Chemistry:Nortriptyline

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Short description: Antidepressant medication
Nortriptyline
Skeletal formula of nortriptyline
Ball-and-stick model of the nortriptyline molecule
Clinical data
Trade namesPamelor, Noritren, Nortrilen, others
Other namesDesitriptyline; ELF-101; E.L.F. 101; N-7048
AHFS/Drugs.comMonograph
MedlinePlusa682620
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classTricyclic antidepressant (TCA)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability32–79%[2]
Protein binding92%[2]
MetabolismLiver
Metabolites10-E-Hydroxynortriptyline
Elimination half-life18–44 hours (mean 30 hours)[2]
ExcretionUrine: 40%[2]
Feces: minor[2]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC19H21N
Molar mass263.384 g·mol−1
3D model (JSmol)
  (verify)

Nortriptyline, sold under the brand name Pamelor, among others, is a medication used to treat depression. This medicine is also sometimes used for neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety.[3][4] 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.[4] Nortriptyline is a less preferred treatment for ADHD and stopping smoking.[4] It is taken by mouth.[4]

Common side effects include dry mouth, constipation, blurry vision, sleepiness, low blood pressure with standing, and weakness.[4] Serious side effects may include seizures, an increased risk of suicide in those less than 25 years of age, urinary retention, glaucoma, mania, and a number of heart issues.[4] Nortriptyline may cause problems if taken during pregnancy.[4] Use during breastfeeding appears to be relatively safe.[3] It is a tricyclic antidepressant (TCA) and is believed to work by altering levels of serotonin and norepinephrine.[4][lower-alpha 1]

Nortriptyline was approved for medical use in the United States in 1964.[4] It is available as a generic medication.[3] In 2020, it was the 155th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[5][6]

Medical uses

Nortriptyline is used to treat depression.[7] This medication is in capsule or liquid and is taken by the mouth one to four times a day, with or without food.[7] Usually people are started on a low dose and it is gradually increased.[7] A level between 50 and 150 ng/mL of nortriptyline in the blood generally corresponds with an antidepressant effect.[8]

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 for the treatment of panic disorder, irritable bowel syndrome, migraine prophylaxis and chronic pain or neuralgia modification, particularly temporomandibular joint disorder.[9]

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.[10] However, in a 2015 Cochrane systematic review the authors did not recommend nortriptyline as a first-line agent for neuropathic pain.[11]

Irritable bowel syndrome

Nortriptyline has also been used as an off-label treatment for irritable bowel syndrome (IBS).[12]

Contraindications

Nortriptyline should not be used in the acute recovery phase after myocardial infarction (viz, heart attack).[13] 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.[14]

Closer monitoring is required for those with a history of cardiovascular disease,[15] 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.[16][17] An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects.[16]

Overdose

Main page: Medicine: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, agitation, fever, low body temperature, stiff muscles and vomiting.[7]

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:[18]

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).[19][20]

Pharmacodynamics

Site Ki (nM) Species Ref
NET 1.8–4.4 Human [21][22]
DAT 1,140 Human [21]
5-HT1A 294 Human [23]
5-HT2A 5.0–41 Human/rat [24][23]
5-HT2C 8.5 Rat [24]
5-HT3 1,400 Rat [25]
5-HT6 148 Rat [26]
α1 55 Human [23]
α2 2,030 Human [23]
β >10,000 Rat [27]
D2 2,570 Human [23]
H1 3.0–15 Human [28][23][29]
H2 646 Human [28]
H3 45,700 Human [28]
H4 6,920 Human [28]
mACh 37 Human [23]
  M1 40 Human [30]
  M2 110 Human [30]
  M3 50 Human [30]
  M4 84 Human [30]
  M5 97 Human [30]
σ1 2,000 Guinea pig [31]
Values are Ki (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.[32]

Nortriptyline may also have a sleep-improving effect due to antagonism of the H1 and 5-HT2A receptors.[33] 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 (KD = 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 (KD = 4.37 and 18 nM, respectively).[21]

Pharmacokinetics

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.[34] 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.[35][36][37]

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,[37] 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.[35][36][37]

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.[37] 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.[38]

Chemistry

Nortriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure.[39] Other dibenzocycloheptadiene TCAs include amitriptyline (N-methylnortriptyline), protriptyline, and butriptyline.[39][40] Nortriptyline is a secondary amine TCA, with its N-methylated parent amitriptyline being a tertiary amine.[41][42] Other secondary amine TCAs include desipramine and protriptyline.[43][44] 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.[45] The drug is used commercially mostly as the hydrochloride salt; the free base form is used rarely.[45][46] The CAS Registry Number of the free base is 72-69-5 and of the hydrochloride is 894-71-3.[45][46][47]

History

Nortriptyline was developed by Geigy.[48] It first appeared in the literature in 1962 and was patented the same year.[48] The drug was first introduced for the treatment of depression in 1963.[48][49]

Society and culture

50 mg (left) and 25 mg generic nortriptyline HCl capsules made by Teva Pharmaceutical Industries.

Generic names

Nortriptyline is the English and French generic name of the drug and its INN, BAN, and DCF, while nortriptyline hydrochloride is its USAN, USP, BANM, and JAN.[45][46][50][51] Its generic name in Spanish and Italian and its DCIT are nortriptilina, in German is nortriptylin, and in Latin is nortriptylinum.[45][46][50][51]

Brand names

Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensoval, among many others.[45][46][51]

Footnotes

  1. ↑ Nortriptyline actually belongs to a class of drugs called serotonin–norepinephrine reuptake inhibitors (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 neurotransmitters 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 nociceptive pain.

References

  1. ↑ "Nortriptyline Use During Pregnancy". 22 June 2020. https://www.drugs.com/pregnancy/nortriptyline.html. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. 24 January 2012. pp. 588–. ISBN 978-1-60913-345-0. https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA588. 
  3. ↑ 3.0 3.1 3.2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 374. ISBN 9780857113382. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 "Nortriptyline Hydrochloride Monograph for Professionals" (in en). American Society of Health-System Pharmacists. https://www.drugs.com/monograph/nortriptyline-hydrochloride.html. 
  5. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  6. ↑ "Nortriptyline Hydrochloride - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/NortriptylineHydrochloride. 
  7. ↑ 7.0 7.1 7.2 7.3 "Nortriptyline". National Library of Medicine. https://medlineplus.gov/druginfo/meds/a682620.html. 
  8. ↑ "Therapeutic monitoring of antidepressant drugs: guidelines updated". Therapeutic Drug Monitoring 11 (5): 497–507. September 1989. doi:10.1097/00007691-198909000-00002. PMID 2683251. 
  9. ↑ Martindale. The complete drug reference (33 ed.). Pharmaceutical Press. 2002. ISBN 0-85369-499-0. https://archive.org/details/martindale00sean. 
  10. ↑ "Recommendations for the pharmacological management of neuropathic pain: an overview and literature update". Mayo Clinic Proceedings 85 (3 Suppl): S3-14. March 2010. doi:10.4065/mcp.2009.0649. PMID 20194146. 
  11. ↑ "Nortriptyline for neuropathic pain in adults". The Cochrane Database of Systematic Reviews 1 (1): CD011209. January 2015. doi:10.1002/14651858.CD011605. PMID 25569864. 
  12. ↑ "The Use of Antidepressants in the Treatment of Irritable Bowel Syndrome and Other Functional GI Disorders". https://www.med.unc.edu/ibs/files/2017/10/IBS-and-Antidepressants.pdf. 
  13. ↑ "Nortriptyline label". FDA. 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018013s063lbl.pdf. 
  14. ↑ "Nortriptyline". StatPearls. StatPearls Publishing. 2018. https://www.ncbi.nlm.nih.gov/books/NBK482214/. Retrieved 2018-10-03. 
  15. ↑ "Sudden cardiac arrest associated with use of a non-cardiac drug that reduces cardiac excitability: evidence from bench, bedside, and community". European Heart Journal 34 (20): 1506–16. May 2013. doi:10.1093/eurheartj/eht054. PMID 23425522. 
  16. ↑ 16.0 16.1 "Nortriptyline Hydrochloride – Martindale: The Complete Drug Reference". MedicinesComplete. Pharmaceutical Press. 9 January 2017. https://www.medicinescomplete.com/mc/martindale/current/2530-w.htm. 
  17. ↑ "ALLEGRON". Arrow Pharma Pty Ltd. 13 October 2016. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2016-PI-02638-1. 
  18. ↑ "nortriptyline". https://www.cardiosmart.org/Healthwise/d001/44/d00144. 
  19. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named PDSP
  20. ↑ Brunton L, Chabner B, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.
  21. ↑ 21.0 21.1 21.2 Cite error: Invalid <ref> tag; no text was provided for refs named pmid9537821
  22. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named pmid9400006
  23. ↑ 23.0 23.1 23.2 23.3 23.4 23.5 23.6 "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology 114 (4): 559–65. 1994. doi:10.1007/bf02244985. PMID 7855217. 
  24. ↑ 24.0 24.1 "Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor". Psychopharmacology 126 (3): 234–40. 1996. doi:10.1007/bf02246453. PMID 8876023. 
  25. ↑ "'[3H]quipazine' degradation products label 5-HT uptake sites". Eur. J. Pharmacol. 171 (1): 141–3. 1989. doi:10.1016/0014-2999(89)90439-1. PMID 2533080. 
  26. ↑ "Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs". Mol. Pharmacol. 43 (3): 320–7. 1993. PMID 7680751. 
  27. ↑ "Beta adrenergic receptor binding in membrane preparations from mammalian brain". Mol. Pharmacol. 12 (4): 568–80. 1976. PMID 8699. 
  28. ↑ 28.0 28.1 28.2 28.3 "Interactions of recombinant human histamine H1R, H2R, H3R, and H4R receptors with 34 antidepressants and antipsychotics". Naunyn Schmiedebergs Arch. Pharmacol. 385 (2): 145–70. 2012. doi:10.1007/s00210-011-0704-0. PMID 22033803. 
  29. ↑ "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". Bioorg. Med. Chem. 14 (19): 6640–58. 2006. doi:10.1016/j.bmc.2006.05.077. PMID 16782354. 
  30. ↑ 30.0 30.1 30.2 30.3 30.4 "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics". Biochem. Pharmacol. 45 (11): 2352–4. 1993. doi:10.1016/0006-2952(93)90211-e. PMID 8100134. 
  31. ↑ "1,3-Di(2-[5-3Htolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs"]. Proc. Natl. Acad. Sci. U.S.A. 83 (22): 8784–8. 1986. doi:10.1073/pnas.83.22.8784. PMID 2877462. Bibcode: 1986PNAS...83.8784W. 
  32. ↑ Screening for Depression in Adults and Older Adults in Primary Care: An Updated Systematic Review. Agency for Healthcare Research and Quality (US). 2009. https://www.ncbi.nlm.nih.gov/books/NBK36406/table/ch1.t2/. 
  33. ↑ "Depression and sleep: pathophysiology and treatment". Dialogues in Clinical Neuroscience 8 (2): 217–26. 2006. doi:10.31887/DCNS.2006.8.2/mthase. PMID 16889107. 
  34. ↑ "Metabolism of tricyclic antidepressants". Cellular and Molecular Neurobiology 19 (3): 373–409. Jun 1999. doi:10.1023/A:1006949816036. PMID 10319193. 
  35. ↑ 35.0 35.1 "Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function". Molecular Psychiatry 18 (3): 273–87. Mar 2013. doi:10.1038/mp.2012.42. PMID 22565785. 
  36. ↑ 36.0 36.1 "Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes". Biochimica et Biophysica Acta (BBA) - General Subjects 1770 (3): 489–94. Mar 2007. doi:10.1016/j.bbagen.2006.09.019. PMID 17113714. 
  37. ↑ 37.0 37.1 37.2 37.3 "Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants". Clinical Pharmacology and Therapeutics 93 (5): 402–8. May 2013. doi:10.1038/clpt.2013.2. PMID 23486447. PMC 3689226. https://deepblue.lib.umich.edu/bitstream/2027.42/109971/1/cptclpt20132.pdf. 
  38. ↑ "Pharmacogenetics: from bench to byte—an update of guidelines". Clinical Pharmacology and Therapeutics 89 (5): 662–73. May 2011. doi:10.1038/clpt.2011.34. PMID 21412232. 
  39. ↑ 39.0 39.1 Polypharmacy in Psychiatry Practice, Volume I: Multiple Medication Use Strategies. Springer Science & Business Media. 15 February 2013. pp. 270–271. ISBN 978-94-007-5805-6. https://books.google.com/books?id=jy-LMZU7338C&pg=PA270. 
  40. ↑ Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. 2008. pp. 580–. ISBN 978-0-7817-6879-5. https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA580. 
  41. ↑ Pharmacodynamics and Drug Development: Perspectives in Clinical Pharmacology. John Wiley & Sons. 20 September 1994. pp. 160–. ISBN 978-0-471-95052-3. https://books.google.com/books?id=ncRXa8Dq88QC&pg=PA160. 
  42. ↑ Metabolism of Drugs and Other Xenobiotics. John Wiley & Sons. 23 February 2012. pp. 302–. ISBN 978-3-527-64632-6. https://books.google.com/books?id=f-XHh17NfwgC&pg=PA302. 
  43. ↑ Pharmacology Secrets. Elsevier Health Sciences. 2002. pp. 39–. ISBN 1-56053-470-2. https://books.google.com/books?id=_QQsj3PAUrEC&pg=PA39. 
  44. ↑ Shorter Oxford Textbook of Psychiatry. OUP Oxford. 9 August 2012. pp. 532–. ISBN 978-0-19-162675-3. https://books.google.com/books?id=Y1DtSGq-LnoC&pg=PA532. 
  45. ↑ 45.0 45.1 45.2 45.3 45.4 45.5 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 888–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA888. 
  46. ↑ 46.0 46.1 46.2 46.3 46.4 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 752–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA752. 
  47. ↑ "ChemIDplus - 62265-06-9 - AMLRZIZSGSCSHZ-UHFFFAOYSA-N - Desipramine dibudinate - Similar structures search, synonyms, formulas, resource links, and other chemical information". https://chem.nlm.nih.gov/chemidplus/rn/62265-06-9. 
  48. ↑ 48.0 48.1 48.2 "Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters". Chem. Commun. (25): 3677–92. 2009. doi:10.1039/b903035m. PMID 19557250. 
  49. ↑ Medical Toxicology. Lippincott Williams & Wilkins. 2004. pp. 836–. ISBN 978-0-7817-2845-4. https://books.google.com/books?id=BfdighlyGiwC&pg=PA836. 
  50. ↑ 50.0 50.1 Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 6 December 2012. pp. 202–. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA202. 
  51. ↑ 51.0 51.1 51.2 "Nortriptyline". https://www.drugs.com/international/nortriptyline.html. 

External links



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