DOXEPIN

Uses

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.

Indications

The tricyclic tertiary amine doxepin (Zonalon, Prudox), a potent H1- and H2-receptor antagonist, is indicated for the short-term relief of pruritus associated with topical eczematous dermatitis. Systemic absorption occurs, and the drug may potentiate or alter the metabolism of a va-riety of other systemic agents. Drowsiness is the most common adverse side effect.

Mechanism of action

Because doxepin is administered as an 85:15 mixture of geometric isomers, its mechanism of action and antidepressant properties reflects this ratio. Therefore, dioxepin's selectivity for inhibiting presynaptic NE reuptake is most likely 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 E- and Z-geometric isomers clouds its true efficacy for SERT or NET . The formation of N-desmethyldoxepin 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.
After oral dosing, no significant difference was found between the bioavailability of the E- and Z-isomers. The plasma concentrations of the doxepin isomers remained roughly those of the administered drug, whereas the ratio for the metabolites, E-N-desmethyldoxepin and Z-N-desmethyldoxepin, were approximately 1:1. This similarity in ratios of metabolites is attributed to E-doxepine being primarily metabolized in parallel by CYP2D6 and CYP2C19, whereas Z-doxepine is primarily metabolized only by CYP2C19 and not at all by CYP2D6. Its Z-N-demethylated metabolite is pharmacologically more active than its E-metabolite as an inhibitor of 5-HT and NE reuptake. Both isomers of doxepin showed large volumes of distribution and relatively short half-lives in plasma, suggestive of extensive distribution and/or tissue binding. Renal clearances did not differ for the isomers.

Side effects

Doxepin (Sinequan, Zonalon) is a combined H1 and H2 receptor antagonist. It is also a tricyclic antidepressant with antianxiolytic effects. Adverse side effects include sedation and anticholinergic symptoms, in addition to tachycardia, hypotension, and prolongation of the PR and QRS intervals on electrocardiogram. Side effects are usually mild and may include burning, stinging, drowsiness, and dry mouth. The incidence of side effects increases when applied to more than 10% of the body surface area or when duration of therapy exceeds 8 days. Cases of acute contact dermatitis to topical Zonalon have been reported.

Raw materials

Preparation Products