Editing Amitriptyline (section)

==Pharmacology==
===Pharmacodynamics===
{{See also|Pharmacology of antidepressants|Tricyclic antidepressant#Binding profiles}}
{| class="wikitable floatright" style="font-size:small;"
|+ Molecular targets of amitriptyline (AMI) and main active metabolite nortriptyline (NTI)<ref name="PDSP">{{cite web | title = PDSP K<sub>i</sub> Database | work = Psychoactive Drug Screening Program (PDSP) | author1-link = Bryan Roth | vauthors = Roth BL, Driscol J | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=amitriptyline&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | archive-date = 27 August 2021 | archive-url = https://web.archive.org/web/20210827213623/https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=amitriptyline&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | url-status = live }}</ref>
|-
! Site !! {{abbr|AMI|Amitriptyline}} !! {{abbrlink|NTI|Nortriptyline}} !! Species !! Ref
|-
| {{abbrlink|SERT|Serotonin transporter}} || 2.8–36 || 15–279 || Human ||<ref name="pmid9537821">{{cite journal | vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = European Journal of Pharmacology | volume = 340 | issue = 2–3 | pages = 249–258 | date = December 1997 | pmid = 9537821 | doi = 10.1016/s0014-2999(97)01393-9 }}</ref><ref name="pmid9400006">{{cite journal | vauthors = Owens MJ, Morgan WN, Plott SJ, Nemeroff CB | title = Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 283 | issue = 3 | pages = 1305–1322 | date = December 1997 | doi = 10.1016/S0022-3565(24)37161-7 | pmid = 9400006 }}</ref>
|-
| {{abbrlink|NET|Norepinephrine transporter}} || 19–102 || 1.8–21 || Human ||<ref name="pmid9537821" /><ref name="pmid9400006" />
|-
| {{abbrlink|DAT|Dopamine transporter}} || 3,250 || 1,140 || Human ||<ref name="pmid9537821" />
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 450–1,800 || 294 || Human ||<ref name="pmid7855217">{{cite journal | vauthors = Cusack B, Nelson A, Richelson E | title = Binding of antidepressants to human brain receptors: focus on newer generation compounds | journal = Psychopharmacology | volume = 114 | issue = 4 | pages = 559–565 | date = May 1994 | pmid = 7855217 | doi = 10.1007/bf02244985 | s2cid = 21236268 }}</ref><ref name="pmid2898916">{{cite journal | vauthors = Peroutka SJ | title = Antimigraine drug interactions with serotonin receptor subtypes in human brain | journal = Annals of Neurology | volume = 23 | issue = 5 | pages = 500–504 | date = May 1988 | pmid = 2898916 | doi = 10.1002/ana.410230512 | s2cid = 41570165 }}</ref>
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || 840 || {{abbr|ND|No data}} || Rat ||<ref name="pmid2942638">{{cite journal | vauthors = Peroutka SJ | title = Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B, and 5-HT1C binding sites in rat frontal cortex | journal = Journal of Neurochemistry | volume = 47 | issue = 2 | pages = 529–540 | date = August 1986 | pmid = 2942638 | doi = 10.1111/j.1471-4159.1986.tb04532.x | s2cid = 25108290 }}</ref>
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 18–23 || 41 || Human ||<ref name="pmid7855217" /><ref name="pmid2898916" />
|-
| [[5-HT2B receptor|5-HT<sub>2B</sub>]] || 174 || {{abbr|ND|No data}} || Human ||<ref name="pmid8743744">{{cite journal | vauthors = Schmuck K, Ullmer C, Kalkman HO, Probst A, Lubbert H | title = Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache? | journal = The European Journal of Neuroscience | volume = 8 | issue = 5 | pages = 959–967 | date = May 1996 | pmid = 8743744 | doi = 10.1111/j.1460-9568.1996.tb01583.x | s2cid = 19578349 }}</ref>
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 4-8 || 8.5 || Rat ||<ref name="pmid8876023">{{cite journal | vauthors = Pälvimäki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E, Hietala J | title = Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor | journal = Psychopharmacology | volume = 126 | issue = 3 | pages = 234–240 | date = August 1996 | pmid = 8876023 | doi = 10.1007/bf02246453 | s2cid = 24889381 }}</ref><ref name="pmid10379421">{{cite journal | vauthors = Sánchez C, Hyttel J | title = Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding | journal = Cellular and Molecular Neurobiology | volume = 19 | issue = 4 | pages = 467–489 | date = August 1999 | pmid = 10379421 | doi = 10.1023/a:1006986824213 | s2cid = 19490821 | pmc = 11545528 }}</ref>
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]] || 430 || 1,400 || Rat ||<ref name="pmid2533080">{{cite journal | vauthors = Schmidt AW, Hurt SD, Peroutka SJ | title = '[3H]quipazine' degradation products label 5-HT uptake sites | journal = European Journal of Pharmacology | volume = 171 | issue = 1 | pages = 141–143 | date = November 1989 | pmid = 2533080 | doi = 10.1016/0014-2999(89)90439-1 | doi-access = free }}</ref>
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]] || 65–141 || 148 || Human/rat ||<ref name="pmid8522988">{{cite journal | vauthors = Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, Meltzer HY, Sibley DR, Roth BL, Hamblin MW | title = Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor | journal = Journal of Neurochemistry | volume = 66 | issue = 1 | pages = 47–56 | date = January 1996 | pmid = 8522988 | doi = 10.1046/j.1471-4159.1996.66010047.x | s2cid = 35874409 }}</ref><ref name="pmid14645659">{{cite journal | vauthors = Hirst WD, Abrahamsen B, Blaney FE, Calver AR, Aloj L, Price GW, Medhurst AD | title = Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling | journal = Molecular Pharmacology | volume = 64 | issue = 6 | pages = 1295–1308 | date = December 2003 | pmid = 14645659 | doi = 10.1124/mol.64.6.1295 | s2cid = 33743899 }}</ref><ref name="pmid7680751">{{cite journal | vauthors = Monsma FJ, Shen Y, Ward RP, Hamblin MW, Sibley DR | title = Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs | journal = Molecular Pharmacology | volume = 43 | issue = 3 | pages = 320–327 | date = March 1993 | doi = 10.1016/S0026-895X(25)13616-X | pmid = 7680751 }}</ref>
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]] || 92.8–123 || {{abbr|ND|No data}} || Rat ||<ref name="pmid8394362">{{cite journal | vauthors = Shen Y, Monsma FJ, Metcalf MA, Jose PA, Hamblin MW, Sibley DR | title = Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype | journal = The Journal of Biological Chemistry | volume = 268 | issue = 24 | pages = 18200–18204 | date = August 1993 | pmid = 8394362 | doi = 10.1016/S0021-9258(17)46830-X | doi-access = free }}</ref>
|-
| [[Alpha-1A adrenergic receptor|α<sub>1A</sub>]] || 6.5–25 || 18–37 || Human ||<ref name="pmid20363235">{{cite journal | vauthors = Nojimoto FD, Mueller A, Hebeler-Barbosa F, Akinaga J, Lima V, Kiguti LR, Pupo AS | title = The tricyclic antidepressants amitriptyline, nortriptyline and imipramine are weak antagonists of human and rat alpha1B-adrenoceptors | journal = Neuropharmacology | volume = 59 | issue = 1–2 | pages = 49–57 | date = 2010 | pmid = 20363235 | doi = 10.1016/j.neuropharm.2010.03.015 | s2cid = 207225294 }}</ref><ref name="pmid32608144">{{cite journal | vauthors = Proudman RG, Pupo AS, Baker JG | title = The affinity and selectivity of α-adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D-adrenoceptors | journal = Pharmacology Research & Perspectives | volume = 8 | issue = 4 | pages = e00602 | date = August 2020 | pmid = 32608144 | pmc = 7327383 | doi = 10.1002/prp2.602 }}</ref>

|-
| [[Alpha-1B adrenergic receptor|α<sub>1B</sub>]] || 600–1700|| 850–1300|| Human ||<ref name="pmid20363235"/><ref name="pmid32608144"/>

|-
| [[Alpha-1D adrenergic receptor|α<sub>1D</sub>]] || 560 || 1500 || Human ||<ref name="pmid32608144"/>

|-
| [[alpha-2 adrenergic receptor|α<sub>2</sub>]] || 114–690 || 2,030 || Human ||<ref name="pmid9400006" /><ref name="pmid7855217" />

|-
| [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]] || 88 || {{abbr|ND|No data}} || Human ||<ref name="pmid22982401">{{cite journal | vauthors = Fallarero A, Pohjanoksa K, Wissel G, Parkkisenniemi-Kinnunen UM, Xhaard H, Scheinin M, Vuorela P | title = High-throughput screening with a miniaturized radioligand competition assay identifies new modulators of human α2-adrenoceptors | journal = European Journal of Pharmaceutical Sciences | volume = 47 | issue = 5 | pages = 941–951 | date = December 2012 | pmid = 22982401 | doi = 10.1016/j.ejps.2012.08.021 }}</ref>

|-
| [[Alpha-2B adrenergic receptor|α<sub>2B</sub>]] || >1000 || {{abbr|ND|No data}} || Human ||<ref name="pmid22982401"/>
|-
| [[Alpha-2C adrenergic receptor|α<sub>2C</sub>]] || 120 || {{abbr|ND|No data}} || Human ||<ref name="pmid22982401"/>

|-

| [[Beta adrenergic receptor|β]] || >10,000 || >10,000 || Rat ||<ref name="pmid8699">{{cite journal | vauthors = Bylund DB, Snyder SH | title = Beta adrenergic receptor binding in membrane preparations from mammalian brain | journal = Molecular Pharmacology | volume = 12 | issue = 4 | pages = 568–580 | date = July 1976 | pmid = 8699 }}</ref><ref name="pmid10379421" />
|-
| [[Dopamine D1 receptor|D<sub>1</sub>]] || 89 || 210 (rat) || Human/rat ||<ref name="pmid19091563" /><ref name="pmid10379421"/>
|-
| [[Dopamine D2 receptor|D<sub>2</sub>]] || 196–1,460 || 2,570 || Human ||<ref name="pmid7855217" /><ref name="pmid19091563" />
|-
| [[Dopamine D3 receptor|D<sub>3</sub>]] || 206 || {{abbr|ND|No data}} || Human ||<ref name="pmid19091563" />
|-
| [[Dopamine D4 receptor|D<sub>4</sub>]] || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}} || {{abbr|ND|No data}}
|-
| [[Dopamine D5 receptor|D<sub>5</sub>]] || 170 || {{abbr|ND|No data}} || Human ||<ref name="pmid19091563" />
|-
| [[Histamine H1 receptor|H<sub>1</sub>]] || 0.5–1.1 || 3.0–15 || Human ||<ref name="pmid19091563">{{cite journal | vauthors = von Coburg Y, Kottke T, Weizel L, Ligneau X, Stark H | title = Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics | journal = Bioorganic & Medicinal Chemistry Letters | volume = 19 | issue = 2 | pages = 538–542 | date = January 2009 | pmid = 19091563 | doi = 10.1016/j.bmcl.2008.09.012 }}</ref><ref name="pmid22033803">{{cite journal | vauthors = Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R | title = Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 385 | issue = 2 | pages = 145–170 | date = February 2012 | pmid = 22033803 | doi = 10.1007/s00210-011-0704-0 | s2cid = 14274150 }}</ref><ref name="pmid16782354">{{cite journal | vauthors = Ghoneim OM, Legere JA, Golbraikh A, Tropsha A, Booth RG | title = Novel ligands for the human histamine H1 receptor: synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes | journal = Bioorganic & Medicinal Chemistry | volume = 14 | issue = 19 | pages = 6640–6658 | date = October 2006 | pmid = 16782354 | doi = 10.1016/j.bmc.2006.05.077 }}</ref>
|-
| [[Histamine H2 receptor|H<sub>2</sub>]] || 66 || 646 || Human ||<ref name="pmid22033803" />
|-
| [[Histamine H3 receptor|H<sub>3</sub>]] || 75,900;>1000 || 45,700 || Human ||<ref name="pmid19091563" /><ref name="pmid22033803" />
|-
| [[Histamine H4 receptor|H<sub>4</sub>]] || 34–26,300 || 6,920 || Human ||<ref name="pmid22033803" /><ref name="pmid11179435">{{cite journal | vauthors = Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, Rauser L, Lee SP, Lynch KR, Roth BL, O'Dowd BF | title = Discovery of a novel member of the histamine receptor family | journal = Molecular Pharmacology | volume = 59 | issue = 3 | pages = 427–433 | date = March 2001 | pmid = 11179435 | doi = 10.1124/mol.59.3.427 | url = https://cdr.lib.unc.edu/record/uuid:d42d8e6e-1a6d-40fc-9371-e4a7ab63f3ea | access-date = 11 December 2019 | url-status = live | archive-url = https://web.archive.org/web/20210827213636/https://cdr.lib.unc.edu/concern/articles/b2773x653 | archive-date = 27 August 2021 }}</ref>

|-
| [[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]] || 11.0–14.7 || 40 || Human ||<ref name="pmid8100134">{{cite journal | vauthors = Stanton T, Bolden-Watson C, Cusack B, Richelson E | title = Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics | journal = Biochemical Pharmacology | volume = 45 | issue = 11 | pages = 2352–2354 | date = June 1993 | pmid = 8100134 | doi = 10.1016/0006-2952(93)90211-e }}</ref><ref name="pmid10227113">{{cite journal | vauthors = Bymaster FP, Nelson DL, DeLapp NW, Falcone JF, Eckols K, Truex LL, Foreman MM, Lucaites VL, Calligaro DO | title = Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and alpha 1-adrenergic receptors in vitro | journal = Schizophrenia Research | volume = 37 | issue = 1 | pages = 107–122 | date = May 1999 | pmid = 10227113 | doi = 10.1016/s0920-9964(98)00146-7 | s2cid = 19891653 }}</ref>
|-
| [[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]] || 11.8 || 110 || Human ||<ref name="pmid8100134" />
|-
| [[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]] || 12.8–39 || 50 || Human ||<ref name="pmid8100134" /><ref name="pmid10227113" />
|-
| [[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]] || 7.2 || 84 || Human ||<ref name="pmid8100134" />
|-
| [[Muscarinic acetylcholine receptor M5|M<sub>5</sub>]] || 15.7–24 || 97 || Human ||<ref name="pmid8100134" /><ref name="pmid10227113" />
|-
| [[Sigma-1 receptor|σ<sub>1</sub>]] || 287–300 || 2,000 || Guinea pig/rat ||<ref name="pmid2877462">{{cite journal | vauthors = Weber E, Sonders M, Quarum M, McLean S, Pou S, Keana JF | title = 1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 22 | pages = 8784–8788 | date = November 1986 | pmid = 2877462 | pmc = 387016 | doi = 10.1073/pnas.83.22.8784 | doi-access = free | bibcode = 1986PNAS...83.8784W }}</ref><ref name="pmid17689532">{{cite journal | vauthors = Werling LL, Keller A, Frank JG, Nuwayhid SJ | title = A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder | journal = Experimental Neurology | volume = 207 | issue = 2 | pages = 248–257 | date = October 2007 | pmid = 17689532 | doi = 10.1016/j.expneurol.2007.06.013 | s2cid = 38476281 }}</ref>

|-
| {{abbrlink|hERG|human Ether-à-go-go-Related Gene}} || 3,260 || 31,600 || Human ||<ref name="pmid10742304">{{cite journal | vauthors = Jo SH, Youm JB, Lee CO, Earm YE, Ho WK | title = Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline | journal = British Journal of Pharmacology | volume = 129 | issue = 7 | pages = 1474–1480 | date = April 2000 | pmid = 10742304 | pmc = 1571977 | doi = 10.1038/sj.bjp.0703222 }}</ref><ref name="pmid22244872">{{cite journal | vauthors = Yamakawa Y, Furutani K, Inanobe A, Ohno Y, Kurachi Y | title = Pharmacophore modeling for hERG channel facilitation | journal = Biochemical and Biophysical Research Communications | volume = 418 | issue = 1 | pages = 161–166 | date = February 2012 | pmid = 22244872 | doi = 10.1016/j.bbrc.2011.12.153 }}</ref>

|-
| [[PARP1]] || 1650 || {{abbr|ND|No data}} || Human ||<ref>{{cite journal | vauthors = Fu L, Wang S, Wang X, Wang P, Zheng Y, Yao D, Guo M, Zhang L, Ouyang L | title = Crystal structure-based discovery of a novel synthesized PARP1 inhibitor (OL-1) with apoptosis-inducing mechanisms in triple-negative breast cancer | journal = Scientific Reports | volume = 6 | issue = 1 | pages = 3 | date = December 2016 | pmid = 28442756 | pmc = 5431371 | doi = 10.1038/s41598-016-0007-2 }}</ref>
|-
| [[TrkA]] || 3,000<br />(agonist) || {{abbr|ND|No data}} || Human ||<ref name="pmid19549602">{{cite journal | vauthors = Jang SW, Liu X, Chan CB, Weinshenker D, Hall RA, Xiao G, Ye K | title = Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity | journal = Chemistry & Biology | volume = 16 | issue = 6 | pages = 644–656 | date = June 2009 | pmid = 19549602 | pmc = 2844702 | doi = 10.1016/j.chembiol.2009.05.010 }}</ref>

|-
| [[TrkB]] || 14,000<br />(agonist) || {{abbr|ND|No data}} || Human ||<ref name="pmid19549602"/>
|- class="sortbottom"
| colspan="5" style="width: 1px;" | Values are K<sub>i</sub> (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.
|}

Amitriptyline inhibits [[serotonin transporter]] (SERT) and [[norepinephrine transporter]] (NET). It is metabolized to [[nortriptyline]], a stronger [[norepinephrine reuptake inhibitor]], further augmenting amitriptyline's effects on norepinephrine reuptake (see table in this section).

Amitriptyline additionally acts as a potent inhibitor of the [[serotonin receptor|serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub>]], [[5-HT2C receptor|5-HT<sub>2C</sub>]], the [[alpha-1A adrenergic receptor|α<sub>1A</sub>-adrenergic]], the [[histamine receptor|histamine]] [[H1 receptor|H<sub>1</sub>]] and the M<sub>1</sub>-M<sub>5</sub> [[muscarinic acetylcholine receptor]]s (see table in this section).

Amitriptyline is a non-selective blocker of multiple ion channels, in particular, [[voltage-gated sodium channel]]s [[Nav1.3|Na<sub>v</sub>1.3]], [[Nav1.5|Na<sub>v</sub>1.5]], [[Nav1.6|Na<sub>v</sub>1.6]], [[Nav1.7|Na<sub>v</sub>1.7]], and [[Nav1.8|Na<sub>v</sub>1.8]],<ref name="pmid28905186">{{cite journal | vauthors = Horishita T, Yanagihara N, Ueno S, Okura D, Horishita R, Minami T, Ogata Y, Sudo Y, Uezono Y, Sata T, Kawasaki T | title = Antidepressants inhibit Na<sub>v</sub>1.3, Na<sub>v</sub>1.7, and Na<sub>v</sub>1.8 neuronal voltage-gated sodium channels more potently than Na<sub>v</sub>1.2 and Na<sub>v</sub>1.6 channels expressed in Xenopus oocytes | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 390 | issue = 12 | pages = 1255–1270 | date = December 2017 | pmid = 28905186 | doi = 10.1007/s00210-017-1424-x | s2cid = 23385313 }}</ref><ref name="pmid29574705">{{cite journal | vauthors = Atkin TA, Maher CM, Gerlach AC, Gay BC, Antonio BM, Santos SC, Padilla KM, Rader J, Krafte DS, Fox MA, Stewart GR, Petrovski S, Devinsky O, Might M, Petrou S, Goldstein DB | title = A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy | journal = Epilepsia | volume = 59 | issue = 4 | pages = 802–813 | date = April 2018 | pmid = 29574705 | doi = 10.1111/epi.14037 | s2cid = 4478321 | doi-access = free }}</ref><ref name="pmid10688618">{{cite journal | vauthors = Nau C, Seaver M, Wang SY, Wang GK | title = Block of human heart hH1 sodium channels by amitriptyline | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 292 | issue = 3 | pages = 1015–1023 | date = March 2000 | pmid = 10688618 | doi =  10.1016/S0022-3565(24)35384-4}}</ref> [[voltage-gated potassium channel]]s [[Kv7.2|K<sub>v</sub>7.2]]/ [[Kv7.3|K<sub>v</sub>7.3]],<ref name="pmid17456683">{{cite journal | vauthors = Punke MA, Friederich P | title = Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels | journal = Anesthesia and Analgesia | volume = 104 | issue = 5 | pages = 1256–64, tables of contents | date = May 2007 | pmid = 17456683 | doi = 10.1213/01.ane.0000260310.63117.a2 | url = http://www.anesthesia-analgesia.org/cgi/pmidlookup?view=long&pmid=17456683 | access-date = 15 October 2009 | url-status = live | s2cid = 21924741 | doi-access = free | archive-url = https://web.archive.org/web/20210827213624/https://journals.lww.com/anesthesia-analgesia/pages/default.aspx | archive-date = 27 August 2021 }}</ref> [[Kv7.1|K<sub>v</sub>7.1]], [[Kv7.1|K<sub>v</sub>7.1]]/[[KCNE1]],<ref name="pmid29621539">{{cite journal | vauthors = Villatoro-Gómez K, Pacheco-Rojas DO, Moreno-Galindo EG, Navarro-Polanco RA, Tristani-Firouzi M, Gazgalis D, Cui M, Sánchez-Chapula JA, Ferrer T | title = Molecular determinants of Kv7.1/KCNE1 channel inhibition by amitriptyline | journal = Biochemical Pharmacology | volume = 152 | issue =  | pages = 264–271 | date = June 2018 | pmid = 29621539 | doi = 10.1016/j.bcp.2018.03.016 | s2cid = 4929937 }}</ref> and [[hERG]].<ref name="pmid10742304"/>

===Mechanism of action===
Inhibition of serotonin and norepinephrine transporters by amitriptyline results in interference with neuronal reuptake of [[serotonin]] and [[norepinephrine]]. Since the reuptake process is important physiologically in terminating transmitting activity, this action may potentiate or prolong the activity of serotonergic and adrenergic neurons and is believed to underlie the antidepressant activity of amitriptyline.<ref name=DailyMed/>

Inhibition of norepinephrine reuptake leads to an increased concentration of norepinephrine in the [[posterior gray column]] of the spinal cord appears to be mostly responsible for the analgesic action of amitriptyline. Increased level of norepinephrine increases the basal activity of [[alpha-2 adrenergic receptor]]s, which mediate an analgesic effect by increasing [[gamma-aminobutyric acid]] transmission among [[spinal interneuron]]s. The blocking effect of amitriptyline on sodium channels may also contribute to its efficacy in pain conditions.<ref name="pmid33438398">{{cite journal | vauthors = McClure EW, Daniels RN | title = Classics in Chemical Neuroscience: Amitriptyline | journal = ACS Chemical Neuroscience | volume = 12 | issue = 3 | pages = 354–362 | date = February 2021 | pmid = 33438398 | doi = 10.1021/acschemneuro.0c00467 | s2cid = 231596860 }}</ref>

===Pharmacokinetics===
Amitriptyline is readily absorbed from the gastrointestinal tract (90–95%).<ref name = pmid33438398/> Absorption is gradual with the peak concentration in blood plasma reached after about 4 hours.<ref name="pmid3893842">{{cite journal | vauthors = Schulz P, Dick P, Blaschke TF, Hollister L | title = Discrepancies between pharmacokinetic studies of amitriptyline | journal = Clinical Pharmacokinetics | volume = 10 | issue = 3 | pages = 257–268 | date = 1985 | pmid = 3893842 | doi = 10.2165/00003088-198510030-00005 | s2cid = 41881790 }}</ref> Extensive metabolism on the [[First pass effect|first pass through the liver]] leads to average [[bioavailability]] of about 50% (45%<ref name="pmid3893842"/>-53%<ref name = pmid33438398/>). Amitriptyline is metabolized mostly by [[CYP2C19]] into [[nortriptyline]] and by [[CYP2D6]] leading to a variety of [[Hydroxylation|hydroxylated]] metabolites, with the principal one among them being (''E'')-10-hydroxynortriptyline<ref name="pmid15554244" /> (see metabolism scheme),<ref name = pmid33438398/> and to a lesser degree, by [[CYP3A4]].<ref name="pmid11583471" /> [[File:Amitriptyline metabolism.png|class=skin-invert-image|thumb|left|upright=1.5|Metabolism of amitriptyline to major active metabolites.]]

[[Nortriptyline]], the main active metabolite of amitriptyline, is an antidepressant on its own right. Nortriptyline reaches 10% higher level in the [[blood plasma]] than the parent drug amitriptyline and 40% greater [[Area under the curve (pharmacokinetics)|area under the curve]], and its action is an important part of the overall action of amitriptyline.<ref name="pmid3893842"/><ref name="pmid15554244"/>

Another active metabolite is (''E'')-10-hydroxynortriptyline, which is a norepinephrine uptake inhibitor four times weaker than nortriptyline. (''E'')-10-hydroxynortiptyline blood level is comparable to that of nortriptyline, but its [[cerebrospinal fluid]] level, which is a close proxy of the brain concentration of a drug, is twice higher than nortriptyline's. Based on this, (''E'')-10-hydroxynortriptyline was suggested to significantly contribute to the antidepressant effects of amitriptyline.<ref name="pmid7712660">{{cite journal | vauthors = Nordin C, Bertilsson L | title = Active hydroxymetabolites of antidepressants. Emphasis on E-10-hydroxy-nortriptyline | journal = Clinical Pharmacokinetics | volume = 28 | issue = 1 | pages = 26–40 | date = January 1995 | pmid = 7712660 | doi = 10.2165/00003088-199528010-00004 | s2cid = 38046048 }}</ref>

Blood levels of amitriptyline and nortriptyline and pharmacokinetics of amitriptyline in general, with [[Clearance (pharmacology)|clearance]] difference of up to 10-fold, vary widely between individuals.<ref name="pmid8736630">{{cite journal | vauthors = Bryson HM, Wilde MI | title = Amitriptyline. A review of its pharmacological properties and therapeutic use in chronic pain states | journal = Drugs & Aging | volume = 8 | issue = 6 | pages = 459–476 | date = June 1996 | pmid = 8736630 | doi = 10.2165/00002512-199608060-00008 | s2cid = 22923577 }}</ref> Variability of the area under the curve [[Pharmacokinetics#Metrics|in steady state]] is also high, which makes a slow upward [[drug titration|titration]] of the dose necessary.<ref name="pmid28405886"/>

In the blood, amitriptyline is 96% bound to plasma proteins; nortriptyline is 93–95% bound, and (''E'')-10-hydroxynortiptyline is about 60% bound.<ref name = TGA/><ref name=MSRN>{{cite web|title=Pamelor, Aventyl (nortriptyline) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=2 December 2013|url=http://reference.medscape.com/drug/pamelor-nortriptyline-342944#showall|url-status=live|archive-url=https://web.archive.org/web/20131203024651/http://reference.medscape.com/drug/pamelor-nortriptyline-342944#showall|archive-date=3 December 2013}}</ref><ref name="pmid7712660"/> Amitriptyline has an elimination half life of 21 hours,<ref name="pmid3893842"/> nortriptyline – 23–31 hours,<ref name="pmid7248140">{{cite journal | vauthors = Dawlilng S, Lynn K, Rosser R, Braithwaite R | title = The pharmacokinetics of nortriptyline in patients with chronic renal failure | journal = British Journal of Clinical Pharmacology | volume = 12 | issue = 1 | pages = 39–45 | date = July 1981 | pmid = 7248140 | pmc = 1401753 | doi = 10.1111/j.1365-2125.1981.tb01852.x }}</ref> and (''E'')-10-hydroxynortiptyline − 8–10 hours.<ref name="pmid7712660"/> Within 48 hours, 12−80% of amitriptyline is eliminated in the urine, mostly as metabolites.<ref name="pmid6667101">{{cite journal | vauthors = Schulz P, Balant-Gorgia AE, Kubli A, Gertsch-Genet C, Garrone G | title = Elimination and pharmacological effects following single oral doses of 50 and 75 mg of amitriptyline in man | journal = Archiv für Psychiatrie und Nervenkrankheiten | volume = 233 | issue = 6 | pages = 449–455 | date = 1983 | pmid = 6667101 | doi = 10.1007/BF00342785 | s2cid = 20844722 }}</ref> 2% of the unchanged drug is excreted in the urine.<ref name=drugbank>{{cite web |title=Amitriptyline |url=https://www.drugbank.ca/drugs/DB00321 |website=drugbank.ca |access-date=29 January 2019 |archive-date=30 January 2019 |archive-url=https://web.archive.org/web/20190130053200/https://www.drugbank.ca/drugs/DB00321 |url-status=live }}</ref> Elimination in the feces, apparently, have not been studied.

Therapeutic levels of amitriptyline range from 75 to 175&nbsp;ng/mL (270–631&nbsp;nM),<ref name="SadockSadock2008">{{cite book| vauthors = Sadock BJ, Sadock VA |url=https://books.google.com/books?id=ubG51n2NgfwC&pg=PA18|title=Kaplan & Sadock's Concise Textbook of Clinical Psychiatry|publisher=Lippincott Williams & Wilkins|year=2008|isbn=978-0-7817-8746-8|pages=18–|archive-url=https://web.archive.org/web/20170708005933/https://books.google.com/books?id=ubG51n2NgfwC|archive-date=8 July 2017|url-status=live}}</ref> or 80–250&nbsp;ng/mL of both amitriptyline and its metabolite nortriptyline.<ref name="Orsulak Review TDM">{{cite journal | vauthors = Orsulak PJ | title = Therapeutic monitoring of antidepressant drugs: guidelines updated | journal = Therapeutic Drug Monitoring | volume = 11 | issue = 5 | pages = 497–507 | date = September 1989 | pmid = 2683251 | doi = 10.1097/00007691-198909000-00002 }}</ref>

===Pharmacogenetics===
Since amitriptyline is primarily metabolized by CYP2D6 and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body.<ref name="pmid10319193">{{cite journal | vauthors = Rudorfer MV, Potter WZ | title = Metabolism of tricyclic antidepressants | journal = Cellular and Molecular Neurobiology | volume = 19 | issue = 3 | pages = 373–409 | date = June 1999 | pmid = 10319193 | doi = 10.1023/A:1006949816036 | s2cid = 7940406 | pmc = 11545471 }}</ref> Increased concentrations of amitriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy.<ref name="pmid 22565785">{{cite journal | vauthors = Stingl JC, Brockmöller J, Viviani R | title = Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function | journal = Molecular Psychiatry | volume = 18 | issue = 3 | pages = 273–287 | date = March 2013 | pmid = 22565785 | doi = 10.1038/mp.2012.42 | s2cid = 20888081 }}</ref><ref name="pmid 17113714">{{cite journal | vauthors = Kirchheiner J, Seeringer A | title = Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1770 | issue = 3 | pages = 489–494 | date = March 2007 | pmid = 17113714 | doi = 10.1016/j.bbagen.2006.09.019 }}</ref><ref>{{cite journal | vauthors = Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, Skaar TC, Müller DJ, Gaedigk A, Stingl JC | title = Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants | journal = Clinical Pharmacology and Therapeutics | volume = 93 | issue = 5 | pages = 402–408 | date = May 2013 | pmid = 23486447 | pmc = 3689226 | doi = 10.1038/clpt.2013.2 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/109971/1/cptclpt20132.pdf | access-date = 4 November 2018 | url-status = live | archive-url = https://web.archive.org/web/20210827213631/https://deepblue.lib.umich.edu/bitstream/handle/2027.42/109971/cptclpt20132.pdf;jsessionid=2C1238337B5AD4C28DEA9617A364BC2D?sequence=1 | archive-date = 27 August 2021 }}</ref><ref name=":0">{{cite book | title=Medical Genetics Summaries | chapter=Amitriptyline Therapy and CYP2D6 and CYP2C19 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK425165/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=6 | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2017 | pmid=28520380 | id=Bookshelf ID: NBK425165 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ | access-date=6 February 2020 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026145821/https://www.ncbi.nlm.nih.gov/books/NBK61999/ | url-status=live }}</ref>

Individuals can be categorized into different types of CYP2D6 or CYP2C19 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most individuals (about 77–92%) are extensive metabolizers,<ref name="pmid23486447"/> and have "normal" metabolism of amitriptyline. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use amitriptyline much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure.<ref name="pmid 22565785"/><ref name="pmid 17113714"/><ref name="pmid23486447"/><ref name=":0" />

The Clinical Pharmacogenetics Implementation Consortium recommends avoiding amitriptyline in patients who are CYP2D6 ultrarapid or poor metabolizers, due to the risk of a lack of efficacy and side effects, respectively. The consortium also recommends considering an alternative drug not metabolized by CYP2C19 in patients who are CYP2C19 ultrarapid metabolizers. A reduction in the starting dose is recommended for patients who are CYP2D6 intermediate metabolizers and CYP2C19 poor metabolizers. If the use of amitriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments.<ref name="pmid23486447"/> The Dutch Pharmacogenetics Working Group also recommends selecting an alternative drug or monitoring plasma concentrations of amitriptyline in patients who are [[CYP2D6]] poor or ultrarapid metabolizers, and selecting an alternative drug or reducing initial dose in patients who are [[CYP2D6]] intermediate metabolizers.<ref name="pmid21412232">{{cite journal | vauthors = Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, Rongen GA, van Schaik RH, Schalekamp T, Touw DJ, van der Weide J, Wilffert B, Deneer VH, Guchelaar HJ | title = Pharmacogenetics: from bench to byte--an update of guidelines | journal = Clinical Pharmacology and Therapeutics | volume = 89 | issue = 5 | pages = 662–673 | date = May 2011 | pmid = 21412232 | doi = 10.1038/clpt.2011.34 | s2cid = 2475005 | doi-access =  }}</ref>
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