Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Nortriptyline: Difference between pages

{{Short description|Antidepressant medication}}

{{Use dmy dates|date=February 2024}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 462263374

| alt = Skeletal formula of nortriptyline

| width = 200

| image2 = Nortriptyline-from-4M48-ball-and-stick.png

| alt2 = Ball-and-stick model of the nortriptyline molecule

| width2 = 200

| tradename = Aventyl, others

| DailyMedID = Nortriptyline

| pregnancy_AU = C

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Nortriptyline Use During Pregnancy | website=Drugs.com | date=22 June 2020 | url=https://www.drugs.com/pregnancy/nortriptyline.html | access-date=10 October 2020}}</ref>

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Tricyclic antidepressant]] (TCA)

| ATC_prefix = N06

| ATC_suffix = AA10

| legal_AU = S4

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=Health Canada | date=February 2024 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=24 March 2024}}</ref>

| legal_US = Rx-only

| bioavailability = 32–79%<ref name="LemkeWilliams2012">{{cite book| vauthors = Lemke TL, Williams DA |title= Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA588|date=24 January 2012|publisher=Lippincott Williams & Wilkins|isbn=978-1-60913-345-0|pages=588–}}</ref>

| protein_bound = 92%<ref name="LemkeWilliams2012" />

| metabolism = [[Liver]]

| metabolites = 10-''E''-Hydroxynortriptyline

| elimination_half-life = 18–44 hours (mean 30 hours)<ref name="LemkeWilliams2012" />

| excretion = [[Urine]]: 40%<ref name="LemkeWilliams2012" /><br />[[Feces]]: minor<ref name="LemkeWilliams2012" />

| CAS_number2 = 894-71-3

| ChEBI_Ref = {{ebicite|correct|EBI}}

| synonyms = Desitriptyline; ELF-101; E.L.F. 101; N-7048

| IUPAC_name = 3-(10,11-Dihydro-5''H''-dibenzo[a,d]cyclohepten-5-ylidene)-''N''-methyl-1-propanamine

| C=19 | H=21 | N=1

| SMILES = c3cc2c(/C(c1c(cccc1)CC2)=C/CCNC)cc3

<!-- Definition and medical uses -->

'''Nortriptyline''', sold under the brand name '''Aventyl''', among others, is a [[tricyclic antidepressant]]. This medicine is also sometimes used for [[neuropathic pain]], [[attention deficit hyperactivity disorder]] (ADHD), [[smoking cessation]] and [[anxiety]].<ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=374|edition=76}}</ref><ref name=AHFS2019>{{cite web |title=Nortriptyline Hydrochloride Monograph for Professionals |url=https://www.drugs.com/monograph/nortriptyline-hydrochloride.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=22 March 2019 |language=en}}</ref> As with many antidepressants, its use for young people with depression and other psychiatric disorders may be limited due to increased suicidality in the 18–24 population initiating treatment.<ref name=AHFS2019/> Nortriptyline is a less preferred treatment for ADHD and stopping smoking.<ref name=AHFS2019/> It is taken by mouth.<ref name=AHFS2019/>

<!-- Side effects and mechanisms -->

Common side effects include dry mouth, constipation, blurry vision, sleepiness, [[low blood pressure with standing]], and weakness.<ref name=AHFS2019/> Serious side effects may include [[seizure]]s, an increased risk of [[suicide]] in those less than 25 years of age, [[urinary retention]], [[glaucoma]], [[mania]], and a number of heart issues.<ref name=AHFS2019/> Nortriptyline may cause problems if taken during pregnancy.<ref name=AHFS2019/> Use during [[breastfeeding]] appears to be relatively safe.<ref name=BNF76/> It is a [[tricyclic antidepressant]] (TCA) and is believed to work by altering levels of [[serotonin]] and [[norepinephrine]].<ref name=AHFS2019/>{{efn| Nortriptyline actually belongs to a class of drugs called [[serotonin–norepinephrine reuptake inhibitor]]s (SNRIs). They work at [[synapse]] level, and do not allow reuptake of both serotonin and norepinephrine by the neurons. This increases the amount of these [[neurotransmitter]]s at synpase. In a way, that is not completely clear, this reduces the transmission of pain signals to the brain. It is for this reason, that SNRIs would work in [[neuropathic pain]], but not in [[Nociception|nociceptive pain]].}}

<!-- History and culture -->

Nortriptyline was approved for medical use in the United States in 1964.<ref name=AHFS2019/> It is available as a [[generic medication]].<ref name=BNF76/> In 2021, it was the 139th most commonly prescribed medication in the United States, with more than 4{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Nortriptyline - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Nortriptyline | access-date = 14 January 2024}}</ref>

==Medical uses==

Nortriptyline is used to treat depression.<ref name="medplusnort2019" /> This medication is in capsule or liquid and is taken by the mouth one to four times a day, with or without food.<ref name="medplusnort2019">{{cite web |title=Nortriptyline |url=https://medlineplus.gov/druginfo/meds/a682620.html |website=MedlinePlus |publisher=National Library of Medicine |access-date=6 May 2019}}</ref> Usually people are started on a low dose and it is gradually increased.<ref name="medplusnort2019" /> A level between 50 and 150&nbsp;ng/mL of nortriptyline in the blood generally corresponds with an antidepressant effect.<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>

In the [[United Kingdom]], it may also be used for treating [[nocturnal enuresis]], with courses of treatment lasting no more than three months. It is also used [[off-label use|off-label]] for the treatment of [[panic disorder]], [[irritable bowel syndrome]], [[migraine]] prophylaxis and chronic pain or [[neuralgia]] modification, particularly [[temporomandibular joint disorder]].<ref name="Martindale2002-Sweetman">{{cite book | veditors = Sweetman SC | title = Martindale. The complete drug reference | edition = 33 | year = 2002 | publisher = Pharmaceutical Press | isbn = 0-85369-499-0 | url-access = registration | url = https://archive.org/details/martindale00sean }}</ref>

===Neuropathic pain===

Although not approved by the FDA for [[neuropathic pain]], many randomized controlled trials have demonstrated the effectiveness of TCAs for the treatment of this condition in both depressed and non-depressed individuals. In 2010, an evidence-based guideline sponsored by the International Association for the Study of Pain recommended nortriptyline as a first-line medication for neuropathic pain.<ref>{{cite journal | vauthors = Dworkin RH, O'Connor AB, Audette J, Baron R, Gourlay GK, Haanpää ML, Kent JL, Krane EJ, Lebel AA, Levy RM, Mackey SC, Mayer J, Miaskowski C, Raja SN, Rice AS, Schmader KE, Stacey B, Stanos S, Treede RD, Turk DC, Walco GA, Wells CD | title = Recommendations for the pharmacological management of neuropathic pain: an overview and literature update | journal = Mayo Clinic Proceedings | volume = 85 | issue = 3 Suppl | pages = S3-14 | date = March 2010 | pmid = 20194146 | pmc = 2844007 | doi = 10.4065/mcp.2009.0649 }}</ref> However, in a 2015 [[Cochrane (organisation)|Cochrane systematic review]] the authors did not recommend nortriptyline as a first-line agent for neuropathic pain.<ref>{{cite journal | vauthors = Derry S, Wiffen PJ, Aldington D, Moore RA | title = Nortriptyline for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD011209 | date = January 2015 | pmid = 25569864 | doi = 10.1002/14651858.CD011605 | pmc = 6485407 }}</ref>

===Irritable bowel syndrome===

Nortriptyline has also been used as an off-label treatment for [[irritable bowel syndrome]] (IBS).<ref>{{Cite web | title = The Use of Antidepressants in the Treatment of Irritable Bowel Syndrome and Other Functional GI Disorders | url = https://www.med.unc.edu/ibs/files/2017/10/IBS-and-Antidepressants.pdf}}</ref>

==Contraindications==

Nortriptyline should not be used in the acute recovery phase after [[myocardial infarction]] (viz, heart attack).<ref>{{Cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018013s063lbl.pdf|title=Nortriptyline label|date=2014|publisher=FDA}}</ref> Use of tricyclic antidepressants along with a [[monoamine oxidase inhibitor]] (MAOI), [[linezolid]], or IV [[methylene blue]] are contraindicated as it can cause an increased risk of developing serotonin syndrome.<ref>{{cite book | vauthors = Merwar G, Saadabadi A | chapter = Nortriptyline |date=2018 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK482214/ | title = StatPearls |publisher=StatPearls Publishing |pmid=29489270 |access-date=3 October 2018 }}</ref>

Closer monitoring is required for those with a history of cardiovascular disease,<ref>{{cite journal | vauthors = Bardai A, Amin AS, Blom MT, Bezzina CR, Berdowski J, Langendijk PN, Beekman L, Klemens CA, Souverein PC, Koster RW, de Boer A, Tan HL | title = Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community | journal = European Heart Journal | volume = 34 | issue = 20 | pages = 1506–16 | date = May 2013 | pmid = 23425522 | doi = 10.1093/eurheartj/eht054 | doi-access = free }}</ref> [[stroke]], [[glaucoma]], or [[seizures]], as well as in persons with [[hyperthyroidism]] or receiving thyroid hormones.

==Side effects==

The most common side effects include dry mouth, sedation, constipation, increased appetite, blurred vision and tinnitus.<ref name="MD"/><ref name="PI">{{cite web|title=ALLEGRON|website=TGA eBusiness Services|publisher=Arrow Pharma Pty Ltd|date=13 October 2016|access-date=11 August 2017|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2016-PI-02638-1}}</ref> An occasional side effect is a rapid or [[irregular heartbeat]]. [[Alcohol (drug)|Alcohol]] may exacerbate some of its side effects.<ref name="MD">{{cite web|title=Nortriptyline Hydrochloride – Martindale: The Complete Drug Reference|url=https://www.medicinescomplete.com/mc/martindale/current/2530-w.htm|date=9 January 2017|access-date=11 August 2017|work=MedicinesComplete|publisher=Pharmaceutical Press| veditors = Brayfield A }}</ref>

==Overdose==

{{Main|Tricyclic antidepressant overdose}}

The symptoms and the treatment of an overdose are generally the same as for the other TCAs, including [[anticholinergic]] effects, [[serotonin syndrome]] and adverse cardiac effects. TCAs, particularly nortriptyline, have a relatively narrow [[therapeutic index]], which increase the chance of an overdose (both accidental and intentional). Symptoms of overdose include: [[irregular heartbeat]], [[seizures]], [[coma]], [[confusion]], [[hallucination]], widened pupils, [[drowsiness]], [[Psychomotor agitation|agitation]], [[fever]], low [[body temperature]], [[stiff muscles]] and [[vomiting]].<ref name=medplusnort2019/>

==Interactions==

Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or [[suicidal ideation]].

It may interact with the following drugs:<ref>{{Cite web|url=https://www.cardiosmart.org/Healthwise/d001/44/d00144|title=nortriptyline|website=www.cardiosmart.org|access-date=3 October 2018}}</ref>

* heart rhythm medications such as [[flecainide]] (Tambocor), [[propafenone]] (Rhythmol), or [[quinidine]] (Cardioquin, Quinidex, Quinaglute)

* [[cimetidine]]

* [[guanethidine]]

* [[reserpine]]

==Pharmacology==

Nortriptyline is a strong [[norepinephrine reuptake inhibitor]] and a moderate [[serotonin reuptake inhibitor]]. Its pharmacologic profile is as the table shows with (inhibition or antagonism of all sites).<ref name="PDSP" /><ref name = "GG">Brunton L, Chabner B, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.</ref>

===Pharmacodynamics===

{{See also|Pharmacology of antidepressants|Tricyclic antidepressant#Binding profiles}}

{| class="wikitable floatright" style="font-size:small;"

|+ Nortriptyline<ref name="PDSP">{{cite web | title = PDSP K_i Database | work = Psychoactive Drug Screening Program (PDSP) | vauthors = Roth BL, Driscol J |author1-link=Bryan Roth| 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?receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=nortriptyline&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query}}</ref>

|-

! Site !! K_i (nM) !! Species !! Ref

|-

| {{abbrlink|SERT|Serotonin transporter}} || 15–18 || 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 = Eur. J. Pharmacol. | volume = 340 | issue = 2–3 | pages = 249–58 | year = 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 = J. Pharmacol. Exp. Ther. | volume = 283 | issue = 3 | pages = 1305–22 | year = 1997 | pmid = 9400006 }}</ref>

|-

| {{abbrlink|NET|Norepinephrine transporter}} || 1.8–4.4 || Human || <ref name="pmid9537821" /><ref name="pmid9400006" />

|-

| {{abbrlink|DAT|Dopamine transporter}} || 1,140 || Human || <ref name="pmid9537821" />

|-

| [[5-HT1A receptor|5-HT_1A]] || 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=559–65 |year=1994 |pmid=7855217 |doi= 10.1007/bf02244985|s2cid=21236268 }}</ref>

|-

| [[5-HT2A receptor|5-HT_2A]] || 5.0–41 || Human/rat || <ref name="pmid8876023">{{cite journal |vauthors=Pälvimäki EP, Roth BL, Majasuo H, et al. |title=Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor |journal=Psychopharmacology |volume=126 |issue=3 |pages=234–40 |year=1996 |pmid=8876023 |doi= 10.1007/bf02246453|s2cid=24889381 }}</ref><ref name="pmid7855217" />

|-

| [[5-HT2C receptor|5-HT_2C]] || 8.5 || Rat || <ref name="pmid8876023" />

|-

| [[5-HT3 receptor|5-HT₃]] || 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 = Eur. J. Pharmacol. | volume = 171 | issue = 1 | pages = 141–3 | year = 1989 | pmid = 2533080 | doi = 10.1016/0014-2999(89)90439-1}}</ref>

|-

| [[5-HT6 receptor|5-HT₆]] || 148 || Rat || <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=Mol. Pharmacol. |volume=43 |issue=3 |pages=320–7 |year=1993 |pmid=7680751 }}</ref>

|-

| [[Alpha-1 adrenergic receptor|α₁]] || 55 || Human || <ref name="pmid7855217" />

|-

| [[Alpha-2 adrenergic receptor|α₂]] || 2,030 || Human || <ref name="pmid7855217" />

|-

| [[Beta adrenergic receptor|β]] || >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=Mol. Pharmacol. |volume=12 |issue=4 |pages=568–80 |year=1976 |pmid=8699 }}</ref>

|-

| [[Dopamine receptor D2|D₂]] || 2,570 || Human || <ref name="pmid7855217" />

|-

| [[Histamine H1 receptor|H₁]] || 3.0–15 || Human || <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 Arch. Pharmacol. | volume = 385 | issue = 2 | pages = 145–70 | year = 2012 | pmid = 22033803 | doi = 10.1007/s00210-011-0704-0 | s2cid = 14274150 }}</ref><ref name="pmid7855217" /><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=Bioorg. Med. Chem. |volume=14 |issue=19 |pages=6640–58 |year=2006 |pmid=16782354 |doi=10.1016/j.bmc.2006.05.077 }}</ref>

|-

| [[Histamine H2 receptor|H₂]] || 646 || Human || <ref name="pmid22033803" />

|-

| [[Histamine H3 receptor|H₃]] || 45,700 || Human || <ref name="pmid22033803" />

|-

| [[Histamine H4 receptor|H₄]] || 6,920 || Human || <ref name="pmid22033803" />

|-

| {{abbrlink|mACh|Muscarinic acetylcholine receptor}} || 37 || Human || <ref name="pmid7855217" />

|-

| &nbsp;&nbsp;[[Muscarinic acetylcholine receptor M1|M₁]] || 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=Biochem. Pharmacol. |volume=45 |issue=11 |pages=2352–4 |year=1993 |pmid=8100134 |doi= 10.1016/0006-2952(93)90211-e}}</ref>

|-

| &nbsp;&nbsp;[[Muscarinic acetylcholine receptor M2|M₂]] || 110 || Human || <ref name="pmid8100134" />

|-

| &nbsp;&nbsp;[[Muscarinic acetylcholine receptor M3|M₃]] || 50 || Human || <ref name="pmid8100134" />

|-

| &nbsp;&nbsp;[[Muscarinic acetylcholine receptor M4|M₄]] || 84 || Human || <ref name="pmid8100134" />

|-

| &nbsp;&nbsp;[[Muscarinic acetylcholine receptor M5|M₅]] || 97 || Human || <ref name="pmid8100134" />

|-

| [[Sigma-1 receptor|σ₁]] || 2,000 || Guinea pig || <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=Proc. Natl. Acad. Sci. U.S.A. |volume=83 |issue=22 |pages=8784–8 |year=1986 |pmid=2877462 |pmc=387016 |doi= 10.1073/pnas.83.22.8784|bibcode=1986PNAS...83.8784W |doi-access=free }}</ref>

|- class="sortbottom"

| colspan="4" style="width: 1px;" | Values are K_i (nM). The smaller the value, the more strongly the drug binds to the site.

|}

Nortriptyline is an active metabolite of [[amitriptyline]] by demethylation in the liver. Chemically, it is a [[secondary amine]] [[dibenzocycloheptene]] and pharmacologically it is classed as a first-generation antidepressant.<ref>{{cite book | vauthors = O'Connor EA, Whitlock EP, Gaynes B, Beil TL |title= Screening for Depression in Adults and Older Adults in Primary Care: An Updated Systematic Review |date=2009 |publisher=Agency for Healthcare Research and Quality (US) |url= https://www.ncbi.nlm.nih.gov/books/NBK36406/table/ch1.t2/ |pmid=20722174}}</ref>

Nortriptyline may also have a sleep-improving effect due to antagonism of the H₁ and 5-HT_2A receptors.<ref name="Dialogues Clin Neurosci-Thase">{{cite journal | vauthors = Thase ME | title = Depression and sleep: pathophysiology and treatment | journal = Dialogues in Clinical Neuroscience | volume = 8 | issue = 2 | pages = 217–26 | year = 2006 | doi = 10.31887/DCNS.2006.8.2/mthase | pmid = 16889107 | pmc = 3181772 }}</ref> In the short term, however, nortriptyline may disturb sleep due to its activating effect.

In one study, nortriptyline had the highest affinity for the [[dopamine transporter]] among the TCAs (K_D = 1,140&nbsp;nM) besides [[amineptine]] (a [[norepinephrine–dopamine reuptake inhibitor]]), although its affinity for this transporter was still 261- and 63-fold lower than for the [[norepinephrine transporter|norepinephrine]] and [[serotonin transporter]]s (K_D = 4.37 and 18&nbsp;nM, respectively).<ref name="pmid9537821" />

===Pharmacogenetics===

Nortriptyline is metabolized in the liver by the hepatic enzyme [[CYP2D6]], and genetic variations within the gene coding for this enzyme 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 = Jun 1999 | pmid = 10319193 | doi = 10.1023/A:1006949816036 | s2cid = 7940406 }}</ref> Increased concentrations of nortriptyline 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 = 273–87 | date = Mar 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 = 489–94 | date = Mar 2007 | pmid = 17113714 | doi = 10.1016/j.bbagen.2006.09.019 }}</ref><ref name="pmid23486447">{{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 = 402–8 | 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 }}</ref>

Individuals can be categorized into different types of [[CYP2D6]] 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 nortriptyline. 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 nortriptyline 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"/>

The Clinical Pharmacogenetics Implementation Consortium recommends avoiding nortriptyline in persons who are [[CYP2D6]] ultrarapid or poor metabolizers, due to the risk of a lack of efficacy and side effects, respectively. A reduction in starting dose is recommended for patients who are [[CYP2D6]] intermediate metabolizers. If use of nortriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments.<ref name="pmid23486447"/> The Dutch Pharmacogenetics Working Group recommends reducing the dose of nortriptyline in [[CYP2D6]] poor or intermediate metabolizers, and selecting an alternative drug or increasing the dose in ultrarapid 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 = 662–73 | date = May 2011 | pmid = 21412232 | doi = 10.1038/clpt.2011.34 | s2cid = 2475005 | doi-access = free }}</ref>

==Chemistry==

Nortriptyline is a [[tricyclic compound]], specifically a [[dibenzocycloheptadiene]], and possesses three [[ring (chemistry)|ring]]s fused together with a [[side chain]] attached in its [[chemical structure]].<ref name="Ritsner2013">{{cite book| vauthors = Ritsner MS |title=Polypharmacy in Psychiatry Practice, Volume I: Multiple Medication Use Strategies|url=https://books.google.com/books?id=jy-LMZU7338C&pg=PA270|date=15 February 2013|publisher=Springer Science & Business Media|isbn=978-94-007-5805-6|pages=270–271}}</ref> Other dibenzocycloheptadiene TCAs include [[amitriptyline]] (''N''-methylnortriptyline), [[protriptyline]], and [[butriptyline]].<ref name="Ritsner2013" /><ref name="LemkeWilliams2008">{{cite book| vauthors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry|url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA580 |year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|pages=580–}}</ref> Nortriptyline is a [[secondary amine]] TCA, with its ''N''-[[methylation|methylated]] [[parent compound|parent]] amitriptyline being a [[tertiary amine]].<ref name="CutlerSramek1994">{{cite book| vauthors = Cutler NR, Sramek JJ, Narang PK |title=Pharmacodynamics and Drug Development: Perspectives in Clinical Pharmacology|url=https://books.google.com/books?id=ncRXa8Dq88QC&pg=PA160|date=20 September 1994|publisher=John Wiley & Sons|isbn=978-0-471-95052-3|pages=160–}}</ref><ref name="AnzenbacherZanger2012">{{cite book| vauthors = Anzenbacher P, Zanger JM |title=Metabolism of Drugs and Other Xenobiotics|url=https://books.google.com/books?id=f-XHh17NfwgC&pg=PA302|date=23 February 2012|publisher=John Wiley & Sons|isbn=978-3-527-64632-6|pages=302–}}</ref> Other secondary amine TCAs include [[desipramine]] and [[protriptyline]].<ref name="Anthony2002">{{cite book| vauthors = Anthony PK |title=Pharmacology Secrets|url=https://books.google.com/books?id=_QQsj3PAUrEC&pg=PA39|year=2002|publisher=Elsevier Health Sciences|isbn=1-56053-470-2|pages=39–}}</ref><ref name="CowenHarrison2012">{{cite book| vauthors = Cowen P, Harrison P, Burns T |title=Shorter Oxford Textbook of Psychiatry|url=https://books.google.com/books?id=Y1DtSGq-LnoC&pg=PA532|date=9 August 2012|publisher=OUP Oxford|isbn=978-0-19-162675-3|pages=532–}}</ref> The [[chemical name]] of nortriptyline is 3-(10,11-dihydro-5''H''-dibenzo[''a'',''d'']cyclohepten-5-ylidene)-''N''-methyl-1-propanamine and its [[free base]] form has a [[chemical formula]] of C₁₉H₂₁N₁ with a [[molecular weight]] of 263.384&nbsp;g/mol.<ref name="Elks2014" /> The drug is used commercially mostly as the [[hydrochloride]] [[salt (chemistry)|salt]]; the free base form is used rarely.<ref name="Elks2014" /><ref name="IndexNominum2000" /> The [[CAS Registry Number]] of the free base is 72-69-5 and of the hydrochloride is 894-71-3.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="ChemIDplus">{{Cite web | url=https://chem.nlm.nih.gov/chemidplus/rn/62265-06-9 |title = ChemIDplus - 62265-06-9 - AMLRZIZSGSCSHZ-UHFFFAOYSA-N - Desipramine dibudinate - Similar structures search, synonyms, formulas, resource links, and other chemical information}}</ref>

==History==

Nortriptyline was developed by [[Novartis#Geigy|Geigy]].<ref name="pmid19557250">{{cite journal | vauthors = Andersen J, Kristensen AS, Bang-Andersen B, Strømgaard K | title = Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters | journal = Chem. Commun. | issue = 25 | pages = 3677–92 | year = 2009 | pmid = 19557250 | doi = 10.1039/b903035m }}</ref> It first appeared in the literature in 1962 and was patented the same year.<ref name="pmid19557250" /> The drug was first introduced for the treatment of depression in 1963.<ref name="pmid19557250" /><ref name="Dart2004">{{cite book| vauthors = Dart RC |title=Medical Toxicology|url=https://books.google.com/books?id=BfdighlyGiwC&pg=PA836|year=2004|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-2845-4|pages=836–}}</ref>

==Society and culture==

[[File:Nortriptyline HCL capsules - 50mg and 25mg.JPG|thumb|50&nbsp;mg (left) and 25&nbsp;mg generic nortriptyline HCl capsules made by [[Teva Pharmaceutical Industries]].]]

===Generic names===

Nortriptyline is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|DCF|Dénomination Commune Française}}, while nortriptyline hydrochloride is its {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|USP|United States Pharmacopeia}}, {{abbrlink|BANM|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA888|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=888–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA752|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=752–}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA202|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=202–}}</ref><ref name="Drugs.com">{{Cite web | url= https://www.drugs.com/international/nortriptyline.html | title=Nortriptyline}}</ref> Its generic name in Spanish and Italian and its {{abbrlink|DCIT|Denominazione Comune Italiana}} are nortriptilina, in German is nortriptylin, and in Latin is nortriptylinum.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="MortonHall2012" /><ref name="Drugs.com" />

===Brand names===

Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensival, among many others.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" />

==Footnotes==

{{notelist|1}}

==References==

{{Reflist}}

{{Antidepressants}}

{{Neuropathic pain and fibromyalgia pharmacotherapies}}

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