A medication used to treat major depressive disorder, anxiety disorders, chronic hives, and sleeping difficulties.
A reuptake inhibitor of serotonin and norepinephrine, or a serotonin–norepinephrine reuptake inhibitor (SNRI), and has additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities.
It is 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).
Often prescribed as an effective alternative to SSRI medications.
For hives it is a less pref2242ed option to antihistamines.
For insomnia problems it has a mild to moderate benefit.
Doxepin cream is used for itchiness due to atopic dermatitis or lichen simplex chronicus.
Sinequan is trade name.
Pregnancy category US: B (No risk in non-human studies)
Routes of administration mouth, topical, intravenous, and intramuscular injection.
A Tricyclic antidepressant (TCA).
Bioavailability 13–45%.
Protein binding 76%.
Metabolism is hepatic CYP2D6, CYP2C19 enzymes,
Elimination half-life 8–24 hours.
Nordoxepin metabolite 31 hours.
Excretion Urine: ~50%.
Feces: minor excretion.
Side effects include: sleepiness, dry mouth, constipation, nausea, and blurry vision.
Serious side effects may include suicide in those under the age of 25, mania, and urinary retention.
A withdrawal syndrome may occur.
It’s use is not recommended during pregnancy and breastfeeding.
It is unclear how it works for treating depression.
It is used to treat major depressive disorder, anxiety disorders, and chronic hives, and for short-term help with trouble remaining asleep.
In the form of a cream it is used for short term treatment of itchiness to due atopic dermatitis or lichen simplex chronicus.
Known contraindications include:
Glaucoma
A predisposition to developing urinary retention such as in benign prostatic hyperplasia
Use of monoamine oxidase inhibitors in last 14 days.
Pregnancy and lactation: use in pregnant and lactating women is advised against, although the available evidence suggests it is unlikely to cause negative effects on fetal development.
It is secreted in breast milk and neonatal cases of respiratory depression in association with maternal doxepin use have been reported.
Side effects:
Central nervous system: fatigue, dizziness, drowsiness, lightheadedness, confusion, nightmares, agitation, increased anxiety, difficulty sleeping, seizures, delirium, rarely induction of hypomania and schizophrenia, extrapyramidal side effects, and tinnitus.
Anticholinergic: dry mouth, constipation, ileus, difficulties in urinating, sweating, precipitation of glaucoma.
Antiadrenergic: Low blood pressure, with orthostatic hypotension, abnormal heart rhythms.
Allergic/toxic: rarely, skin rash, photosensitivity, liver damage of the cholestatic type, hepatitis, leuko- or thrombocytopenia, agranulocytosis, hypoplastic anemia.
Frequently associated with increased appetite and weight gain, rarely nausea, and rarely high blood pressure.
Doxepin, like other TCAs is highly toxic with overdose.
Mild symptoms of overdose include.: drowsiness, stupor, blurred vision, and excessive dryness of mouth, while more serious adverse effects include respiratory depression, hypotension, coma, convulsions, cardiac arrhythmia, and tachycardia, urinary retention, decreased gastrointestinal motility, hyperthermia, hypertension, dilated pupils, and hyperactive reflexes.
Management of overdose is mostly supportive and symptomatic.
The drug should not be used within 14 days of using a monoamine oxidase inhibitor (MAOI) due to the potential for hypertensive crisis or serotonin syndrome to develop.
In the presence of potent CYP2D6 inhibitors such as fluoxetine, paroxetine, sertraline, duloxetine, bupropion, and quinidine there is potential for its accumulation in the absence of full CYP2D6 catalytic activity.
Rapid metabolism occurs with hepatic enzyme inducers such as carbamazepine, phenytoin, and barbiturates and should not be used together.
It may potentiate sympathomimetic agent effects, as well as that of anticholinergic agents such as benztropine, atropine and hyoscine.
Alcohol may potentiate some of its CNS depressant effects.
It decreases the effect of some antihypertensive agents.
Coadministration with CNS depressants can cause additive CNS depression.
When given with thyroid hormones it may increase the potential for adverse reactions.
It is also a blocker of voltage-gated sodium channels involved in: lethality in overdose, as an analgesic for neuropathic pain, and as a migraine preventative.
It is a relatively selective for inhibition of norepinephrine reuptake with much weaker effects on serotonin reuptake and negligible influence on dopamine reuptake.
Its major metabolite nordoxepin is pharmacologically active similarly, but much more selective as a norepinephrine reuptake inhibitor.
Antidepressant doses of doxepin are defined as 25 to 300 mg/day, although are typically above 75 mg/day.
At low doses, below 25 mg, doxepin is a pure antihistamine and has more of a sedative effect.
A highly potent antihistamine.
One of the most potent H1 receptor antagonists available.
The affinity of doxepin for the H1 receptor is far greater than its affinity for other sites, and 10- to 100-fold higher doses are needed for antidepressant effects.
Its H1 receptor antagonism is responsible for its hypnotic effects and its effectiveness in the treatment of insomnia at low doses.
The most frequent side effects are: headache and somnolence/sedation, both with an incidence of less than 5%.
In the treatment of insomnia it shows consistent benefits with excellent tolerability and safety, and is the only H1 receptor antagonist that is specifically approved for the treatment of insomnia in the United States.
At very low doses, it has not shown discontinuation or withdrawal effects nor rebound insomnia.
Rebound insomnia and daytime sedation are significantly more frequent than placebo with moderate doses of the drug.
Most of the benefits were lost with chronic treatment.
Doxepin at a dose of 25 mg/day for 3 weeks has been found to increase melatonin production by 26%.
Doxepin has been identified as an inhibitor of CYP2D6.
It is well-absorbed from the gastrointestinal tract but between 55 and 87% undergoes first-pass metabolism in the liver,
It has a mean oral bioavailability of approximately 29%.
It is widely distributed throughout the body and is approximately 80% plasma protein-bound, specifically to albumin and α1-acid glycoprotein.
It is extensively metabolized by the liver via oxidation and N-demethylation.
The major enzymes involved in the metabolism of doxepin are the cytochrome P450 enzymes CYP2D6 and CYP2C19, with CYP1A2, CYP2C9, and CYP3A4 involved to a lesser degree.
The major active metabolite of doxepin is nordoxepin.
The elimination half-life of doxepin is about 15–18 hours.
The elimination half-life of nordoxepin is around 28–31 hours.
Approximately 10% of Caucasian individuals show substantially reduced metabolism of doxepin that can result in up to 8-fold elevated plasma concentrations of the drug compared to normal.
It 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.
It is mainly metabolized by CYP2D6, CYP2C9, and CYP2C19 enzymes.