Antidepressants, Imipraminic

Miscellaneous. The iminostilbene carbama2epiae [294-46-4] congener of the tricycHc antidepressant, imipramine. 

Trigclic Antidepressants. Imipramine (38) was introduced in the late 1950s as one of the first pharmacotherapies for depression. At that time, chlorproma2ine [50-53-3] was the first effective antipsychotic treatment to be discovered. Researchers looked for similar chemical stmctures and imipramine was found to be effective in the symptomatic treatment of depression. Over the years, other congeners, such as desipramine (39), amitriptyline (40), and dothiepin (41), were synthesized and shown to be clinically efficacious antidepressant dmgs (121). These substances, known under the general mbric of tricycHc antidepressants, share a basic chemical stmcture comprising... 

Tricyclic Antidepressants. Imipramine [50-49-7] (32), which was the first tricycHc antidepressant to be developed, is one of many useful psychoactive compounds derived from systematic molecular modifications of the antihistamine prometha2ine [60-87-7] (see Histamine and histamine antagonists). The sulfur atom of prometha2ine was replaced with an ethylene bridge and the dimethylamino group attached to an / -propyl group, rather than to an isopropyl one, of the side chain. The actual synthesis of (32) is typical of the compounds in this class (37). 

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 ... 

Metabolism converts a lipophilic molecule into a more hydrophilic (water-loving) metabolite that can be excreted in urine by the kidneys. In the majority of cases the drug is detoxified, or made pharmacologically inactive by this metabolic breakdown. However, a few drugs need to be metabolised to become psychoactive for instance, the sedative-hypnotic chloral hydrate is converted to the active metabolite trichloroethanol. In this case the parent molecule is referred to as a prodrug. With many drugs, both the parent compound and its metabolites are psychoactive. An example of this is the tricyclic antidepressant imipramine which is metabolised to desipramine, with... 

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. 

Pharmaceutical Comparison. At least 8 studies to date have examined the effectiveness of hypericum compared to the pharmaceutical antidepressants imipramine, amitriptyline, and maprotiline. Preliminary results indicate that hypericum is equivalent to standard antidepressants in effectiveness (Linde et al. 1996 Vorbach 1997). Similar to the pharmaceutical antidepressants, there is a 10-14 day lag for therapeutic effects of hypericum (Harrer et al. 1994). Indeed, the differences seen between hypericum and placebo groups becomes apparent between 2 and 4 weeks (Sommer and Harrer 1994). Hypericum has been reported to have a more favorable side-effect profile than several pharmaceutical antidepressants as well (Vorbach et al. 1994 Harrer et al. 1994). In double-blind studies, subjects have reported fewer and less-severe side effects. Although these initial results are promising, Linde and colleagues (1996) have concluded that the present evidence is inadequate to establish... 

There are four classes of antidepressants tricyclic antidepressants (imipramine, trimipramine, amitriptyline, doxepin, desipramine, protriptyline, nortriptyline, amoxapine, maprotiline) monoaminooxidase (MAO) inhibitors (phenelzine, isocarboxazid, tranylcypromine) second-generation antidepressants or atypical antidepressants, which are a chemically dissimilar group of recently proposed drugs (bupropion, trazodone, fluoxetine) and amphetamines and other stimulators of the CNS (dextroamphetamine, methylphenidate). 

In the case of social anxiety disorder, research suggests that some of the antidepressants that are effective in other anxiety disorders do not work to ease the symptoms of social anxiety disorder. This is true of the tricyclic antidepressant imipramine and fluoxetine (Prozac). The first line of treatment for the generalized form of social anxiety disorder is an SSRI such as paroxetine or sertraline. 

Effective pharmacological treatment of panic disorder began with the antidepressant imipramine, but today a variety of efficacious agents are available for treating the symptoms of panic disorder. The four primary classes of... 

It is thus understandable why some earlier authors previously doubted the efficacy of antidepressants in general (Weiner et al.. 1980) or the advantages of newer antidepressants compared with classical products (Song et al., 1993). However, the great majority of doctors and scientific authors consider that the efficacy of first-generation antidepressants (imipramine, amitriptyline, nortriptyline) has been proved beyond any reasonable doubt, and that efficacy also has been demonstrated for newer products such as trazodone, the selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake... 

The synthesis of 614, a conformationally rigid analogue of the tricylic antidepressant imipramine, also begins with an A,A-diisopropyl nicotinamide ortho metalation (Scheme 181) [87H(26)3165]. Thus, LiTMP depro-... 

The discovery that drugs elevating extracellular levels of noradrenaline and/or serotonin have analgesic potential was circumstantial. In I960, Paoli et al. reported that during an attempt to treat reactive depression in chronic pain patients with the tricyclic antidepressant imipramine they observed an improvement of the patients neuralgic pain. Subsequently, it became well established that antidepressant drugs can improve both depression and chronic pain states. 

Tricyclic antidepressants. Imipramine and clomipramine have been the most extensively studied of the tricyclic antidepressants and both have demonstrated efficacy in treating panic disorder. Other tricyclic antidepressants that have shown some evidence of efficacy include desipramine, doxepin, amitriptyline, and nortriptyline. 

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

In addition to known antidepressants increasing endogenous opioids, opioid ligands have also been administered to depressed patients to determine if opioid compounds have clinical efficacy to treat depression. The opioid ligand cyclazocine improved symptoms in severely depressed, chronically ill mental patients in an open clinical trial and in clinical trials with patients unresponsive to the tricyclic antidepressant imipramine [16]. Intravenous (5-endorphin infusions improved mood in depressed patients in open case studies [17] and in depressed patients in a double-blind placebo-controlled study [18,19]. However, one study found a trend to improve depression scores in patients after acute and chronic (5-endorphin infusions, but it was not significant [20]. 

Fig. 1.5 The tricyclic antidepressants (imipramine and maprotiline) are characterized by a dihedral angle of 55° to 55° between the two benzo rings this angle is only 25° for the tricyclic neuroleptics (chlorpromazine, chlorprothixene) [12].

For the two antidepressants (imipramine and maprotiline), the bioisosterism is geometrical insofar that the dihedral angle a formed by the two benzo rings is comparable a = 65° for the dibenzazepine and a = 55° for the dibenzocyclohepta-diene [12]. This angle is only 25° for the neuroleptic phenothiazines and for the thioxanthenes. In these examples, the part of the molecule modified by isosterism is not involved in the interaction with the receptor. It serves only to position correctly the other elements of the molecule. 

Brorson L, Wennerblom B. Electrophysiological methods in assessing cardiac effects of the tricyclic antidepressant imipramine. Acta Med Scand 1978 203(5) 429-32. 

TERBINAFINE ANTIDEPRESSANTS- IMIPRAMINE, NORTRIPTYLINE Possible T plasma concentrations ofTCAs Terbinafine strongly inhibits CYP2D6-mediated metabolism of nortriptyline Warn patients to report t side-effects of TCAs such as dry mouth, blurred vision and constipation, which may be an early sign of t TCA levels. In this case, consider i dose of TCA... 

In humans, a prominent effect of cocaine consists in increased vigilance and elevated mood. While cocaine itself is not used clinically, several catecholamine and serotonin reuptake blockers are used as antidepressants. Imipramine (Figure 10.13) is a classic but not so very specific in addition to inhibiting the reuptake of serotonin and of norepinephrine, it also has antihistaminic and antimuscarinic activity. This will lead to side effects in both the central nervous system and the peripheral autonomic system. A prominent one is the causation or deterioration of cardiac arrhythmias due to its antimuscarinic action. 

Among the tricylic antidepressants, imipramine, 54, was the first commercially available drug, which was introduced in 1960 [9],... 

Tricyclic antidepressants. Imipramine, amitriptyline and nortriptyline are effective, especially for nocturnal but also for daytime incontinence. Their parasympathetic blocking (antimuscarinic) action is probably in part responsible but imipramine... 

Dryness of the mouth may also result in other problems. For example, the tricyclic antidepressant imipramine (e.g., Tofranil) can cause persistent dryness of the mouth. If nitroglycerin tablets are administered sublingually for the management of exertional angina, the relief of the symptoms may be delayed due to the slower dissolution of the sublingual tablets. 

There is one report of the use of the tricyclic antidepressant imipramine hydrochloride to control urospermia in a stallion with detrusor dysfunction and decreased urethral sphincter tone (Oristaglio Turner et al 1995 see Ch. 11). Imipramine is a phe-nothiazine analog and appears to have a adrenergic effects via the blockade of norepinephrine reuptake at nerve terminals. It was administered orally at 0.8 mg/kg to this stallion 2-3 h prior to semen collection and was thought to improve urethral sphincter tone and limit urospermia. However, this improvement was not documented using urethral pressure profilometry and the owner of the stallion was also instructed to collect from the stallion shortly after it was observed to urinate. Consequently, it is not clear whether the imipramine treatment was really of any benefit. 

Adrenergic agents and/or tricyclic antidepressants may be used to induce ejaculation ex copula (also known as "chemical ejaculation") in stallions that have inadequate erection prior to or following insertion. Ejaculation is either observed within 3 min of (associated with the onset of sedation) or 15-20 min after (associated with recovery from sedation) the i.v. administration of the U2 adrenoceptor agonist xylazine (0.66mg/kg) (McDonnell 1999). Ejaculation typically occurs 10-60min after the i.v. administration of the tricyclic antidepressant imipramine (2.2mg/kg) (McDonnell 1999). These two medications may be used in combination imipramine is administered p.o. at a dose rate of 0.075-2.0 mg/kg followed 1-2 h later by xylazine (0.3 mg/kg i.v.). Ejaculation occurs 3-15 min after the xylazine (McDonnell 1993, McDonnell 2001). PGF2a i.m. at 0.005-0.01 mg/kg results in ejaculation 5-90 min later (McDonnell 1999). 

CYP2C19 Benzodiazepines diazepam Antidepressants imipramine, amitriptyline, clomipramine, citalopram Others propranolol, hexobarbital, mephobarbital, proguanil, omeprazole, S-mephenytoin 2 no activity 23%-39% in Asians 13% in Caucasians 25% in African Americans 3 no activity 6%-10% in Asians 0% in others... 

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