proteins. J Pharmacol Exp Ther 287 744-751 Arndt lO, Dorozynsky L, Woody GE, McLeUan AT, O Brien CP (1992) Desipramine treatment of cocaine dependence in methadone-maintained patients. Arch Gen Psychiatry 49 888-893 Balkovetz DP, Tiruppathi C, Leibach PH, Mahesh VB, Gtmapathy V (1989) Evidence for an imipramine-sensitive serotonin transporter in humtm placenttil bmsh-border membranes. J Biol Chem 264 2195-2198... [Pg.186]

Since dopamine is inactivated by norepinephrine reuptake in trontal cortex, which largely lacks dopamine transporters, imipramine can increase dopamine neurotransmission in this part otthe brain... [Pg.223]

NE secretion can be effectively decreased by administration of reseipine, an alkaloid isolated from a small woody perennial found in India (Rauwolfia), which has a high affinity for the vesicular monoamine h ansporter-2 (VMAT-2) and as such prevents NE storage. Alternatively, NE secretion can be increased by administration of tyramine (decarboxylated tyrosine), which is a constituent of a variety of foods including red wine, pickled herring and cheese. Amphetamine has a similar effect, which is most prominently manifested in the CNS. The termination of NE effects can be circumvented by the administration of cocaine, which blocks NE transport into presynaptic nerve endings (NET) an effect, which is also shared by some of the first generation antidepressants, such as imipramine. [Pg.549]


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See also in sourсe #XX -- [ Pg.6 , Pg.500 ]




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