Amitriptyline

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Amitriptyline
Systematic (IUPAC) name
3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethylpropan-1-amine
Clinical data
Trade namesAmitrip, Elavil, Endep, Levate
AHFS/Drugs.commonograph
MedlinePlusa682388
Licence dataUS FDA:link
Pregnancy cat.C (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
RoutesOral, intramuscular
Pharmacokinetic data
Bioavailability30–60% due to first pass metabolism
Protein binding96%[1][2][3][4]
MetabolismHepatic (CYP2D6)[1][2][3][4]
Half-life22.4 hr (26 hr for active metabolite, nortriptyline)[1][2][3][4]
ExcretionRenal[1][2][3][4]
Identifiers
CAS number50-48-6 YesY
549-18-8 (hydrochloride)
ATC codeN06AA09
PubChemCID 2160
IUPHAR ligand200
DrugBankDB00321
ChemSpider2075 YesY
UNII1806D8D52K YesY
KEGGD07448 YesY
ChEBICHEBI:2666 YesY
ChEMBLCHEMBL629 YesY
Chemical data
FormulaC20H23N 
Mol. mass277.403 g/mol
 YesY (what is this?)  (verify)
 
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Amitriptyline
Systematic (IUPAC) name
3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)-N,N-dimethylpropan-1-amine
Clinical data
Trade namesAmitrip, Elavil, Endep, Levate
AHFS/Drugs.commonograph
MedlinePlusa682388
Licence dataUS FDA:link
Pregnancy cat.C (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
RoutesOral, intramuscular
Pharmacokinetic data
Bioavailability30–60% due to first pass metabolism
Protein binding96%[1][2][3][4]
MetabolismHepatic (CYP2D6)[1][2][3][4]
Half-life22.4 hr (26 hr for active metabolite, nortriptyline)[1][2][3][4]
ExcretionRenal[1][2][3][4]
Identifiers
CAS number50-48-6 YesY
549-18-8 (hydrochloride)
ATC codeN06AA09
PubChemCID 2160
IUPHAR ligand200
DrugBankDB00321
ChemSpider2075 YesY
UNII1806D8D52K YesY
KEGGD07448 YesY
ChEBICHEBI:2666 YesY
ChEMBLCHEMBL629 YesY
Chemical data
FormulaC20H23N 
Mol. mass277.403 g/mol
 YesY (what is this?)  (verify)

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 and was initially approved by the United States Food and Drug Administration (FDA) on 7 April 1961.[5]

Medical uses[edit]

Widely accepted medical uses[edit]

Amitriptyline is used for a number of medical conditions including major depressive disorder (MDD) which is its only FDA-labelled indication.[1] This is also a TGA- and MHRA-labelled indication.[6][7] Some evidence suggests that amitriptyline may have superior efficacy compared to other antidepressants,[8] including the SSRIs.[9] 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).[6]

It is TGA-labelled for migraine prophylaxis, as it is also is in cases of neuropathic pain disorders,[6] fibromyalgia[10] and nocturnal enuresis.[6][11] Amitriptyline is a popular off-label treatment for irritable bowel syndrome.[12] 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.[12] Amitriptyline can also be used as an anticholinergic drug in the treatment of early stage Parkinson disease if depression also needs to be treated.[13]

Investigational uses[edit]

Adverse effects[edit]

Adverse effects by frequency[edit]

Adverse effects include the following:[1][2][3][4][6][7]

Common (≥1% frequency)[edit]

  • Weight gain
  • Anticholinergic side effects (it tends to produce more anticholinergic effects than the other TCAs) such as:
    • Constipation
    • Xerostomia (dry mouth)
    • Mydriasis (dilated pupils)
    • Blurred vision
    • Urinary hesitancy
    • Reduced GI motility
    • Anticholinergic delirium (particularly in the elderly and in Parkinson's disease)
  • Dizziness
  • Headache
  • Somnolence (drowsiness) it tends to be a more sedating TCA.[24][25]
  • Decreased lacrimation (that is, decreased ability to cry)
  • Orthostatic hypotension
  • Sinus tachycardia
  • Impotence
  • Loss of libido
  • Other sexual adverse effects
  • Tremor
  • Dizziness
  • Sweating
  • Agitation
  • Insomnia
  • Anxiety
  • Confusion

Uncommon (0.1–1% frequency)[edit]

  • Slowed cardiac conduction
  • T wave inversion or flattening (particularly at high doses)
  • Arrhythmias
  • Sinus tachycardia
  • Nausea
  • Hyperglycaemia
  • Gynaecomastia (breast enlargement in men)
  • Breast enlargement and galactorrhoea in females
  • Allergic skin reactions
  • Mania
  • Hypomania

Rare (<0.1% frequency)[edit]

Unknown frequency adverse effects[edit]

Contraindications[edit]

The following are the known contraindications of amitriptyline.[4]

Interactions[edit]

Amitriptyline is known to interact with:[3]

Overdose[edit]

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,[7] 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:[3]

The treatment of overdose is mostly supportive as there is no specific antidote for amitriptyline overdose.[3] Activated charcoal may reduce absorption if given within 1-2 hours of ingestion.[3] 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.[3] ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised.[3] Body temperature should be regulated with measures such as heating blankets if necessary.[3] Likewise cardiac arrhythmias can be treated with propanolol and should heart failure occur digitalis may be used.[3] Cardiac monitoring is advised for at least five days after the overdose.[3] Other measures include the use of inhalation anaesthetics or diazepam for convulsions and barbiturates should be avoided if possible due to the potential for additive CNS depression (that is, on top of the CNS depression caused by the amitriptyline).[3] Dialysis is of no use due to the high degree of protein binding with amitriptyline.[3]

Mechanism of action[edit]

ReceptorKi [nM][Note 1]
(amitriptyline)[26][25]
Ki [nM][Note 2]
(nortriptyline)[26][25]
SERT3.1316.5
NET22.44.37
DAT53803100
5-HT1A450294
5-HT1B840-
5-HT2A4.35
5-HT2C6.158.5
5-HT6103148
5-HT7114-
H11.115.1
H31000-
H433.6-
M112.940
M211.8110
M325.950
M47.284
M519.997
α12455
α26902030
D189-
D214602570
D3206-
D5170-
σ3002000

Amitriptyline acts primarily as a serotonin-norepinephrine reuptake inhibitor, with strong actions on the serotonin transporter and moderate effects on the norepinephrine transporter.[27][28] 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.[28] It is metabolised to nortriptyline — a more potent and selective norepinephrine reuptake inhibitor — which may hence compliment its effects on norepinephrine reuptake.[3]

Amitriptyline additionally functions as a 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, α1-adrenergic, H1, H2,[29] H4,[30][31] and mACh receptorantagonist, and σ1 receptor agonist.[32][33][34][35] It has also been shown to be a relatively weak NMDA receptor negative allosteric modulator at the same binding site as phencyclidine.[36] 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.[37][38]

Recently, amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors.[39] 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.[39][40] 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).[41]

Pharmacokinetics[edit]

Nortriptyline, amitriptyline's chief active metabolite

Amitriptyline is readily absorbed from the gastrointestinal tract and is extensively metabolised on first-pass through the liver.[3] It is metabolised mostly via CYP2D6, CYP3A4, CYP2C9-mediated N-demethylation into nortriptyline,[3] which is another tricyclic antidepressant in its own right.[42] It is 96% bound to plasma proteins, nortriptyline is 93-95% bound to plasma proteins.[3][43]It is mostly excreted in the urine (around 30-50%) as metabolites either free or as glucuronide and sulfate conjugates.[3]Small amounts are also excreted in faeces.[2]

Brand names[edit]

Brand names include (just including those used in English-speaking countries with † to indicate discontinued brands):[42][44]

  • 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)
  • Sarotena (IN)
  • Tadamit (IN)
  • Trepiline (ZA)
  • Tripta (SG)
  • Tryptanol (ZA)
  • Tryptomer (IN)

Notes[edit]

  1. ^ These Ki values are averaged binding affinities towards cloned human receptors when available.
  2. ^ As with amitriptyline, these Kivalues are averaged binding affinities towards cloned human receptors when available.

See also[edit]

References[edit]

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Further reading[edit]