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HomeProduct name listDOXEPIN

DOXEPIN

  • Empirical Formula: C19H21NO
  • Molecular Weight: 0
  • MDL number: MFCD00837217
  • Update Date: 2023-04-26 16:55:04
DOXEPIN Structural

What is DOXEPIN?

The Uses of DOXEPIN

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.

Clinical Use

Tricyclic antidepressant

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.

Synthesis

Doxepin, (11[16H]-(3-dimethylaminopropyliden)-6,11-dihydrobenz[b,e] oxepine) (7.1.11), is synthesized in an analogous manner by reacting 6,11-dihydrodibenz-[b,e]oxepin- 11-one (7.1.9) with 3-dimethylaminopropylmagnesium bromide and the subsequent dehydration of the resulting tertiary alcohol (7.1.10) by hydrochloric acid [14–17].


The initial 6,11-dihydrodibenz[b,e]oxepin-11-one (7.1.9) is synthesized from the ethyl ester of 2-phenoxymethyl benzoic acid (7.1.7), which is easily synthesized by reacting ethyl 2-bromomethylbenzoate with phenol in the presence of a base. The resulting ester (7.1.5) is hydrolyzed into 2-phenoxymethylbenzoic acid (7.1.8), which is cyclized to 6,11- dihydrodibenz[b,e]oxepin-11-one (7.1.9) by trifluoroacetic acid anhydride.

Drug interactions

Potentially hazardous interactions with other drugs
Analgesics: increased risk of CNS toxicity with tramadol; possibly increased risk of side effects with nefopam; possibly increased sedative effects with opioids
Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone - avoid; increased risk of ventricular arrhythmias with disopyramide, flecainide or propafenone; avoid with dronedarone.
Antibacterials: increased risk of ventricular arrhythmias with moxifloxacin and possibly delamanid and telithromycin - avoid with moxifloxacin
Anticoagulants: may alter anticoagulant effect of coumarins.
Antidepressants: enhanced CNS excitation and hypertension with MAOIs and moclobemide - avoid; concentration possibly increased with SSRIs; risk of ventricular arrhythmias with citalopram and escitalopram - avoid; possible increased risk of convulsions with vortioxetine.
Antiepileptics: convulsive threshold lowered; concentration reduced by carbamazepine, phenobarbital and possibly fosphenytoin, phenytoin and primidone
Antimalarials: avoid with artemether/lumefantrine and piperaquine with artenimol.
Antipsychotics: increased risk of ventricular arrhythmias especially with droperidol, fluphenazine, haloperidol, pimozide, risperidone, sulpiride and zuclopenthixol - avoid; increased antimuscarinic effects with clozapine and phenothiazines; concentration increased by antipsychotics.
Antivirals: increased risk of ventricular arrhythmias with saquinavir - avoid; concentration possibly increased with ritonavir
Atomoxetine: increased risk of ventricular arrhythmias and possibly convulsions
Beta-blockers: increased risk of ventricular arrhythmias with sotalol.
Clonidine: tricyclics antagonise hypotensive effect; increased risk of hypertension on clonidine withdrawal.
Dapoxetine: possible increased risk of serotonergic effects - avoid.
Dopaminergics: avoid use with entacapone; CNS toxicity reported with selegiline and rasagiline.
Pentamidine: increased risk of ventricular arrhythmias.
Sympathomimetics: increased risk of hypertension and arrhythmias with adrenaline and noradrenaline; metabolism possibly inhibited by methylphenidate.

Metabolism

Approximately 55-87% of doxepin undergoes first pass metabolism in the liver, forming the primary active metabolite desmethyldoxepin.
Doxepin is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form.

Dosage forms

Tablets: 10 mg PO q.i.d., may increase dose as tolerated. Zonalon cream: apply to affected areas t.i.d. to q.i.d. up to 8 days.

Properties of DOXEPIN

pka pKa 8.0 (Uncertain)

Safety information for DOXEPIN

Computed Descriptors for DOXEPIN

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