DOXEPIN

Absorption

Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%. The median peak concentration of doxepin ranges from 8.8-45.8 ng/ml and it is achieved 3.5 hours after initial administration. Its absorption is increased with concomitant administration of a high-fat meal.

Toxicity

Oral LD50 values of doxepin in mouse and rat are 180 mg/kg and 147 mg/kg, respectively. In an overdose state, symptoms of convulsions, dysrhythmias, coma, severe hypotension, central nervous system depression, changes on electrocardiography results and death have been observed.
On fertility studies, doxepin was shown to increase the copulatory interval, decrease the corpora lutea, decrease implantation, decreased the number of viable embryos, decrease litter size, increase the number of abnormal sperm and decrease the sperm motility. There is no evidence indicating carcinogenic and mutagenic potential.

Originator

Sinequan,Pfizer,US,1969

The Uses of DOXEPIN

Used clinically to treat anxiety and depression. Antidepressant

Background

Doxepin is a psychotropic agent with antidepressant and anxiolytic properties. It is a tertiary amine that can be presented as (E) and (Z) stereoisomers with the (Z) stereoisomer corresponding to cidoxepin. Doxepin commonly produces a 5:1 (E):(Z) racemic mixture.
In a strict sense, doxepin is not a tricyclic antidepressant but it is commonly associated with the class since it shares a lot of properties with members of the drug family including amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, protriptyline and trimipramine.
Doxepin was developed by Pfizer and FDA approved in 1969 as an antidepressant. However, in 2010 it was approved for the treatment of insomnia. The latter indication was presented by Pernix Therapeutics.

Indications

Oral doxepin is approved for the following indications:
Topical doxepin is also approved for short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis, pruritus or lichen simplex chronicus.
Off-label, doxepin is used topically for the management of neuropathic pain.
Depression is a common medical illness that causes feelings of sadness and or loss of interest in prior enjoyable activities. This condition can lead to emotional and physical disturbances that can decrease the ability of a person to function in a regular environment.
Anxiety is a normal reaction of the body towards a normal danger. When the anxious state is exacerbated or appears on situations without danger, it is defined as an anxiety disorder. This disorders can appear in different forms such as phobias, panic, obsessive-compulsive disorder and post-traumatic stress disorder.
Insomnia is a sleep disorder that directly affects the quality of life of the individual. It is characterized by the complication either to fall asleep or to stay asleep. This condition can be occasional or chronic.
Pruritus is defined as an unpleasant skin reaction that provokes the urge to scratch. It can be localized or generalized and it can appear in an acute or chronic manner.
Neuropathic pain occurs due to the damage or dysfunction of the peripheral or central nervous system rather than stimulation of the pain receptors.

Definition

ChEBI: A dibenzooxepine that is 6,11-dihydrodibenzo[b,e]oxepine substituted by a 3-(dimethylamino)propylidene group at position 11. It is used as an antidepressant drug.

Manufacturing Process

(A) Preparation of 3-bromopropyltriphenylphosphonium bromide: Triphenylphosphine, 1.0 kg, and 770 grams of 1,3-dibromopropane are dissolved in 2.0 liters of xylene and the solution is stirred under a nitrogen atmosphere at 130°C. After 20 hours the mixture is cooled, and the crystalline product, which precipitates, is collected and washed with 20 liters of benzene. After drying in vacuo the product weighs 1,578 grams, MP 229°-230°C;titration for bromide ion: Found, 17.1%; calculated, 17.2%.
(B) Preparation of 3-dimethylaminopropyltriphenylphosphonium bromide hydrobromide: A solution of 595 grams of anhydrous dimethylamine and 1,358 grams of 3-bromopropyl-triphenylphosphonium bromide in 4 liters of ethanol is warmed to 70°C until solution is complete and the solution then is allowed to stand at room temperature for 20 hours. Volatile components are removed by distillation in a vacuum and the residue is suspended in 2.0 liters of ethanol and is redistilled to remove excess amine. The residue is dissolved in 3.0 liters of warm ethanol and gaseous hydrogen bromide is passed into the solution until the mixture is acidic. After filtration the solution is concentrated to a volume of 3.0 liters, is cooled, whereupon the product precipitates, and the precipitate is collected; it weighs 1,265 grams, MP 274- 281°C. Recrystallization from ethanol raises the MP to 280.5°-282.5°C. Bromide ion titration: Found, 31.2%; calculated 31.3%.
(C) Preparation of doxepin: 1,530 grams of the product from step (B) is suspended in 4.5 liters dry tetrahydrofuran and 6.0 mols of butyl lithium in heptane is added during 1 hour. After an additional 30 minutes, 483 grams of 6,11-dihydrodibenz-(b,e)oxepin-11-one, prepared as described in Belgian Patent 641,498, is added to the deep red solution and the reaction was maintained at reflux for 10 hours. Water, 500 ml, is added at room temperature and the solvent is removed in vacuo. The crude residue is treated with 10% hydrochloric acid until acidic (pH 2) and then 1.5 liters benzene is added. After stirring, the mixture separates into 3 phases (an insoluble hydrochloride salt product phase, an aqueous phase and an organic phase).
The benzene layer is removed by decantation and the remaining mixture is rendered basic with 10% sodium hydroxide solution and is extracted with three 1,500 ml portions of benzene. The benzene extracts are washed, then dried with anhydrous sodium sulfate and concentrated in a vacuum leaving a residue of 1,530 grams, gas and thin layer chromatography analysis show this to be a cis/trans mixture (approx. 4:l) of 11-dimethylaminopropylidene-6,11- dihydrodibenz-(b,e)oxepin (90% yield). This mixture has substantially more activity pharmacologically than the cis/trans mixture obtained by the Grignard route disclosed in the Belgian Patent 641,498. This base is then converted to the hydrochloride with HCl.

brand name

Apo-doxepin;Co dox;Deptran;Doksapan;Dolat;Doxal;Doxedyn;Doxepin hcl;Gilex;Novo-doxepin;Novoxapin;Sinequan;Sinquan concentrate;Sinquane;Tolllluan;Triadapin;Zonalon.

Therapeutic Function

Tranquilizer

World Health Organization (WHO)

Doxepin, a tricyclic antidepressant was introduced in 1964 for the management of endogenous depression. Much of the adverse effects are caused by its antimuscarinic actions. These include dry mouth, cardiac arrhythmias, central nervous system disturbances, blood disorders and risk of suicide. The risk of suicide and dangers related to overdosage led the Norwegian Medicines Control Authority to put the higher strength formulation under prescribing restriction in 1992. The risk of death following overdosage is apparently higher for products containing tricyclic compounds as compared with nontricyclic products.

Biological Activity

Highly potent H 1 histamine receptor antagonist (K d = 310 pM) and tricyclic antidepressant. Also binds to the H 4 histamine receptor (pK i = 6.79).

Contact allergens

This benzoxepin tricylcic drug has antidepressant, anticholinergic, antiitching, and antihistamine properties. After oral use, it has been developed as a topical antiitching agent. Allergic contact dermatitis is not infrequent.

Pharmacokinetics

Similar to other tricyclic antidepressants, doxepin was shown, in preclinical trials, to decrease the electrical activity of the brain, prolong the hexobarbital-induced sleep and block avoidance behavior without affecting the conditioned emotional response. At high doses, it also produces symptoms of central nervous system depression.
Doxepin is known to cause antidepressant, sedative, and anticholinergic effects. At high doses, its anticholinergic and antiadrenergic properties are the most prevalent which limit its efficacy. These effects are observed at high doses where its affinity for H1 histamine receptor is lost and its binding to other receptors is observed.
The maximal antidepressive effects of doxepin are present around two weeks following initiation of therapy. However, the sedative effects of doxepin, usually used for the treatment of insomnia or anxiety, are observed immediately after administration.

Metabolism

Doxepin is extensively metabolized to N-desmethyldoxepin which is a biologically active metabolite and other inactive metabolites. The first-pass metabolism accounts for 55-87% of the administered dose. After, the secondary metabolism is driven by the transformation of N-desmethyldoxepin to its glucuronide conjugates.
The main metabolic enzymes involved in the transformation of doxepin are the members of the cytochrome P450 family, CYP2C19 and CYP2D6 with minor involvement of CYP1A2 and CYP2C9.