Doxepin

Doxepin
Systematic (IUPAC) name
(E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine
Clinical data
Trade names Sinequan, Zonalon
AHFS/Drugs.com monograph
MedlinePlus a682390
Licence data US FDA:link
  • AU: C
  • US: B (No risk in non-human studies)
Oral, topical, intravenous, intramuscular[1]
Pharmacokinetic data
Protein binding 76%[2]
Metabolism Hepatic (CYP2D6, CYP2C19, CYP1A2,& CYP3A4 mediated)[3][4]
Half-life 8-24 hr (mean 17 hours); 31 hr for active metabolite, desmethyldoxepin[2]
Excretion Urine
Identifiers
1668-19-5 Yes
N06AA12
PubChem CID 3158
IUPHAR ligand 1225
DrugBank DB01142 Yes
ChemSpider 3046 Yes
UNII 5ASJ6HUZ7D Yes
KEGG D07875 Yes
ChEBI CHEBI:4710 Yes
ChEMBL CHEMBL101740 
Chemical data
Formula C19H21NO
279.376 g/mol
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Doxepin is a tricyclic antidepressant marketed worldwide.[1] Brand names of oral formulations include Deptran and Sinequan, and brand names of topical (cream) formulations include Prudoxin.

Medical uses

Doxepin is used to treat depression, anxiety disorders, pruritus, insomnia,[5] and as a second-line treatment of chronic idiopathic urticaria (hives).[1][6] Its oral formulations are FDA-approved for the treatment of depression, anxiety, and insomnia and its topical formulations are FDA-approved the short-term management (up to 8 days) of atopic dermatitis and lichen simplex chronicus.[7] Whereas in Australia and the UK, the only licensed indication(s) is/are in the treatment of major depression and of major depression and pruritus in eczema, respectively.[8][9]

Pregnancy and lactation

Its use in pregnant and lactating women is advised against, although the available preclinical (based on animal studies) evidence suggests it is unlikely to cause any deleterious effects on foetal development.[2] The lack of evidence from human studies, however, means it is currently impossible to rule out any risk to the foetus[2] and it is known to cross the placenta.[2] Doxepin is secreted in breast milk[1] and neonatal cases of respiratory depression in association with maternal doxepin use have been reported.[8]

Contraindications

Known contraindications include:[10]

Adverse effects

Overdose

Like other tricyclics (TCAs), doxepin is highly toxic in cases of overdose.[14] Mild symptoms include drowsiness, stupor, blurred vision, and excessive dryness of mouth. More serious adverse effects include respiratory depression, hypotension, coma, convulsions, cardiac arrhythmia, and tachycardia. Urinary retention, decreased gastrointestinal motility (paralytic ileus), hyperthermia (or hypothermia), hypertension, dilated pupils, and hyperactive reflexes are other possible symptoms of doxepin overdose.[2] Management of overdose is mostly supportive and symptomatic, and can include the administration of a gastric lavage so as to reduce absorption of the doxepin.[2] Supportive measures to prevent respiratory aspiration is also advisable.[2] Antiarrhythmic agents may an appropriate measure to treat cardiac arrhythmias resulting from doxepin overdose.[2] Slow intravenous administration of physostigmine may reverse some of the toxic effects of overdose such as anticholinergic effects.[2] Haemodialysis is not recommended due to the high degree of protein binding with doxepin.[2] ECG monitoring is recommended for several days after doxepin overdose due to the potential for cardiac conduction abnormalities.[2]

Interactions

It should not be used within 14 days of using a monoamine oxidase inhibitor such as phenelzine due to the potential for serotonin syndrome to develop.[10] Its use in those on CYP2D6 inhibitors such as fluoxetine or quinidine is recommended against due to the potential for its accumulation in the absence of full CYP2D6 catalytic activity.[10] Hepatic enzyme inducers such as carbamazepine, phenytoin, and barbiturates are advised against in patients receiving TCAs like doxepin due to the potential for problematically rapid metabolism of doxepin to occur in these individuals.[10] Sympathomimietic agents may have their effects potentiated by TCAs like doxepin.[10] Doxepin also may potentiate the adverse effects of anticholinergic agents such as benztropine, atropine and hyoscine (scopolamine).[10] Tolazamide, when used in conjunction with doxepin has been associated with a case of severe hypoglycaemia in a type II diabetic individual.[10] Cimetidine may influence the absorption of doxepin.[10] Alcohol may potentiate some of the CNS depressant effects of doxepin.[10] Antihypertensive agents may have their effects mitigated by doxepin.[10] Cotreatment with CNS depressants such as the benzodiazepines can cause additive CNS depression.[2] Cotreatment with thyroid hormones may also increase the potential for adverse reactions.[2]

Pharmacology

Doxepin is a reuptake inhibitor of serotonin and norepinephrine and acts as a antagonist of various serotonin, adrenergic, muscarinic, dopamine, and histamine receptors:[15]

Protein Ki [nM][15]
Serotonin transporter 68
Norepinephrine transporter 29.5
Dopamine transporter >10000
5-HT1A 276
5-HT2A 26
5-HT2C 8.8
5-HT6 136
α1 23.5
α2 1270
M1 38
M2 160
M3 52
M4 82
M5 75
D2 360
H1 0.24
H4 105.9
Pharmacokinetic parameter Value[2][10]
Vd 20 l/kg
Tmax 2–4 hours (mean 2.9 hours)
Cmax 8.8-45.8 ng/ml
Tmax for active metabolite 2–10 hours
Cmax for active metabolite 4.8-14.5 ng/ml (mean 9.7 ng/ml)
Protein binding 76%
t1/2 8–24 hours (mean 17 hours)
t1/2 for active metabolite 31 hours
Enzymes involved in the metabolism CYP2D6, CYP1A2, CYP3A4, CYP2C19
Metabolic pathways N-demethylation, N-oxidation, hydroxylation and glucuronidation


Synthesis

Doxepin synthesis:[16][17] U.S. Patent 3,420,851 DE 1232161

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "Doxepin Hydrochloride". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. 30 January 2013. Retrieved 3 December 2013.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 2.12 2.13 2.14 "Sinepin Capsules 25mg - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Marlborough Pharmaceuticals Ltd. 22 September 2011. Retrieved 3 December 2013.
  3. ↑ Product Information: ZONALON(R) cream, doxepin hcl cream. Doak Dermatologics, Fairfield, NJ, 2005.
  4. ↑ Product Information: SILENOR(R) oral tablets, doxepin oral tablets. Somaxon Pharmaceuticals, Inc., San Diego, CA, 2010.
  5. ↑ Hajak G; Rodenbeck A; Voderholzer U et al. (2001). "Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study". J Clin Psychiatry 62 (6): 453–63. doi:10.4088/JCP.v62n0609. PMID 11465523.
  6. ↑ "Doxepin". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  7. ↑ "PRUDOXIN (doxepin hydrochloride) cream [HEALTHPOINT, LTD]". DailyMed. HEALTHPOINT, LTD. August 2010. Retrieved 3 December 2013.
  8. ↑ 8.0 8.1 Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  9. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 "Deptran Doxepin (as hydrochloride)" (PDF). TGA eBusiness Services. Alphapharm Pty Ltd. 6 May 2013. Retrieved 3 December 2013.
  11. ↑ "Silenor (doxepin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 3 December 2013.
  12. ↑ Lippincot"nursing 2007 drug handbook" LWW press. 2007
  13. ↑ Gray, Shelly L.; Anderson, Melissa L. (January 26, 2015). "Cumulative Use of Strong Anticholinergics and Incident Dementia: A Prospective Cohort Study". JAMA Intern. Med. doi:10.1001/jamainternmed.2014.7663. Retrieved January 27, 2015.
  14. ↑ White, N; Litovitz, T; Clancy, C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type" (PDF). Journal of Medical Toxicology 4 (4): 238–250. doi:10.1007/BF03161207. PMC 3550116. PMID 19031375.
  15. ↑ 15.0 15.1 Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 20 October 2013.
  16. ↑ Stach, K.; Bickelhaupt, F. (1962). "Beitr�ge zur Entwicklung psychotroper Stoffe, 2. Mitt.: Basisch substituierte Dibenzo-oxepin-, Dibenzo-thiepin- und Dibenzo-cycloocten-Derivate". Monatshefte f�r Chemie 93 (4): 896. doi:10.1007/BF00904459.
  17. ↑ Bickelhaupt, F.; Stach, K.; Thiel, M. (1964). "Beitr�ge zur Entwicklung psychotroper Stoffe, 5. Mitt". Monatshefte f�r Chemie 95 (2): 485. doi:10.1007/BF00901313.