Nortriptyline

Nortriptyline is used to treat depression.{{cite web |title=Nortriptyline |url=https://medlineplus.gov/druginfo/meds/a682620.html |website=MedlinePlus |publisher=National Library of Medicine |access-date=6 May 2019}} A level between 50 and 150 ng/mL of nortriptyline in the blood generally corresponds with an antidepressant effect.{{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 }}

It is also used off-label for the treatment of panic disorder, ADHD, irritable bowel syndrome, tobacco-cessation, migraine prophylaxis and chronic pain or neuralgia modification, particularly temporomandibular joint disorder.{{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 }}{{cite journal | doi=10.1097/00004583-199303000-00015 | title=Nortriptyline in the Treatment of ADHD: A Chart Review of 58 Cases | date=1993 | journal=Journal of the American Academy of Child & Adolescent Psychiatry | volume=32 | issue=2 | pages=343–349 | pmid=8444763 | vauthors = Wilens TE, Biederman J, Geist DE, Steingard R, Spencer T }}{{cite journal | doi=10.1089/10445460050167304 | title=A Controlled Study of Nortriptyline in Children and Adolescents with Attention Deficit Hyperactivity Disorder | date=2000 | journal=Journal of Child and Adolescent Psychopharmacology | volume=10 | issue=3 | pages=193–204 | pmid=11052409 | vauthors = Prince JB, Wilens TE, Biederman J, Spencer TJ, Millstein R, Polisner DA, Bostic JQ }}{{cite journal | doi=10.1016/j.psc.2003.12.001 | title=Nonstimulant treatment of adult attention-deficit/Hyperactivity disorder | date=2004 | journal=Psychiatric Clinics of North America | volume=27 | issue=2 | pages=373–383 | pmid=15064003 | vauthors = Spencer T, Biederman J, Wilens T }}

Nortriptyline has also been used as an off-label treatment for irritable bowel syndrome (IBS).{{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}}

Nortriptyline should not be used in the acute recovery phase after myocardial infarction (heart attack). 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.{{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 }}

Closer monitoring is required for those with a history of cardiovascular disease,{{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 }} stroke, glaucoma, or seizures, as well as in persons with hyperthyroidism or receiving thyroid hormones.

The most common side effects include dry mouth, sedation, constipation, increased appetite, blurred vision and tinnitus.{{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}} An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects.{{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 }}

{{Main|Tricyclic antidepressant overdose}}

The symptoms and the treatment of an overdose are generally the same as for the other tricyclic antidepressants, 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, agitation, fever, low body temperature, stiff muscles and vomiting.

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:{{Cite web|url=https://www.cardiosmart.org/Healthwise/d001/44/d00144|title=nortriptyline|website=Cardiosmart|access-date=3 October 2018}}{{failed verification|date=October 2024}}

• heart rhythm medications such as flecainide (Tambocor), propafenone (Rhythmol), or quinidine (Cardioquin, Quinidex, Quinaglute)
• cimetidine
• guanethidine
• reserpine

Nortriptyline is a strong norepinephrine reuptake inhibitor and a moderate serotonin reuptake inhibitor. Additionally, nortriptyline inhibits the activity of histamine and acetylcholine. Its pharmacologic profile is as the table shows with (inhibition or antagonism of all sites).Brunton L, Chabner B, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.

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

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.{{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}}

Nortriptyline may also have a sleep-improving effect due to antagonism of the H₁ and 5-HT_2A receptors.{{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 }} 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 tricyclic antidepressants (K_D = 1,140 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 and serotonin transporters (K_D = 4.37 and 18 nM, respectively).

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.{{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 | pmc = 11545471 }} 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.{{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 }}{{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 }}{{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 }}

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, 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.

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. 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.{{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 }}

Nortriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure.{{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}} Other dibenzocycloheptadiene tricyclic antidepressants include amitriptyline (N-methylnortriptyline), protriptyline, and butriptyline.{{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–}} Nortriptyline is a secondary amine tricyclic antidepressant, with its N-methylated parent amitriptyline being a tertiary amine.{{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–}}{{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–}} Other secondary amine tricyclic antidepressants include desipramine and protriptyline.{{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–}}{{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–}} The chemical name of nortriptyline is 3-(10,11-dihydro-5H-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 g/mol. The drug is used commercially mostly as the hydrochloride salt; the free base form is used rarely. The CAS Registry Number of the free base is 72-69-5 and of the hydrochloride is 894-71-3.{{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}}

Nortriptyline was developed by Geigy.{{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 }} It first appeared in the literature in 1962 and was patented the same year. The drug was first introduced for the treatment of depression in 1963.{{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–}}

File:Nortriptyline HCL capsules - 50mg and 25mg.JPG.]]

Nortriptyline is the 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}}.{{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–}}{{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–}}{{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–}}{{Cite web | url= https://www.drugs.com/international/nortriptyline.html | title=Nortriptyline}} 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.

Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensival, among many others.

Although not approved by the US Food and Drug Administration (FDA) for neuropathic pain, randomized controlled trials have demonstrated the effectiveness of tricyclic antidepressants 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.{{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 }} However, in a 2015 Cochrane systematic review the authors did not recommend nortriptyline as a first-line agent for neuropathic pain.{{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 }}{{cite journal | vauthors = Rungruanghiranya S, Tulatamakit S, Chittawatanarat K, Preedapornpakorn K, Wongphan T, Sutanthavibul N, Preechawong S, Petborom P | title = Efficacy and safety of cytisine versus nortriptyline for smoking cessation: A multicentre, randomized, double-blinded and placebo-controlled trial | journal = Respirology | volume = 29| issue = 10| pages = 880–887| date = July 2024 | pmid = 39004954 | doi = 10.1111/resp.14787 }}

It may be effective in the treatment of tobacco-cessation.{{cite journal | vauthors = Pajai DD, Paul P, Reche A | title = Pharmacotherapy in Tobacco Cessation: A Narrative Review | journal = Cureus | volume = 15 | issue = 2 | pages = e35086 | date = February 2023 | pmid = 36938244 | pmc = 10023046 | doi = 10.7759/cureus.35086 | doi-access = free }}{{cite journal | vauthors = Hajizadeh A, Howes S, Theodoulou A, Klemperer E, Hartmann-Boyce J, Livingstone-Banks J, Lindson N | title = Antidepressants for smoking cessation | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 5 | pages = CD000031 | date = May 2023 | pmid = 37230961 | pmc = 10207863 | doi = 10.1002/14651858.CD000031.pub6 }}

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