Imipramine inhibition

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. 

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. 

Imipramine inhibits the reuptake of previously released noradrenaline in isolated tissues. 

Iwashita, T., Shimizu, T. Imipramine inhibits intrathecal substance P induced behavior and blocks spinal cord substance P receptors in mice, Brain Res. 1992, 581, 59-66. 

AMOXAPINE, CLOMIPRAMINE, DOXEPIN, IMIPRAMINE, NORTRIPTYLINE, TRIMIPRAMINE PROTEASE INHIBITORS Possibly t adverse effects of amoxapine with atazanavir and ritonavir Inhibition of CYP3A4-mediated metabolism of amoxapine, clomipramine and doxepin inhibition of CYP3A4-, CYP2D6-and CYP2C9-mediated metabolism of imipramine inhibition of CYP2D6-mediated metabolism of nortriptyline and trimipramine Monitor closely... 

Both drugs block reuptake of norepinephrine released from sympathetic nerve endings Imipramine inhibits the metabolism of diphenhydramine Both drugs block muscarinic receptors The drugs compete with each other for renal elimination 7. If phenelzine is administered to a patient taking fluoxetine, the most likely result is (A) Antagonism of the antidepressant action of fluoxetine A decrease in the plasma levels of fluoxetine Hypertensive crisis Priapism... 

One suggestion is that imipramine inhibits the metabolism of the phenytoin by the liver, which results in its accumulation in the body. In vitro study has shown that the tricyclics can inhibit the cytochrome P450 isoenzyme CYP2C19, but this isoenzyme usually has only a minor role in phenytoin metabolism (see Antiepileptics , (p.517)). The reduced desipramine levels may be a result of enzyme induction by the phenytoin. 

Care must taken, however, with compounds which interfere with the metabolism of amphetamine. For instance, compound SKF 525A, an inhibitor of detoxification by the liver and lacking antidepressant properties, was found to be active. It has also been shown that imipramine inhibits the hydroxylation of amphetamine in the liver [17], a fact which complicates the interpretation of these test results. 

Most of the widely used antidepressants are tricyclics related to imipramine. A 1-phenyltetrahy-droisoquinoline analogue, nomifensine (60), departs from this structural pattern. Hiarmacologi-cally it inhibits the reuptake of catecholamines such as dopamine at neurons. It can be synthesized by alkylation of 2-nitrobenzyl-methylamine with phenacyl bromide followed by catalytic reduction of the nitro group (Pd-C) and then hydride reduction of the keto moiety to give 59. Strong acid treatment leads to cyclodehydration to nomifensine (60) [17]. 

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]. 

Tricyclics Preferential inhibition of noradrenaline Imipramine Potent antagonists of M-receptors, i-adrenoceptors... 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

Set against this background is the finding that the inhibition of [ H]noradrenaline uptake by the neuroleptic, chlorpromazine, is even greater than that of imipramine and yet chlorpromazine has no apparent antidepressant effects. This serves as a testimony... 

There was a problem with this first version of the biochemical theory of depression. Iproniazid was not the only drug that had been reported to be effective as an antidepressant. Imipramine, the drug that had been tested by the Swiss psychiatrist Roland Kuhn, seemed to have similar effects. But imipramine is not an MAOI it does not inhibit the destruction of neurotransmitters in the synapse. So if antidepressants worked by inhibiting monoamine oxidase, why was imipramine effective How could its apparent effectiveness be reconciled with the chemical-imbalance theory ... 

The answer is that there are two ways in which neurotransmitter levels might be increased. One is to inhibit their destruction after they have been released into the synaptic gap. That is how MAOIs are supposed to work. Recall, however, that after a neurotransmitter is released, some of its molecules are reabsorbed by the presynaptic neuron that released them in a process that is called reuptake . Blocking this reuptake process should also increase the level of neuro transmitters in the brain. In 1961, Julius Axelrod, who later received the Nobel Prize in Medicine for his work on the release and reuptake of neurotransmitters, reported that imipramine, as well as a few other drugs, inhibited the reuptake of norepinephrine in cats. Two years later he reported that these drugs also inhibited the reuptake of serotonin.13... 

Axelrod s discovery provided an answer to the question of why imipramine might alleviate depression, even if it did not inhibit the destruction of neurotransmitters in the brain. With the problem of imipramine solved, the chemical-imbalance theory seemed to work. Two different types of drugs relieve depression, the theory went,... 

Until the introduction of selective serotonin reuptake inhibitors (SSRIs) in the 1980s, tricyclic antidepressants were the most widely used drugs. The therapeutic effect of amitriptyline and imipramine are related to their ability to inhibit the presynaptic reuptake of both NA and 5-HT. They are referred to as non-selective reuptake inhibitors, whereas many of the other tricyclics are more selective thus, clomipramine is a selective reuptake inhibitor for 5-HT and desipramine and nortriptyline are selective... 

Desipramine An active metabolite of imipramine that is more selective for inhibiting noradrenaline reuptake into the presynaptic neuron. 

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

Tricyclic antidepressants such as imipramine (25), clomipramine (26), amitriptyline (27), and doxepine (28) were found to be weak inhibitors of GST Pl-1 in vitro. Inhibition of GST Pl-1 was enhanced with the introduction of a chloro group on the dibenzazepine ring (25 40% inhibition at 15 mM 26 70% inhibition at 10 mM). The same result was observed with the substitution of an oxygen for a carbon in the heptadiene ring (27 18% inhibition at 10 mM 28 48% inhibition at 15 mM) [35],... 

Additional ADRs linked to diet pills include psychosis myocardial ischemia drug interactions, such as the interaction of fenfluramine with imipramine, fenfluramine with amitriptyline or desipramine, or the toxic reaction between fluoxetine and phentermine and the release of serotonin while inhibiting its reuptake, contributing to hyperserotonin reactions. When the next craze takes hold of patients and their physicians, hopefully physicians and pharmacists will take a more vocal position and recommend restraint, xmtil some proof of efficacy and lack of toxicity is shown for new faddish off-label combinations. 

A breakthrough in the treatment of major depression was the discovery of fluoxetine, marketed as Prozac. Fluoxetine has a mechanism of action similar to that of imipramine with an important exception. It is a selective serotonin reuptake inhibitor, an SSRI. This strongly suggests that, in some sense, the symptoms of major depression result from a deficit in serotonin specifically. By inhibiting its reuptake from the synapse, the activity of serotonin is enhanced. Two other important drugs for major depression, sertraline (Zoloft) and paroxetine (Paxil), among several others,... 

Iproniazid, an MAOI no longer available because of its hepatotoxicity, was the first effective antidepressant to be discovered it was introduced shortly before the discovery of imipramine. All MAOIs are presumed to have a similar mode of action, namely to inhibit the intra- and interneuronal metabolism of the biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin). These amines are primarily metabolized by MAO-A (noradrenaline and serotonin) or MAO-B (dopamine). The irreversible MAOIs are inhibitors of MAO-A while selegiline (deprenyl), used as an adjunctive treatment for Parkinson s disease, is a selective, irreversible inhibitor of MAO-B. 

Imidazolone synthesis, 291 Imidoline, 259 Imipramine, 420 Indapamide, 349 Indazole synthesis, 350 Indoles, as starting material for benzodiazepines, 405 Indomethacin, 345 Indoramin, 344 Incfoxoie, 254, 340 Inflammation, 63 Influenza A, 18 Inhibition,... 

Imipramine is the primary representative of typical tricyclic antidepressants. It acts by blocking the mechanism of renptake of biogenic amines. It does not inhibit MAO activity. Imipramine lessens sadness, lethargy, improves mood, and improves the mental and overall tone of the body. It is nsed in depression of varions etiology accompanied by motor cinmsiness and ennresis in children and Parkinson s disease. Primary synonyms of this drag are tofranil, snrplix, imizin, melipramin, and others. 

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