Amitriptyline, sold under the brand name Elavil among others, is a medicine primarily used to treat a number of mental illnesses.[2] These include major depressive disorder and anxiety disorders, 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.[2] 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.[2] 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 World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[9] It is available as a generic medication.[2] The wholesale cost in the developing world as of 2014[update] was between 0.01 and 0.04 USD per dose.[10] In the United States it costs about 0.20 USD per dose.[2] 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][15] including selective serotonin reuptake inhibitors (SSRIs),[16] although it is rarely used as a first-line antidepressant due to its higher toxicity in overdose and generally poorer tolerability.[12] It is used in addition to other medications for pain.[17] It is TGA-labeled in Australia for migraine prevention, also in cases of neuropathic pain disorders,[12] fibromyalgia[4] and nocturnal enuresis.[12][18] Amitriptyline is a popular off-label treatment for irritable bowel syndrome (IBS),[19] 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.[19] 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.[20] Amitriptyline is the most widely researched agent for prevention of frequent tension headaches.[21] The known contraindications of amitriptyline are:[30] 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, sinus tachycardia, and QT-interval prolongation,[31] sexual side effects such as loss of libido and impotence, and sleep disturbances such as drowsiness, insomnia and nightmares.[11][12][13][22][32][30] Of the TCAs, amitriptyline is said to have the most anticholinergic side effects and to be the most likely to produce delirium.[33] 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 TCAs 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.[34] The possible symptoms of amitriptyline overdose include:[32] The treatment of overdose is mostly supportive as no specific antidote for amitriptyline overdose is available.[32] Activated charcoal may reduce absorption if given within 1–2 hours of ingestion.[32] 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.[32] ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised.[32] Body temperature should be regulated with measures such as heating blankets if necessary.[32] Cardiac monitoring is advised for at least five days after the overdose.[32] Benzodiazepines are recommended for control of seizures.[32] Dialysis is of no use due to the high degree of protein binding with amitriptyline.[32] Amitriptyline is known to interact with:[32] Amitriptyline acts primarily as a serotonin–norepinephrine reuptake inhibitor (SNRI), with strong actions on the serotonin transporter (SERT) and moderate effects on the norepinephrine transporter (NET).[59][36] It has negligible influence on the dopamine transporter (DAT) and therefore does not affect dopamine reuptake, being nearly 1,000 times weaker on inhibition of the reuptake of this neurotransmitter than on serotonin.[36] It is metabolized to nortriptyline, a more potent and selective norepinephrine reuptake inhibitor, and this may serve to complement its effects on norepinephrine reuptake.[32] Amitriptyline additionally acts as an antagonist or inverse agonist of the serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, the α1-adrenergic receptor, the histamine H1 and H2 receptors,[60] and the muscarinic acetylcholine receptors, and as an agonist of the sigma σ1 receptor.[37][61][62][63] It has also been shown to be a relatively weak NMDA receptor antagonist via the dizocilpine (MK-801)/phencyclidine (PCP) site.[64] 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.[65][66] Amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors.[67] 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.[67][68] 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,[69] and as a PARP1 inhibitor.[70] Amitriptyline is a highly lipophilic molecule having a log D (octanol/water, pH 7.4) of 3.0,[71] while the log P of the free base was reported as 4.92.[72] Solubility in water is 9.71 mg/litre at 24 °C.[73] Amitriptyline is readily absorbed from the gastrointestinal tract and is extensively metabolized on first pass through the liver.[32] It is metabolized mostly by CYP2D6, CYP3A4, and CYP2C19-mediated N-demethylation into nortriptyline,[32] which is another TCA in its own right.[74] It is 96% bound to plasma proteins; nortriptyline is 93-95% bound to plasma proteins.[32][75] It is mostly excreted in the urine (around 30–50%) as metabolites either free or as glucuronide and sulfate conjugates.[32] Small amounts are also excreted in feces.[22] Therapeutic levels of amitriptyline range from 75 to 175 ng/ml (270–631 nM).[76] 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.[77] 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.[78][79][80] 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,[80] 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.[78][79][80] 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.[80] 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.[81] Amitriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure.[82] Other dibenzocycloheptadiene TCAs include nortriptyline (noramitriptyline, N-desmethylamitriptyline), protriptyline, and butriptyline.[82] Amitriptyline is a tertiary amine TCA, with its side chain-demethylated metabolite nortriptyline being a secondary amine.[83][84] Other tertiary amine TCAs include imipramine, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine.[85][86] The chemical name of amitriptyline is 3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C20H23N with a molecular weight of 277.403 g/mol.[87] The drug is used commercially mostly as the hydrochloride salt; the free base form is used rarely and the embonate (pamoate) salt is used for intramuscular administration.[87][88] The CAS Registry Number of the free base is 50-48-6, of the hydrochloride is 549-18-8, and of the embonate is 17086-03-2.[87][88] Amitriptyline was first synthesized in 1960 and was introduced for medical use in United States in 1961 and in the United Kingdom in 1962, in both countries under the brand name Elavil.[89][90][91][92] It was the second TCA to be introduced, following the introduction of imipramine in 1957.[90][91] Amitriptyline is the English and French generic name of the drug and its INN, BAN, and DCF, while amitriptyline hydrochloride is its USAN, USP, BANM, and JAN.[87][88][93][94] Its generic name in Spanish and Italian and its DCIT are amitriptilina, in German is Amitriptylin, and in Latin is amitriptylinum.[88][94] The embonate salt is known as amitriptyline embonate, which is its BANM, or as amitriptyline pamoate unofficially.[88] Major brand names of amitriptyline include Elavil, Endep, Lentizol, Saroten, Tryptanol, and Tryptizol.[88][94] An extensive list of brand names used in English-speaking countries (with † to indicate discontinued brand names) includes:[74][95]