Nortriptyline

Source: Wikipedia, the free encyclopedia.

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%[4]
Protein binding92%[4]
MetabolismLiver
Metabolites10-E-Hydroxynortriptyline
Elimination half-life18–44 hours (mean 30 hours)[4]
ExcretionUrine: 40%[4]
Feces: minor[4]
Identifiers
  • 3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine
JSmol)
  • c3cc2c(/C(c1c(cccc1)CC2)=C/CCNC)cc3
  • InChI=1S/C19H21N/c1-20-14-6-11-19-17-9-4-2-7-15(17)12-13-16-8-3-5-10-18(16)19/h2-5,7-11,20H,6,12-14H2,1H3 checkY
  • Key:PHVGLTMQBUFIQQ-UHFFFAOYSA-N checkY
  (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.[5][6] 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.[6] Nortriptyline is a less preferred treatment for ADHD and stopping smoking.[6] It is taken by mouth.[6]

Common side effects include dry mouth, constipation, blurry vision, sleepiness,

low blood pressure with standing, and weakness.[6] 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.[6] Nortriptyline may cause problems if taken during pregnancy.[6] Use during breastfeeding appears to be relatively safe.[5] It is a tricyclic antidepressant (TCA) and is believed to work by altering levels of serotonin and norepinephrine.[6][a]

Nortriptyline was approved for medical use in the United States in 1964.

generic medication.[5] In 2021, it was the 139th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[7][8]

Medical uses

Nortriptyline is used to treat depression.[9] This medication is in capsule or liquid and is taken by the mouth one to four times a day, with or without food.[9] Usually people are started on a low dose and it is gradually increased.[9] A level between 50 and 150 ng/mL of nortriptyline in the blood generally corresponds with an antidepressant effect.[10]

In the

temporomandibular joint disorder.[11]

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.[12] However, in a 2015 Cochrane systematic review the authors did not recommend nortriptyline as a first-line agent for neuropathic pain.[13]

Irritable bowel syndrome

Nortriptyline has also been used as an off-label treatment for irritable bowel syndrome (IBS).[14]

Contraindications

Nortriptyline should not be used in the acute recovery phase after myocardial infarction (viz, heart attack).[15] 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.[16]

Closer monitoring is required for those with a history of cardiovascular disease,

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.

irregular heartbeat. Alcohol may exacerbate some of its side effects.[18]

Overdose

Main article: Tricyclic antidepressant overdose

The symptoms and the treatment of an overdose are generally the same as for the other TCAs, including

stiff muscles and vomiting.[9]

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:[20]

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).[21][22]

Pharmacodynamics

See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles
Nortriptyline[21]
Site Ki (nM) Species Ref
SERTTooltip Serotonin transporter 15–18 Human [23][24]
NETTooltip Norepinephrine transporter 1.8–4.4 Human [23][24]
DATTooltip Dopamine transporter 1,140 Human [23]
5-HT1A 294 Human [25]
5-HT2A 5.0–41 Human/rat [26][25]
5-HT2C 8.5 Rat [26]
5-HT3 1,400 Rat [27]
5-HT6 148 Rat [28]
α1 55 Human [25]
α2 2,030 Human [25]
β
 >10,000 Rat [29]
D2 2,570 Human [25]
H1 3.0–15 Human [30][25][31]
H2 646 Human [30]
H3 45,700 Human [30]
H4 6,920 Human [30]
mAChTooltip Muscarinic acetylcholine receptor 37 Human [25]
  M1 40 Human [32]
  M2 110 Human [32]
  M3 50 Human [32]
  M4 84 Human [32]
  M5 97 Human [32]
σ1 2,000 Guinea pig [33]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Nortriptyline is an active metabolite of

secondary amine dibenzocycloheptene and pharmacologically it is classed as a first-generation antidepressant.[34]

Nortriptyline may also have a sleep-improving effect due to antagonism of the H1 and 5-HT2A receptors.[35] 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).[23]

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.[36] 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.[37][38][39]

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,[39] 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.[37][38][39]

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.[39] 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.[40]

Chemistry

Nortriptyline is a

molecular weight of 263.384 g/mol.[47] The drug is used commercially mostly as the hydrochloride salt; the free base form is used rarely.[47][48] The CAS Registry Number of the free base is 72-69-5 and of the hydrochloride is 894-71-3.[47][48][49]

History

Nortriptyline was developed by Geigy.[50] It first appeared in the literature in 1962 and was patented the same year.[50] The drug was first introduced for the treatment of depression in 1963.[50][51]

Society and culture

Teva Pharmaceutical Industries
.

Generic names

Nortriptyline is the

Latin is nortriptylinum.[47][48][52][53]

Brand names

Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensoval, among many others.[47][48][53]

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". Drugs.com. 22 June 2020. Retrieved 10 October 2020.
  2. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  3. ^ "Product monograph brand safety updates". Health Canada. February 2024. Retrieved 24 March 2024.
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  6. ^ a b c d e f g h i "Nortriptyline Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 22 March 2019.
  7. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  8. ^ "Nortriptyline - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  9. ^ a b c d "Nortriptyline". MedlinePlus. National Library of Medicine. Retrieved 6 May 2019.
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  15. ^ "Nortriptyline label" (PDF). FDA. 2014.
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  18. ^ a b Brayfield A, ed. (9 January 2017). "Nortriptyline Hydrochloride – Martindale: The Complete Drug Reference". MedicinesComplete. Pharmaceutical Press. Retrieved 11 August 2017.
  19. ^ "ALLEGRON". TGA eBusiness Services. Arrow Pharma Pty Ltd. 13 October 2016. Retrieved 11 August 2017.
  20. ^ "nortriptyline". www.cardiosmart.org. Retrieved 3 October 2018.
  21. ^ a b Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  22. ^ Brunton L, Chabner B, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.
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