General
Preferred name
DOXEPIN
Synonyms
Doxepin HCl ()
Novoxapin ()
Aponal ()
Toruan ()
DOXEPIN HYDROCHLORIDE ()
Sinequan ()
P-3693A ()
Sinepin ()
Zonalon ()
Adapin ()
Silenor ()
Xepin ()
Quitaxon ()
NSC-108160 ()
P&D ID
PD009782
CAS
1229-29-4
1668-19-5
Tags
natural product
drug
available
Approved by
FDA
First approval
1969
Drug Status
investigational
approved
Max Phase
Phase 4
Drug indication
Antidepressant
Structure
Probe scores
P&D probe-likeness score
[[ v.score ]]%
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
INDICATION Oral doxepin is approved for the following indications:; ; - Treatment of depression and/or anxiety.[A177163]; - Treatment of depression and/or anxiety associated with different conditions, including alcoholism, organic disease and manic-depressive disorders.[T249]; - Treatment of psychotic depressive disorders with associated anxiety.[T249]; - Treatment of involutional depression.[T249] ; - Treatment of manic-depressive disorder.[T249]; - Treatment of insomnia characterized by difficulties with sleep maintenance.[A177163]; ; Topical doxepin is also approved for short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis, pruritus or lichen simplex chronicus.[T249]; ; Off-label, doxepin is used topically for the management of neuropathic pain.[A177172]; ; Depression is a common medical illness that causes feelings of sadness and or loss of interest in prior enjoyable activities. This condition can lead to emotional and physical disturbances that can decrease the ability of a person to function in a regular environment.[L5980]; ; Anxiety is a normal reaction of the body towards a normal danger. When the anxious state is exacerbated or appears on situations without danger, it is defined as an anxiety disorder. This disorders can appear in different forms such as phobias, panic, obsessive-compulsive disorder and post-traumatic stress disorder.[L5983]; ; Insomnia is a sleep disorder that directly affects the quality of life of the individual. It is characterized by the complication either to fall asleep or to stay asleep. This condition can be occasional or chronic.[L5986]; ; Pruritus is defined as an unpleasant skin reaction that provokes the urge to scratch. It can be localized or generalized and it can appear in an acute or chronic manner.[L5989]; ; Neuropathic pain occurs due to the damage or dysfunction of the peripheral or central nervous system rather than stimulation of the pain receptors.[L5992]
MOA Doxepin exact mechanism of action is not very clear. However, doxepin is known to be a selective histamine H1 receptor blocker.[A177163] This effect on histamine receptors indicates effectiveness in skin conditions.[T249]; ; Breaking its function according to the different effect, doxepin's antidepressive action is primarily associated with the inhibition of the central nervous system biogenic amine reuptake; more specifically, norepinephrine and serotonin at synaptic nerve terminals. This effect increases the level of monoamines in the synaptic site which in order increases the activity at the post-synaptic neuron receptor sites.[T388] It has been suggested that doxepin also desensitizes both serotonin 1A receptors and beta-adrenergic receptors.[T249]; ; It is known that the lack of dopamine transporters in the frontal cortex and the transmission of dopamine in this region is largely inactivated by the effect of norepinephrine reuptake. Hence, doxepin action on the frontal cortex is suggested to increase dopamine neurotransmission in this area.[T249]
METABOLISM Doxepin is extensively metabolized to N-desmethyldoxepin which is a biologically active metabolite and other inactive metabolites.[A177172] The first-pass metabolism accounts for 55-87% of the administered dose.[A177196] After, the secondary metabolism is driven by the transformation of N-desmethyldoxepin to its glucuronide conjugates.[L5995]; ; The main metabolic enzymes involved in the transformation of doxepin are the members of the cytochrome P450 family, CYP2C19 and CYP2D6 with minor involvement of CYP1A2 and CYP2C9.[L5995]
HALF-LIFE The mean elimination half-life is reported to be of 15 hours.[T388]
ABSORPTION Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%.[T388] The median peak concentration of doxepin ranges from 8.8-45.8 ng/ml and it is achieved 3.5 hours after initial administration. Its absorption is increased with concomitant administration of a high-fat meal.[L5995]
TOXICITY Oral LD50 values of doxepin in mouse and rat are 180 mg/kg and 147 mg/kg, respectively.[MSDS] In an overdose state, symptoms of convulsions, dysrhythmias, coma, severe hypotension, central nervous system depression, changes on electrocardiography results and death have been observed.[T249]; ; On fertility studies, doxepin was shown to increase the copulatory interval, decrease the corpora lutea, decrease implantation, decreased the number of viable embryos, decrease litter size, increase the number of abnormal sperm and decrease the sperm motility. There is no evidence indicating carcinogenic and mutagenic potential.[FDA label]
ROE The elimination profile of doxepin is presented as biphasic.[A1945] It is excreted in the urine mainly in the form of glucuronide conjugates. Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin.[L1347];
PHARMACODYNAMICS Similar to other tricyclic antidepressants, doxepin was showed, in preclinical trials, to decrease the electrical activity of the brain, prolong the hexobarbital-induced sleep and block avoidance behavior without affecting the conditioned emotional response. At high doses, it also produces symptoms of central nervous system depression.[L5998]; ; Doxepin is known to present antidepressive, sedative and anticholinergic effects. At high doses, its anticholinergic and antiadrenergic properties are the most prevalent which limit its effect. These effects are observed at high doses where its affinity for H1 histamine receptor is lost and its binding to other receptors is observed.[A177163]; ; The maximal antidepressive effects of doxepin are present around two weeks following initiation of therapy.[T388] However, the sedative effects of doxepin, usually used for the treatment of insomnia or anxiety, are observed immediately after administration.[T249]
Cell lines
0
Organisms
1
Compound Sets
12
ChEMBL Approved Drugs
CHEMBL1628227
CHEMBL1628234
ChEMBL Drugs
CHEMBL1628227
CHEMBL1628234
DrugBank
DB01142
DrugBank Approved Drugs
DB01142
DrugCentral
956
DrugCentral Approved Drugs
956
DrugMatrix
Enamine BioReference Compounds
Ki Database
DOXEPIN
LSP-MoA library (Laboratory of Systems Pharmacology)
CHEMBL1628227
NPC Screening Collection
TargetMol Bioactive Compound Library
T1540
External IDs
35
Properties
(calculated by RDKit )
Molecular Weight
279.16
Hydrogen Bond Acceptors
2
Hydrogen Bond Donors
0
Rotatable Bonds
3
Ring Count
3
Aromatic Ring Count
2
cLogP
3.96
TPSA
12.47
Fraction CSP3
0.26
Chiral centers
0.0
Largest ring
7.0
QED
0.84
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Pathway
Neuroscience
GPCR/G protein
Target
5-HT
HT
Sert (Sodium-dependent)
mAChR
Adrenergic Receptor
dopamine
Noradrenaline transporter (Sodium-dependent)
MOA
Norepinephrine antagonist
Source data