|Systematic (IUPAC) name|
|Trade names||Amitrip, Elavil, Endep, Levate|
|Licence data||US FDA:|
|Bioavailability||30–60% due to first pass metabolism|
|Half-life||22.4 hr (26 hr for active metabolite, nortriptyline)|
|Mol. mass||277.403 g/mol|
|(what is this?)|
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, first synthesised in 1960 and was first approved by the United States Food and Drug Administration (FDA) on 7 April 1961. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
- 1 Medical uses
- 2 Adverse effects
- 3 Mechanism of action
- 4 Pharmacokinetics
- 5 Pharmacogenetics
- 6 Brand names
- 7 Synthesis
- 8 See also
- 9 Notes
- 10 References
- 11 Further reading
Amitriptyline is used for a number of medical conditions including major depressive disorder (MDD) which is its only FDA-labeled indication. This is also a TGA- and MHRA-labelled indication. Some evidence suggests that amitriptyline may have superior efficacy compared to other antidepressants, including the SSRIs, 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).
It is TGA-labeled for migraine prophylaxis, as it is also is in cases of neuropathic pain disorders, fibromyalgia and nocturnal enuresis. Amitriptyline is a popular off-label treatment for irritable bowel syndrome. 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. Amitriptyline can also be used as an anticholinergic drug in the treatment of early stage Parkinson disease if depression also needs to be treated.
- Eating disorders The few randomized controlled trials investigating its efficacy in eating disorders have been discouraging.
- Pseudobulbar affect. A new agent containing a combination of dextromethorphan and quinidine is currently under development for the treatment of pseudobulbar affect.
- Insomnia. 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)
Common (≥1% frequency)
- Weight gain
- Anticholinergic side effects (it tends to produce more anticholinergic effects than the other TCAs) such as:
- Somnolence (drowsiness) it tends to be a more sedating TCA.
- Decreased lacrimation
- Orthostatic hypotension
- Sinus tachycardia
- Loss of libido
- Other sexual adverse effects
Uncommon (0.1–1% frequency)
Rare (<0.1% frequency)
- Liver failure
- Lupus-like syndrome (migratory arthritis, positive ANA and rheumatoid factor)
- Hypotension (low blood pressure)
- Syncope (fainting)
- Myocardial infarction
- Heart block
- Neuroleptic malignant syndrome
- Skin rash
- Urticaria (hives)
- Testicular swelling
- Increased or decreased libido
- Urinary retention
- Dilatation of the urinary tract
- Disturbance of accommodation[clarification needed]
- Increased intraocular pressure
- Paralytic ileus
- Epigastric distress
- Peculiar taste
- Parotid swelling
- Black tongue
- Alopecia (hair loss)
- Urinary frequency
- Myocardial infarction
- Weight loss
- Increased perspiration
- Urinary frequency
- Confusional states
- Peripheral neuropathy
- Extrapyramidal symptoms
- Tardive dyskinesia
- Disturbed concentration
- Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
- Tinnitus (ringing in the ears)
- Alteration in EEG patterns
The following are the known contraindications of amitriptyline.
- 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
- Children under 7 years
- 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. 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.
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 in QRS axis or width
- Hyperactive reflexes
- Muscle rigidity
The treatment of overdose is mostly supportive as there is no specific antidote for amitriptyline overdose. Activated charcoal may reduce absorption if given within 1–2 hours of ingestion. 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. 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 propanolol 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 FIASMA (functional inhibitor of acid sphingomyelinase).
Amitriptyline is readily absorbed from the gastrointestinal tract and is extensively metabolised on first-pass through the liver. It is metabolised mostly via CYP2D6, CYP3A4, 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 faeces.
Since amitriptyline is primarily metabolized via 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 metabolizers, intermediate metabolizers, extensive metabolizers and ultrarapid metabolizers. Most individuals (~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 have an increased probability of experiencing side effects. Ultrarapid metabolizers metabolize 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 (CPIC) 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 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)
- Saroten (CH)
- Sarotena (IN)
- Tadamit (IN)
- Trepiline (ZA)
- Tripta (SG)
- Tryptanol (ZA)
- 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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