Nortriptyline

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Nortriptyline
Skeletal formula of nortriptyline
Ball-and-stick model of the nortriptyline molecule
Systematic (IUPAC) name
3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine
Clinical data
Trade names Aventyl
AHFS/Drugs.com monograph
MedlinePlus a682620
Pregnancy
category
  • AU: C
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability High
Metabolism Hepatic
Biological half-life 16 and 90 hours
Excretion Renal
Identifiers
CAS Number 72-69-5 YesY
894-71-3 (hydrochloride)
ATC code N06AA10 (WHO)
PubChem CID: 4543
IUPHAR/BPS 2404
DrugBank DB00540 YesY
ChemSpider 4384 YesY
UNII BL03SY4LXB YesY
KEGG D08288 YesY
ChEBI CHEBI:7640 YesY
ChEMBL CHEMBL445 YesY
Chemical data
Formula C19H21N
Molecular mass 263.38 g/mol
  • 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 YesY
  • Key:PHVGLTMQBUFIQQ-UHFFFAOYSA-N YesY
  (verify)

Nortriptyline is a second-generation tricyclic antidepressant (TCA) marketed as the hydrochloride salt under the trade names Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen. It is used in the treatment of major depression and childhood nocturnal enuresis (bedwetting). In addition, it is sometimes used for chronic illnesses such as chronic fatigue syndrome[citation needed], chronic pain and migraine, and labile affect in some neurological conditions.

Medical uses

Nortriptyline is FDA-approved for the treatment of major depression. 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.[1] It can also aid in quitting smoking, with one study showing a six-month abstinence rate of 14% for subjects receiving nortriptyline compared to 3% for subjects not undergoing pharmacological treatment.[2] A controlled study suggests it reduces symptoms of ADHD.[3][4]

Neuropathic pain

Although not approved by the FDA for neuropathic pain, a large number of randomized controlled trials have demonstrated the efficacy of tricyclic antidepressants for the treatment of this condition in both depressed and non-depressed individuals. Recently, an evidence-based guideline sponsored by the International Association for the Study of Pain recommends nortriptyline as a first-line medication for neuropathic pain.[5]

Side effects

The most common side effects include dry mouth, sedation, constipation, and increased appetite, mild blurred vision, tinnitus, often euphoria and mania.[citation needed] An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects and should be avoided.

However, the incidence of side effects with nortriptyline is lower than with the first-generation tricyclics (e.g., imipramine (Tofranil), amitriptyline (Elavil)). For this reason it is often used in elder patients instead of other TCAs to reduce side effects and improving patient's compliance.

A study with men has found that treatment with nortriptyline is associated with higher risk of suicidal ideation compared to escitalopram.[6]

Warnings

Closer monitoring is required for those with a history of cardiovascular disease, stroke, glaucoma, or seizures, as well as those that have hyperthyroidism or are receiving thyroid medication.

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.

Contraindications

Nortriptyline should not be used in the acute recovery phase after myocardial infarction (e.g., heart attack). Unlike TCAs Clomipramine and Imipramine, concurrent use of Nortriptyline with MAO inhibitors is safe within recommended dosage ranges.[medical citation needed]

Overdose

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Main article: Tricyclic antidepressant overdose

The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants, including serotonin syndrome and adverse cardiac effects. As tricyclic antidepressants have a relatively narrow therapeutic index, the likelihood of overdose (both accidental and intentional) is fairly high and should be considered carefully by the prescribing physician prior to patient use.

A nortriptyline overdose should always be considered a medical emergency and can result in death. In the event of a known or suspected overdose, poison control (1-800-222-1222 in the U.S.) or 911 (999 in the U.K.) should be contacted immediately. If no phone services are available the overdose victim should be brought to the nearest hospital as soon as possible.

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.[7] 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.[8][9][10]

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,[10] 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.[8][9][10]

The Clinical Pharmacogenetics Implementation Consortium recommends avoiding nortriptyline in patients who are CYP2D6 ultrarapid or poor metabolizers, due to the risk for 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.[10] 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.[11]

Pharmacology

Nortriptyline is an active metabolite of amitriptyline that is demethylated in the liver. Its pharmacologic profile is as follows:[12][13]

Receptor/Transporter Protein Binding Affinity (Ki[nM]) Receptor location and species
SERT 16.5 Human, cloned
NET 4.37 Human, cloned
DAT 3100 Human, cloned
5-HT1A 294 Human, brain
5-HT2A 5 Rat, cloned
5-HT2C 8.5 Rat, cloned
5-HT6 148 Rat, cloned
α1 55 Human, brain
α2 2030 Human, brain
β >10000 Mammalian, brain
M1 40 Human, cloned
M2 110 Human, cloned
M3 50 Human, cloned
M4 84 Human, cloned
M5 97 Human, cloned
D2 2570 Human, brain
H1 15.1 Human, cloned
Sigma receptor 2000 Guinea pig, brain

These effects account for some therapeutic actions as well as for most side effects such as sedation, hypotension, anticholinergic effects, etc. Nortriptyline may also have a sleep-improving effect due to its affinity for 5HT2A and histaminergic receptors.[14] In the short term; however, nortriptyline may disturb sleep due to its activating effect.

Like other tricyclic antidepressants, nortriptyline also blocks sodium channels, possibly accounting in part for its analgesic action.

In one study of long-term efficacy, nortriptyline showed a higher relapse rate in comparison with phenelzine in individuals being treated for depression, possibly due to the metabolite 10-hydroxynortriptyline being produced.[15] The authors of a review noted that the nortriptyline group had more episodes prior to treatment.[15]

References

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  10. ↑ 10.0 10.1 10.2 10.3 Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Oct 3]. Chapel Hill (NC): University of North Carolina. 1998-2013. Available from: http://pdsp.med.unc.edu/pdsp.php
  13. ↑ Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ 15.0 15.1 Lua error in package.lua at line 80: module 'strict' not found.

External links

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