Doxepin

Doxepin
Clinical data
Trade names Sinequan, Silenor, others
AHFS/Drugs.com Monograph
MedlinePlus a682390
License data
Pregnancy
category
  • AU: C
  • US: B (No risk in non-human studies)
Routes of
administration		 Oral, topical, intravenous, intramuscular[1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 29%[2]
Protein binding 76%[3]
Metabolism Hepatic (CYP2D6, CYP2C19, CYP1A2, CYP3A4)[4]
Metabolites Nordoxepin, glucuronide conjugates[4]
Biological half-life 8–24 hours (mean 17 hours); 31 hours for nordoxepin[3]
Excretion Urine[4]
Identifiers
Synonyms NSC-108160[5]
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C19H21NO
Molar mass 279.376 g/mol
3D model (JSmol)
 NYesY (what is this?)  (verify)

Doxepin, sold under the brand names Sinequan and Silenor among others, is an antidepressant and sleep aid medication used to treat depression and trouble sleeping.[1] It belongs to a class of antidepressants known as the tricyclic antidepressants (TCAs). It is believed to counteract depression by inhibiting the reuptake of serotonin and norepinephrine (via blocking their transporters), thereby increasing the concentrations of these neurotransmitters in the synapse and increasing the activity of their respective receptors. The drug also has antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities, which are thought to contribute largely to its side effects. At very low doses, it is a pure antihistamine and is used in the treatment of insomnia.[4]

Medical uses

Doxepin is used to treat depression, anxiety disorders, itchiness, trouble sleeping,[6] and as a second-line treatment of chronic idiopathic urticaria (hives).[1][7] 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.[8] Whereas in Australia and the United Kingdom, the only licensed indication(s) is/are in the treatment of major depression and pruritus in eczema, respectively.[9][10]

Contraindications

Known contraindications include:[11]

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.[3] The lack of evidence from human studies, however, means it is currently impossible to rule out any risk to the fetus[3] and it is known to cross the placenta.[3] Doxepin is secreted in breast milk[1] and neonatal cases of respiratory depression in association with maternal doxepin use have been reported.[9]

Adverse effects

Overdose

Like other TCAs, doxepin is highly toxic in cases of overdose.[15] 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.[3] 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.[3] Supportive measures to prevent respiratory aspiration is also advisable.[3] Antiarrhythmic agents may be an appropriate measure to treat cardiac arrhythmias resulting from doxepin overdose.[3] Slow intravenous administration of physostigmine may reverse some of the toxic effects of overdose such as anticholinergic effects.[3] Haemodialysis is not recommended due to the high degree of protein binding with doxepin.[3] ECG monitoring is recommended for several days after doxepin overdose due to the potential for cardiac conduction abnormalities.[3]

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.[11] 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.[11] 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.[11] Sympathomimetic agents may have their effects potentiated by TCAs like doxepin.[11] Doxepin also may potentiate the adverse effects of anticholinergic agents such as benztropine, atropine and hyoscine (scopolamine).[11] Tolazamide, when used in conjunction with doxepin has been associated with a case of severe hypoglycaemia in a type II diabetic individual.[11] Cimetidine may influence the absorption of doxepin.[11] Alcohol may potentiate some of the CNS depressant effects of doxepin.[11] Antihypertensive agents may have their effects mitigated by doxepin.[11] Cotreatment with CNS depressants such as the benzodiazepines can cause additive CNS depression.[3] Co-treatment with thyroid hormones may also increase the potential for adverse reactions.[3]

Pharmacology

Doxepin[16]
Site Ki (nM)
SERT 95
NET 58
DAT 4,600[17]
H1 0.78
H2 150[18][19]
H3 >10,000
H4 106[20]
α1b 12
α2a 1,100
α2b 28
α2c 96
5-HT1A 276[21]
5-HT2A 11
5-HT2C 200
5-HT6 136[20]
M1 18
M2 230
M3 25
M4 20
M5 5.6
D2 360[21]

Doxepin is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin–norepinephrine reuptake inhibitor (SNRI), and has additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities.[20] It is specifically an antagonist of the histamine H1 and H2 receptors, the serotonin 5-HT2A and 5-HT2C receptors, the α1-adrenergic receptor, and the muscarinic acetylcholine receptors (M1–M5).[20] Similarly to other TCAs, doxepin is also a potent blocker of voltage-gated sodium channels, and this action is thought to be involved in both its lethality in overdose[22] and its effectiveness as an analgesic (including in the treatment of neuropathic pain,[23] as a migraine prophylactic,[24] and as a local anesthetic).[25] The potencies of doxepin in terms of its receptor antagonism specifically are as follows:[25][26]

Antidepressant doses of doxepin are defined as 25 to 300 mg/day, although are typically above 75 mg/day.[27][28] Antihistamine doses, including for dermatological uses and as a sedative/hypnotic for insomnia, are considered to be 3 to 25 mg,[29][28] although higher doses between 25 and 50 mg and in some cases even up to 150 mg have been used to treat insomnia.[30] At low doses, below 25 mg, doxepin is a pure antihistamine.[27] At antidepressant doses of above 25 mg, doxepin has significant antiadrenergic, antiserotonergic, and anticholinergic effects, and these activities contribute to its side effects.[29][27][28]

A study reported the IC50 values of doxepin for human monoamine reuptake inhibition as 13 nM for norepinephrine, 210 nM for serotonin, and 4,600 nM for dopamine.[17]

As a hypnotic


TCAs and TeCAs[31]
Drug H1 mACh
Amitriptyline 1.1 18
Amoxapine 25 1,000
Clomipramine 31 37
Desipramine 110 196
Dosulepin[29] 4.0 38
Doxepin 0.24 83
Imipramine 11 91
Lofepramine[21] 360 67
Maprotiline 2.0 560
Mianserin 0.40 820
Mirtazapine 0.14 670
Nortriptyline 10 149
Protriptyline 25 25
Trimipramine 0.3 59
All values are Ki (nM)

Doxepin is a highly potent antihistamine, with this being its strongest activity.[26][27][32][4] In fact, doxepin has been said to be the most or one of the most potent H1 receptor antagonists available, with one study finding an in vitro Ki of 0.17 nM.[21] It is the most potent and selective H1 receptor antagonist of the TCAs (although the tetracyclic antidepressant (TeCA) mirtazapine is slightly more potent),[29][33][34] and other sedating antihistamines, for instance the over-the-counter diphenhydramine (Ki = 16 nM) and doxylamine (Ki = 42 nM), show far lower affinities for this receptor.[4] The affinity of doxepin for the H1 receptor is far greater than its affinity for other sites,[4] and 10- to 100-fold higher doses are needed for antidepressant effects.[35][32] In accordance, although it is often described as a "dirty drug" due to its highly promiscuous binding profile,[32] doxepin acts as a highly selective antagonist of the H1 receptor at very low doses (less than 10 mg; typically 3 to 6 mg).[27][4][28] At these doses, it notably has no clinically relevant anticholinergic effects such as dry mouth or cognitive/memory impairment, unlike most other sedating antihistamines, and similarly has no effect on other receptors such as adrenergic and serotonin receptors.[27][4][28]

The H1 receptor antagonism of doxepin is responsible for its hypnotic effects and its effectiveness in the treatment of insomnia at low doses.[4][32] The incidence of side effects with doxepin and its safety at these doses was similar to that of placebo in clinical trials; the most frequent side effects were headache and somnolence/sedation, both with an incidence of less than 5%.[27][4] Other side effects sometimes associated with antihistamines, including daytime sedation, increased appetite, and weight gain, all were not observed.[32] Clinical evidence of H1 receptor antagonists and TCAs for the treatment insomnia shows mixed effectiveness and is limited in its quality due to weaknesses like small sample sizes and poor generalizability.[28][36] However, doxepin is a unique and notable exception; it has been well-studied in the treatment of insomnia and shows consistent benefits with excellent tolerability and safety.[28][36] Aside from diphenhydramine and doxylamine, which have historical approval as hypnotics, doxepin is the only H1 receptor antagonist that is specifically approved for the treatment of insomnia in the United States.[36][37]

The effect sizes of very-low-dose doxepin in the treatment of insomnia range from small to medium.[28] These include subjective and objective measures of sleep maintenance, sleep duration, and sleep efficiency.[28] Conversely, very-low-dose doxepin shows relatively weak effects on sleep initiation and does not significantly separate from placebo on this measure.[28] This is in contrast to benzodiazepines and nonbenzodiazepine (Z-drug) hypnotics, which are additionally effective in improving sleep onset latency.[28] However, it is also in contrast to higher doses of doxepin (50 to 300 mg/day), which have been found to significantly reduce latency to sleep onset.[28] A positive dose–response relationship on sleep measures was observed for doses of doxepin between 1 and 6 mg in clinical studies, whereas the incidence of adverse effects remained constant across this dose range in both young and and older adults.[28] However, the incidence of adverse effects appeared to increase with longer treatment duration.[28] A dose of doxepin as low as 1 mg/day was found to significantly improve most of the assessed sleep measures, but unlike the 3 and 6 mg/day doses, was not able to improve wake time during sleep.[28] This, along with greater effect sizes with the higher doses, was likely the basis for the approval of the 3 and 6 mg doses of doxepin for insomnia and not the 1 mg dose.[28]

At very low doses, doxepin has not shown discontinuation or withdrawal effects nor rebound insomnia.[4] Sustained effectiveness without apparent tolerance was demonstrated in clinical studies of up to 12 weeks duration.[36] This appears to be in contrast to over-the-counter antihistamines like diphenhydramine and doxylamine and all other first-generation antihistamines, which are associated with rapid development of tolerance and dependence (by day 3 or 4 of continuous dosing) and loss of hypnotic effectiveness.[36] It is for this reason that, unlike doxepin, they are not recommended for the chronic management of insomnia and are advised for only short-term treatment (i.e., 1 week).[36] It is not entirely clear why doxepin and first-generation antihistamines are different in this regard, but it has been suggested that it may have to do with the lack of selectivity for the H1 receptor of the latter or with optimal doses.[32] Unlike very-low-dose doxepin, most first-generation antihistamines also have marked anticholinergic activity as well as associated side effects such as dry mouth, constipation, urinary retention, and confusion.[36] This is particularly true in older people, and antihistamines with concomitant anticholinergic effects are not recommended in adults over the age of 65.[36] Anticholinergic activity notably may interfere with the sleep-promoting effects of H1 receptor blockade.[16]

Antagonism of the H1, 5-HT2A, 5-HT2C, and α1-adrenergic receptors is thought to have sleep-promoting effects and to be responsible for the sedative effects of TCAs including those of doxepin.[38][39][40] Although doxepin is selective for the H1 receptor at doses lower than 25 mg, blockade of serotonin and adrenergic receptors may also be involved in the hypnotic effects of doxepin at higher doses.[38] However, in contrast to very low doses of doxepin, rebound insomnia and daytime sedation are significantly more frequent than placebo with moderate doses (25 to 50 mg/day) of the drug.[28] In addition, one study found that although such doses of doxepin improved sleep measures initially, most of the benefits were lost with chronic treatment (by 4 weeks).[28] Due to limited data however, more research on potential tolerance and withdrawal effects of moderate doses of doxepin is needed.[28] At these doses of doxepin, dry mouth, an anticholinergic effect, was common (71%), and other side effects such as headache (25%), increased appetite (21%), and dizziness (21%) were also frequently observed, although these adverse effects were notably not significantly more frequent than with placebo in the study in question.[28] In any case, taken together, higher doses of doxepin than very low doses are associated with an increased rate of side effects as well as apparent loss of hypnotic effectiveness with chronic treatment.[32]

Doxepin at a dose of 25 mg/day for 3 weeks has been found to decrease cortisol levels by 16% in adults with chronic insomnia and to increase melatonin production by 26% in healthy volunteers.[4] In individuals with neuroendocrine dysregulation in the form of nocturnal melatonin deficiency presumably due to chronic insomnia, very-low-dose doxepin was found to restore melatonin levels to near-normal values after 3 weeks of treatment.[25] These findings suggest that normalization of the hypothalamic–pituitary–adrenal axis and the circadian sleep–wake cycle may be involved in the beneficial effects of doxepin on sleep and insomnia.[4][25]

Pharmacokinetics

 Pharmacokinetics of doxepin[3][11]
Parameters Value
VD 20 L/kg
Tmax (doxepin) 2–4 hours (mean 2.9 hours)
Cmax (doxepin) 8.8–45.8 ng/mL
Tmax (nordoxepin) 2–10 hours
Cmax (nordoxepin) 4.8–14.5 ng/mL (mean 9.7 ng/mL)
Protein bound 76%
t1/2 (doxepin) 8–24 hours (mean 17 hours)
t1/2 (nordoxepin) 31 hours
Metabolic
enzymes 		CYP2D6, CYP1A2,
CYP3A4, CYP2C19
Metabolic
pathways 		N-demethylation, N-oxidation,
hydroxylation, and glucuronidation

Doxepin is well-absorbed from the gastrointestinal tract but between 55 and 87% undergoes first-pass metabolism in the liver,[4] resulting in a mean oral bioavailability of approximately 29%.[2] Following a single very low dose of 6 mg, peak plasma levels of doxepin are 0.854 ng/mL (3.06 nmol/L) at 3 hours without food and 0.951 ng/mL (3.40 nmol/L) at 6 hours with food.[4] Plasma concentrations of doxepin with higher doses are far greater, ranging between 50 to 250 ng/mL.[41] Area-under-curve levels of of the drug are increased significantly when it is taken with food.[4] It is widely distributed throughout the body and is approximately 80% plasma protein bound, specifically to albumin and α1-acid glycoprotein.[4][42]

Doxepin is extensively metabolized via oxidation and demethylation.[4] The major enzymes involved in its metabolism are the cytochrome P450 enzymes CYP2D6 and CYP2C19, with CYP1A2 and CYP2C9 also involved to a lesser extent.[4] The major metabolite of doxepin is nordoxepin (N-desmethyldoxepin), which is pharmacologically active similarly to doxepin.[4] Its formation is catalyzed mainly by CYP2C19.[43] Both doxepin and nordoxepin are transformed into glucuronide conjugates.[25][4] The terminal half-life of doxepin is about 15–18 hours, whereas that of nordoxepin is around 28–31 hours.[4][44] Up to 10% of Caucasian individuals show reduced metabolism of doxepin that can result in up to 8-fold elevated plasma concentrations of the drug compared to normal.[26][25]

Doxepin is eliminated primarily in the urine and predominantly in the form of glucuronide conjugates, with less than 3% of a dose excreted unchanged as doxepin or nordoxepin.[4]

Chemistry

Doxepin is a tricyclic compound, specifically a dibenzoxepin, and possesses three rings fused together in its chemical structure.[25] It is the only tricyclic medication with a dibenzoxepin ring system to have been marketed.[45] Doxepin is a mixture of (E) and (Z) stereoisomers (the latter being known as cidoxepin or cis-doxepin) and is used commercially in a ratio of approximately 85:15.[5][46] Its chemical name is (E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1-amine[25][47] and its free base form has a chemical formula of C19H21NO with a molecular weight of 279.376 g/mol.[47] The drug is used commercially almost exclusively as the hydrochloride salt; the free base has been used rarely.[5][48] The CAS Registry Number of the free base is 1668-19-5 and of the hydrochloride is 1229-29-4.[5][48]

History

Doxepin was discovered in Germany in 1963 and was introduced in the United States as an antidepressant in 1969.[25] It was subsequently approved at very low doses in the United States for the treatment of insomnia in 2010.[28][48]

Society and culture

Generic names

Doxepin is the generic name of the drug in English and German and its INN and BAN, while doxepin hydrochloride is its USAN, USP, BANM, and JAN.[5][48][49][50] Its generic name in Spanish and Italian and its DCIT are doxepina, in French and its DCF are doxépine, and in Latin is doxepinum.[50]

The cis or (Z) stereoisomer of doxepin is known as cidoxepin, and this is its INN while cidoxepin hydrochloride is its USAN.[5]

Brand names

Doxepin has been marketed as an antidepressant most commonly under the brand names Adapin, Curatin, and Sinequan.[5][48][49][50] It is approved specifically for the treatment of insomnia under the brand name Silenor in the United States and Canada.[4][50]

Research

Antihistamine

Cidoxepin is under development by Elorac, Inc. for the treatment of chronic urticaria (hives).[51] As of 2017, it is in phase II clinical trials for this indication.[51] The drug was also under investigation for the treatment of allergic rhinitis, atopic dermatitis, and contact dermatitis, but development for these indications was discontinued.[51]

References

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  2. 1 2 Yan JH, Hubbard JW, McKay G, Korchinski ED, Midha KK (2002). "Absolute bioavailability and stereoselective pharmacokinetics of doxepin". Xenobiotica. 32 (7): 615–23. PMID 12162857. doi:10.1080/00498250210131879.
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