|Trade names||Amitrip, Elavil, Levate, other|
|by mouth, intramuscular|
|Bioavailability||30–60% due to first pass metabolism|
|Biological half-life||10 to 50 hrs|
|Chemical and physical data|
|Molar mass||277.403 g/mol|
|3D model (Jmol)|
Amitriptyline, sold under the brand name Elavil among others, is a medicine used to treat a number of mental illnesses. These include major depressive disorder and anxiety disorder, and less commonly attention deficit hyperactivity disorder and bipolar disorder. Other uses include prevention of migraines, treatment of neuropathic pain such as fibromyalgia and postherpetic neuralgia, and less commonly insomnia. It is in the tricyclic antidepressant (TCA) class and its exact mechanism of action is unclear. Amitriptyline is taken by mouth.
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. Amitriptyline may cause problems if taken during pregnancy. Use during breastfeeding appears to be relatively safe.
Amitriptyline was discovered in 1960 and approved by the US Food and Drug Administration (FDA) in 1961. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. It is available as a generic medication. The wholesale cost in the developing world as of 2014 is between 0.01 and 0.04 USD per dose. In the United States it costs about 0.20 USD per dose.
Amitriptyline is used for a number of medical conditions including major depressive disorder (MDD). Some evidence suggests amitriptyline may be more effective than other antidepressants, including selective serotonin reuptake inhibitors (SSRIs), although it is rarely used as a first-line antidepressant due to its higher toxicity in overdose and generally poorer tolerability.
It is TGA-labeled for migraine prevention, also in cases of neuropathic pain disorders, fibromyalgia and nocturnal enuresis. Amitriptyline is a popular off-label treatment for irritable bowel syndrome (IBS), 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. 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. Amitriptyline is the most widely researched agent for prevention of frequent tension headaches.
- Eating disorders: The few randomized controlled trials investigating its efficacy in eating disorders have been discouraging.
- Insomnia: As of 2004, amitriptyline was the most commonly prescribed off-label prescription sleep aid in the United States. Owing to the development of tolerance and the potential for adverse effects such as constipation, its use in the elderly for this indication is recommended against.
- Urinary incontinence. An accepted use for amitriptyline in Australia is the treatment of urinary urge incontinence.
- Cyclic vomiting syndrome
- Chronic cough
- Preventive treatment for patients with recurring biliary dyskinesia (sphincter of Oddi dysfunction)
- Attention deficit/hyperactivity disorder (in addition to, or sometimes in place of ADHD stimulant drugs)
- Retching/dry heaving, especially after the anti-reflux procedure Nissen fundoplication
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, sexual side effects such as loss of libido and impotence, and sleep disturbances such as drowsiness, insomnia and nightmares.
The known contraindications of amitriptyline are:
- 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
- Severe liver disease
- Being under 7 years of age
- Breast feeding
- Patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken them within the last 14 days.
Amitriptyline is known to interact with:
- 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, because 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 have a potential for increased adverse effects such as CNS stimulation and arrhythmias.
- Analgesics, such as tramadol and pethidine due to the potential for an increase in seizure risk and serotonin syndrome.
- Medications subject to gastric inactivation (e.g. levodopa) due to the potential for amitriptyline to delay gastric emptying and reduce intestinal motility
- Medications 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.
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, 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:
- Hypothermia (low body temperature)
- Tachycardia (high heart rate)
- Other arrhythmic abnormalities, such as bundle branch block
- ECG evidence of impaired conduction
- Congestive heart failure
- Dilated pupils
- Convulsions (e.g. seizures, myoclonus)
- Severe hypotension (very low blood pressure)
- Changes in the electrocardiogram, particularly QT-interval prolongation and change in QRS axis or width
- Hyperactive reflexes
- Muscle rigidity
The treatment of overdose is mostly supportive as no specific antidote for amitriptyline overdose is available. Activated charcoal may reduce absorption if given within 1–2 hours of ingestion. 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. ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised. Body temperature should be regulated with measures such as heating blankets if necessary. Likewise, cardiac arrhythmias can be treated with propranolol and should heart failure occur, digitalis may be used. Cardiac monitoring is advised for at least five days after the overdose. 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. Dialysis is of no use due to the high degree of protein binding with amitriptyline.
Mechanism of action
|Receptor||Ki [nM][Note 1]
|Ki [nM][Note 2]
Amitriptyline acts primarily as a serotonin-norepinephrine reuptake inhibitor, with strong actions on the serotonin transporter and moderate effects on the norepinephrine transporter. 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. It is metabolised to nortriptyline—a more potent and selective norepinephrine reuptake inhibitor—which may complement its effects on norepinephrine reuptake.
Amitriptyline additionally functions as a 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, α1-adrenergic, H1, H2, H4, and mACh receptor antagonist, and σ1 receptor agonist. It has also been shown to be a relatively weak NMDA receptor negative allosteric modulator at the same binding site as phencyclidine. 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.
Recently, amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors. 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. 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.
Amitriptyline is a highly lipophilic molecule having a log D (octanol/water, pH 7.4) of 3.0, while the log P of the free base was reported as 4.92. Solubility in water is 9.71 mg/L at 24 °C.
Amitriptyline is readily absorbed from the gastrointestinal tract and is extensively metabolised on first pass through the liver. It is metabolised mostly by CYP2D6, CYP3A4, and CYP2C19-mediated N-demethylation into nortriptyline, which is another tricyclic antidepressant in its own right. It is 96% bound to plasma proteins, nortriptyline is 93-95% bound to plasma proteins. It is mostly excreted in the urine (around 30–50%) as metabolites either free or as glucuronide and sulfate conjugates. Small amounts are also excreted in feces.
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. 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.
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, 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.
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. 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.
- Amirol (NZ)
- Amit (IN)
- Amitone (IN)
- Amitor (IN)
- Amitrip (AU,† IN, NZ)
- Amitriptyline (UK)
- Amitriptyline Hydrochloride (UK)(US)
- Amitrol† (AU)
- Amrea (IN)
- Amypres (IN)
- 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)
- Odep (IN)
- Redomex (BE)
- Qualitriptine (HK)
- Saroten (CH)
- Sarotena (IN)
- Sarotex (NO)
- Tadamit (IN)
- Trepiline (ZA)
- Triad (NP)
- Tripta (SG) (TH)
- Triptaz (IN)
- Tryptanol (ZA)
- Tryptizol (Spain)
- Triptyl (FI)
- Tryptomer (IN)
- These Ki values are averaged binding affinities towards cloned human receptors when available.
- As with amitriptyline, these Kivalues are averaged binding affinities towards cloned human receptors when available.
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