Nortriptyline

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Nortriptyline
Nortriptyline.svg
Systematic (IUPAC) name
3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine
Clinical data
Trade namesAventyl
AHFS/Drugs.commonograph
MedlinePlusa682620
Pregnancy cat.
Legal status
RoutesOral
Pharmacokinetic data
BioavailabilityHigh
MetabolismHepatic
Half-life16 and 90 hours
ExcretionRenal
Identifiers
CAS number72-69-5 YesY
894-71-3 (hydrochloride)
ATC codeN06AA10
PubChemCID 4543
IUPHAR ligand2404
DrugBankDB00540
ChemSpider4384 YesY
UNIIBL03SY4LXB YesY
KEGGD08288 YesY
ChEBICHEBI:7640 YesY
ChEMBLCHEMBL445 YesY
Chemical data
FormulaC19H21N 
Mol. mass263.38 g/mol
 YesY (what is this?)  (verify)
 
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Nortriptyline
Nortriptyline.svg
Systematic (IUPAC) name
3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine
Clinical data
Trade namesAventyl
AHFS/Drugs.commonograph
MedlinePlusa682620
Pregnancy cat.
Legal status
RoutesOral
Pharmacokinetic data
BioavailabilityHigh
MetabolismHepatic
Half-life16 and 90 hours
ExcretionRenal
Identifiers
CAS number72-69-5 YesY
894-71-3 (hydrochloride)
ATC codeN06AA10
PubChemCID 4543
IUPHAR ligand2404
DrugBankDB00540
ChemSpider4384 YesY
UNIIBL03SY4LXB YesY
KEGGD08288 YesY
ChEBICHEBI:7640 YesY
ChEMBLCHEMBL445 YesY
Chemical data
FormulaC19H21N 
Mol. mass263.38 g/mol
 YesY (what is this?)  (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[edit]

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] Research has been done suggesting it can also reduce symptoms of ADHD.[3]

Neuropathic pain[edit]

Although not approved by the FDA for neuropathic pain, a large number of randomized controlled trials have proven 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.[4]

Side effects[edit]

The most common side effects include dry mouth, sedation, constipation, and increased appetite, mild blurred vision, tinnitus, often euphoria and mania. 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.[5]

Warnings[edit]

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[edit]

Nortriptyline should not be used in the acute recovery phase after myocardial infarction (e.g., heart attack). As for all tricyclic antidepressants, concurrent use, or failure to allow a two-week gap with monoamine oxidase inhibitors (MAO inhibitors, e.g., phenelzine, tranylcypromine, etc.) may precipitate hyperpyretic crisis caused by serotonin syndrome or severe convulsions.

Overdose[edit]

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.

Metabolism[edit]

Nortriptyline is metabolized in the liver by the hepatic enzyme CYP2D6. Approximately 7-10% of caucasians are poor metabolizers and might experience more adverse effects, so a lower dosage is often necessary in these individuals.[6] Blood levels of nortriptyline should be obtained during long term treatment to avoid toxicity and optimize response.

Clinical pharmacology[edit]

Nortriptyline is an active metabolite of amitriptyline that is demethylated in the liver. Its pharmacologic profile is as follows:[7][8]

Receptor/Transporter ProteinBinding Affinity (Ki[nM])Receptor location and species
SERT16.5Human, cloned
NET4.37Human, cloned
DAT3100Human, cloned
5-HT1A294Human, brain
5-HT2A5Rat, cloned
5-HT2C8.5Rat, cloned
5-HT6148Rat, cloned
α155Human, brain
α22030Human, brain
β>10000Mammalian, brain
M140Human, cloned
M2110Human, cloned
M350Human, cloned
M484Human, cloned
M597Human, cloned
D22570Human, brain
H115.1Human, cloned
Sigma receptor2000Guinea 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.[9] 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.[10] The authors of a review noted that the nortriptyline group had more episodes prior to treatment.[10]

References[edit]

  1. ^ Sweetman SC, ed. (2002). Martindale. The complete drug reference (33 ed.). Pharmaceutical Press. ISBN 0-85369-499-0. 
  2. ^ Prochazka A, Weaver M, Keller R, Fryer G, Licari P, Lofaso D (1998). "A randomized trial of nortriptyline for smoking cessation". Arch Intern Med 158 (18): 2035–9. doi:10.1001/archinte.158.18.2035. PMID 9778204. 
  3. ^ Wilens, Timothy E.; Biederman, Joseph M.D.; Geist, David E.; Steingard, Ronald M.D.; Spencer, Thomas M.D. (1993). "Nortriptyline in the Treatment of ADHD: A Chart Review of 58 Cases". J. Am. Acad. Child Adolesc. Psychiatry (American Academy of Child and Adolescent Psychiatry) 32 (2): 343–349. doi:10.1097/00004583-199303000-00015. PMID 8444763. 
  4. ^ Robert H. Dworkin et al. (2010). "Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update". Mayo Clinic Proceedings 85 (3): S3–S14. doi:10.4065/mcp.2009.0649. PMC 2844007. PMID 20194146. 
  5. ^ Perroud, N.; Uher, R.; Marusic, A.; Rietschel, M.; Mors, O.; Henigsberg, N.; Hauser, J.; Maier, W.; Souery, D.; Placentino, A.; Szczepankiewicz, A.; Jorgensen, L.; Strohmaier, J.; Zobel, A.; Giovannini, C.; Elkin, A.; Gunasinghe, C.; Gray, J.; Campbell, D.; Gupta, B.; Farmer, A. E.; McGuffin, P.; Aitchison, K. J. (2009). "Suicidal ideation during treatment of depression with escitalopram and nortriptyline in Genome-Based Therapeutic Drugs for Depression (GENDEP): a clinical trial". BMC medicine 7: 60. doi:10.1186/1741-7015-7-60. PMC 2768737. PMID 19832967.  edit
  6. ^ "Pamelor (nortriptyline HCl) drug information". Retrieved 15 February 2010. 
  7. ^ 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
  8. ^ Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.
  9. ^ Thase ME (2006). "Depression and sleep: pathophysiology and treatment". Dialogues Clin Neurosci 8 (2): 217–26. PMC 3181772. PMID 16889107. 
  10. ^ a b Kennedy SH (March 1997). "Continuation and maintenance treatments in major depression: the neglected role of monoamine oxidase inhibitors". J Psychiatry Neurosci 22 (2): 127–31. PMC 1188835. PMID 9074307. 

External links[edit]