Doxepin

Structural formula
	cis -form (left) and trans -form (right)
General
Non-proprietary name	Doxepin
other names	3- (6 H -dibenzo [ b , e ] oxepin-11-ylidene) - N , N -dimethylpropan-1-amine; ( E ) -3- (Dibenzo [ b , e ] oxepin-11- (6 H ) -ylidene) - N , N -dimethylpropan-1-amine; ( Z ) -3- (Dibenzo [ b , e ] oxepin-11- (6 H ) -ylidene) - N , N -dimethylpropan-1-amine; trans -3- (Dibenzo [ b , e ] oxepin-11- (6 H ) -ylidene) - N , N -dimethylpropan-1-amine; cis -3- (dibenzo [ b , e ] oxepin-11- (6 H ) -ylidene) - N , N -dimethylpropan-1-amine;
Molecular formula	C 19 H 21 NO (doxepin) ; C 19 H 21 NO HCl (doxepin hydrochloride) ;
External identifiers / databases
PubChem	3158
ChemSpider	3046
DrugBank	DB01142
Wikidata	Q71704041
Drug information
ATC code	N06 AA12
Drug class	Antidepressants
properties
Molar mass	279.38 g mol −1 (doxepin) ; 315.84 g mol −1 ( doxepin hydrochloride) ;
Melting point	184–186 or 188–189 ° C (Doxepin hydrochloride) ; 192–193 ° C ( trans -Doxepin hydrochloride) ; 209–210.5 or 188–189 ° C ( cis -doxepin hydrochloride) ;
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances danger
H and P phrases	H: 301
	P: 301 + 310
Toxicological data	147 mg kg −1 ( LD 50 , rat , oral , doxepin) ; 16 mg kg −1 ( LD 50 , rat , iv , doxepin) ; 135 mg kg −1 ( LD 50 , mouse , oral , doxepin) ; 26 mg kg −1 ( LD 50 , mouse , iv , doxepin) ; 147 mg kg −1 ( LD 50 , rat , oral , hydrochloride) ; 13 mg kg −1 ( LD 50 , rat , iv , hydrochloride) ; 180 mg kg −1 ( LD 50 , mouse , oral , hydrochloride) ; 15 mg kg −1 ( LD 50 , mouse , iv , hydrochloride) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Doxepin is a drug belonging to the group of tricyclic antidepressants .

Chemical structure and isomerism

Doxepin is the hydrochloride used and is a cis , trans -Stoffgemisch from

approx. 85% ( E ) -3- (dibenzo [ b , e ] oxepin-11- (6 H ) -ylidene) - N , N -dimethylpropan-1-amine hydrochloride (synonym: trans -3- (dibenzo [ b , e ] oxepin-11- (6 H ) -ylidene) - N , N -dimethylpropan-1-amine · hydrochloride) and
approx. 15% ( Z ) -3- (dibenzo [ b , e ] oxepin-11- (6 H ) -ylidene) - N , N -dimethylpropan-1-amine hydrochloride (synonym: cis -3- (dibenzo [ b , e ] oxepin-11- (6 H ) -ylidene) - N , N -dimethylpropan-1-amine · hydrochloride).

properties

Doxepin has a strong depressant effect and is therefore often used for sedation in addition to lightening the mood .

effect

Doxepin acts in the CNS as an inhibitor of monoamine uptake from the synaptic cleft into the presynaptic vesicle , as well as anticholinergic , antihistaminic and adrenolytic (neutralizes the effect of adrenaline ). The increased availability of serotonin and noradrenaline for neuronal transmission due to the (unselective) inhibition of withdrawal leads to an alleviation of depressive symptoms .

The influencing of several transmitter systems by Doxepin produces its characteristic side effects, which largely correspond to those of the other tricyclic antidepressants .

The sedative effect often diminishes with prolonged use.

The desired lightening of mood only occurs after an intake period of two to three weeks.

The optimal maintenance dose is usually between 30 and 50 mg per day.

Indications

Doxepin is approved for the treatment of anxiety and depression in:

Anxiety neuroses (with or without somatic symptoms), reactive depression, depressive anxiety, alcoholism;
psychotic depression, including endogenous depression;
depressive phases of manic-depressive reactions;
Post partum depression and old age depression (involutional depression );

(Mild) withdrawal symptoms from alcohol, drug or drug addiction.

Patients with the following symptoms usually respond to treatment with Doxepin: internal tension, over-anxiety, restlessness, insomnia, functional somatic complaints, lack of interest, feelings of guilt, psychomotor retardation, hypochondria .

In addition to its use as an antidepressant, Doxepin is also used in addiction therapy, especially for opiate addicts.

unwanted effects

Like other tricyclic antidepressants, Doxepin mainly has anticholinergic side effects (dry mouth, hypotension and tachycardia , mydriasis and accommodation disorders , gastrointestinal problems and micturition disorders ).

It also carries special risks for the heart (conduction and cardiac arrhythmias with a prolonged QTc time in the ECG ), and changes in the blood count such as leukopenia or agranulocytosis can occur. Because of the strong anticholinergic component, pharmacogenic delirium occurs more frequently with Doxepin than with other tricyclics . The syndrome of inadequate ADH secretion SIADH also occurs rarely .

Interactions with UV light

The interaction of the UV component of natural sunlight or artificial UV sources ( solarium or UV therapy equipment) with the doxepin molecule can cause a phototoxic reaction at a UV dose that is normally easily tolerated. The symptoms correspond to those of acute dermatitis or acute sunburn with reddening, edema, blistering and scaling (the degree of severity depends on the UV dose, the doxepin dose and the skin type ) .

Interactions with alcohol

It should be remembered that there is a risk of intentional or unintentional overdose of Doxepin in patients with high alcohol consumption.

Use during pregnancy / breastfeeding

There is currently insufficient experience with the use of Doxepin during pregnancy. Data from 118 newborns exposed to doxepin during the first trimester of pregnancy suggest that the malformation rate may be increased. In animal studies, doxepin did not show any teratogenic effects, but impaired fertility was observed. Therefore, Doxepin may only be used if absolutely necessary and after a strict risk-benefit analysis.

Doxepin and its active metabolite are excreted in breast milk. One report has been made of apnea and drowsiness in an infant whose mother took doxepin. Because of its potential for side effects in infants, breastfeeding is not recommended during doxepin therapy.

Pharmacokinetics

Absorption : 2–4 hours after a single ingestion of 75 mg doxepin, peak serum values of 26.1 (8.8–47.4) ng / ml are achieved.

Distribution : The volume of distribution is 20.2 (9.1–33.3) l / kg. The protein binding for doxepin as well as for its metabolite desmethyldoxepin is around 76%.

Metabolism : The metabolism of doxepin includes demethylation, N -oxidation, hydroxylation and glucuronide formation. Doxepin is metabolized to a considerable extent in the liver ( first-pass effect : 55–87%) to form desmethyldoxepin, which is also effective; its mean peak serum values were 9.7 (4.8-14.5) ng / ml after 2-10 hours.

Elimination : The average half-life of unchanged doxepin is 17 (8–24) hours, the average plasma clearance 0.84 l / kg / hour. The half-life of desmethyldoxepine is 51 (33–80) hours. With 75 mg daily, steady-state levels are reached on day 9.

Genotoxic potential

For some tricyclic antidepressants including doxepin an increase in the risk of breast cancer is being discussed, although a number of reviews and meta-analyzes have not been able to confirm this hypothesis. According to the product information, Doxepin has not been adequately tested for mutagenic effects. Previous tests were negative. Long-term studies on animals for a tumorigenic potential are not available.

Dosage forms

In addition to tablets , coated tablets and other preparations for oral use, there is also a solution for injection .

Trade names

Monopreparations

Aponal (D), Doneurin (D), Sinequan (A, no longer on the market), Sinquan (CH), various generics (D)

Individual evidence

↑ ^a ^b ^c The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition. 2006, ISBN 0-911910-00-X , p. 581.

↑ ^a ^b Doxepin hydrochloride data sheet from Sigma-Aldrich , accessed on March 28, 2011 ( PDF ).

↑ ^a ^b ^c ^d ^e ^f ^g ^h A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications. 4th edition. (2000), Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9 .

↑ European Pharmacopoeia. 6th edition. Deutscher Apotheker Verlag, Stuttgart 2008, ISBN 978-3-7692-3962-1 , pp. 2390-2392.

↑ ^a ^b Aktories u. a .: General and special pharmacology and toxicology. 9th edition. P. 345 f.

↑ ^a ^b ^c ^d Specialist information from the Swiss Medicines Compendium: Sinquan; Status: June 2010.

↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, p. 512.

↑ CR Sharpe, JP Collet, E. Belzile, JA Hanley, JF Boivin: The effects of tricyclic antidepressants on breast cancer risk . (PDF; 94 kB). In: British Journal of Cancer . Volume 86, 2002, pp. 92-97, PMID 11857018 .

↑ DA Lawlor, P. Jüni, S. Ebrahim, M. Egger: Systematic review of the epidemiologic and trial evidence of an association between antidepressant medication and breast cancer. In: J Clin Epidemiol. 56 (2), Feb 2003, pp. 155-163, PMID 12654410 .

↑ S. Bahl, M. Cotterchio, N. Kreiger: Use of antidepressant medications and the possible association with breast cancer risk. A review. In: Psychother Psychosom. 72 (4), Jul-Aug 2003, pp. 185-194, PMID 12792123 .

^ PF Coogan: Review of the epidemiological literature on antidepressant use and breast cancer risk. In: Expert Rev Neurother . 6 (9), Sep 2006, pp. 1363-1374, PMID 17009923 .

↑ CS Eom, SM Park, KH Cho: Use of antidepressants and the risk of breast cancer: a meta-analysis. In: Breast Cancer Res Treat . 136, 2012, pp. 635-645, PMID 23139055 .

↑ Rote Liste Service GmbH (Ed.): Rote Liste 2017 - drug directory for Germany (including EU approvals and certain medical devices) , Rote Liste Service GmbH, Frankfurt / Main, 2017, edition 57, ISBN 978-3-946057-10 -9 , p. 1045.

[MerckIndex-1] The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition. 2006, ISBN 0-911910-00-X , p. 581.