Doxepine antidepressant

Doxepin [1668-19-5] (38), unlike other commercially available tricyclics, has an oxygen atom in the bridge between the two aromatic rings. It is marketed as a cis—trans mixture (1 5) of isomers, both of which are active. This close relative of amitriptyline (33) has both sedative and anxiolytic properties associated with its antidepressant profile. Maprotiline [10262-69-8] (39) and amoxapine [14028-44-5] (40) are pharmacologically, although not chemically, similar to the tricycHc secondary amines. Clomipramine [303-49-1] (41) has similar pharmacological and antidepressant efficacy. However, clomipramine is approved by the U.S. FDA only for the treatment of obsessive—compulsive disorder. Representative brands of tricycHc antidepressants marketed in the United States are Hsted in Table 2. 

Figure 15.3 Separation of tricyclic antidepressants by using multidimensional LC-LC. Peak identification is as follows DOX, doxepin DES, desipramine NOR, noitryptylene IMI, imipramine AMI, amiti yptyline. Adapted from Journal of Chromatography, 507, J. V. Posluszny et al., Optimization of multidimensional high-performance liquid cliromatography for the deterTnination of drugs in plasma by direct injection, micellar cleanup and photodiode array detection , pp. 267 - 276, copyright 1990, with permission from Elsevier Science.

Older tricyclic antidepressants are set in italics. The specificity of action of tricyclic antidepressants (in particular of amitritpyline, imipmmine, doxepine, noitriptyline, maprotiline) is limited because at therapeutic levels ihese drugs also block receptors (H t-histamine, a,-adrenergic, muscarinic). 

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. 

Tricyclic antidepressants (TCAs) such as amitriptyline and doxepin have been used with some success in the treatment of IBS-related pain (Table 18-5). They modulate pain principally through their effect on neurotransmitter reuptake, especially norepinephrine and serotonin. Their helpfulness in functional gastrointestinal disorders seems independent of mood-altering effects normally associated with these agents. Low-dose TCAs (e.g., amitriptyline, desipramine, or doxepin 10 to 25 mg daily) may help patients with IBS who predominantly experience diarrhea or pain. 

Tricyclic antidepressants Nortriptyline Doxepin Given by mouth once daily or in two divided doses 75-150 mg/day 150-250 mg/day... 

Doxepin is a tricyclic antidepressant that inhibits histamine receptors. It may be helpful in atopic patients who have a component of depression. Doses of 10 to 75 mg at night and up to 75 mg twice daily in adults have been used. 

Amitriptyline appears to be the tricyclic antidepressant (TCA) of choice, but imipramine, doxepin, nortriptyline, and protriptyline have also been used. 

Rao et al.20 demonstrated a fluorescence polarization immunoassay for evaluating serum concentrations of tricyclic antidepressants (amitriptyline, imipramine, clomipramine, and doxepin) with respect to nonresponse, compliance, therapeutic window, and influences of age, sex, substance abuse, and toxicity. Abbott Laboratories TDx/TDxFLx Toxicology Tricyclic Assay FPIA (fluorescence polarization immunoassay) was used. This assay of 50 /uL samples contained tricyclic antidepressant antibodies raised in rabbits and fluorescein-labeled tricyclic antidepressant as a tracer. The assay was calibrated with imipramine in the range of 75 to 1000 fig/L (268 to 3571 nmol/L). Intra-assay and inter-assay coefficients of variation for internal quality control samples from the manufacturer were 4.2 and 4.7%, respectively. The limits of detection were 72,71,64, and 72 nmol/L for amitriptyline, imipramine, clomipramine, and doxepin, respectively. This high-throughput immunoassay was easy to use although amitriptyline, dosulepine, desipramine, and nortriptyline showed cross-reactivities ranging from 74 to 100%. 

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],... 

The tricyclic antidepressives, doxepin (394) and dothiepin (395), were photo-isomerized when aqueous solutions of their hydrochlorides were irradiated with a medium-pressure mercury lamp [195]. Doxepin was photodegraded by... 

Antidepressants. For three apparent reasons, antidepressants have long been used to treat insomnia. First, some of them are quite sedating. In particular, doxepin (Sinequan), amitriptyline (Elavil), and trazodone (Desyrel) have been used to treat... 

When treating insomnia without depression, doxepin and amitriptyline (both tricyclic antidepressants) can be administered in low doses (25-100 mg) at bedtime. These antidepressants, however, do have troublesome anticholinergic side effects (dry mouth, constipation, blurred vision, dizziness) and adverse effects on the heart, and they can be lethal if taken in overdose. Because of their effect on heart function, these antidepressants should be avoided in patients with heart problems and administered cautiously, if at all, to those who are already receiving one of any number of newer antidepressants that inhibit the metabolism of the TCAs. 

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). 

Doxepin is a tricyclic antidepressant which also has antianxiety effects. The following is an abbreviated monograph for doxepin. For complete information, refer to the Tricyclic.Antidepressants.monograph. 

The adsorption isotherms of three basic drngs, the anxiolytic bnspirone hydrochloride, the antidepressant doxepin hydrochloride, and the Ca + blocker diltiazem hydrochloride, were fitted to the Bilangmnir model, as shown in Figure 10.12 [27]. This finding snggested that the adsorption took place on two different types of sites and that there were two different adsorption mechanisms. 

Doxepin (Sinequan) Because of its strong anticholinergic and sedating properties, doxepin is rarely the antidepressant of choice for elderly patients. High... 

Most antidepressants did not considerably change SWS. Nonetheless, evidence indicates that doxepine [Roth et al. 1982), imipramine (Kupfer et al. 1979), and fluoxetine [Kerkhofs et al. 1990) suppress SWS, whereas... 

Tricyclic antidepressants Amitriptyline Clomipramine Desipramine Doxepin Imipramine Trimipramine... 

HCA is the term is used to refer to both TCAs and analogues of these agents, such as maprotiline and amoxapine. TCAs are by far the most commonly used HCAs and include tertiary amines such as amitriptyline, doxepin, and imipramine and secondary amines such as desipramine and nortriptyline. Most secondary amines could also be viewed as NE-selective antidepressants, while the hallmark of tertiary amine TCAs is their effects on multiple neurotransmitters over their clinically relevant dosing range. 

Sedative antidepressants, such as amitriptyline, doxepin, or trazodone, in low doses, have hypnotic efficacy and may be less likely to evoke the adverse effects associated with higher doses. 

To manage withdrawal insomnia, we recommend the supplemental use of hypnotics such as zolpidem or a sedating antidepressant such as trazodone. Rickels et al. recommend the supplemental use of hypnotics such as diphenhydramine, doxylamine, or chloral hydrate or a sedating TCA such as doxepin ( 259). These investigators also recommend that chronic BZD users with evidence of depression or panic be treated with adequate doses of an appropriate antidepressant, a management technique that may help patients succeed in discontinuation. 

Tricyclic antidepressants (eg, amitriptyline, desipramine, doxepin, many others see Chapter 30) are among the most common prescription drugs involved in life-threatening drug overdose. Ingestion of more than 1 g of a tricyclic (or about 15-20 mg/kg) is considered potentially lethal. 

Plasma levels of doxepin similar to those achieved during oral therapy may be obtained with topical application the usual drug interactions associated with tricyclic antidepressants may occur. Therefore, monoamine oxidase inhibitors must be discontinued at least 2 weeks prior to the initiation of doxepin cream. Topical application of the cream should be performed four times daily for up to 8 days of therapy. The safety and efficacy of chronic dosing has not been established. Adverse local effects include marked burning and stinging of the treatment site which may necessitate discontinuation of the cream in some patients. Allergic contact dermatitis appears to be frequent, and patients should be monitored for symptoms of hypersensitivity. 

Antidepressants as analgesics are almost a closed book as far as preclinical and clinical development is concerned. TCAs are an old drug class, and because of the rather problematic side-effect profile, interest in developing new drugs from this class is small. BL-1834 (Bioglan Lab.) is an intranasal formulation of doxepine that is in clinical development (phase II) for the treatment of severe pain. In patents on novel monoamine reuptake inhibitors, pain is usually claimed as a possible indication, but depression and anxiety are mentioned as the primary indications in most cases, and we are not aware of novel... 

Several antidepressants share the ability to block serotonin 2A receptors as well as serotonin reuptake. In fact, some of the tricyclic antidepressants, such as amitriptyline, nortriptyline, doxepine, and especially amoxapine, have this combination of actions at the serotonin synapse. Since the potency of blockade of serotonin 2A receptors varies considerably among the tricyclics, it is not clear how important this action is to the therapeutic actions of tricyclic antidepressants in general. 

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