Doxepin action

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. 

The mechanism of action of doxepin is presumable linked to the effect on the adrenergic transmission in the CNS, in particular to the blockage of neuronal norepinephrine uptake. Doxepin is used in anxious-depressive and anxious conditions, neuroses, alcoholism, organic illnesses of the CNS, and psychoses. The most frequently used synonyms are adapin and sinequan. 

Short-term Rx pruritus (atopic dermatitis or lichen simplex chronicus) Action Antipruritic Hi- H2-receptor antagonism Dose Apply thin coating qid, 8 d max Caution [C, /-] Contra Component sensitivity Disp Cream SE X BP, tach, drowsiness EMS Widespread use can lead to systemic absorption see Doxepin, earlier OD Unlikely... 

Topical doxepin hydrochloride 5% cream (Zonalon) may provide significant antipruritic activity when utilized in the treatment of pruritus associated with atopic dermatitis or lichen simplex chronicus. The precise mechanism of action is... 

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. 

Topical doxepin hydrochloride 5% cream (Zonalon) may provide significant antipruritic activity when utilized in the treatment of pruritus associated with atopic dermatitis or lichen simplex chronicus. The precise mechanism of action is unknown but may relate to the potent Hi and H2-receptor antagonist properties of dibenzoxepin tricyclic compounds. Percutaneous absorption is variable and may result in significant drowsiness in some patients. In view of the anticholinergic effect of doxepin, topical use is contraindicated in patients with untreated narrow-angle glaucoma or a tendency to urinary retention. 

Mattila MJ, Anyos K, Puisto EL. 1986. Cardiotoxic actions of doxepin and barium chloride in conscious rabbits. Arch Toxicol, Suppl, Toxic Interfaces Neurones, Smoke Genes 9 205-208. 

Inhibition of ejaculation was reported in a middle-aged man 1 week after he started taking trazodone 100 mg at night (27). The symptoms abated 3 days after withdrawal and did not return when treatment was changed to dox-epin 50 mg/day. Because trazodone has relatively more alpha-adrenoceptor blocking action and less anticholinergic activity than doxepin, the author speculated that this was the mechanism. 

The cardiac safety of nomlfensin was established by measurements of cardiac conduction in depressed patients receiving therapeutic doses over 3 weeks, and it was less toxic than doxepin or amitriptyline In Isolated hearts. 3 Nomlfensin Inhibited NA uptake in the same way as TCA but its principal actions may be on dopaminergic (DA) systems, both as an uptake inhibitor and as an agonist.5 The metabolites (, Ri=0H, R2=H 2c, Ri= OCH3, R2=0H Ri=0H, R2=OCH3) Inhibit the uptake of DA and 5-HT, but another potential metabolite, the catechol (2e, Rx=R2=0H) is a potent DA agonist in behavioral and neurochemical studies. 5 However, the beneficial effects of 7 in parkinsonism may be due to its improvement of depressive s3nnptoms. 6... 

Alternatively, one could group ConMeds into mechanism of action. If a drug is metabolized by cytochrome p450 (CYP), then one such grouping is by CYP isozyme, metabolic pathway or interaction. For example, doxepin is metabolized by CYP 2C19 to des-methyldoxepin. Meyer-Barner et al. (2002) classified concomitant medications into three groups substrates of CYP 3A4, CYP 2D6, CYP 2C19, CYP 2C9, CYP 2C8, CYP 1A2, CYP 2A6, CYP 2B6, CYP 1A1 and CYP 1B1 inducers of CYP 2E1, CYP 3A4, CYP 3A1, CYP 3A2, CYP 1A2, and CYP 2B6 and inhibitors of... 

Because doxepin is administered as an 85 15 mixture of geometric isomers, its mechanism of action and antidepressant properties refiects this ratio. Therefore, dioxepin s seiectivity for inhibiting presynaptic NE reuptake is most iikeiy caused by the 85% presence of the E-isomer in the geometric mixture. Its antidepressant activity is similar to amitriptyline. Data suggest NE reuptake inhibitory potency comparable to imipramine and clomipramine the fact that doxepin is an 85 15 mixture of - and Z-geometric isomers clouds its true efficacy for SERT or NET. The formation of N-desmethyIdoxepin results in inhibition of NE reuptake with enhanced noradrenergic activity. As a result of these mixed effects on the 5-HT and NE transporters, doxepin shares the pharmacological and adverse-effect profile of the other TCAs. 

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