Amitriptyline

Amitriptyline

Systematic (IUPAC) name
3-(10,11-dihydro-5H-dibenzo[[a,d]]cycloheptene-5-ylidene)-N,N-dimethyl-1-propanamine
Identifiers
CAS number	50-48-6
ATC code	N06AA09
PubChem	CID 2160
IUPHAR ligand	200
DrugBank	APRD00227
ChemSpider	2075
Chemical data
Formula	C20H23N
Mol. mass	277.403 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	30–60% due to first pass metabolism
Protein binding	> 90%
Metabolism	Hepatic CYP2C19, CYP1A2, CYP2D6
Half-life	10–50 hours, with an average of 15 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	D(US)
Legal status	℞ Prescription only
Routes	Oral
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Amitriptyline (Elavil, Tryptizol, Laroxyl, Sarotex, Lentizol) is a tricyclic antidepressant (TCA).^[1] It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs.

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.^[2] It has seen widespread usage throughout the world ever since.

Indications

Approved

Amitriptyline is approved for the treatment of major depression, as well as clinical/endogenous depression and also involutional melancholia or "depression of late life", which is no longer seen as a disease in its own right. Adult typical dosages are 25 to 150 mg daily, with half this dose initially for elderly or adolescent patients.

Children between the ages of 7 to 10 years typically have a dose of 10 to 20 mg; older children 25 to 50 mg at night. It should be gradually withdrawn at the end of the course, which overall should be of no more than three months.^[3]

Amitriptyline is used in ankylosing spondylitis for pain relief and in some European countries it is officially approved as a preventive for patients with frequent/chronic migraines, usually 25 to 75 mg. It is also used as a preventive for patients with recurring biliary dyskinesia (sphincter of Oddi dysfunction), usually 10 mg daily^[4].

Unapproved/off-label

Amitriptyline may be prescribed for other conditions such as insomnia, post-traumatic stress disorder (PTSD),^[5] migraine, rebound headache, chronic pain, tinnitus, chronic cough, postherpetic neuralgia (persistent pain following a shingles attack), carpal tunnel syndrome (CTS), fibromyalgia, vulvodynia, interstitial cystitis, male chronic pelvic pain syndrome, irritable bowel syndrome (IBS), diabetic peripheral neuropathy, neurological pain, laryngeal sensory neuropathy, and painful paresthesias related to multiple sclerosis and at low doses as a prophylaxis (preventive) for patients with chronic migraines.^[6] Typically lower dosages are required for pain modification of 10 to 50 mg daily.^[3]

Amitriptyline in low doses is also sometimes prescribed to help ease the symptoms of chronic fatigue syndrome. It is thought to help combat symptoms of insomnia primarily, in addition to other selected symptoms of the affliction. Additionally, Amitriptyline is often used to relieve the pain of the Herpes Zoster virus, typically at a dose of between 10–20 mg at night.

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).^[7]

Pharmacology

Amitriptyline acts primarily as a serotonin-norepinephrine reuptake inhibitor, with strong actions on the norepinephrine transporter, and moderate effects on the serotonin transporter.^[8][9] 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.^[9]

Amitriptyline additionally functions as a 5-HT_2A, 5-HT_2C, 5-HT₆, 5-HT₇, α₁-adrenergic, H₁, and mACh receptor antagonist, and σ₁ receptor agonist.^{[10][11][12][13]} It has also been shown to be a relatively weak NMDA receptor negative allosteric modulator at the same binding site as phencyclidine.^[14] Amitriptyline inhibits sodium channels, L-type calcium channels, and K_v1.1, K_v7.2, and K_v7.3 voltage-gated potassium channels, and therefore acts as a sodium, calcium, and potassium channel blocker as well.^[15][16][17]

Recently, amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors.^[18] 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.^[18]

Side effects

Common side effects of using amitriptyline are mostly due to its anticholinergic activity, including: weight gain, dry mouth, changes in appetite, drowsiness, muscle stiffness, nausea, constipation, nervousness, dizziness, blurred vision, urinary retention, insomnia and changes in sexual function. Some rare side effects include tinnitus, hypotension, mania, psychosis, sleep paralysis, hypnagogia, hypnopompia, heart block, arrhythmias, lip and mouth ulcers, extrapyramidal symptoms, depression, and hepatic toxicity.

Overdose

The symptoms and the treatment of an overdose are largely the same as for the other TCAs.

See also

• Tricyclic antidepressant

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.
• MedlinePlus Drug Information: Amitriptyline. US National Institutes of Health. January 2008.