Amitriptyline

For the song Amitriptyline, see Life and Death of an American Fourtracker.
Amitriptyline
Clinical data
Pronunciation /ˌæmɪˈtrɪptɪliːn/[1]
Trade names Amitrip, Elavil, Endep, Levate
AHFS/Drugs.com Monograph
MedlinePlus a682388
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration		 Oral, intramuscular
ATC code N06AA09 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 30–60% due to first pass metabolism
Protein binding 96%<[2]
Metabolism Liver[2]
Biological half-life 10 to 50 hrs[2]
Excretion Mostly kidney[2]
Identifiers
CAS Number 50-48-6 YesY
549-18-8 (hydrochloride)
PubChem (CID) 2160
IUPHAR/BPS 200
DrugBank DB00321 YesY
ChemSpider 2075 YesY
UNII 1806D8D52K YesY
KEGG D07448 YesY
ChEBI CHEBI:2666 YesY
ChEMBL CHEMBL629 YesY
Chemical and physical data
Formula C20H23N
Molar mass 277.403 g/mol
3D model (Jmol) Interactive image
  (verify)

Amitriptyline, sold under the brand name Elavil among others, is a medicine used to treat a number of mental illnesses.[2] These include major depressive disorder and anxiety disorder, and less commonly attention deficit hyperactivity disorder and bipolar disorder.[2][3] Other uses include prevention of migraines, treatment of neuropathic pain such as fibromyalgia and postherpetic neuralgia, and less commonly insomnia.[2][4] It is in the tricyclic antidepressant (TCA) class and its exact mechanism of action is unclear.[2] Amitriptyline is taken by mouth.[2]

Common side effects include a dry mouth, trouble seeing, low blood pressure on standing, sleepiness, and constipation. Serious side effects may include seizures, an increased risk of suicide in those less than 25 years of age, urinary retention, glaucoma, and a number of heart issues. It should not be taken with MAO inhibitors or the medication cisapride.[2] Amitriptyline may cause problems if taken during pregnancy.[2][5] Use during breastfeeding appears to be relatively safe.[6]

Amitriptyline was discovered in 1960[7] and approved by the US Food and Drug Administration (FDA) in 1961.[8] It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[9] It is available as a generic medication.[2] The wholesale cost in the developing world as of 2014 is between 0.01 and 0.04 USD per dose.[10] In the United States it costs about 0.20 USD per dose.[2]

Medical uses

Two boxes of amitriptyline (Endep) in 10- and 25-mg doses

Amitriptyline is used for a number of medical conditions including major depressive disorder (MDD).[11][12][13] Some evidence suggests amitriptyline may be more effective than other antidepressants,[14] including selective serotonin reuptake inhibitors (SSRIs),[15] although it is rarely used as a first-line antidepressant due to its higher toxicity in overdose and generally poorer tolerability.[12]

It is TGA-labeled for migraine prevention, also in cases of neuropathic pain disorders,[12] fibromyalgia[4] and nocturnal enuresis.[12][16] Amitriptyline is a popular off-label treatment for irritable bowel syndrome (IBS),[17] although it is most frequently reserved for severe cases of abdominal pain in patients with IBS because it needs to be taken regularly to work and has a generally poor tolerability profile, although a firm evidence base supports its efficacy in this indication.[17] Amitriptyline can also be used as an anticholinergic drug in the treatment of early-stage Parkinson's disease if depression also needs to be treated.[18] Amitriptyline is the most widely researched agent for prevention of frequent tension headaches.[19]

Investigational uses

Adverse effects

Common (≥1% frequency) side effects include dizziness, headache, weight gain, side effects common to anticholinergics, but more such effects than other TCAs, cognitive effects such as delirium and confusion, mood disturbances such as anxiety and agitation, cardiovascular side effects such as orthostatic hypotension and sinus tachycardia, sexual side effects such as loss of libido and impotence, and sleep disturbances such as drowsiness, insomnia and nightmares.[11][12][13][20][29][30]

Contraindications

The known contraindications of amitriptyline are:[30]

  • Hypersensitivity to tricyclic antidepressants or to any of its excipients
  • History of myocardial infarction
  • History of arrhythmias, particularly heart block to any degree
  • Congestive heart failure
  • Coronary artery insufficiency
  • Mania
  • Severe liver disease
  • Children under 7 years
  • Breast feeding
  • Patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken them within the last 14 days.

Interactions

Amitriptyline is known to interact with:[29]

Overdose

The symptoms and the treatment of an overdose are largely the same as for the other TCAs, including the presentation of serotonin syndrome and adverse cardiac effects. The British National Formulary notes that amitriptyline can be particularly dangerous in overdose,[13] thus it and other tricyclic antidepressants are no longer recommended as first-line therapy for depression. Alternative agents, SSRIs and SNRIs, are safer in overdose, though they are no more efficacious than TCAs. English folk singer Nick Drake died from an overdose of Tryptizol in 1974.

The possible symptoms of amitriptyline overdose include:[29]

The treatment of overdose is mostly supportive as no specific antidote for amitriptyline overdose is available.[29] Activated charcoal may reduce absorption if given within 1–2 hours of ingestion.[29] If the affected person is unconscious or has an impaired gag reflex, a nasogastric tube may be used to deliver the activated charcoal into the stomach.[29] ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised.[29] Body temperature should be regulated with measures such as heating blankets if necessary.[29] Likewise, cardiac arrhythmias can be treated with propranolol and should heart failure occur, digitalis may be used.[29] Cardiac monitoring is advised for at least five days after the overdose.[29] Amitriptyline increases the CNS depressant action, but not the anticonvulsant action of barbiturates; therefore, an inhalation anaesthetic or diazepam is recommended for control of convulsions.[29] Dialysis is of no use due to the high degree of protein binding with amitriptyline.[29]

Mechanism of action

Receptor Ki [nM][Note 1]
(amitriptyline)[31][32]		 Ki [nM][Note 2]
(nortriptyline)[31][32]
SERT 3.13 16.5
NET 22.4 4.37
DAT 5380 3100
5-HT1A 450 294
5-HT1B 840 -
5-HT2A 4.3 5
5-HT2C 6.15 8.5
5-HT6 103 148
5-HT7 114 -
H1 1.1 15.1
H3 1000 -
H4 33.6 -
M1 12.9 40
M2 11.8 110
M3 25.9 50
M4 7.2 84
M5 19.9 97
α1 24 55
α2 690 2030
D1 89 -
D2 1460 2570
D3 206 -
D5 170 -
σ 300 2000

Amitriptyline acts primarily as a serotonin-norepinephrine reuptake inhibitor, with strong actions on the serotonin transporter and moderate effects on the norepinephrine transporter.[33][34] It has negligible influence on the dopamine transporter and therefore does not affect dopamine reuptake, being nearly 1,000 times weaker on it than on serotonin.[34] It is metabolised to nortriptyline—a more potent and selective norepinephrine reuptake inhibitor—which may complement its effects on norepinephrine reuptake.[29]

Amitriptyline additionally functions as a 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, α1-adrenergic, H1, H2,[35] H4,[36][37] and mACh receptor antagonist, and σ1 receptor agonist.[38][39][40][41] It has also been shown to be a relatively weak NMDA receptor negative allosteric modulator at the same binding site as phencyclidine.[42] Amitriptyline inhibits sodium channels, L-type calcium channels, and Kv1.1, Kv7.2, and Kv7.3 voltage-gated potassium channels, and therefore acts as a sodium, calcium, and potassium channel blocker as well.[43][44]

Recently, amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors.[45] It promotes the heterodimerization of these proteins in the absence of NGF and has potent neurotrophic activity both in-vivo and in-vitro in mouse models.[45][46] These are the same receptors BDNF activates, an endogenous neurotrophin with powerful antidepressant effects, and as such this property may contribute significantly to its therapeutic efficacy against depression. Amitriptyline also acts as a functional inhibitor of acid sphingomyelinase.[47]

Pharmacokinetics

Nortriptyline, amitriptyline's chief active metabolite

Amitriptyline is a highly lipophilic molecule having a log P (octanol/water, pH 7.4) of 3.0,[48] while the intrinsic log P of the free base was reported as 5.04.[49]

Amitriptyline is readily absorbed from the gastrointestinal tract and is extensively metabolised on first pass through the liver.[29] It is metabolised mostly by CYP2D6, CYP3A4, and CYP2C19-mediated N-demethylation into nortriptyline,[29] which is another tricyclic antidepressant in its own right.[50] It is 96% bound to plasma proteins, nortriptyline is 93-95% bound to plasma proteins.[29][51] It is mostly excreted in the urine (around 30–50%) as metabolites either free or as glucuronide and sulfate conjugates.[29] Small amounts are also excreted in feces.[20]

Pharmacogenetics

Since amitriptyline is primarily metabolized by CYP2D6 and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body.[52] Increased concentrations of amitriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy.[53][54][55]

Individuals can be categorized into different types of CYP2D6 or CYP2C19 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,[55] and have "normal" metabolism of amitriptyline. 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 amitriptyline much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure.[53][54][55]

The Clinical Pharmacogenetics Implementation Consortium recommends avoiding amitriptyline in patients who are CYP2D6 ultrarapid or poor metabolizers, due to the risk for a lack of efficacy and side effects, respectively. The consortium also recommends considering an alternative drug not metabolized by CYP2C19 in patients who are CYP2C19 ultrarapid metabolizers. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers and CYP2C19 poor metabolizers. If use of amitriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments.[55] The Dutch Pharmacogenetics Working Group also recommends selecting an alternative drug or monitoring plasma concentrations of amitriptyline in patients who are CYP2D6 poor or ultrarapid metabolizers, and selecting an alternative drug or reducing initial dose in patients who are CYP2D6 intermediate metabolizers.[56]

Brand names

Brand names include (just including those used in English-speaking countries with † to indicate discontinued brands):[50][57]

  • Amirol (NZ)
  • Amit (IN)
  • Amitone (IN)
  • Amitor (IN)
  • Amitrip (AU,† IN, NZ)
  • Amitriptyline (UK)
  • Amitriptyline Hydrochloride (UK)
  • Amitriptyline Hydrochloride Caraco (US)
  • Amitriptyline Hydrochloride Mutual (US)
  • Amitriptyline Hydrochloride Mylan (US)
  • Amitriptyline Hydrochloride Sandoz (US)
  • Amitriptyline Hydrochloride Vintage (US)
  • Amitrol† (AU)
  • Amrea (IN)
  • Amypres (IN)
  • Apo-Amitriptyline (CA, HK, SG)
  • Crypton (IN)
  • Elavil (CA, UK†, US†)
  • Eliwel (IN)
  • Endep (AU, HK]]† , ZA†, US†)
  • Enovil† (US)
  • Gentrip (IN)
  • Kamitrin (IN)
  • Laroxyl(FR)
  • Latilin (IN)
  • Levate (US)
  • Maxitrip (IN)
  • Mitryp (IN)
  • Mitryp-10 (IN)
  • Odep (IN)
  • Redomex (BE)
  • Qualitriptine (HK)
  • Sandoz Amitriptyline (ZA)
  • Saroten (CH)
  • Sarotena (IN)
  • Tadamit (IN)
  • Trepiline (ZA)
  • Tripta (SG) (TH)
  • Triptaz (IN)
  • Tryptanol (ZA)
  • Tryptizol (Spain)
  • Triptyl (FI)
  • Tryptomer (IN)

Notes

  1. ↑ These Ki values are averaged binding affinities towards cloned human receptors when available.
  2. ↑ As with amitriptyline, these Kivalues are averaged binding affinities towards cloned human receptors when available.

References

  1. ↑ Oxford Dictionary: Definition of amitriptyline (British & World English)
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Amitriptyline Hydrochloride". The American Society of Health-System Pharmacists. Retrieved Sep 25, 2014.
  3. ↑ Leucht, C; Huhn, M; Leucht, S (December 2012). "Amitriptyline versus placebo for major depressive disorder.". The Cochrane Database of Systematic Reviews. 12: CD009138. doi:10.1002/14651858.CD009138.pub2. PMID 23235671.
  4. 1 2 Moore, RA; Derry, S; Aldington, D; Cole, P; Wiffen, PJ (6 July 2015). "Amitriptyline for neuropathic pain in adults.". The Cochrane database of systematic reviews. 7: CD008242. doi:10.1002/14651858.CD008242.pub3. PMID 26146793.
  5. ↑ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Retrieved 22 April 2014.
  6. ↑ "Amitriptyline Levels and Effects while Breastfeeding". drugs.com. Sep 8, 2014. Retrieved 25 September 2014.
  7. ↑ Sneader, Walter (2005). Drug Discovery a History. Chichester: John Wiley & Sons. p. 414. ISBN 9780470015520.
  8. ↑ Fangmann P, Assion HJ, Juckel G, González CA, López-Muñoz F (February 2008). "Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part II: tricyclics and tetracyclics". Journal of Clinical Psychopharmacology. 28 (1): 1–4. doi:10.1097/jcp.0b013e3181627b60. PMID 18204333.
  9. ↑ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  10. ↑ "Amitriptyline". International Drug Price Indicator Guide. Retrieved 2 December 2015.
  11. 1 2 "AMITRIPTYLINE HYDROCHLORIDE tablet, film coated [Dispensing Solutions, Inc.]". DailyMed. Dispensing Solutions, Inc. September 2013. Retrieved 1 December 2013.
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  28. ↑ http://gi.org/guideline/management-of-gastroparesis
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  37. ↑ D. Sriram; P. Yogeeswari (1 September 2010). Medicinal Chemistry. Pearson Education India. p. 299. ISBN 978-81-317-3144-4. Retrieved 27 November 2011.
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  42. ↑ Sills MA, Loo PS (July 1989). "Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate". Mol. Pharmacol. 36 (1): 160–5. PMID 2568580.
  43. ↑ Pancrazio JJ, Kamatchi GL, Roscoe AK, Lynch C (January 1998). "Inhibition of neuronal Na+ channels by antidepressant drugs". J. Pharmacol. Exp. Ther. 284 (1): 208–14. PMID 9435180.
  44. ↑ Punke MA, Friederich P (May 2007). "Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels". Anesthesia and Analgesia. 104 (5): 1256–1264. doi:10.1213/01.ane.0000260310.63117.a2. PMID 17456683.
  45. 1 2 Jang SW, Liu X, Chan CB, Weinshenker D, Hall RA, Xiao G, Ye K (June 2009). "Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity". Chem. Biol. 16 (6): 644–56. doi:10.1016/j.chembiol.2009.05.010. PMC 2844702Freely accessible. PMID 19549602.
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  55. 1 2 3 4 Hicks JK, Swen JJ, Thorn CF, Sangkuhl K, Kharasch ED, Ellingrod VL, Skaar TC, Muller DJ, Gaedigk A, Stingl JC (2013). "Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants". Clinical Pharmacology & Therapeutics. 93 (5): 402–8. doi:10.1038/clpt.2013.2. PMC 3689226Freely accessible. PMID 23486447.
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Further reading

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