Amitriptyline: Difference between revisions

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! Receptor !! K<sub>i</sub> [nM]<ref group = Note>These K<sub>i</sub> values are averaged binding affinities towards cloned human receptors when available.</ref> <br>(amitriptyline)<ref name = PDSP>{{cite web | title = PDSP K<sub>i</sub> Database |work = Psychoactive Drug Screening Program (PDSP)|author =  Roth, BL; Driscol, J | url =http://pdsp.med.unc.edu/pdsp.php | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | accessdate = 1 December 2013 |date = 12 January 2011}}</ref><ref name = GG>{{cite isbn|9780071624428}}</ref>!! K<sub>i</sub> [nM]<ref group = Note>As with amitriptyline, these K<sub>i</sub>values are averaged binding affinities towards cloned human receptors when available.</ref> <br>([[nortriptyline]])<ref name = PDSP/><ref name = GG/>
! Receptor !! K<sub>i</sub> [nM]These K<sub>i</sub> values are averaged binding affinities towards cloned human receptors when available.</ref> <br>(amitriptyline)<ref name = PDSP>{{cite web | title = PDSP K<sub>i</sub> Database |work = Psychoactive Drug Screening Program (PDSP)|author =  Roth, BL; Driscol, J | url =http://pdsp.med.unc.edu/pdsp.php | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | accessdate = 1 December 2013 |date = 12 January 2011}}</ref><ref name = GG>{{cite isbn|9780071624428}}</ref>!! K<sub>i</sub> [nM]As with amitriptyline, these K<sub>i</sub>values are averaged binding affinities towards cloned human receptors when available.</ref> <br>([[nortriptyline]])<ref name = PDSP/><ref name = GG/>
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| [[Serotonin transporter|SERT]] || 3.13 || 16.5
| [[Serotonin transporter|SERT]] || 3.13 || 16.5

Revision as of 01:43, 10 February 2014

Amitriptyline
AMITRIPTYLINE HYDROCHLORIDE®
FDA Package Insert
Indications and Usage
Dosage and Administration
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Overdosage
Description
Clinical Pharmacology
How Supplied/Storage and Handling
Patient Counseling Information
Labels and Packages
Clinical Trials on Amitriptyline
ClinicalTrials.gov

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

For patient information about Amitriptyline, click here.

Synonyms / Brand Names: Amitriptyline Hydrochloride, Amitriptyline HCL, Amitriprolidine, Amitriptylin, Amitryptiline, Amitryptyline, Amytriptiline, Adepress, Adepril, Amitid, Amitril, Damilan, Damilen, dAmitriptyline, Elanil, Elavil, Endep, Flavyl, Hexathane, Horizon, Lantron, Laroxil, Laroxyl, Lentizol, Proheptadiene, Redomex, Saroten, Sarotex, Seroten, Sylvemid, Triptanol, Triptilin, Triptisol, Tryptanol, Tryptizol

Overview

Amitriptyline (Elavil, Endep, Levate and many others) is a tricyclic antidepressant (TCA). It is the most widely used TCA and is an efficacious treatment for major depressive disorder (clinical depression). It was originally developed by Merck and was initially approved by the United States Food and Drug Administration (FDA) on 7 April 1961.[1]

Category

Antidepressants

FDA Package Insert

AMITRIPTYLINE HYDROCHLORIDE tablet, film coated

Indications and Usage | Dosage and Administration | Dosage Forms and Strengths | Contraindications | Warnings and Precautions | Adverse Reactions | Drug Interactions | Use in Specific Populations | Overdosage | Description | Clinical Pharmacology | Nonclinical Toxicology | Clinical Studies | How Supplied/Storage and Handling | Patient Counseling Information | Labels and Packages

Medical uses

Widely accepted medical uses

Amitriptyline is used for a number of medical conditions including major depressive disorder (MDD) which is its only FDA-labelled indication.[2] This is also a TGA- and MHRA-labelled indication.[3][4] Some evidence suggests that amitriptyline may have superior efficacy compared to other antidepressants,[5] including the SSRIs.[6] Although it is rarely used as a first-line antidepressant nowadays due to its high degree of toxicity in overdose and generally poorer tolerability than the newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).[3]

It is TGA-labelled for migraine prophylaxis, as it is also is in cases of neuropathic pain disorders,[3] fibromyalgia[7] and nocturnal enuresis.[3][8] Amitriptyline is a popular off-label treatment for irritable bowel syndrome.[9] Although it is most frequently reserved for severe cases of abdominal pain in patients with IBS due to the fact that 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.[9] Amitriptyline can also be used as an anticholinergic drug in the treatment of early stage Parkinson disease if depression also needs to be treated.[10]

Investigational uses

Adverse effects

Adverse effects by frequency

Adverse effects include the following:[2][11][22][23][3][4]

Common (≥1% frequency)

  • Weight gain
  • Anticholinergic side effects (it tends to produce more anticholinergic effects than the other TCAs) such as:
    • Constipation
    • Xerostomia (dry mouth)
    • Mydriasis (dilated pupils)
    • Blurred vision
    • Urinary hesitancy
    • Reduced GI motility
    • Anticholinergic delirium (particularly in the elderly and in Parkinson's disease)
  • Dizziness
  • Headache
  • Somnolence (drowsiness) it tends to be a more sedating TCA.[24][25]
  • Decreased lacrimation (that is, decreased ability to cry)
  • Orthostatic hypotension
  • Sinus tachycardia
  • Impotence
  • Loss of libido
  • Other sexual adverse effects
  • Tremor
  • Dizziness
  • Sweating
  • Agitation
  • Insomnia
  • Anxiety
  • Confusion

Uncommon (0.1–1% frequency)

  • Slowed cardiac conduction
  • T wave inversion or flattening (particularly at high doses)
  • Arrhythmias
  • Sinus tachycardia
  • Nausea
  • Hyperglycaemia
  • Gynaecomastia (breast enlargement in men)
  • Breast enlargement and galactorrhoea in females
  • Allergic skin reactions
  • Mania
  • Hypomania

Rare (<0.1% frequency)

Unknown frequency adverse effects

Contraindications

The following are the known contraindications of amitriptyline.[23]

  • 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:[22]

  • Monoamine oxidase inhibitors as it can potentially induce a serotonin syndrome
  • CYP2D6 inhibitors and substrates such as fluoxetine due to the potential for an increase in plasma concentrations of the drug to be seen.
  • Guanethidine — as it can reduce the antihypertensive effects of this drug.
  • Anticholinergic agents such as benztropine, hyoscine (scopolamine) and atropine. Due to the fact that the two might exacerbate each other's anticholinergic effects, including paralytic ileus and tachycardia.
  • Antipsychotics due to the potential for them to exacerbate the sedative, anticholinergic, epileptogenic and pyrexic (fever-promoting) effects. Also increases the risk of neuroleptic malignant syndrome
  • Cimetidine due to the potential for it to interfere with hepatic metabolism of amitriptyline and hence increasing steady-state concentrations of the drug.
  • Disulfiram due to the potential for the development of delirium
  • ECT may increase the risks associated with this treatment
  • Antithyroid medications — may increase the risk of agranulocytosis
  • Thyroid hormones — potential for increased adverse effects such as CNS stimulation and arrhythmias.
  • Analgesics, such as tramadol due to the potential for an increase in seizure risk.
  • Medications that are subject to gastric inactivation (e.g. levodopa) due to the potential for amitriptyline to delay gastric emptying and reduce intestinal motility
  • Medications that may be subject to increased absorption given more time in the small intestine (e.g. anticoagulants)
  • Serotoninergic agents such as the SSRIs and triptans due to the potential for serotonin syndrome.

Overdose

Main article: Tricyclic antidepressant 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,[4] 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:[22]

The treatment of overdose is mostly supportive as there is no specific antidote for amitriptyline overdose.[22] Activated charcoal may reduce absorption if given within 1-2 hours of ingestion.[22] If the affected person is unconscious or have an impaired gag reflex a nasograstic tube may be used to deliver the activated charcoal in the stomach.[22] ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised.[22] Body temperature should be regulated with measures such as heating blankets if necessary.[22] Likewise cardiac arrhythmias can be treated with propanolol and should heart failure occur digitalis may be used.[22] Cardiac monitoring is advised for at least five days after the overdose.[22] Other measures include the use of inhalation anaesthetics or diazepam for convulsions and barbiturates should be avoided if possible due to the potential for additive CNS depression (that is, on top of the CNS depression caused by the amitriptyline).[22] Dialysis is of no use due to the high degree of protein binding with amitriptyline.[22]

Mechanism of action

Receptor Ki [nM]These Ki values are averaged binding affinities towards cloned human receptors when available.</ref>
(amitriptyline)[26][25]		 Ki [nM]As with amitriptyline, these Kivalues are averaged binding affinities towards cloned human receptors when available.</ref>
(nortriptyline)[26][25]
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.[27][28] 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.[28] It is metabolised to nortriptyline — a more potent and selective norepinephrine reuptake inhibitor — which may hence compliment its effects on norepinephrine reuptake.[22]

Amitriptyline additionally functions as a 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, α1-adrenergic, H1, H2,[29] H4,[30][31] and mACh receptorantagonist, and σ1 receptor agonist.[32][33][34][35] It has also been shown to be a relatively weak NMDA receptor negative allosteric modulator at the same binding site as phencyclidine.[36] 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.[37][38]

Recently, amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors.[39] 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.[39][40] 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 FIASMA (functional inhibitor of acid sphingomyelinase).[41]

Pharmacokinetics

Amitriptyline is readily absorbed from the gastrointestinal tract and is extensively metabolised on first-pass through the liver.[22] It is metabolised mostly via CYP2D6, CYP3A4, CYP2C9-mediated N-demethylation into nortriptyline,[22] which is another tricyclic antidepressant in its own right.[42] It is 96% bound to plasma proteins, nortriptyline is 93-95% bound to plasma proteins.[22][43]It is mostly excreted in the urine (around 30-50%) as metabolites either free or as glucuronide and sulfate conjugates.[22]Small amounts are also excreted in faeces.[11]

Brand names

Brand names include (just including those used in English-speaking countries with † to indicate discontinued brands):[42][44]

  • Amirol (NZ)
  • Amit (IN)
  • Amitone (IN)
  • Amitor (IN)
  • Amitrip (AU,† IN, NZ)
  • Amitriptyline (UK)
  • Amitriptyline Hydrochloride Caraco (US)
  • Amitriptyline Hydrochloride Mutual (US)
  • Amitriptyline Hydrochloride Mylan (US)
  • Amitriptyline Hydrochloride Sandoz (US)
  • Amitriptyline Hydrochloride Vintage (US)
  • Amitriptyline Hydrochloride (UK)
  • 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)
  • Latilin (IN)
  • Levate (US)
  • Maxitrip (IN)
  • Mitryp (IN)
  • Mitryp-10 (IN)
  • Odep (IN)
  • Qualitriptine (HK)
  • Sandoz Amitriptyline (ZA)
  • Sarotena (IN)
  • Tadamit (IN)
  • Trepiline (ZA)
  • Tripta (SG)
  • Tryptanol (ZA)
  • Tryptomer (IN)

See also

References

  1. ↑ 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.
  2. ↑ 2.0 2.1 "AMITRIPTYLINE HYDROCHLORIDE tablet, film coated [Dispensing Solutions, Inc.]". DailyMed. Dispensing Solutions, Inc. September 2013. Retrieved 1 December 2013.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Template:Cite isbn
  4. ↑ 4.0 4.1 4.2 Template:Cite isbn
  5. ↑ Barbui, C; Hotopf, M (February 2001). "Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomised controlled trials". The British Journal of Psychiatry : the Journal of Mental Science. 178 (2): 129–144. doi:10.1192/bjp.178.2.129. PMID 11157426.
  6. ↑ Anderson, IM (April 2000). "Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability". Journal of Affective Disorders. 58 (1): 19–36. doi:10.1016/S0165-0327(99)00092-0. PMID 10760555.
  7. ↑ Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ (2012). Moore, RA, ed. "Amitriptyline for neuropathic pain and fibromyalgia in adults". Cochrane Database of Systematic Reviews. 12: CD008242. doi:10.1002/14651858.CD008242.pub2. PMID 23235657.
  8. ↑ Kennea, NL; Evans, JHC (June 2000). "Drug Treatment of Nocturnal Enuresis" (PDF). Paediatric and Perinatal Drug Therapy. Informa Healthcare. 4 (1): 12–18.
  9. ↑ 9.0 9.1 Viera, AJ; Hoag, S; Shaughnessy, J (November 2002). "Management of Irritable Bowel Syndrome" (PDF). American Family Physician. 66 (10): 1867–1874.
  10. ↑ Parkinson's Disease. Merck Sharp & Dohme Corp. August 2007. Retrieved on 2013-12-22.
  11. ↑ 11.0 11.1 11.2 "Levate (amitriptyline), dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 1 December 2013.
  12. ↑ Flament, MF; Bissada, H; Spettigue, W (March 2012). "Evidence-based pharmacotherapy of eating disorders". International Journal of Neuropsychopharmacology. 15 (2): 189–207. doi:10.1017/S1461145711000381. PMID 21414249.
  13. ↑ Rosen, H (May 2010). "Dextromethorphan/quinidine sulfate (Zenvia) for Pseudobulbar Affect" (PDF). Drugs Today (Barc). 44 (9): 661–668. doi:10.1358/dot.2008.44.9.1258664. PMC 2872986. PMID 19137121.
  14. ↑ Sim Y-J, Kim J-M, Kwon S, Choe B-H (2009). "Clinical experience with amitriptyline for management of children with cyclic vomiting syndrome". Korean Journal of Pediatrics. 52 (5): 538–43. doi:10.3345/kjp.2009.52.5.538.
  15. ↑ Boles RG, Lovett-Barr MR, Preston A, Li BU, Adams K (2010). "Treatment of cyclic vomiting syndrome with co-enzyme Q10 and amitriptyline, a retrospective study". BMC Neurol. 10: 10. doi:10.1186/1471-2377-10-10. PMC 2825193. PMID 20109231.
  16. ↑ Bayar N, Böke B, Turan E, Belgin E (October 2001). "Efficacy of amitriptyline in the treatment of subjective tinnitus". J Otolaryngol. 30 (5): 300–3. doi:10.2310/7070.2001.19597. PMID 11771024.
  17. ↑ Jeyakumar A, Brickman TM, Haben M (December 2006). "Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy". Laryngoscope. 116 (12): 2108–12. doi:10.1097/01.mlg.0000244377.60334.e3. PMID 17146380.
  18. ↑ Brown CS, Wan J, Bachmann G, Rosen R (February 2009). "Self-management, amitriptyline, and amitripyline plus triamcinolone in the management of vulvodynia". J Womens Health (Larchmt). 18 (2): 163–9. doi:10.1089/jwh.2007.0676. PMC 2945720. PMID 19183087.
  19. ↑ van Ophoven A, Pokupic S, Heinecke A, Hertle L (August 2004). "A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis". J. Urol. 172 (2): 533–6. doi:10.1097/01.ju.0000132388.54703.4d. PMID 15247722.
  20. ↑ Wald, Arnold (2006). "Functional biliary type pain syndrome". In Pasricha, Pankaj Jay; Willis, William D.; Gebhart, G. F. Chronic Abdominal and Visceral Pain. London: Informa Healthcare. pp. 453–62. ISBN 978-0-8493-2897-8.
  21. ↑ Otaka M, Jin M, Odashima M, Matsuhashi T, Wada I, Horikawa Y, Komatsu K, Ohba R, Oyake J, Hatakeyama N, Watanabe S (June 2005). "New strategy of therapy for functional dyspepsia using famotidine, mosapride and amitriptyline". Aliment. Pharmacol. Ther. 21 Suppl 2: 42–6. doi:10.1111/j.1365-2036.2005.02473.x. PMID 15943846.
  22. ↑ 22.00 22.01 22.02 22.03 22.04 22.05 22.06 22.07 22.08 22.09 22.10 22.11 22.12 22.13 22.14 22.15 22.16 "Endep Amitriptyline hydrochloride" (PDF). TGA eBusiness Services. Alphapharm Pty Limited. 10 December 2012. Retrieved 1 December 2013.
  23. ↑ 23.0 23.1 "Amitriptyline Tablets BP 50mg - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Actavis UK Ltd. 24 March 2013. Retrieved 1 December 2013.
  24. ↑ Template:Cite isbn
  25. ↑ 25.0 25.1 25.2 Template:Cite isbn
  26. ↑ 26.0 26.1 Roth, BL; Driscol, J (12 January 2011). "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 1 December 2013.
  27. ↑ "Potency of antidepressants to block noradrenaline reuptake". CNS Forum. Retrieved 2013-02-16.
  28. ↑ 28.0 28.1 Tatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". Eur. J. Pharmacol. 340 (2–3): 249–58. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821.
  29. ↑ Albert Ellis; Gwynn Pennant Ellis (1 January 1987). Progress in Medicinal Chemistry. Elsevier. p. 56. ISBN 978-0-444-80876-9. Retrieved 27 November 2011.
  30. ↑ Nguyen T, Shapiro DA, George SR; et al. (March 2001). "Discovery of a novel member of the histamine receptor family". Molecular Pharmacology. 59 (3): 427–33. PMID 11179435.
  31. ↑ D. Sriram & P. Yogeeswari (1 September 2010). Medicinal Chemistry. Pearson Education India. p. 299. ISBN 978-81-317-3144-4. Retrieved 27 November 2011.
  32. ↑ Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (December 1997). "Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites". J. Pharmacol. Exp. Ther. 283 (3): 1305–22. PMID 9400006.
  33. ↑ Alan F. Schatzberg, Charles B. (2006). Essentials of clinical psychopharmacology. American Psychiatric Pub. p. 7. ISBN 978-1-58562-243-6.
  34. ↑ Rauser L, Savage JE, Meltzer HY, Roth BL (October 2001). "Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine(2C) receptor". J. Pharmacol. Exp. Ther. 299 (1): 83–9. PMID 11561066.
  35. ↑ Werling LL, Keller A, Frank JG, Nuwayhid SJ (October 2007). "A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder". Exp. Neurol. 207 (2): 248–57. doi:10.1016/j.expneurol.2007.06.013. PMID 17689532.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 39.0 39.1 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 2844702. PMID 19549602.
  40. ↑ "Pharmaceutical Information - AMITRIPTYLINE". RxMed. Retrieved 2013-02-16.
  41. ↑ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P (2011). Riezman, Howard, ed. "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE. 6 (8): e23852. doi:10.1371/journal.pone.0023852. PMC 3166082. PMID 21909365.
  42. ↑ 42.0 42.1 Amitriptyline. Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. 30 January 2013. Retrieved 2 December 2013.
  43. ↑ "Pamelor, Aventyl (nortriptyline) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 2 December 2013.
  44. ↑ "Amitriptyline". Drugs.com. Retrieved 2 December 2013.
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