Doxepin

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Doxepin
Systematic (IUPAC) name
(E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine
Clinical data
Trade namesSinequan, Zonalon
AHFS/Drugs.commonograph
MedlinePlusa682390
Licence dataUS FDA:link
Pregnancy cat.C (AU)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
RoutesOral, topical, intravenous, intramuscular[1]
Pharmacokinetic data
Protein binding76%[2]
MetabolismHepatic (CYP2D6-, CYP2C19-, CYP1A2- & CYP3A4-mediated)[3][4]
Half-life8-24 hr (mean 17 hours); 31 hr for active metabolite, desmethyldoxepin[2]
ExcretionUrine
Identifiers
CAS number1668-19-5 YesY
ATC codeN06AA12
PubChemCID 3158
IUPHAR ligand1225
DrugBankDB01142
ChemSpider3046 YesY
UNII5ASJ6HUZ7D YesY
KEGGD07875 YesY
ChEBICHEBI:4710 YesY
ChEMBLCHEMBL101740 N
Chemical data
FormulaC19H21NO 
Mol. mass279.376 g/mol
 N (what is this?)  (verify)
 
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Doxepin
Systematic (IUPAC) name
(E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine
Clinical data
Trade namesSinequan, Zonalon
AHFS/Drugs.commonograph
MedlinePlusa682390
Licence dataUS FDA:link
Pregnancy cat.C (AU)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
RoutesOral, topical, intravenous, intramuscular[1]
Pharmacokinetic data
Protein binding76%[2]
MetabolismHepatic (CYP2D6-, CYP2C19-, CYP1A2- & CYP3A4-mediated)[3][4]
Half-life8-24 hr (mean 17 hours); 31 hr for active metabolite, desmethyldoxepin[2]
ExcretionUrine
Identifiers
CAS number1668-19-5 YesY
ATC codeN06AA12
PubChemCID 3158
IUPHAR ligand1225
DrugBankDB01142
ChemSpider3046 YesY
UNII5ASJ6HUZ7D YesY
KEGGD07875 YesY
ChEBICHEBI:4710 YesY
ChEMBLCHEMBL101740 N
Chemical data
FormulaC19H21NO 
Mol. mass279.376 g/mol
 N (what is this?)  (verify)

Doxepin (brand names of oral formulations include Deptran, Sinequan. Whereas brand names of topical (cream) formulations include Prudoxin) is a tricyclic antidepressant that is marketed worldwide, including Australia, Canada, New Zealand, South Africa, the United Kingdom and the United States of America.[1]

Medical uses[edit]

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[edit]

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

Adverse effects[edit]

Doxepin has been associated with a number of different adverse effects, including the following:[2][10][11][Note 1]

  • Nausea*
  • Dizziness*
  • Drowsiness*
  • Dry mouth*
  • Constipation*
  • Blurred vision*
  • Headache*
  • Urinary hesitancy*
  • Agitation*
  • Insomnia*
  • Sexual dysfunction*
  • Hypotension (low blood pressure)
  • Hypertension (high blood pressure)
  • Tachycardia (high heart rate)
  • Skin rash
  • Facial oedema
  • Photosensitisation
  • Urticaria (hives)
  • Pruritus (itching)
  • Indigestion
  • Bone fractures
  • Taste disturbances
  • Diarrhoea
  • Anorexia (weight loss)
  • Aphthous stomatitis (canker sores)
  • Gynaecomastia (swelling of the breasts in men)
  • Galactorrhoea (lactation that is unassociated with breast feeding or pregnancy)
  • Chills
  • Fatigue
  • Weakness
  • Flushing
  • Alopecia (hair loss)
  • Eosinohpilia
  • Blood dyscrasias (abnormalities in the cellular composition of blood)
  • Increased liver function tests
  • Hyperpyrexia (high fever ≥41.5°C)
  • Seizures
  • Confusion
  • Malaise
  • Increased appetite*
  • Changes in ECG parameters (e.g. QRS & PR interval)
  • Ataxia
  • Hallucinations
  • Paraesthesias
  • Nervousness
  • Numbness
  • Tinnitus
  • Hepatitis (liver swelling)
  • Exacerbation of asthma
  • Hepatic (liver) abnormalities
  • Urinary retention
  • Extrapyramidal symptoms
  • Testicular swelling
  • Hyperglycaemia (high blood sugar)
  • Hypoglycaemia (low blood sugar)
  • Hyponatraemia (low blood sodium)
  • Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
  • Closed-angle glaucoma

Contraindications[edit]

Known contraindications include:[10]

Interactions[edit]

It should not be used within fourteen 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]

Overdose[edit]

Like other TCAs doxepin is highly toxic in cases of overdose.[12] Mild symptoms include: drowsiness, stupor, blurred vision, excessive dryness of mouth. More serious adverse effects include: respiratory depression, hypotension, coma, convulsions, cardiac arrhythmias and tachycardias. Urinary retention, decreased gastrointestinal motility (paralytic ileus), hyperthermia (or hypothermia), hypertension, dilated pupils and hyperactive reflexes are other possible symptoms of doxepin overdose.[2] Mananagement of doxepin 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] Anti-arrhythmic 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 TCA 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]

Pharmacology[edit]

Doxepin inhibits the reuptake of serotonin and norepinephrine and acts as a antagonist at various serotonergic, adrenergic, musacrinic, dopaminergic and histaminergic receptors (see following table).[13]

ProteinKi [nM][13]
SERT68
NET29.5
DAT>10000
5-HT1A276
5-HT2A26
5-HT2C8.8
5-HT6136
α123.5
α21270
M138
M2160
M352
M482
M575
D2360
H10.24
H4105.9
Pharmacokinetic parameterValue[2][10]
Vd20 L/kg
Tmax2-4 hours (mean 2.9 hours)
Cmax8.8-45.8 ng/mL
Tmax for active metabolite2-10 hours
Cmax for active metabolite4.8-14.5 ng/mL (mean 9.7 ng/mL)
Protein binding76%
t1/28-24 hours (mean 17 hours)
t1/2 for active metabolite31 hours
Enzymes involved in the metabolismCYP2D6, CYP1A2, CYP3A4, CYP2C19
Metabolic pathwaysN-demethylation, N-oxidation, hydroxylation and glucuronidation


Notes[edit]

  1. ^ The incidence of these adverse effects is not totally known as the scarcity of well-designed clinical trials involving doxepin prohibits it. Side effects that are common (based on its pharmacology or the frequency of these side effects with related agents) appear with a * superscript whereas the side effects which are serious are in bold

See also[edit]

References[edit]

  1. ^ a b c d "Doxepin Hydrochloride". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. 30 January 2013. Retrieved 3 December 2013. 
  2. ^ a b c d e f g h i j k l m n o p "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. ^ a b Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 9780980579093.  edit
  9. ^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 9780857110848.  edit
  10. ^ a b c d e f g h i j k l "Deptran Doxepin (as hydrochloride)" (PDF). TGA eBusiness Services. Alphapharm Pty Ltd. 6 May 2013. Retrieved 3 December 2013. 
  11. ^ a b "Silenor (doxepin) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 3 December 2013. 
  12. ^ White, N; Litovitz, T; Clancy, C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type". Journal of Medical Toxicology 4 (4): 238–250. doi:10.1007/BF03161207. PMC 3550116. PMID 19031375.  edit
  13. ^ a b 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.