Mirtazapine: Difference between revisions

Mirtazapine inhibits presynaptic serotonin (5-HT)-2 and alpha-2 adrenergic auto- and hetero-receptors, thereby increasing serotonergic and noradrenergic neurotransmission. The increased amount of 5-HT released interacts with postsynaptic 5-HT1 receptors, which may be relevant to the antidepressant effects of the drug. The affinity of mirtazapine for central alpha-2 adrenoreceptors is 10 times higher than for peripheral receptors, resulting in fewer peripheral effects related to increased blood pressure. Mirtazapine is an antagonist at postsynaptic 5-HT2A, 5-HT2C, and 5-HT3 receptors. The blockade of these receptors may result in a lower incidence of certain adverse effects (e.g., anxiety, insomnia, nausea) than occurs with antidepressants that do not antagonize these receptors. Mirtazapine significantly antagonizes histamine H1 receptors at low doses, and this activity is associated with sedation and appetite stimulation. Higher doses have a greater effect on norepinephrine release relative to antihistamine effects, which may offset the sedative potential and appetite stimulation observed at low doses. Mirtazapine has muscarinic antagonist properties, which may be associated with xerostomia, constipation, and other anticholinergic effects. Orthostatic hypotension is the result of the peripheral alpha-1 adrenergic antagonism of the drug. Mirtazapine does not have clinically significant receptor affinity for dopamine, 5-HT1A, or 5-HT1B, and has no effects on the central reuptake of either norepinephrine or serotonin.:<ref name="Fernandez2005">{{cite journal | vauthors=((Fernández, J.)), ((Alonso, J. M.)), ((Andrés, J. I.)), ((Cid, J. M.)), ((Díaz, A.)), ((Iturrino, L.)), ((Gil, P.)), ((Megens, A.)), ((Sipido, V. K.)), ((Trabanco, A. A.)) | journal=Journal of Medicinal Chemistry | title=Discovery of New Tetracyclic Tetrahydrofuran Derivatives as Potential Broad-Spectrum Psychotropic Agents | volume=48 | issue=6 | pages=1709–1712 | date=1 March 2005 | url=https://pubs.acs.org/doi/10.1021/jm049632c | issn=0022-2623 | doi=10.1021/jm049632c}}</ref><ref>{{cite journal | vauthors=((Boer, Th. de)), ((Maura, G.)), ((Raiteri, M.)), ((Vos, C. J. de)), ((Wieringa, J.)), ((Pinder, R. M.)) | journal=Neuropharmacology | title=Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, org 3770 and its enantiomers | volume=27 | issue=4 | pages=399–408 | date=1 April 1988 | url=https://www.sciencedirect.com/science/article/pii/0028390888901499 | issn=0028-3908 | doi=10.1016/0028-3908(88)90149-9}}</ref>

Mirtazapine has also been found to modulate the κ₃ opioid receptor, supporting the claim that mirtazapine causes pain relief<ref>{{cite journal | vauthors=((Dapoigny, M.)), ((Abitbol, J. L.)), ((Fraitag, B.)) | journal=Digestive Diseases and Sciences | title=Efficacy of peripheral kappa agonist fedotozine versus placebo in treatment of irritable bowel syndrome. A multicenter dose-response study | volume=40 | issue=10 | pages=2244–2249 | date= October 1995 | issn=0163-2116 | doi=10.1007/BF02209014}}</ref> and adds to the [[sedative]] and [[hallucinogenic]] effects of mirtazapine<ref>{{cite journal | vauthors=((Pande, A. C.)), ((Pyke, R. E.)), ((Greiner, M.)), ((Wideman, G. L.)), ((Benjamin, R.)), ((Pierce, M. W.)) | journal=Clinical Neuropharmacology | title=Analgesic efficacy of enadoline versus placebo or morphine in postsurgical pain | volume=19 | issue=5 | pages=451–456 | date= October 1996 | issn=0362-5664 | doi=10.1097/00002826-199619050-00009}}</ref><ref>{{cite journal | vauthors=((Rimoy, G. H.)), ((Wright, D. M.)), ((Bhaskar, N. K.)), ((Rubin, P. C.)) | journal=European Journal of Clinical Pharmacology | title=The cardiovascular and central nervous system effects in the human of U-62066E. A selective opioid receptor agonist | volume=46 | issue=3 | pages=203–207 | date= 1994 | issn=0031-6970 | doi=10.1007/BF00192549}}</ref>

Mirtazapine is administered orally. Plasma protein binding is approximately 85%. Mirtazapine is extensively metabolized in the liver, primarily by demethylation and hydroxylation followed by glucuronide conjugation. The isoenzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine and CYP3A is responsible for the formation of the N-desmethyl and N-oxide metabolite. Several unconjugated metabolites possess pharmacological activity but levels are very low in the plasma. The half-life of mirtazapine ranges from 20 to 40 hours. Elimination occurs primarily in the urine (75%) and to a lesser extent in the feces (15%).<ref name="Anttila2006" />,<ref>{{cite journal | vauthors=((Al-Majed, A.)), ((Bakheit, A. H.)), ((Alharbi, R. M.)), ((Abdel Aziz, H. A.)) | journal=Profiles of Drug Substances, Excipients, and Related Methodology | title=Mirtazapine | volume=43 | pages=209–254 | date= 2018 | issn=1871-5125 | doi=10.1016/bs.podrm.2018.01.002}}</ref>.<ref>{{cite book | veditors=((Schatzberg, A. F.)), ((Nemeroff, C. B.)) | date= 2009 | title=The American Psychiatric Publishing textbook of psychopharmacology | publisher=American Psychiatric Pub | edition=4th ed | isbn=9781585623099}}</ref>