Pharmacodynamics<unk>  Ki (nM) Species Ref >10,000 Human ≥4,600 Human >10,000 Human 5-HT1A 3,330–5,010 Human 5-HT1B 3,534–12,600 Human 5-HT1D 794–5,010 Human 5-HT1E 728 Human 5-HT1F 583 Human 5-HT2A 6.3–69 Human 5-HT2B 200 Human 5-HT2C 8.9–39 Human 5-HT3 8.1 Human 5-HT4L >10,000 Human 5-HT5A 670 Human 5-HT6 5-HT7 265 Human α1A 1,815 Human α2A 20 Human α2B 88 Human α2C 18 Human β >10,000 Human D1 4,167 Rat D2 >5,454 Human D3 5,723 Human D4 2,518 Human H1 0.14–1.6 Human H2 >10,000 Rat H3 83,200 Human H4 >100,000 Human 670 Human 6,905 Rat >10,000 Rat Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.<unk>  is sometimes described as a noradrenergic and specific serotonergic antidepressant (NaSSA), although the actual evidence in support of this label has been regarded as poor. It is a tetracyclic piperazine-azepine.<unk>  has antihistamine, α2-blocker, and antiserotonergic activity. It is specifically a potent antagonist or inverse agonist of the α2A-, α2B-, and α2C-adrenergic receptors, the serotonin 5-HT2A, 5-HT2C, and the histamine H1 receptor. Unlike many other antidepressants, it does not inhibit the reuptake of serotonin, norepinephrine, or dopamine, nor does it inhibit monoamine oxidase. Similarly,<unk>  has weak or no activity as an anticholinergic or blocker of sodium or calcium channels, in contrast to most TCAs. In accordance, it has better tolerability and low toxicity in overdose. As an H1 receptor antagonist,<unk>  is extremely potent, and is in fact the most potent of all the TCAs and TeCAs. Antagonism of the H1 receptor is by far the strongest activity of<unk> , with the drug acting as a selective H1 receptor antagonist at low concentrations. The (S)-(+) enantiomer of<unk>  is responsible for antagonism of the serotonin 5-HT2A and 5-HT2C receptors, while the (R)-(–) enantiomer is responsible for antagonism of the 5-HT3 receptor. Both enantiomers are involved in antagonism of the H1 and α2-adrenergic receptors, although the (S)-(+) enantiomer is the stronger antihistamine. Although not clinically relevant,<unk>  has been found to act as a partial agonist of the κ-opioid receptor at high concentrations (EC50 = 7.2 μM). α2-Adrenergic receptor Antagonism of the α2-adrenergic receptors, which function largely as inhibitory autoreceptors and heteroreceptors, enhances adrenergic and serotonergic neurotransmission, notably central 5-HT1A receptor mediated transmission in the dorsal raphe nucleus and hippocampus; hence,<unk> 's classification as a NaSSA. Indirect α1 adrenoceptor-mediated enhancement of serotonin cell firing and direct blockade of inhibitory α2 heteroreceptors located on serotonin terminals are held responsible for the increase in extracellular serotonin. Because of this,<unk>  has been said to be a functional "indirect agonist" of the 5-HT1A receptor. Increased activation of the central 5-HT1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs. 5-HT2 receptor Antagonism of the 5-HT2 subfamily of receptors and inverse agonism of the 5-HT2C receptor appears to be in part responsible for<unk> 's efficacy in the treatment of depressive states.<unk>  increases dopamine release in the prefrontal cortex. Accordingly, it was shown that by blocking the α2-adrenergic receptors and 5-HT2C receptors<unk>  disinhibited dopamine and norepinephrine activity in these areas in rats. In addition,<unk> 's antagonism of 5-HT2A receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor.<unk>  has been shown to lower drug seeking behaviour(more specifically to methamfetamine) in various human and animal studies. It is also being investigated in substance abuse disorders to reduce withdrawal effects and improve remission rates.<unk>  significantly improves pre-existing symptoms of nausea, vomiting, diarrhea, and irritable bowel syndrome in afflicted individuals.<unk>  may be used as an inexpensive antiemetic alternative to Ondansetron. In conjunction with substance abuse counseling,<unk>  has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success. In contrast to<unk> , the selective serotonin reuptake inhibitors (SSRI), serotonin–norepinephrine reuptake inhibitors (SNRI), Monoamine oxidase inhibitors (MAOI), and some Tricyclic antidepressants (TCA) increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors leading to a host of negative changes and side effects, the most prominent of which including anorexia, insomnia, sexual dysfunction (loss of libido and anorgasmia), nausea, and diarrhea, among others. As a result, it is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.<unk>  does not have pro-serotonergic activity and thus does not cause serotonin syndrome. This is in accordance with the fact that it is not a serotonin reuptake inhibitor or monoamine oxidase inhibitor (MAOI), nor a serotonin receptor agonist. There are no reports of serotonin syndrome in association with<unk>  alone, and<unk>  has not been found to cause serotonin syndrome in overdose. However, there are a handful of case reports of serotonin syndrome occurring with<unk>  in combination with serotonergic drugs like SSRIs, although such reports are very rare, and do not necessarily implicate<unk>  as causative. 5-HT3 receptor It is a potent 5-HT3 blocker. It may relieve chemotherapy-related and advanced cancer-related nausea. H1 receptor<unk>  is a very strong H1 receptor inverse agonist and, as a result, it can cause powerful sedative and hypnotic effects. A single 15 mg dose of<unk>  to healthy volunteers has been found to result in over 80% occupancy of the H1 receptor and to induce intense sleepiness. After a short period of chronic treatment, however, the H1 receptor tends to desensitize and the antihistamine effects become more tolerable. Many patients may also dose at night to avoid the effects, and this appears to be an effective strategy for combating them. Blockade of the H1 receptor may improve pre-existing allergies, pruritus, nausea, and insomnia in afflicted individuals. It may also contribute to weight gain, however. In contrast to the H1 receptor,<unk>  has only low affinity for the muscarinic acetylcholine receptors, although anticholinergic side effects like dry mouth, constipation, and mydriasis are still sometimes seen in clinical practice. Pharmacokinetics The oral bioavailability of<unk>  is about 50%. It is found mostly bound to plasma proteins, about 85%. It is metabolized primarily in the liver by demethylation and hydroxylation via cytochrome P450 enzymes, CYP1A2, CYP2D6, CYP3A4. One of its major metabolites is desmethylmirtazapine. The overall elimination half-life is 20–40 hours. It is conjugated in the kidney for excretion in the urine, where 75% of the drug is excreted, and about 15% is eliminated in feces.
Mirtazapine
Sertraline
Citalopram
Fluparoxan
Quetiapine
Asenapine
Loxapine
Escitalopram