Desipramine properties

Cocaine and desipramine inhibit the reuptake of monoamine neurotransmitters whereas amphetamine, which is a phenylalkylamine - similar in structure to the catecholamines, see Fig. 4 - competes for uptake and more importantly, evokes efflux of the monoamine neurotransmitters. All of them exert antidepressant effects. Cocaine and amphetamine are addictive whereas tricyclic antidepressants and their modern successors are not. The corollaty of the addictive properties is interference with DAT activity. Blockade of DAT by cocaine or efflux elicited by amphetamine produces a psychostimulant effect despite the different mechanisms even the experienced individual can hardly discern their actions. Because of the risk associated with inhibiting DAT mediated dopamine clearance the antidepressant effects of psychostimulants has not been exploited. 

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). 

Several drugs sharing a number of chemical features and therapeutic properties are included in this category. The most widely used at the present time are imipramine, desipramine, amitriptyline, and nortriptyline. Not all authors have distinguished clearly between them, and some have uncritically equated results obtained with two different drugs as though they were identical (B34). 

The relative sedating properties of TCAs appear to parallel their respective histamine receptor binding affinities. Trimipramine, amitriptyline, and doxepin are the most sedating TCAs. Desipramine and protriptyline are less sedating. 

The actions of amoxapine and maprotiline resemble those of TCAs such as desipramine. Both are potent NET inhibitors and less potent SERT inhibitors. In addition, both possess anticholinergic properties. Unlike the TCAs or other antidepressants, amoxapine is a moderate inhibitor of the postsynaptic D2 receptor. As such, amoxapine possesses some antipsychotic properties. 

The primary adverse effects of TCAs have been described in the previous text. Anticholinergic effects are perhaps the most common. These effects result in dry mouth, constipation, urinary retention, blurred vision, and confusion. They are more common with tertiary amine TCAs such as amitriptyline and imipramine than with the secondary amine TCAs desipramine and nortriptyline. The potent a-blocking property of TCAs often results in orthostatic hypotension. Hi... 

For chronic abdominal pain, low doses of tricyclic antidepressants (eg, amitriptyline or desipramine, 10-50 mg/d) appear to be helpful (see Chapter 30). At these doses, these agents have no effect on mood but may alter central processing of visceral afferent information. The anticholinergic properties of these agents also may have effects on gastrointestinal motility and secretion, reducing stool frequency and liquidity. Finally, tricyclic antidepressants may alter receptors for enteric neurotransmitters such as serotonin, affecting visceral afferent sensation. 

Long after their antidepressant properties were observed, the tricyclics were discovered to block the reuptake pumps for both serotonin and norepinephrine, and to a lesser extent, dopamine (Figs. 5 — 16, 6—5, and 6—6). Some tricyclics have more potency for inhibition of the serotonin reuptake pump (e.g., clomipramine) others are more selective for norepinephrine over serotonin (e.g., desipramine, maprotilene, nortriptyline, protriptyline). Most, however, block both serotonin and norepinephrine reuptake. 

Tricyclic antidepressants, like some of the phenothiazine derivatives (e.g., thioridazine), have an anticholinergic property. Amitriptyline is the strongest in this regard, and desipramine is the weakest. 

Fluoxetine, in addition to its antidepressant property, has been used as an appetite suppressant. Imipramine and desipramine have been used as antibulimic substances. 

The beneficial effect of mirtazapine in the treatment of depression might be explained by its a2-adrenoceptor antagonistic property. Bupropion and desipramine might be also beneficial in depression because of their ability to increase extracellular NE levels (Femandez-Pastor et al., 2005 Li et al., 2002 Parini et al., 2005 Sacchetti et al., 1999). The beneficial effect of NE in depression can be explained by the excitatory effect of NE on 5-HT neurotransmission and by the direct involvement of NE transmission in anxiety, energy feeling and motivation (Guiard et al., 2008 Stahl, 2000). 

The neuroleptic malignant syndrome has also been reported in association with the antidepressants trimipra-mine (SEDA-21, 11) (83), desipramine (SEDA-17, 18), and amoxapine (SEDA-16, 9 SEDA-17, 18) (84). Amoxapine in particular has significant dopamine D2 receptor antagonistic properties. In most cases the patients were taking several other drugs, but there have been reports of the syndrome in association with amoxapine or desipramine alone. 

Desipramine Hydrochloride, U5P. The structure and caliciit properties of desipramine hydrochloride, 10,11 -dihy-dro-iV-methyl-5H-dibenz b/ a/epine-5-propanamine mono-bydrochloride. S-(3-mclhylaminopropyl)-IO,l l-dihydro-5/y-diben/. b azepine hydrochloride (Norpramin, Perto-frane). arc discussed under the heading, Imipramine, above,. mnng tricyclics, desipramine would be considered when few iinticholincrgic effects or a low level of sedation arc important. It is a SNERI. ... 

Chronic pain patients tend to have concurrent depression however, the antidepressants chosen may not have any pain-relieving properties. Antidepressants that affect one neurotransmitter in the brain, such as selective serotonin reuptake inhibitors have not appeared to be effective in the management of pain in clinical trials. Antidepressants that affect multiple neurotransmitters— namely, serotonin and norepinephrine—have been shown to be effective pain relievers.Two published metaanalyses have shown that tricyclic antidepressants amitriptyline, desipramine, imipramine, and nortriptyline are the most effective treatment for the management of neuropathic pain. ° These publications review the published clinical trial data for all agents available for the management of neuropathic pain. 

Tricyclic antidepressants, like some of the phenothiazine derivatives, are sedative in nature. Those compounds containing tertiary amines (imipramine, amitriptyline, and doxepin) are the most sedative. Those compounds containing a secondary amine (nortriptyline and desipramine) are less so, and protriptyline has no sedative effect (see Table 5). Tricyclic antidepressants, like some of the phenothiazine derivatives (e.g., thioridazine), have an anticholinergic property. Amitriptyline is the strongest in this regard, and desipramine is the weakest (see Tables 5 through 7). 

FIGURE 41 Desipramine, a tricyclic antidepressant, causes a strong blockade of the serotonin uptake mechanism. It causes a mild degree of sedation and orthostatic hypotension and has a weak anticholinergic property. 

The SSRIs are reported to have fewer side effects than the TCAs, which have strong anticholinergic and cardiotoxic properties (50). Among the SSRIs, there are few differences in adverse effects. The adverse effects observed for the SSRIs include nausea, diarrhea, anxiety, agitation, insomnia, and sexual dysfunction. Fewer patients have discontinued SSRIs than TCAs (amitriptyline and imipramine, and not nortriptyline, desipramine, doxepin, and clomipramine). 

Venlafaxine is a virtually non-selective inhibitor of the uptake of 5-HT and NE by rat brain synaptosomes. It is structurally related to gamfexine a compound with antidepressant and psychostimulant properties (fig. 4). The potency of venlafaxine to inhibit in vitro monoamine uptake is the same range as that of imipramine and desipramine under the experimental conditions described by Muth et al. [45] and Yardley et al. [46]. 

Consider, for example, the structurally similar tricyclic antidepressants shown in Figure 4. These compounds exhibit a different adsorptive stripping response because of their different interfacial properties . For example. Figure 5 shows adsorptive stripping calibration plots for the compounds shown in Figure 4. For trimipramine (c), the peak current increases linearly with concentration. In contrast, desipramine and imipramine exhibit a curvature in the response at high concentrations. 

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