Doxepin

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Doxepin
Doxepin2DACS.svg
Doxepin3Dan.gif
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
Pregnancy
category
  • AU: C
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration		 Oral, topical, intravenous, intramuscular[1]
Pharmacokinetic data
Protein binding 76%[2]
Metabolism Hepatic (CYP2D6, CYP2C19, CYP1A2,& CYP3A4 mediated)[3][4]
Biological half-life 8-24 hr (mean 17 hours); 31 hr for active metabolite, desmethyldoxepin[2]
Excretion Urine
Identifiers
CAS Number 1668-19-5 YesY
ATC code N06AA12 (WHO)
PubChem CID: 3158
IUPHAR/BPS 1225
DrugBank DB01142 YesY
ChemSpider 3046 YesY
UNII 5ASJ6HUZ7D YesY
KEGG D07875 YesY
ChEBI CHEBI:4710 YesY
ChEMBL CHEMBL101740 N
Chemical data
Formula C19H21NO
Molecular mass 279.376 g/mol
  • CN(C)CC/C=C1C2=C(C=CC=C2)OCC3=C/1C=CC=C3
  • InChI=1S/C19H21NO/c1-20(2)13-7-11-17-16-9-4-3-8-15(16)14-21-19-12-6-5-10-18(17)19/h3-6,8-12H,7,13-14H2,1-2H3 YesY
  • Key:ODQWQRRAPPTVAG-UHFFFAOYSA-N YesY
 NYesY (what is this?)  (verify)

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 fetal development.[2] The lack of evidence from human studies, however, means it is currently impossible to rule out any risk to the fetus[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]

  • Hypersensitivities to other tricyclic antidepressants, doxepin, or any of the excipients inside the product used
  • Glaucoma
  • A predisposition to developing urinary retention such as prostatic hypertrophy
  • Poor metabolisers, those with a reduced biochemical activity of their CYP2D6 enzyme
  • Hyperthyroidism may increase the potential for adverse effects such as hypertension and tachycardia.[11]
  • Respiratory impairments
  • Brain tumours

Adverse effects

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See also: List of adverse effects of doxepin
  • Central nervous system: fatigue, dizziness, drowsiness, lightheadedness, confusion, nightmares, agitation, increased anxiety, insomnia, seizures (infrequently), delirium, rarely induction of hypomania and schizophrenia (stop medication immediately), extrapyramidal side effects (rarely), abuse in patients with polytoxicomania (rarely), tinnitus
  • Anticholinergic: dry mouth, constipation, even ileus (rarely), difficulties in urinating, sweating, precepitation of glaucoma
  • Antiadrenergic: hypotension, postural collapse (if patient arises too fast from lying/sitting position to standing), arrhythmias (sinus-tachycardia, bradycardia, AV-blockade)
  • Allergic/toxic: skin rash, photosensitivity, liver damage of the cholostatic type (rarely), hepatitis (extremely rare), leuko- or thrombopenia (rarely), agranulocytosis (very rarely), hypoplastic anemia (rarely)
  • Others: frequently increased appetite, weight gain, rarely nausea, frequently impaired sexual function in men (impotence, ejaculation-difficulties), rarely hypertension, rarely polyneuropathy, in both sexes breast-enlargement and galactorrhea (rarely)
  • May increase or decrease liver function in some patients.[12]
  • A large study linked the development of Alzheimer's disease and other forms of dementia to the use of doxepin, due to its anticholinergic properties.[13]

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 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 Lua error in package.lua at line 80: module 'strict' not found.
  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. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ 8.0 8.1 Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lippincot"nursing 2007 drug handbook" LWW press. 2007
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ 15.0 15.1 Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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