<unk>  is a tricyclic antidepressant (TCA). It acts as a serotonin–norepinephrine reuptake inhibitor (SNRI) (a reuptake inhibitor of serotonin and norepinephrine), with additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities. Pharmacodynamics +<unk>  Site Ki (nM) Species Ref 68–95210 () Human 30–5813 () Human >10,0004,600 () Human 5-HT1A 276 Human 5-HT2A 11–27 Human 5-HT2B 5-HT2C 2008.8 HumanRat 5-HT3 Human 5-HT6 136 Rat 5-HT7 α1 24 Human α1B 12 Human α2A 1,100–1,270 Human α2B 28 Human α2C 96 Human D2 360 Human H1 0.09–1.23 Human H2 174 Human H3 39,800 Human H4 15,100 Human 23–80 Human M1 18–38 Human M2 160–230 Human M3 25–52 Human M4 20–82 Human M5 5.6–75 Human 6,500 () Human Values are Ki, unless otherwise specified. The smaller the value, the more strongly the drug binds to the site.<unk>  is 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 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). Similarly to other tricyclic antidepressants,<unk>  is often prescribed as an effective alternative to SSRI medications.<unk>  is also a potent blocker of voltage-gated sodium channels, and this action is thought to be involved in both its lethality in overdose and its effectiveness as an analgesic (including in the treatment of neuropathic pain, and as a local anesthetic). The potencies of<unk>  in terms of its receptor antagonism specifically are as follows: * Extremely strong: Histamine H1 receptor * Strong: α1-adrenergic receptor, 5-HT2A and muscarinic acetylcholine receptors * Moderate: 5-HT2C and 5-HT1A receptors * Weak: α2-adrenergic and D2 receptors Based on its values for monoamine reuptake inhibition,<unk>  is relatively selective for the inhibition of norepinephrine reuptake, with a much weaker effect on the serotonin transporter. Although there is a significant effect that takes place at one of the specific serotonergic binding sites, the 5-HT2A serotonin receptor subtype. There is negligible influence on dopamine reuptake. The major metabolite of<unk> , nordoxepin (desmethyldoxepin), is pharmacologically active similarly, but relative to<unk> , is much more selective as a norepinephrine reuptake inhibitor. In general, the demethylated variants of tertiary amine TCAs like nordoxepin are much more potent inhibitors of norepinephrine reuptake, less potent inhibitors of serotonin reuptake, and less potent in their antiadrenergic, antihistamine, and anticholinergic activities. Antidepressant doses of<unk>  are defined as 25 to 300 mg/day, although are typically above 75 mg/day. Antihistamine doses, including for dermatological uses and as a sedative/hypnotic for insomnia, are considered to be 3 to 25 mg, although higher doses between 25 and 50 mg and in some cases even up to 150 mg have been used to treat insomnia. At low doses, below 25 mg,<unk>  is a pure antihistamine and has more of a sedative effect. At antidepressant doses of above 75 mg,<unk>  is more stimulating with antiadrenergic, antiserotonergic, and anticholinergic effects, and these activities contribute to its side effects.<unk>  is a mixture of (E) and (Z) stereoisomers with an approximate ratio of 85:15. When<unk>  was developed, no effort was made to separate or balance the mixture following its synthesis, resulting in the asymmetric ratio. (Z)-Doxepin is more active as an inhibitor of serotonin and norepinephrine reuptake than (E)-doxepin. The selectivity of<unk>  for inhibition of norepinephrine reuptake over that of serotonin is likely due to the 85% presence of (E)-doxepin in the mixture. Most other tertiary amine TCAs like amitriptyline and imipramine do not exhibit E-Z isomerism or such mixture asymmetry and are comparatively more balanced inhibitors of serotonin and norepinephrine reuptake. As a hypnotic + TCAs and TeCAs at H1and mACh receptors Drug H1 Ratio Amitriptyline 1.1 18 1:16 Amoxapine 25 1,000 1:40 Clomipramine 31 37 1:1.2 Desipramine 110 196 1:1.8 Dosulepin 4.0 38 1:9.5<unk>  0.24 83 1:346 Imipramine 11 91 1:8.3 Lofepramine 360 67 1:0.2 Maprotiline 2.0 560 1:280 Mianserin 0.40 820 1:2050 Mirtazapine 0.14 670 1:4786 Nortriptyline 10 149 1:15 Protriptyline 25 25 1:1 Trimipramine 0.27 58 1:215 Values are Ki (nM).<unk>  is a highly potent antihistamine, with this being its strongest activity. In fact,<unk>  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. It is the most potent and selective H1 receptor antagonist of the TCAs (although the tetracyclic antidepressant (TeCA) mirtazapine is slightly more potent), and other sedating antihistamines, for instance the over-the-counter diphenhydramine (Ki = 16 nM) and<unk> ylamine (Ki = 42 nM), show far lower affinities for this receptor in comparison. The affinity of<unk>  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. In accordance, although it is often described as a "dirty drug" due to its highly promiscuous binding profile,<unk>  acts as a highly selective antagonist of the H1 receptor at very low doses (less than 10 mg; typically 3 to 6 mg). 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. The H1 receptor antagonism of<unk>  is responsible for its hypnotic effects and its effectiveness in the treatment of insomnia at low doses. The incidence of side effects with<unk>  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%. Other side effects sometimes associated with antihistamines, including daytime sedation, increased appetite, and weight gain, all were not observed. 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. However,<unk>  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. Aside from diphenhydramine and<unk> ylamine, which have historical approval as hypnotics,<unk>  is the only H1 receptor antagonist that is specifically approved for the treatment of insomnia in the United States. The effect sizes of very low-dose<unk>  in the treatment of insomnia range from small to medium. These include subjective and objective measures of sleep maintenance, sleep duration, and sleep efficiency. Conversely, very low-dose<unk>  shows relatively weak effects on sleep initiation and does not significantly separate from placebo on this measure. This is in contrast to benzodiazepines and nonbenzodiazepine (Z-drug) hypnotics, which are additionally effective in improving sleep onset latency. However, it is also in contrast to higher doses of<unk>  (50 to 300 mg/day), which have been found to significantly reduce latency to sleep onset. A positive dose–response relationship on sleep measures was observed for doses of<unk>  between 1 and 6 mg in clinical studies, whereas the incidence of adverse effects remained constant across this dose range in both young and older adults. However, the incidence of adverse effects appeared to increase with longer treatment duration. A dose of<unk>  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. 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<unk>  for insomnia and not the 1 mg dose. At very low doses,<unk>  has not shown discontinuation or withdrawal effects nor rebound insomnia. Sustained effectiveness without apparent tolerance was demonstrated in clinical studies of up to 12 weeks duration. This appears to be in contrast to over-the-counter antihistamines like diphenhydramine and<unk> ylamine 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. It is for this reason that, unlike<unk> , they are not recommended for the chronic management of insomnia and are advised for only short-term treatment (i.e., 1 week). It is not entirely clear why<unk>  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 may have to do with the use of optimal doses. Unlike very-low-dose<unk> , most first-generation antihistamines also have marked anticholinergic activity as well as associated side effects such as dry mouth, constipation, urinary retention, and confusion. This is particularly true in older people, and antihistamines with concomitant anticholinergic effects are not recommended in adults over the age of 65. Anticholinergic activity notably may interfere with the sleep-promoting effects of H1 receptor blockade. 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
Doxepin
Chlorpropamide
Pheniramine
Mebanazine
Bromazine
Propranolol
Metkefamide
Bolazine