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Amitryptyline

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Amitryptyline

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Amitriptyline (Tryptomer, Elavil (US), Tryptizol, Laroxyl, Saroten, Sarotex, Lentizol, Endep (AU)) is a tricyclic antidepressant (TCA). It is the most widely used TCA and may be efficacious for the treatment of depression, with effects similar to SSRIs according to a meta-analysis from early 2001.[1] These types of tricyclics have been used historically for the treatment of migraines, tension headaches, anxiety, psychosis, aggression and violent behavior. It is also associated with abdominal pain, stomatitis, palpitation, oedema, hypertension, restlessness, fatigue, mydriasis, and increased intra-ocular pressure.

Medical uses

Amitriptyline is used for a number of medical conditions including:

A randomized controlled trial published in June 2005 found that amitriptyline was effective in functional dyspepsia that did not respond to a first-line treatment (famotidine or mosapride).[16]

Adverse effects

Information sources:[4][17][18][19][20]

Common/Uncommon (≥0.1% incidence) adverse effects include
  • Nausea
  • Drowsiness: Similar effects of Ambien (Zolpidem)
  • Anticholinergic side effects such as:
    • Amnesia
    • Blurred vision
    • Constipation
    • Dry mouth
    • Mydriasis
    • Fever
  • Dizziness
  • Headache
  • Somnolence, due to the potent antihistamine effects of amitriptyline
  • Weight gain
  • Weight loss
Rare (<0.1%) adverse effects
Unknown frequency adverse effects include

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,[21] 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.

An amitriptyline 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.

A dangerous interaction exists between fluoxetine (Prozac) and amitriptyline which can result in unsafe blood plasma concentrations of amitriptyline (likely the result of fluoxetine's inhibitory effects on CYP2D6).[22]

Pharmacology

Amitriptyline acts primarily as a serotonin-norepinephrine reuptake inhibitor, with strong actions on the serotonin transporter and moderate effects on the norepinephrine transporter.[23][24] 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.[24]

Amitriptyline additionally functions as a 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, α1-adrenergic, H1, H2,[25] H4,[26][27] and mACh receptor antagonist, and σ1 receptor agonist.[28][29][30][31] It has also been shown to be a relatively weak NMDA receptor negative allosteric modulator at the same binding site as phencyclidine.[32] 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.[33][34]

Recently, amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors.[35] 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.[35][36] 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).[37]

Binding profile (values given are binding affinities Ki for cloned human receptors unless otherwise specified):[38][39]

Receptor Binding affinity (Ki [nM] for amitriptyline) Receptor location and species Binding affinity (Ki [nM] for nortriptyline) Receptor location and species
SERT 3.13 Human, cloned 16.5 Human, cloned
NET 22.4 Human, cloned 4.37 Human, cloned
DAT 5380 Human, cloned 3100 Human, cloned
5-HT1A 450 Human, brain 294 Human, brain
5-HT1B 840 Rat, cortex - -
5-HT2A 4.3 Rat, cloned 5 Rat, cloned
5-HT2C 6.15 Rat, cloned 8.5 Rat, cloned
5-HT6 103 Human, cloned 148 Rat, cloned
5-HT7 114 Rat, cloned - -
H1 1.1 Human, cloned 15.1 Human, cloned
H3 1000 Human, undefined - -
H4 33.6 Human, cloned - -
M1 12.9 Human, cloned 40 Human, cloned
M2 11.8 Human, cloned 110 Human, cloned
M3 25.9 Human, cloned 50 Human, cloned
M4 7.2 Human, cloned 84 Human, cloned
M5 19.9 Human, cloned 97 Human, cloned
α1 24 Human, brain 55 Human, brain
α2 690 Human, brain 2030 Human, brain
D1 89 Human, undefined - -
D2 1460 Human, brain 2570 Human, brain
D3 206 Human, undefined - -
D5 170 Human, undefined - -
σ 300 Guinea pig, brain 2000 Guinea pig, brain

History

Amitriptyline, under the brand name Elavil, was developed by Merck and approved by the FDA on April 7, 1961, for the treatment of major depression in the United States.[40] In India, Merck & Co launched amitriptyline under the brand name Tryptomer, which is now with Merind, a division of Wockhardt.

See also

References

Further reading

  • PubChem Substance Summary: Amitriptyline National Center for Biotechnology Information.
  • TREPILINE-10 TABLETS; TREPILINE-25 TABLETS South African Electronic Package Inserts. 12 May 1978. Revised February 2004.
  • SAROTEN RETARD 25 mg Capsules; SAROTEN RETARD 50 mg Capsules South African Electronic Package Inserts. December 1987. Updated May 2000.
  • AMITRIP Amitriptyline hydrochloride 10 mg, 25 mg and 50 mg Capsules Medsafe NZ Physician Data Sheet. November 2004.
  • Endep Consumer Medicine Information, Australia. December 2005.
  • National Institutes of Health. January 2008.

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