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Amitriptyline

PubChem CID
2160
Structure
Amitriptyline_small.png
Amitriptyline_3D_Structure.png
Molecular Formula
Synonyms
  • amitriptyline
  • 50-48-6
  • Amitriptylin
  • Damitriptyline
  • Triptanol
Molecular Weight
277.4 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-18
Description
Amitriptyline is an organic tricyclic compound that is 10,11-dihydro-5H-dibenzo[a,d][7]annulene substituted by a 3-(dimethylamino)propylidene group at position 5. It has a role as an adrenergic uptake inhibitor, an antidepressant, an environmental contaminant, a xenobiotic and a tropomyosin-related kinase B receptor agonist. It is a tertiary amine and a carbotricyclic compound. It derives from a hydride of a dibenzo[a,d][7]annulene.
Amitriptyline is a tricyclic antidepressant that has been used to treat depression for decades. ELAVIL, a previously approved branded product of amitriptyline, was first approved by the FDA in 1961. Amitriptyline has been investigated in the treatment of pain-related conditions, attributed to its analgesic properties.
Amitriptyline is a Tricyclic Antidepressant.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Amitriptyline.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

N,N-dimethyl-3-(2-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaenylidene)propan-1-amine
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C20H23N/c1-21(2)15-7-12-20-18-10-5-3-8-16(18)13-14-17-9-4-6-11-19(17)20/h3-6,8-12H,7,13-15H2,1-2H3
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

KRMDCWKBEZIMAB-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CN(C)CCC=C1C2=CC=CC=C2CCC3=CC=CC=C31
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C20H23N
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 HMDB ID

2.3.10 KEGG ID

2.3.11 Metabolomics Workbench ID

2.3.12 NCI Thesaurus Code

2.3.13 Nikkaji Number

2.3.14 PharmGKB ID

2.3.15 Pharos Ligand ID

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Amineurin
  • Amitrip
  • Amitriptylin beta
  • Amitriptylin Desitin
  • Amitriptylin neuraxpharm
  • Amitriptylin RPh
  • Amitriptylin-neuraxpharm
  • Amitriptyline
  • Amitriptyline Hydrochloride
  • Amitrol
  • Anapsique
  • Apo Amitriptyline
  • Apo-Amitriptyline
  • Damilen
  • Desitin, Amitriptylin
  • Domical
  • Elavil
  • Endep
  • Laroxyl
  • Lentizol
  • Novoprotect
  • RPh, Amitriptylin
  • Saroten
  • Sarotex
  • Syneudon
  • Triptafen
  • Tryptanol
  • Tryptine
  • Tryptizol

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
277.4 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
5
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
0
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
277.183049738 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
277.183049738 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
3.2 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
21
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
331
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Color / Form

Crystals
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-26

3.2.3 Boiling Point

3.2.4 Melting Point

196-197
196 - 197 °C

3.2.5 Solubility

freely soluble in water
In water, 9.71 mg/L at 24 °C
Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Ver 5. Tucson, AZ: Univ AZ, College of Pharmacy (1992)
4.50e-03 g/L

3.2.6 LogP

4.92
log Kow = 4.92
Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 167
4.9

3.2.7 LogS

3.2.8 Stability / Shelf Life

Following the date of manufacture, amitriptyline hydrochloride preparations have expiration dates of 3-5 years depending on the manufacturer and dosage form.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2399
Stable under recommended storage conditions. /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

3.2.9 Decomposition

When heated to decomposition it emits toxic fumes of /nitrogen oxides/
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1562

3.2.10 Ionization Efficiency

Ionization mode
Positive
logIE
4.449405165
pH
2.7
Instrument
Thermo LTQ
Ion source
Electrospray ionization
Additive
formic acid (5.3nM)
Organic modifier
MeCN (80%)
Reference

3.2.11 Dissociation Constants

Basic pKa
9.49
Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res. 2014; 31(4):1082-95. DOI:10.1007/s11095-013-1232-z. PMID:24249037
Basic pKa
9.4
Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res. 2014; 31(4):1082-95. DOI:10.1007/s11095-013-1232-z. PMID:24249037
Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res. 2014; 31(4):1082-95. DOI:10.1007/s11095-013-1232-z. PMID:24249037
Basic pKa
8.2
Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res. 2014; 31(4):1082-95. DOI:10.1007/s11095-013-1232-z. PMID:24249037

3.2.12 Collision Cross Section

167.2 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]
164.99 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]
Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.13 Kovats Retention Index

Standard non-polar
2208 , 2194 , 2181 , 2179 , 2169 , 2179 , 2187 , 2192 , 2162 , 2190 , 2182 , 2188 , 2194 , 2201 , 2236 , 2195 , 2220 , 2185 , 2200 , 2196 , 2185.7 , 2187.9 , 2162 , 2174 , 2179 , 2181 , 2181 , 2191 , 2200 , 2200 , 2209 , 2204 , 2162 , 2210 , 2210 , 2196 , 2199.1 , 2222.6 , 2200 , 2208 , 2190 , 2190 , 2212.5
Semi-standard non-polar
2252 , 2185.1 , 2170 , 2207.5 , 2202.8 , 2187.6 , 2189.2 , 2166 , 2188.4
Standard polar
2924

3.2.14 Other Experimental Properties

Minute crystals. MP: 196-197 °C. UV max (methanol): 240 nm (epsilon 13800). pKa 9.4. Freely soluble in water, chloroform, alcohol; insoluble in ether /Amitriptyline hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 87

3.3 Chemical Classes

Pharmaceutical

3.3.1 Drugs

Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
Pharmaceuticals -> Antipsychotics
S56 | UOATARGPHARMA | Target Pharmaceutical/Drug List from University of Athens | DOI:10.5281/zenodo.3248837
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Antidepressive Agents; Antidepressive Agents, Tricyclic
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

Medicines for depressive disorders

Medicines for other common symptoms in palliative care

3.3.2 Endocrine Disruptors

Potential endocrine disrupting compound
S109 | PARCEDC | List of 7074 potential endocrine disrupting compounds (EDCs) by PARC T4.2 | DOI:10.5281/zenodo.10944198

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 GC-MS

1 of 12
View All
Spectra ID
Instrument Type
EI-B
Ionization Mode
positive
Top 5 Peaks

58.0 99.99

202.0 3.10

203.0 2.40

91.0 2.40

218.0 2.10

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Notes
instrument=Unknown
2 of 12
View All
MoNA ID
MS Category
Experimental
MS Type
GC-MS
MS Level
MS1
Instrument
Unknown
Instrument Type
EI-B
Ionization Mode
positive
Top 5 Peaks

58 99.99

202 3.10

91 2.40

203 2.40

218 2.10

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License
CC BY-NC-SA

4.1.2 MS-MS

1 of 9
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

191.0854 100

233.1324 99.29

117.07 79.55

218.1089 64.87

105.07 61.68

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2 of 9
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Spectra ID
Ionization Mode
Positive
Top 5 Peaks

191.0853 100

117.0701 62.96

218.1085 53.75

203.0853 47.95

105.0701 47.85

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4.1.3 LC-MS

1 of 53
View All
Authors
Nikiforos Alygizakis, Katerina Galani, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
10 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
8.015 min
Precursor m/z
278.1903
Precursor Adduct
[M+H]+
Top 5 Peaks

278.191 999

279.1931 351

233.1316 48

280.196 27

234.1347 9

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License
CC BY
2 of 53
View All
Authors
Nikiforos Alygizakis, Katerina Galani, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
20 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
8.048 min
Precursor m/z
278.1903
Precursor Adduct
[M+H]+
Top 5 Peaks

278.1902 999

233.1318 715

279.1933 204

191.0847 126

234.1353 111

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License
CC BY

4.1.4 Other MS

1 of 2
Authors
SASAKI S, TOYOHASHI UNIV. OF TECH.
Instrument
Unknown
Instrument Type
EI-B
MS Level
MS
Ionization Mode
POSITIVE
Ionization
ENERGY 70 eV
Top 5 Peaks

58 999

202 31

91 24

203 24

218 21

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License
CC BY-NC-SA
2 of 2
Authors
Tara J. Bowen, University of Birmingham, UK
Instrument
Vanquish Horizon UHPLC Thermo Scientific; Orbitrap ID-X Tribrid MS Thermo Scientific
Instrument Type
LC-ESI-FT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
20,40,130% (stepped)
Fragmentation Mode
HCD
Column Name
Accucore 150 Amide, 2.6um, 2.1x100mm, Thermo Scientific
Retention Time
0.018 min
Precursor m/z
278.1903
Precursor Adduct
[M+H]+
Top 5 Peaks

91.0542 999

105.0699 657

117.0699 583

278.1904 464

115.0542 265

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License
CC BY
Reference
Bowen, T.J.; Southam, A.D.; Hall, A.R.; Weber, R.J.M.; Lloyd, G.R.; Macdonald, R.; Wilson, A.; Pointon, A.; Viant, M.R. Simultaneously discovering the fate and biochemical effects of xenobiotics through untargeted metabolomics. Nat. Commun. (under review)

4.2 IR Spectra

4.2.1 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Film (MeCl2) (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Alltech Associates, Inc., Grace Davison Discovery Sciences
Catalog Number
Free base of 01775
Lot Number
Free base of 514
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

This drug in indicated for the following conditions: Major depressive disorder in adults Management of neuropathic pain in adults Prophylactic treatment of chronic tension-type headache (CTTH) in adults Prophylactic treatment of migraine in adults Treatment of nocturnal enuresis in children aged 6 years and above when organic pathology, including spina bifida and related disorders, have been excluded and no response has been achieved to all other non-drug and drug treatments, including antispasmodics and vasopressin-related products. This product should only be prescribed by a healthcare professional with expertise in the management of persistent enuresis Off-label uses: irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation, fibromyalgia, and insomnia

7.2 LiverTox Summary

Amitriptyline is a tricyclic antidepressant that is widely used in the therapy of depression. Amitriptyline can cause mild and transient serum enzyme elevations and is rare cause of clinically apparent acute cholestatic liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Antidepressive Agents; Antidepressive Agents, Tricyclic
Antidepressant Agents

7.4 Drug Transformations

Amitriptyline has known transformation products that include Nortriptyline.
S66 | EAWAGTPS | Parent-Transformation Product Pairs from Eawag | DOI:10.5281/zenodo.3754448

7.5 WHO Essential Medicines

Drug
Drug Classes
Medicines for depressive disorders
Formulation
Oral - Solid: 25 mg; 75 mg
Indication
Depressive disorders
Drug
Drug Classes
Medicines for other common symptoms in palliative care
Formulation
Oral - Solid: 25 mg; 10 mg; 75 mg
Indication
Palliative care

7.6 Clinical Trials

7.6.1 ClinicalTrials.gov

7.6.2 EU Clinical Trials Register

7.6.3 NIPH Clinical Trials Search of Japan

7.7 Therapeutic Uses

Adrenergic Uptake Inhibitors; Analgesics, Non-Narcotic; Antidepressive Agents, Tricyclic
National Library of Medicine's Medical Subject Headings. Amitriptyline. Online file (MeSH, 2016). Available from, as of January 20, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Amitriptyline is included in the database.
NIH/NLM; ClinicalTrials.Gov. Available from, as of March 17, 2016: https://clinicaltrials.gov/ct2/results?term=AMITRIPTYLINE&Search=Search
For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than are other depressive states. /Included in US product labeling/
NIH; DailyMed. Current Medication Information for Amitriptyline Hydrochloride Tablet, Film Coated (Updated: November 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6d2c80-fbc8-444e-bdd3-6a91fe1b95bd
Tricyclic antidepressants have been used for the treatment of attention deficit hyperactivity disorder (ADHD). /Tricyclic antidepressant; NOT included in US product label/
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2392
For more Therapeutic Uses (Complete) data for AMITRIPTYLINE (13 total), please visit the HSDB record page.

7.8 Drug Warnings

/BOXED WARNING/ Suicidality and Antidepressant Drugs: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of amitriptyline hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Amitriptyline hydrochloride is not approved for use in pediatric patients.
NIH; DailyMed. Current Medication Information for Amitriptyline Hydrochloride Tablet, Film Coated (Updated: November 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6d2c80-fbc8-444e-bdd3-6a91fe1b95bd
A syndrome resembling neuroleptic malignant syndrome (NMS) has been very rarely reported after starting or increasing the dose of amitriptyline hydrochloride, with and without concomitant medications known to cause NMS. Symptoms have included muscle rigidity, fever, mental status changes, diaphoresis, tachycardia, and tremor.
NIH; DailyMed. Current Medication Information for Amitriptyline Hydrochloride Tablet, Film Coated (Updated: November 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6d2c80-fbc8-444e-bdd3-6a91fe1b95bd
Very rare cases of serotonin syndrome (SS) have been reported with amitriptyline hydrochloride in combination with other drugs that have a recognized association with SS.
NIH; DailyMed. Current Medication Information for Amitriptyline Hydrochloride Tablet, Film Coated (Updated: November 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6d2c80-fbc8-444e-bdd3-6a91fe1b95bd
Amitriptyline hydrochloride ... should be used with caution in patients with a history of seizures and, because of its atropine-like action, in patients with a history of urinary retention, angle-closure glaucoma or increased intraocular pressure. In patients with angle-closure glaucoma, even average doses may precipitate an attack.
NIH; DailyMed. Current Medication Information for Amitriptyline Hydrochloride Tablet, Film Coated (Updated: November 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6d2c80-fbc8-444e-bdd3-6a91fe1b95bd
For more Drug Warnings (Complete) data for AMITRIPTYLINE (39 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

**Effects in pain and depression** Amitriptyline is a tricyclic antidepressant and an analgesic. It has anticholinergic and sedative properties. Clinical studies have shown that oral amitriptyline achieves, at a minimum, good to moderate response in up to 2/3 of patients diagnosed with post-herpetic neuralgia and 3/4 of patients diagnosed with diabetic neuropathic pain, and neurogenic pain syndromes that are frequently unresponsive to narcotic analgesics. Amitriptyline has also shown efficacy in diverse groups of patients with chronic non-malignant pain. There have also been some studies showing efficacy in managing fibromyalgia (an off-label use of this drug),. **Cardiovascular and Anticholinergic Effects** Amitriptyline has strong anticholinergic properties and may cause ECG changes and quinidine-like effects on the heart. Amitriptyline may inhibit ion channels, which are necessary for cardiac repolarization (hERG channels), in the upper micromolar range of therapeutic plasma concentrations. Therefore, amitriptyline may increase the risk for cardiac arrhythmia. Orthostatic hypotension and tachycardia can be a problem in elderly patients receiving this drug at normal doses for depression. There is evidence in the literature that these effects may occur, rarely, at the lower dosages utilized in the treatment of pain. As with any other tricyclic antidepressant agent, increased glucose levels can occur with amitriptyline. **Effects on seizure threshold** This drug also decreases the convulsive threshold and causes alterations in EEG and sleep patterns.

8.2 MeSH Pharmacological Classification

Adrenergic Uptake Inhibitors
Drugs that block the transport of adrenergic transmitters into axon terminals or into storage vesicles within terminals. The tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC) and amphetamines are among the therapeutically important drugs that may act via inhibition of adrenergic transport. Many of these drugs also block transport of serotonin. (See all compounds classified as Adrenergic Uptake Inhibitors.)
Antidepressive Agents, Tricyclic
Substances that contain a fused three-ring moiety and are used in the treatment of depression. These drugs block the uptake of norepinephrine and serotonin into axon terminals and may block some subtypes of serotonin, adrenergic, and histamine receptors. However, the mechanism of their antidepressant effects is not clear because the therapeutic effects usually take weeks to develop and may reflect compensatory changes in the central nervous system. (See all compounds classified as Antidepressive Agents, Tricyclic.)
Analgesics, Non-Narcotic
A subclass of analgesic agents that typically do not bind to OPIOID RECEPTORS and are not addictive. Many non-narcotic analgesics are offered as NONPRESCRIPTION DRUGS. (See all compounds classified as Analgesics, Non-Narcotic.)

8.3 FDA Pharmacological Classification

FDA UNII
1806D8D52K
Active Moiety
AMITRIPTYLINE
Pharmacological Classes
Established Pharmacologic Class [EPC] - Tricyclic Antidepressant
FDA Pharmacology Summary
Amitriptyline is a Tricyclic Antidepressant.

8.4 ATC Code

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

N - Nervous system

N06 - Psychoanaleptics

N06A - Antidepressants

N06AA - Non-selective monoamine reuptake inhibitors

N06AA09 - Amitriptyline

8.5 Absorption, Distribution and Excretion

Absorption
Rapidly absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations are reached 2-12 hours after oral or intramuscular administration. Steady-state plasma concentrations vary greatly and this variation may be due to genetic differences.
Route of Elimination
Amitriptyline and its metabolites are mainly excreted in the urine. Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with approximately 2% of unchanged drug appearing in the urine. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours. Small amounts are excreted in feces via biliary elimination.
Volume of Distribution
The apparent volume of distribution (Vd)β estimated after intravenous administration is 1221 L±280 L; range 769-1702 L (16±3 L/kg). It is found widely distributed throughout the body. Amitriptyline and the main metabolite _nortriptyline_ pass across the placental barrier and small amounts are present in breast milk.
Clearance
The mean systemic clearance (Cls) is 39.24 ± 10.18 L/h (range: 24.53-53.73 L/h). No clear effect of older age on the pharmacokinetics of amitriptyline has been determined, although it is possible that clearance may be decreased.
This study reports the pharmacokinetics of oral amitriptyline and its active metabolite nortriptyline in Greyhound dogs. Five healthy Greyhound dogs were enrolled in a randomized crossover design. A single oral dose of amitriptyline hydrochloride (actual mean dose 8.1 per kg) was administered to fasted or fed dogs. Blood samples were collected at predetermined times from 0 to 24 hr after administration, and plasma drug concentrations were measured by liquid chromatography with mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Two dogs in the fasted group vomited following amitriptyline administration and were excluded from analysis. The range of amitriptyline CMAX for the remaining fasted dogs (n = 3) was 22.8-64.5 ng/mL compared to 30.6-127 ng/mL for the fed dogs (n = 5). The range of the amitriptyline AUCINF for the three fasted dogs was 167-720 hr ng/mL compared to 287-1146 hr ng/mL for fed dogs. The relative bioavailability of amitriptyline in fasted dogs compared to fed dogs was 69-91% (n = 3). The exposure of the active metabolite nortriptyline was correlated to amitriptyline exposure (R(2) = 0.84). Due to pharmacokinetic variability and the small number of dogs completing this study, further studies are needed assessing the impact of feeding on oral amitriptyline pharmacokinetics. Amitriptyline may be more likely to cause vomiting in fasted dogs.
Norkus C et al; J Vet Pharmacol Ther. 2015 Dec;38(6):619-22 (2015)
The inability of a 30-yr-old female with graft-versus-host disease to absorb oral doses of amitriptyline was reported. Only trace plasma levels of the drug were determined following 4 wk therapy with 50 mg daily doses. Additional therapy with 75 mg daily doses for 10 days failed to incr the antidepressant's plasma levels.
Freed E et al; Med J Aust 140 (Apr 14): 509-510 (1984)
An experimental rat model was used to study postmortem redistribution of amitriptyline. Two hr after a sc injection with 20 mg of amitriptyline, the rats (n=40) were anesthetized and blood samples were drawn from the femoral vein and the heart. The rats were then sacrificed by CO2 and left at room temp for either 0.1, 1, 2, 5, 24, 48, or 96 hr. Postmortem blood samples from the heart and the inferior vena cava, and tissue samples from the lungs, heart, liver, right kidney, thigh muscle, the wall of the abdominal vena cava and brain were analyzed by HPLC. A significant incr was observed within 2 hr postmortem in heart blood and later also in blood from the inferior vena cava. At 96 hr postmortem the concn incr was 4.4 + or - 0.5-fold (p < 0.01) and 3.0 + or - 1.1-fold (p < 0.05) as compared to the antemortem values observed in heart blood and blood from the inferior vena cava, respectively (mean + or - SEM). In the lungs there was a fall in the concn of AMI from 148 + or - 16.7 umol/kg at 0.1 hr to 49.1 + or - 7.8 umol/kg at 96 hr postmortem (p < 0.01). In the vessel wall of the abdominal vena cava there was also a significant fall in drug concn, while in heart muscle and liver an incr in drug concn was observed. In animals where the lungs were removed agonally (n = 7), the drug concn in heart blood had incr significantly less at 2 hr postmortem.
Hilberg T et al; Forensic Sci Int 64 (1): 47-55 (1994)
The percutaneous absorption of amitriptyline, nortriptyline, imipramine, and desipramine as their hydrochloride salts in vivo was demonstrated without use of a vehicle using the hairless (hr-1/hr-1) mouse as an experimental model for human skin. After topical application of 2 mg of each compound in distilled water, followed by rapid evaporation of the water, concn were measured in heart, lung, brain, liver, and blood in 1-, 2-, 4-, and 6-hr study groups. Lung consistently demonstrated the highest concn for all four compounds while heart and liver had the lowest. Concn in heart remained essentially constant for all compounds during the 6-hour study period. The concn in solid tissues were much lower than those commonly seen in man after overdose, whereas the concn in blood resembled low therapeutic to toxic concn in humans. Percutaneous absorption may provide a feasible route of admin for the tricyclic antidepressants which may lead to improved compliance with fewer GI side effects. /Amitriptyline hydrochloride/
Bailey DN; J Anal Toxicol 14 (4): 217-8 (1990)
For more Absorption, Distribution and Excretion (Complete) data for AMITRIPTYLINE (17 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

In vitro, the metabolism of amitriptyline occurs mainly by demethylation (CYP2C19, CYP3A4) as well as hydroxylation (CYP2D6) followed by conjugation with glucuronic acid. Other isozymes involved in amitriptyline metabolism are CYP1A2 and CYP2C9. The metabolism of this drug is subject to genetic polymorphisms. The main active metabolite is the secondary amine, _nortriptyline_. Nortriptyline is a stronger inhibitor of noradrenaline than of serotonin uptake, while amitriptyline inhibits the uptake of noradrenaline and serotonin with equal efficacy. Other metabolites such as _cis-_ and _trans-10-hydroxyamitriptyline_ and _cis-_ and _trans-10-hydroxynortriptyline_ have the same pharmacologic profile as nortriptyline but are significantly weaker. _Demethylnortriptyline_ and amitriptyline N oxide are only present in plasma in negligible amounts; the latter is mostly inactive.
A method for the determination of amitriptyline and some of its metabolites in serum on a reversed phase system consisting of C-8 bonded phase material as the stationary phase and water-methanol-dichloromethane-propylamine as the mobile phase by liquid chromatography with UV detection at 254 nm is described. ... Serum levels of amitriptyline and its 4 main metabolites (nortriptyline, desmethylnortriptyline, trans-10-hydroxyamitriptyline and trans-10-hydroxynortriptyline) in a patient receiving 150 mg of oral amitriptyline daily are reported.
Kraak JC, Bijster P; J Chromatogr Biomed 143 (Sep 1): 499-512 (1977)
Amitriptyline is metabolized via the same pathways as are other tricyclic antidepressants; nortriptyline, its N-monodemethylated metabolite, is pharmacologically active.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2399
To investigate the metabolism of amitriptyline and debrisoquine ... 8 healthy Chinese volunteers received a single oral dose of 100 mg amitriptyline and the ratios between the area under the curve (AUC) of amitriptyline and its 3 metabolites were evaluated. Results indicated that large interindividual differences in AUC were observed. In addition, hydroxylation of amitriptyline and debrisoquine may be regulated by similar enzymatic processes.
Zhang XH et al; Acta Pharm Sinica (Yao Hsueh Hsueh Pao) 28 (Feb): 85-91 (1993)
Biotransformation of amitriptyline to its demethylated product nortriptyline was studied in vitro with human liver microsomes from four different donors, preselected to reflect a range of metabolic rates. Reaction velocity versus substrate concn was consistent with a sigmoid Vmax model. Vmax varied from 0.42 to 3.42 nmol/mg/min, Km from 33 to 89 uM amitriptyline. Ketoconazole was a highly potent inhibitor of N-demethylation, with a mean Ki value of 0.11 + or - 0.013 uM ... whereas quinidine (up to 50 uM), a CYP2D6 inhibitor, and alpha-naphthoflavone (up to 5 uM), a CYP1A2 inhibitor only at low concn, showed no effect. All selective serotonin reuptake inhibitors tested had an inhibitory effect on the formation of nortriptyline, with mean Ki values of 4.37 (+ or - 3.38) uM for sertraline, 5.46 (+ or - 1.95) uM for desmethylsertraline, 9.22 (+ or - 3.69) uM for fluvoxamine, 12.26 (+ or - 5.67) uM for norfluoxetine, 15.76 (+ or - 5.50) uM for paroxetine, and 43.55 (+ or - 18.28) uM for fluoxetine. A polyclonal rabbit antibody against rat liver CYP3A1, in antibody/microsomal protein rations varying from 1:1 to 10:1, inhibited N-demethylation of amitriptyline to an asymptotic max of 60%.
Schmider J et al; J Pharmacol Exp Ther 275 (2): 592-7 (1995)
For more Metabolism/Metabolites (Complete) data for AMITRIPTYLINE (8 total), please visit the HSDB record page.
Amitriptyline has known human metabolites that include nortriptyline and E-10-hydroxyamitriptyline.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560
Amitriptyline is rapidly and well absorbed following oral administration. Exclusively hepatic, with first pass effect. Amitriptyline is demethylated in the liver to its primary active metabolite, nortriptyline. Route of Elimination: Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with little unchanged drug appearing in the urine. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours. Small amounts are excreted in feces via biliary elimination. Half Life: 10 to 50 hours, with an average of 15 hours

8.7 Biological Half-Life

The elimination half-life (t1⁄2 β) amitriptyline after peroral administration is about 25 hours (24.65 ± 6.31 hours; range 16.49-40.36 hours).
The plasma half-life of amitriptyline ranges from 10 to 50 hours.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2399
The toxicokinetics of amitriptyline were studied in nine patients admitted to hospital in Matthew-Lawson Coma Scale grade III-IV after an estimated ingestion of 1-5 g amitriptyline. ... The T1/2 alpha and T1/2 beta for amitriptyline were 1.5 - 3.1 and 15 - 43 hr respectively. ...
Hulten BA et al; J Toxicol Clin Toxicol 30 (2): 181-201 (1992)
... The purpose of this pilot study was to describe the individual and population pharmacokinetic parameters of amitriptyline after a single oral dose at 1.5 mg/kg, 4.5 mg/kg, and 9 mg/kg in healthy African grey parrots ( Psittacus erithacus , n = 3) and cockatoos (Cacatua species, n = 3). Three birds received an initial 1.5 mg/kg oral dose, and blood samples were collected for 24 hours at fixed time intervals. Serum concentrations of amitriptyline and its metabolites were determined by polarized immunofluorescence. After determining the initial parameters and a 14-day washout period, 2 African grey parrots and 1 cockatoo received a single oral dose at 4.5 mg/kg, and 3 cockatoos and 1 African grey parrot received a single oral dose at 9 mg/kg. ... Elimination half-life varied from 1.6 to 91.2 hours. ...
Visser M et al; J Avian Med Surg 29 (4): 275-81 (2015)

8.8 Mechanism of Action

The mechanism of action of this drug is not fully elucidated. It is suggested that amitriptyline inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines, such as norepinephrine and serotonin, thereby increasing their concentration at the synaptic clefts of the brain,. These amines are important in regulating mood. The monoamine hypothesis in depression, one of the oldest hypotheses, postulates that deficiencies of serotonin (5-HT) and/or norepinephrine (NE) neurotransmission in the brain lead to depressive effects. This drug counteracts these mechanisms, and this may be the mechanism of amitriptyline in improving depressive symptoms. Whether its analgesic effects are related to its mood-altering activities or attributable to a different, less obvious pharmacological action (or a combination of both) is unknown.
Acute and chronic effects of the antidepressant drugs tranylcypromine, a monoamine oxidase inhibitor, and amitriptyline, a monoamine uptake inhibitor, were studied on beta-adrenergic receptor function in mouse astrocytes in primary cultures. In clinically relevant concentrations, acute administration of either antidepressant drug had a direct inhibitory effect on the binding of the beta-adrenergic ligand dihydroalprenolol and on the isoproterenol-induced accumulation of cyclic AMP. However, in the absence of isoproterenol, these drugs enhanced the formation of cyclic AMP in the astrocytes. Chronic exposure to amitriptyline or tranylcypromine led to a decrease in isoproterenol-induced accumulation of cyclic AMP, and the time course for the development of this phenomenon was similar to that reported for whole brain in vivo. These findings suggest that these antidepressant drugs act as a partial agonists at beta-adrenergic receptors on astrocytes, and that the down-regulation of beta-adrenergic activity that occurs in vivo after chronic administration of antidepressant drugs may, to a large extent, take place in astrocytes and may result from the partial beta-agonist nature of the drugs.
Hertz L, Richardson JS; J Neurosci Res. 1983;9(2):173-82 (1983)
Astrocytes play important roles in guiding the construction of the nervous system, controlling extracellular ions and neurotransmitters, and regulating CNS synaptogenesis. Egr-1 is a transcription factor involved in neuronal differentiation and astrocyte cell proliferation. In this study, we investigated whether the tricyclic antidepressant (TCA) amitriptyline induces Egr-1 expression in astrocytes using rat C6 glioma cells as a model. We found that amitriptyline increased the expression of Egr-1 in a dose- and time-dependent manner. The amitriptyline-induced Egr-1 expression was mediated through serum response elements (SREs) in the Egr-1 promoter. SREs were activated by the Ets-domain transcription factor Elk-1 through the ERK and JNK mitogen-activated protein (MAP) kinase pathways. The inhibition of the ERK and JNK MAP kinase signals attenuated amitriptyline-induced transactivation of Gal4-Elk-1 and Egr-1 promoter activity. Our findings suggest that the induction of Egr-1 expression in astrocytes may be required to attain the therapeutic effects of antidepressant drugs.
Chung EY et al; Neurosci Lett 422 (1): 43-8 (2007)
Antidepressants such as serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) are frequently used for the management of neuropathic pain. Noradrenaline (NA) and serotonin (5-HT) increase in the spinal cord by reuptake inhibition is considered to be main mechanism of the therapeutic effect of antidepressants in neuropathic pain. In the present study, we examined the analgesic effects of duloxetine (SNRI) and amitriptyline (TCA) in a rat model of neuropathic pain induced by spinal nerve ligation (SNL). Intraperitoneal administration of duloxetine and amitriptyline dose-dependently (3,10 and 30 mg/kg) suppressed hyperalgesia induced by SNL. In vivo microdialysis in the lumbar spinal dorsal horn revealed that NA and 5-HT concentrations increased after intraperitoneal administration of duloxetine and amitriptyline (10 mg/kg, respectively). We further determined NA and 5-HT contents in homogenized samples from the ipsilateral dorsal spinal cord after SNL. Although the NA content in SNL rats 2 weeks after ligation was higher than that in SNL rats 4 weeks after ligation, the analgesic efficacy of duloxetine and amitriptyline was similar between two groups. The present study suggests that NA/5-HT increase in the spinal cord is crucial in the antihyperalgesic effect of duloxetine and amitriptyline. The plastic change of the descending noradrenergic system does not obviously affect the analgesic efficacy of duloxetine and amitriptyline.
Hoshino H et al; Neurosci Lett 602: 62-7 (2015)
Recent studies show that neuronal and glial plasticity are important for the therapeutic action of antidepressants. Here, we demonstrated that amitriptyline, a tricyclic antidepressant, significantly increased GDNF mRNA and GDNF release in C6 cells. Furthermore, different classes of antidepressants increased GDNF release, but non-antidepressant psychotropic drugs did not. The amitriptyline-induced GDNF release was completely inhibited by U0126, a mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89, a protein kinase A inhibitor or calphostin C, a protein kinase C inhibitor. These results suggest that the amitriptyline-induced GDNF release may be regulated through a MEK/MAPK pathway. Next, we examined the effects of monoamines on GDNF release, because antidepressants are known to increase monoamines. 5-HT increased GDNF mRNA and GDNF release, but noradrenaline and dopamine did not. The 5-HT-induced GDNF release was partially, but significantly, blocked by ketanserin, a 5-HT2A receptor antagonist. The 5-HT-induced GDNF release was completely inhibited by U0126, but was not inhibited by H-89 or calphostin C. These results suggest that the 5-HT-induced GDNF release was mediated through a MEK/MAPK pathway and, at least, 5-HT2A receptors. GDNF, as well as other neurotrophic factors, may contribute to explain the therapeutic action of antidepressants and suggest a novel strategy of pharmacological intervention.
Hisaoka K et al; Nihon Shinkei Seishin Yakurigaku Zasshi 25 (1): 25-31 (2005)
For more Mechanism of Action (Complete) data for AMITRIPTYLINE (13 total), please visit the HSDB record page.

8.9 Human Metabolite Information

8.9.1 Cellular Locations

  • Extracellular
  • Membrane

8.10 Transformations

9 Use and Manufacturing

9.1 Uses

MEDICATION
Adrenergic Uptake Inhibitors; Analgesics, Non-Narcotic; Antidepressive Agents, Tricyclic
National Library of Medicine's Medical Subject Headings. Amitriptyline. Online file (MeSH, 2016). Available from, as of January 20, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html

Use (kg; approx.) in Germany (2009): >7500

Use (kg) in USA (2002): 17300

Consumption (g per capita; approx.) in Germany (2009): 0.0916

Consumption (g per capita) in the USA (2002): 0.0613

Excretion rate: 0.02

Calculated removal (%): 87.4

For the treatment of depression, chronic pain, irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation and insomnia, and migraine prophylaxis.

9.1.1 Use Classification

Pharmaceuticals -> Antidepressants
S66 | EAWAGTPS | Parent-Transformation Product Pairs from Eawag | DOI:10.5281/zenodo.3754448
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Methods of Manufacturing

Phthalic anhydride is reacted with phenylacetic acid to form 3-benzylidenephthalide, which is hydrogenated to 2-phenethylbenzoic acid. Conversion to the acid chloride followed by intramolecular dehydrochlorination yields the ketone (5H-dibenzo[a,d]cyclohepten-5-one), which is grignardized with 3-(dimethylamino)propyl chloride. Dehydration of the resulting tertiary carbinol gives amitriptyline, which is dissolved in a suitable solvent and converted to the hydrochloride by a stream of HCl. USA patent 3,205,264.
Troy, D.B. (Ed); Remmington The Science and Practice of Pharmacy. 21 st Edition. Lippincott Williams & Williams, Philadelphia, PA 2005, p. 1519
... Prepared from 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (well known under the trivial name dibenzosuberone) and 3-dimethylaminopropylmagnesium chloride and subsequent dehydration with HCl in ethanol. ... a versatile alternative process makes use of cyclopropylmagnesium bromide as Grignard reagent.
Kleemann A; Antidepressants. Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2016). NY, NY: John Wiley & Sons. Online Posting Date: January 31, 2014
... Prepared by reaction of 5-oxo-10,11-dihydro-5H-dibenzo(a,d)cycloheptene with the Grignard reagent of 3-dimethylaminopropyl chloride followed by dehydration of the resulting tertiary alcohol in a strongly acidic medium.
Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley-VCH Verlag GmbH & Co. 2003 to Present, p. V30 412 (2003)

9.3 Formulations / Preparations

Table: Amitriptyline Hydrochloride Preparations
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg
Brand or Generic Form (Manufacturer)
Amitriptyline Hydrochloride Film-coated Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
25 mg
Brand or Generic Form (Manufacturer)
Amitriptyline Hydrochloride Film-coated Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
50 mg
Brand or Generic Form (Manufacturer)
Amitriptyline Hydrochloride Film-coated Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
75 mg
Brand or Generic Form (Manufacturer)
Amitriptyline Hydrochloride Film-coated Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
100 mg
Brand or Generic Form (Manufacturer)
Amitriptyline Hydrochloride Film-coated Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
150 mg
Brand or Generic Form (Manufacturer)
Amitriptyline Hydrochloride Film-coated Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2399
Table: Chlordiazepoxide and Amitriptyline Hydrochloride Preparations
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg Chlordiazepoxide and Amitriptyline Hydrochloride 12.5 mg (of amitriptyline)
Brand or Generic Form (Manufacturer)
Chlordiazepoxide and Amitriptyline Hydrochloride Tablets, C-IV (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
5 mg Chlordiazepoxide and Amitriptyline Hydrochloride 12.5 mg (of amitriptyline)
Brand or Generic Form (Manufacturer)
Limbitrol, C-IV (Valeant)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg Chlordiazepoxide and Amitriptyline Hydrochloride 25 mg (of amitriptyline)
Brand or Generic Form (Manufacturer)
Chlordiazepoxide and Amitriptyline Hydrochloride Tablets, C-IV (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
10 mg Chlordiazepoxide and Amitriptyline Hydrochloride 25 mg (of amitriptyline)
Brand or Generic Form (Manufacturer)
Limbitrol, C-IV (Valeant)
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2399
Table: Perphenazine and Amitriptyline Preparations
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
2 mg Perphenazine and Amitriptyline Hydrochloride 10 mg
Brand or Generic Form (Manufacturer)
Perphenazine and Amitriptyline Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
2 mg Perphenazine and Amitriptyline Hydrochloride 25 mg
Brand or Generic Form (Manufacturer)
Perphenazine and Amitriptyline Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
4 mg Perphenazine and Amitriptyline Hydrochloride 10 mg
Brand or Generic Form (Manufacturer)
Perphenazine and Amitriptyline Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
4 mg Perphenazine and Amitriptyline Hydrochloride 25 mg
Brand or Generic Form (Manufacturer)
Perphenazine and Amitriptyline Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets, film-coated
Strength
4 mg Perphenazine and Amitriptyline Hydrochloride 50 mg
Brand or Generic Form (Manufacturer)
Perphenazine and Amitriptyline Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2399
Adepril; Amineurin; Domical; Elavi; Endep; Euplit; Laroxyl; Lentizol; Miketorin; Redomex; Saroten; Sarotex; Triptizol; Tryptanol; Tryptizol. /Amitriptyline hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 87

9.4 Consumption Patterns

ESSENTIALLY 100% AS AN ANTIDEPRESSANT
SRI

9.5 U.S. Production

(1976) PROBABLY GREATER THAN 4.54X10+5 GRAMS
SRI
(1979) PROBABLY GREATER THAN 4.54X10+5 G-HCL
SRI

9.6 U.S. Imports

(1977) 5.32X10+6 GRAMS (PRINCPL CUSTMS DISTS)
SRI
(1979) 1.00X10+6 GRAMS (PRINCPL CUSTMS DISTS)
SRI

9.7 General Manufacturing Information

The product is available as the free base or hydrochloride.
Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994., p. 76

10 Identification

10.1 Analytic Laboratory Methods

A comparison of the UV absorption spectra of imipramine, clomipramine, dibenzepin, amitriptyline, doxepin and loxapine was carried out in aq solutions using a deconvolution procedure. The spectra were studied between 200-400 nm at 25DGC in terms of molar absorptivities. The use of this technique in the analysis of these drugs was discussed.
Minguez AC et al; Farmaco Ed Prat 42 (June): 165-170 (1987)
Analyte: amitriptyline hydrochloride; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 27/The National Formulary, NF 22; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p130 (2004)
Analyte: amitriptyline hydrochloride; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 27/The National Formulary, NF 22; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p130 (2004)
Analyte: amitriptyline hydrochloride; matrix: chemical identification; procedure: visual reaction (white, curdy precipitate) with silver nitrate (Chloride test)
U.S. Pharmacopeia. The United States Pharmacopeia, USP 27/The National Formulary, NF 22; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p130 (2004)
For more Analytic Laboratory Methods (Complete) data for AMITRIPTYLINE (12 total), please visit the HSDB record page.

10.2 Clinical Laboratory Methods

A method is described for analysis of free, total plasma and saliva amitriptyline by dialysis and gas chromatography/mass sSpectrometry.
Baumann P et al; Eur J Mass Spectrom Biochem, Med Environ Res 2 (1-2): 19 (1982)
High-performance liquid chromatographic method is described for determining amitriptyline in serum.
Edelbroek PM et al; Clin Chem (Winston-Salem, NC) 28 (10): 2143 (1982)
A simple sensitive, and selective RP HPLC method with UV detection is described for the determination of amitriptyline and its metabolites in plasma and brain tissue of animals. The method was used to determine levels of the drug and metabolites in plasma and brain of mice after a single ip admin of 20 mg/kg amitriptyline.
Coudore F et al; J Chromatogr Biomed Appl 122 (Dec): 249-255 (1992)
A column switching system followed by RP isocratic HPLC with UV detection is described for the simultaneous determination of amitriptyline, nortriptyline, and hydroxylated metabolites in human plasma or serum. The method allowed routine measurements of amitriptyline, nortriptyline, and hydroxylated metabolites in blood of patients treated with amitriptyline or nortriptyline.
Hartter S, Hiemke C; J Chromatogr Biomed Appl 116 (Jul): 273-282 (1992)
For more Clinical Laboratory Methods (Complete) data for AMITRIPTYLINE (6 total), please visit the HSDB record page.

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

1 of 2
View All
Pictogram(s)
Corrosive
Acute Toxic
Irritant
Health Hazard
Environmental Hazard
Signal
Danger
GHS Hazard Statements

H301+H311+H331 (41.8%): Toxic if swallowed, in contact with skin or if inhaled [Danger Acute toxicity, oral; acute toxicity, dermal; acute toxicity, inhalation]

H301 (41.8%): Toxic if swallowed [Danger Acute toxicity, oral]

H302 (56.7%): Harmful if swallowed [Warning Acute toxicity, oral]

H311 (41.8%): Toxic in contact with skin [Danger Acute toxicity, dermal]

H318 (41.8%): Causes serious eye damage [Danger Serious eye damage/eye irritation]

H331 (41.8%): Toxic if inhaled [Danger Acute toxicity, inhalation]

H361 (41.8%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

H410 (41.8%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P203, P261, P262, P264, P264+P265, P270, P271, P273, P280, P301+P316, P301+P317, P302+P352, P304+P340, P305+P354+P338, P316, P317, P318, P321, P330, P361+P364, P391, P403+P233, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 67 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 3 (41.8%)

Acute Tox. 4 (56.7%)

Acute Tox. 3 (41.8%)

Eye Dam. 1 (41.8%)

Acute Tox. 3 (41.8%)

Repr. 2 (41.8%)

Aquatic Chronic 1 (41.8%)

11.2 Fire Fighting

11.2.1 Fire Fighting Procedures

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3 Accidental Release Measures

11.3.1 Cleanup Methods

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided; Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product. /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3.3 Preventive Measures

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product. /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

11.4 Handling and Storage

11.4.1 Storage Conditions

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2 - 8 °C. Keep in a dry place. /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Amitriptyline hydrochloride tablets should be stored in well-closed containers at a temperature preferably between 15-30 °C; exposure to temperatures exceeding 30 °C should be avoided.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2399

11.5 Exposure Control and Personal Protection

11.5.1 Personal Protective Equipment (PPE)

Eye/face protection: Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Skin protection: Handle with gloves. /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html
Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.6 Stability and Reactivity

11.6.1 Hazardous Reactivities and Incompatibilities

Incompatible materials: Strong oxidizing agents /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.7 Regulatory Information

REACH Registered Substance
New Zealand EPA Inventory of Chemical Status
Amitriptyline: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

11.7.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including amitriptyline hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Amitriptyline hydrochloride/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 22, 2016: https://www.fda.gov/cder/ob/

11.8 Other Safety Information

11.8.1 Toxic Combustion Products

Special hazards arising from the substance or mixture: Carbon oxides, nitrogen oxides (NOx), Hydrogen chloride gas /Amitriptyline hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Amitriptyline hydrochloride. Product Number: A8404, Version 4.6 (Revision Date 06/29/2014). Available from, as of January 27, 2016: https://www.sigmaaldrich.com/safety-center.html

11.8.2 Special Reports

Sarris J et al; Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. Am J Psychiatry 173 (6): 575-87 (2016)

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

IDENTIFICATION AND USE: Amitriptyline is in the form of crystals. It is a tricyclic antidepressant. HUMAN EXPOSURE AND TOXICITY: Symptoms of overdose/poisoning may include the following: hypothermia, respiratory depression, seizures, abnormal tendon reflexes, disorientation, agitation, myoclonic jerks, coma, pyramidal signs, arrhythmias, bundle branch block, cardiac arrest, hypotension, circulatory collapse, mydriasis, blurred vision, tachycardia, vasodilation, urinary retention, decreased gastrointestinal motility, decreased bronchial secretions, and dry mucous membranes and skin. A study on children showed that initial symptoms and signs of acute amitriptyline intoxication appeared severe, but they disappeared with only supportive care required in most children except for cases that ingested high doses of drug within a few days. However, antidepressants have been shown to increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. An experiment with amitriptyline demonstrated that antidepressants reduce the release of non-neuronal acetylcholine in the human placenta, but only at concentrations roughly 30-fold above the therapeutic range. Antidepressant therapy of pregnant women should still be done with caution. Amitriptyline HCl was evaluated for its genotoxicity. The evaluation was performed in somatic (bone marrow) and germ (spermatocytes) cells, as well as the sperm morphology (i.e., head and tail) and count of the resulting sperm. The results showed that the treatment induced structural and numerical chromosome abnormalities in somatic cells (bone marrow) and germ cells (spermatocytes). Moreover, the drug significantly reduced both the mitotic index and meiotic activity after the different treatments used. Amitriptyline was found to increase significantly the incidence of sperm-cell head and tail abnormalities. The sperm-cell count was also significantly decreased. These results showed that the effect of the drug was dose dependent. In another study, amitriptyline was found to be nongenotoxic at plasma levels. However, frequencies of chromosome aberrations and sister chromatid exchanges were significantly increased at concentrations 4 and 40 times the plasma level. ANIMAL STUDIES: Symptoms of exposure in dogs include lethargy, tachycardia, vomiting, and hyperthermia. Symptoms in cats have included mydriasis and/or tachycardia, ataxia, lethargy, disorientation, and vomiting. In mice, amitriptyline produces rapid but reversible clouding of the lens, if the eyes are allowed to remain open and unprotected from evaporation. In a study on dogs, oral doses of 20 and 40 mg/kg/day were tolerated for 6 months without hematologic, biochemical or anatomical evidence of drug toxicity. Oral doses of 80 mg/kg/day were not well tolerated: 2 of 4 dogs died within 3 weeks after exhibiting severe ataxia and sedation. Doses of 100 mg/kg/day or greater were not tolerated for more than a few days. Offspring of amitriptyline-treated rats showed reduced locomotor activity. In rats, an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies. In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of cranial bones. Amitriptyline was tested for genotoxicity using the somatic mutation and recombination test (SMART) in wing cells of Drosophila melanogaster. The drug was not genotoxic at concentrations up to 100 mM.
Amitriptyline is metabolized to nortriptyline which inhibits the reuptake of norepinephrine and serotonin almost equally. Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity. This interference with the reuptake of norepinephrine and/or serotonin is believed by some to underlie the antidepressant activity of amitriptyline.

12.1.2 USGS Health-Based Screening Levels for Evaluating Water-Quality

Chemical
Amitriptyline
Chemical Classes
Pharmaceutical
Reference
Smith, C.D. and Nowell, L.H., 2024. Health-Based Screening Levels for evaluating water-quality data (3rd ed.). DOI:10.5066/F71C1TWP

12.1.3 Hepatotoxicity

Liver test abnormalities have been reported to occur in 10% to 12% of patients on amitriptyline, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported in patients on amitriptyline. The latency to onset is quite variable, ranging from 1 to 14 months of starting the medication. The reported pattern of serum enzyme elevations has varied from hepatocellular to cholestatic. An acute hepatitis-like syndrome with acute liver failure has been reported, as well as acute cholestatic hepatitis and prolonged jaundice compatible with vanishing bile duct syndrome. Signs or symptoms of hypersensitivity (rash, fever and eosinophilia) are frequent, but are usually mild and transient. Autoantibody formation is rare.

Likelihood score: B (highly likely cause of clinically apparent liver injury).

12.1.4 Drug Induced Liver Injury

Compound
amitriptyline
DILI Annotation
Less-DILI-Concern
Severity Grade
5
Label Section
Adverse reactions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.5 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

12.1.6 Health Effects

Some rare side effects include tinnitus, hypotension, mania, psychosis, heart block, arrhythmias, lip and mouth ulcers, extrapyramidal symptoms, depression, and hepatic toxicity.Amitriptyline exhibits strong anticholinergic activity, cardiovascular effects including orthostatic hypotension, changes in heart rhythm and conduction, and a lowering of the seizure threshold (A308, L1032).
A308: Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. PMID:18048412
L1032: Wikipedia. Amitriptyline. Last Updated 7 August 2009. http://en.wikipedia.org/wiki/Amitriptyline

12.1.7 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Milk levels of amitriptyline and its metabolites are low. Immediate side effects have not been reported and a limited amount of follow-up has found no adverse effects on infant growth and development. Amitriptyline use during breastfeeding would usually not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. A safety scoring system finds amitriptyline use to be possible with caution during breastfeeding. However, rare sedation has been reported in a neonate. Other agents with fewer active metabolites may be preferred when large doses are required or while nursing a newborn or preterm infant.

◉ Effects in Breastfed Infants

At least 23 infants have been reported to have been exposed to amitriptyline in breastmilk up to 2002 with no reports of adverse reactions with maternal dosages from 75 to 175 mg daily.

Follow-up for 1 to 3 years in a group of 20 breastfed infants whose mothers were taking a tricyclic antidepressant found no adverse effects on growth and development. One of the mothers whose infant was followed up at 18 months of age was taking amitriptyline 150 mg daily.

Two small controlled studies indicate that other tricyclic antidepressants have no adverse effect on infant development. In one of the studies, 2 mothers were taking amitriptyline 100 and 175 mg daily. One of the infants tested in the low normal range from birth and on repeat testing.

In another study, 25 infants whose mothers took a tricyclic antidepressant during pregnancy and lactation were tested formally between 15 to 71 months and found to have normal growth and development. Some of the mothers were taking amitriptyline.

A nursing mother was prescribed amitriptyline 10 mg daily for insomnia. After 3 days of the medication, her 15-day-old infant developed severe sedation and an estimated 80% decrease in breastfeeding because of the sedation. The infant was otherwise normal on examination. The drug was discontinued and symptoms decreased within 24 hours and were absent after 48 hours. Amitriptyline was restarted at 10 mg daily. The same effects reappeared in the infant and again disappeared by 48 hours after discontinuation of the drug. The infant’s sedation was probably caused by amitriptyline in breastmilk.

A case-control study in Israel compared 280 infants of nursing mothers taking long-term psychotropic drugs to the infants of 152 women taking antibiotics. Neonatal infant sleepiness was reported by 1 mother taking amitriptyline and none taking antibiotics.

◉ Effects on Lactation and Breastmilk

Amitriptyline has caused increased prolactin levels in nonpregnant, nonnursing patients. The clinical relevance of these findings in nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.

A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575; amitriptyline n = 30) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis.

In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.

◈ What is amitriptyline?

Amitriptyline belongs to a class of medications known as tricyclic antidepressants. Amitriptyline is approved to treat depression. However, it ha#s also been used to treat pain, tinnitus (noise or ringing sounds in the ear), Irritable bowel syndrome, neuropathy (nerve damage) due to diabetes mellitus, and to treat and prevent migraine headaches. Amitriptyline has been sold under many different brand names. Some brand names are Amaril®, Amitrid®, Elavil®, Endep®, and Vanatrip®. Amitriptyline has also been sold in combination with other medications.Pregnancy might affect how the body breaks down this medication. For this reason, some people might need to have their medication doses changed as a pregnancy progresses. Your healthcare provider can discuss this with you, if needed.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy. Some people might have a return of their symptoms (relapse) if they stop taking amitriptyline. If you plan to stop this medication, your healthcare provider may suggest that you slowly lower the dose instead of stopping all at once. Stopping this medication suddenly can cause some people to have withdrawal symptoms.

◈ I take amitrivptyline. Can it make it harder for me to get pregnant?

Studies have not been done to see if amitriptyline could make it harder to get pregnant.

◈ Does taking amitriptyline increase the chance for miscarriage?

Miscarriage is common and can occur in any pregnancy for many different reasons. Based on the studies reviewed, it is not known if amitriptyline increases the chance for miscarriage. However, depression itself might increase the chance for miscarriage.

◈ Does taking amitriptyline increase the chance of birth defects?

Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Based on the studies reviewed, it is not known if amitriptyline increases the chance for birth defects above the background risk. A small number of human studies have not found a higher chance for birth defects with doses of amitriptyline used for treatment of depression.

◈ Does taking amitriptyline in pregnancy increase the chance of other pregnancy related problems?

One report found a small increased chance of preeclampsia (a pregnancy related condition that can cause symptoms such as high blood pressure and kidney problems in the pregnant person) when amitriptyline was used in the second and third trimester of pregnancy. Studies have not been done to see if amitriptyline increases the chance for other pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth). However, research has shown that when depression is left untreated during pregnancy, there could be an increased chance for pregnancy complications. This makes it hard to know if it is the medication, untreated depression or factors that are increasing the chance for these problems. For more information, please see our fact sheet on Depression at https://mothertobaby.org/fact-sheets/depression-pregnancy/.

◈ I need to take amitriptyline throughout my entire pregnancy. Will it cause withdrawal symptoms in my baby after birth?

Studies have not been done to see if amitriptyline use in pregnant might lead to withdrawal or toxicity in a newborn soon after delivery. There is one case report of an infant who had temporary withdrawal symptoms after being exposed throughout pregnancy. The infant and the mother were found to have high blood levels of amitriptyline.Some babies exposed to other tricyclic antidepressant class medications in pregnancy have been reported to have withdrawal symptoms in the newborn period. The symptoms seen during the first month of life included colic, low oxygen levels, breathing problems, and irritability. If a baby developed these symptoms, in most cases the symptoms would go away in a few days without any long-term health effects.

◈ Does taking amitriptyline in pregnancy affect future behavior or learning for the child?

One study looking at 29 children exposed to amitriptyline during pregnancy did not find any behavioral or learning problems.

◈ Breastfeeding while taking amitriptyline:

Amitriptyline gets into breast milk in small amounts. There are several reports of the use of amitriptyline being used during breasting. No side effects in nursing infants have been reported with a dose between 75 mg to 175 mg per day.There was one report of a person who was taking 10 mg of amitriptyline per day while breastfeeding. The breastfeeding baby (15 days old) was reported to be very sleepy. When the medication was stopped, the infant’s symptom resolved.If you suspect that your baby has symptoms of sleepiness or sedation, or have other concerns, contact the child’s healthcare provider. Be sure to talk with your healthcare providers about your breastfeeding questions

◈ If a male takes amitriptyline, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?

In some studies, it was reported that amitriptyline lowered sex drive and caused sexual dysfunction in males, which may make it harder to get a partner pregnant. These problems can also be side effects of untreated depression. Studies have not been done to see if amitriptyline could increase the chance of birth defects. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

12.1.8 Exposure Routes

Oral (A308) Rapidly and well absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations occur 2-12 hours following oral or intramuscular administration.
A308: Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. PMID:18048412

12.1.9 Symptoms

Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia.

12.1.10 Acute Effects

12.1.11 Toxicity Data

LD50: 350 mg/kg (Oral, Mouse) (A308)
A308: Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. PMID:18048412

12.1.12 Treatment

Consider gastric lavage only if within one hour of a potentially fatal overdose. Give 50 grams of charcoal if within one hour of ingestion. Prolonged resuscitation may be successful in case of cardiac arrest. Give sodium bicarbonate in case of arrhythmias. (A311)
A311: Kerr GW, McGuffie AC, Wilkie S: Tricyclic antidepressant overdose: a review. Emerg Med J. 2001 Jul;18(4):236-41. PMID:11435353

12.1.13 Interactions

The teratogenic potential of a combination of chlordiazepoxide (Cdz) and amitriptyline (Amt) was examined with regard to both internal and external anomalies. Timed pregnant golden hamsters were given a single intraperitoneal injection on day 8 of gestation of one of the following: chlordiazepoxide hydrochloride (28.5 mg/kg), amitriptyline hydrochloride (70.3 mg/kg), Cdz-Amt combination (28.5 mg/kg Cdz + 70.3 mg/kg Amt, in order to retain the 1:2.5 dose ratio utilized in a clinically-used preparation of these agents), or saline vehicle (control). Fetuses were recovered on gestation day 15 following maternal sacrifice. Cranial malformations were analyzed in Bouin's-fixed fetuses by making 1-mm coronal sections through each head, whereas visceral anomalies were examined following general dissection of each body. Amt alone produced a significant (P less than 0.05) incidence of bent tail and encephalocele, whereas Cdz significantly (P less than 0.05) altered the male:female ratio of surviving fetuses when compared with saline-injected controls. The Cdz-Amt combination caused significant increases in cranial malformations, open eye, bent tail, abnormal lung, and urogenital anomalies. The teratogenic effects of potentiation between the components of this combination are discussed in terms of external and internal malformations.
Beyer BK et al; Teratology 30 (1): 39-45 (1984)
Caution is advised if patients receive large doses of ethchlorvynol concurrently. Transient delirium has been reported in patients who were treated with one gram of ethchlorvynol and 75 to 150 mg of amitriptyline hydrochloride.
NIH; DailyMed. Current Medication Information for Amitriptyline Hydrochloride Tablet, Film Coated (Updated: November 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6d2c80-fbc8-444e-bdd3-6a91fe1b95bd
The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7 to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA). In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6. /Tricyclic antidepressants/
NIH; DailyMed. Current Medication Information for Amitriptyline Hydrochloride Tablet, Film Coated (Updated: November 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6d2c80-fbc8-444e-bdd3-6a91fe1b95bd
The combination (ethanol and amitriptyline) produced greater impairment of 3 psychomotor functions in animals than did either drug alone. Ethanol pretreatment also produced A 2.23% increase in the total tricyclic antidepressant brain concentration.
Preskorn SH, hughes CW; Psychopharmacology (Berlin) 80 (3): 217 (1983)
For more Interactions (Complete) data for AMITRIPTYLINE (33 total), please visit the HSDB record page.

12.1.14 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160-1
Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. Caution: Respiratory arrest can occur abruptly and without warning. 2. Treat coma, seizures, hyperthermia, hypotension, and arrhythmias if they occur. Note: Do not use procainamide or other type Ia or Ic antiarrhythmic agents for ventricular tachycardia because these drugs may aggravate cardiotoxicity. 3. Consider cardiac pacing for bradyarrhythmias and high-degree AV block, and overdrive pacing for torsade de pointes. 4. Mechanical support of the circulation (eg, cardiopulmonary bypass) may be useful (based on anecdotal reports) in stabilizing patients with refractory shock, allowing time for the body to eliminate some of the drug. 5. If seizures are not immediately controlled with usual anticonvulsants, paralyze the patient with a neuromuscular blocker to prevent hyperthermia, which may induce further seizures, and lactic acidosis, which cardiotoxicity. Note: Paralysis abolishes the muscular manifestations of seizures but has no effect on brain seizure activity. After paralysis, electroencephalographic (EEG) monitoring is necessary to determine the efficiency of anticonvulsant therapy. 6. Continuously monitor the temperature, other vital signs, and ECG in asymptomatic patients for a minimum of 6 hours, and admit patients to an intensive care setting for at least 24 hours if there are any signs of toxicity. /Antidepressants, tricyclic/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 99
For more Antidote and Emergency Treatment (Complete) data for AMITRIPTYLINE (9 total), please visit the HSDB record page.

12.1.15 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ A total of 103 cases of amitriptyline overdose (group 1) and 81 cases of overdose with a fixed combo of amitriptyline and chlordiazepoxide (group 2), treated at our ICU or reported to our Poison Info Center between 1985-1990, were evaluated with respect to clinical course, symptoms and outcome, as well as efficacy of therapy. The mean amt of amitriptyline was considerably higher in group 1 compared to group 2 (13 mg/kg versus 7.7 mg/kg). The most frequent symptoms in both groups were impaired consciousness, anticholinergic symptoms, seizures, arrhythmia and hypotension. Respiratory insufficiency necessitated respiratory therapy in 63 of the patients. Two patients in group 1 and one patient in group 2 did not survive. Therapy included primary detoxification by gastric lavage and repeated admin of activated charcoal. In 4/8 patients with cardiac conduction disturbances, hypertonic sodium bicarbonate led to a significant reduction in QRS duration and AV interval. Physostigmine was effective in 8/14 patients with pronounced anticholinergic symptoms. No effect was observed in the other 6 patients. Hemoperfusion, which was performed in 5 patients, led to rapid improvement of coma after initiation of therapy in 4 patients.
Koppel C et al; Hum Exp Toxicol 11 (6): 458-65 (1992)
/SIGNS AND SYMPTOMS/ Characteristics of acute tricyclic antidepressant poisoning: CNS effects: hypothermia, respiratory depression, seizures, abnormal tendon reflexes, disorientation, agitation, myoclonic jerks, coma and pyramidal signs. /Tricyclic Antidepressants; From table/
Gossel, T.A., J.D. Bricker. Principles of Clinical Toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 1994., p. 331
/SIGNS AND SYMPTOMS/ Characteristics of acute tricyclic antidepressant poisoning: Cardiovascular effects: ventricular rate >120 beats/min, QRS duration >100 msec, arrhythmias, bundle branch block, cardiac arrest, hypotension, and circulatory collapse. /Tricyclic Antidepressants; From table/
Gossel, T.A., J.D. Bricker. Principles of Clinical Toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 1994., p. 331
/SIGNS AND SYMPTOMS/ Characteristics of acute tricyclic antidepressant poisoning: Anticholinergic effects: mydriasis, blurred vision, tachycardia, vasodilation, urinary retention, decreased gastrointestinal motility, decreased bronchial secretions, and dry mucous membranes and skin. /Tricyclic Antidepressants; From table/
Gossel, T.A., J.D. Bricker. Principles of Clinical Toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 1994., p. 331
For more Human Toxicity Excerpts (Complete) data for AMITRIPTYLINE (43 total), please visit the HSDB record page.

12.1.16 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ Cardiac depression is the main adverse effect of severe tricyclic antidepressant poisoning. The aim of this study was to compare the effects of several inotropic drugs on survival and the occurrence of arrhythmias in the treatment of amitriptyline poisoning. ... Nonrandomized, controlled intervention trial. ... Eighty-six male Wistar rats anesthetized with pentobarbital and mechanically ventilated. ... Rats subjected to a 60-min continuous infusion of amitriptyline (1.25 mg/kg/min) were treated with a continuous infusion of either epinephrine, norepinephrine, milrinone, magnesium, epinephrine + magnesium, or norepinephrine + magnesium. ... Without treatment, all animals exhibited arrhythmias on the electrocardiogram within 20 min. All treatment drugs delayed the onset of arrhythmias, but significant differences were only observed after admin of epinephrine, epinephrine + magnesium sulfate, and norepinephrine + magnesium sulfate. All the inotropic drugs markedly incr survival. Sodium concn were unaffected by all treatments. In control animals, potassium concn incr during amitriptyline infusion. Norepinephrine treatment had no effect on potassium concn, whereas all other treatments resulted in decr potassium concn. ... All inotropic drugs used in the study incr survival in tricyclic antidepressant poisoning in rats without incr the risk of arrhythmias. Furthermore, epinephrine and norepinephrine + magnesium sulfate were effective in preventing arrhythmias, possibly due to improved hemodynamic performance or potassium homeostasis.
Knudsen K, Abrahamsson J; Crit Care Med 22 (11): 1851-5 (1994)
/LABORATORY ANIMALS: Acute Exposure/ In mice amitriptyline... produces rapid but reversible clouding of the lens, if the eyes are allowed to remain open and unprotected from evaporation.
Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 85
/LABORATORY ANIMALS: Acute Exposure/ The ventricular tachycardia caused by high-dose tricyclic antidepressants has been hypothesized to be due to a quinidinelike effect with generation of repolarization abnormalities and afterdepolarizations. To test this hypothesis further, we infused amitriptyline in a graded fashion (0.5-1 mg/kg/min) in 23 chloralose-anesthetized dogs during endocardial monophasic action potential (AP) recording and continuous hemodynamic monitoring. Three groups of dogs were studied: group A (n=5), crushed sinus node and fixed atrial pacing at 100 beats/min; group B (n=12), crushed sinus node and fixed atrial pace plus intermittent accelerated pacing to mimic group C; and group C (n=6) intact sinus node and unimpeded sinus tachycardia. Amitriptyline infusion induced ventricular tachycardia in no (0 of 5) group A dogs, all (12 of 12) group B dogs during accelerated pacing, and 83% (5 of 6) of group C dogs. Dogs with ventricular tachycardia had significantly higher heart rates (HR 184.8 + or - 39.3 beats/min) as compared with dogs without ventricular tachycardia (115.2 + or - 12.5 beats/min, p = 0.0015). There was a strong positive correlation between the last RR coupling interval to the first ventricular tachycardia interval (r = 0.85; p = 0.0033). Amitriptyline infusion caused rate-dependent QRS prolongation in each group, esp group C (p < 0.001). Action potential duration at 50% and 90% of repolarization ... showed a biphasic response with progressive shortening followed by prolongation as amitriptyline serum concn incr. After depolarizations were not detected from any monophasic AP recording, even in dogs with ventricular tachycardia.
Ansel GM et al; J Cardiovasc Pharmacol 22 (6): 798-803 (1993)
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Dogs: Oral doses of 20 and 40 mg/kg/day were tolerated for 6 months without hematologic, biochemical or anatomical evidence of drug toxicity. Signs of drug effect included slight to marked sedation, a slight tachycardia, slight ataxia, and occasionally, excessive salivation and emesis. Oral doses of 80 mg/kg/day in a 6 month study were not well tolerated: 2 of 4 dogs died within 3 weeks after exhibiting severe ataxia and sedation. No other drug-related effects were observed. Doses of 100 mg/kg/day or greater were not tolerated for more than a few days. The only effect observed was a small amount of fat in the periportal region of the liver without evidence of necrosis.
Health Canada; Product Monograph for Amitriptyline Hydrochloride Tablets USP, Drug Identification Number (DIN): 02403137 p.16 (Date of Preparation: March 14, 2013). Available from, as of March 18, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
For more Non-Human Toxicity Excerpts (Complete) data for AMITRIPTYLINE (21 total), please visit the HSDB record page.

12.1.17 Human Toxicity Values

Therapeutic, toxic, and lethal blood concentrations: 5-20 ug/dL, >50 ug/dL, and 1-2 mg/dL, respectively. /From table/
Gossel, T.A., J.D. Bricker. Principles of Clinical Toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 1994., p. 421

12.1.18 Non-Human Toxicity Values

LD50 Mouse iv 16 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1562
LD50 Mouse sc 140 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1562
LD50 Mouse ip 56 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1562
LD50 Mouse oral 140 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1562
For more Non-Human Toxicity Values (Complete) data for AMITRIPTYLINE (6 total), please visit the HSDB record page.

12.1.19 Populations at Special Risk

Amitriptyline hydrochloride ... should be used with caution in patients with a history of seizures and, because of its atropine-like action, in patients with a history of urinary retention, angle-closure glaucoma or increased intraocular pressure. In patients with angle-closure glaucoma, even average doses may precipitate an attack.
NIH; DailyMed. Current Medication Information for Amitriptyline Hydrochloride Tablet, Film Coated (Updated: November 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6d2c80-fbc8-444e-bdd3-6a91fe1b95bd
Schizophrenic patients may develop increased symptoms of psychosis; patients with paranoid symptomatology may have an exaggeration of such symptoms. Depressed patients, particularly those with known manic-depressive illness, may experience a shift to mania or hypomania. In these circumstances the dose of amitriptyline may be reduced or a major tranquilizer such as perphenazine may be administered concurrently.
NIH; DailyMed. Current Medication Information for Amitriptyline Hydrochloride Tablet, Film Coated (Updated: November 2015). Available from, as of January 20, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6d2c80-fbc8-444e-bdd3-6a91fe1b95bd
Patients with preexisting cardiovascular disease may be especially sensitive to the cardiotoxicity of tricyclic antidepressants. In addition, those with disturbed eating behaviors (e.g., purging) that result in adequate hydration and/or compromised cardiac status also may be at greater risk of severe adverse cardiovascular effects (e.g., hypotension, increased cardiac conduction time, arrhythmia). /Tricyclic antidepressants/
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2393
Tricyclic antidepressants should be administered with caution to hyperthyroid patients or patients receiving thyroid agents. /Tricyclic antidepressants/
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2394
For more Populations at Special Risk (Complete) data for AMITRIPTYLINE (15 total), please visit the HSDB record page.

12.1.20 Protein Binding

Very highly protein bound (95%) in plasma and tissues.

12.2 Ecological Information

12.2.1 Ecotoxicity Values

EC50; Species: Daphnia magna (Water Flea) age <24 hr neonate; Conditions: freshwater, static, 21 °C, pH 7.6; Concentration: 0.00415 mM for 24 hr; Effect: intoxication, immobilization
Lilius H et al; Aquat Toxicol 30: 47-60 (1994) as cited in the ECOTOX database. Available from, as of February 11, 2016
EC50; Species: Daphnia pulex (Water Flea) age <24 hr; Conditions: freshwater, static, 20 °C, pH 7.6; Concentration: 0.00373 mM for 24 hr; Effect: intoxication, immobilization /formulation/
Lilius H et al; Environ Toxicol Chem 14 (12): 2085-2088 (1995) as cited in the ECOTOX database. Available from, as of February 11, 2016

12.2.2 Environmental Fate / Exposure Summary

Amitriptyline's production and administration as an antidepressant may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 3.6X10-7 mm Hg at 25 °C indicates amitriptyline will exist in both the vapor and particulate phases in the atmosphere. Vapor-phase amitriptyline will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 0.72 hours. Particulate-phase amitriptyline will be removed from the atmosphere by wet and dry deposition. Amitriptyline contains chromophores that absorb at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, amitriptyline is expected to have slight mobility based upon a Koc of 3530. The estimated pKa of amitriptyline is 9.76, indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Amitriptyline is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Utilizing the various loam soils, half-lives of 34-85 days were observed with the formation of degradation products over 80 days indicating that biodegradation is an environmental fate process in soil or water, with rate dependent on conditions. If released into water, amitriptyline is expected to adsorb to suspended solids and sediment based upon the estimated Koc. The estimated pKa indicates amitriptyline will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. An estimated BCF of 820 suggests the potential for bioconcentration in aquatic organisms is high. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to amitriptyline may occur through inhalation and dermal contact with this compound at workplaces where amitriptyline is produced or used. Limited monitoring data indicate that the general population may be exposed to amitriptyline via ingestion of contaminated drinking water. Use data indicate that some of the general public are likely to be exposed to amitriptyline by direct medical treatment. (SRC)

12.2.3 Artificial Pollution Sources

Amitriptyline hydrochloride's production and administration as an antidepressant(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil M, ed; The Merck Index. 15th ed. Cambridge, UK: The Royal Society of Chemistry. p. 87 (2013)

12.2.4 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), a measured Koc value of 3530(2) indicates that amitriptyline is expected to have slight mobility in soil(SRC). The estimated pKa of amitriptyline is 9.76(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Amitriptyline is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.6X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Utilizing the various loam soils, half-lives of 34-85 days were observed with the formation of degradation products over 80 days(6) indicating that biodegradation is an environmental fate process in soil, with rate dependent on conditions(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Barron L et al; Analyst 134: 663-670 (2009)
(3) ChemSpider; Nortriptyline. (72-69-5). London, UK: Royal Chemical Society. Available from, as of Feb 18, 2016: https://www.chemspider.com/Search.aspx
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(5) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 4, 2016: https://www2.epa.gov/tsca-screening-tools
(6) Li H et al; Environ Toxicol Chem 32: 509-516 (2013)
AQUATIC FATE: Based on a classification scheme(1), a meaured Koc value of 3530(2) indicates that amitriptyline is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 9.76(3) indicates amitriptyline will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 820(SRC), from its log Kow of 4.92(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Utilizing the various loam soils, half-lives of 34-85 days were observed with the formation of degradation products over 80 days(6) indicating that biodegradation is an environmental fate process in water, with rate dependent on conditions(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Barron L et al; Analyst 134: 663-670 (2009)
(3) ChemSpider; Nortriptyline. (72-69-5). London, UK: Royal Chemical Society. Available from, as of Feb 18, 2016: https://www.chemspider.com/Search.aspx
(4) Franke C et al; Chemosphere 29: 1501-14 (1994)
(5) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 167 (1995)
(6) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 4, 2016: https://www2.epa.gov/tsca-screening-tools
(7) Li H et al; Environ Toxicol Chem 32: 509-516 (2013)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), amitriptyline, which has an estimated vapor pressure of 3.6X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase amitriptyline is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 0.72 hours(SRC), calculated from its rate constant of 1.8X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase amitriptyline may be removed from the air by wet and dry deposition(SRC). Amitriptyline contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 4, 2016: https://www2.epa.gov/tsca-screening-tools
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

12.2.5 Environmental Biodegradation

AEROBIC: 3H-Labeled amitriptyline, present at 1 ug/g, exhibited half-lives of 34.1, 56.1 and 85.2 days using a loam soil, clay loam soil and sandy loam soil (all from Ontario, Canada), respectively, incubated at 30 °C for 78 days. The major degradation product identified was amitriptyline-N-oxide; nortriptyline was also detected(1).
(1) Li H et al; Environ Toxicol Chem 32(3): 509-516 (2013)

12.2.6 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of amitriptyline with photochemically-produced hydroxyl radicals has been reported as 3.60X10-14 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 0.718 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of amitriptyline with ozone has been estimated as 1.65X10-15 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(1). This corresponds to an atmospheric half-life of about 11 minutes at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). Amitriptyline is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). Amitriptyline does contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(2) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)

12.2.7 Environmental Bioconcentration

An estimated BCF of 820 was calculated in fish for amitriptyline(SRC), using a log Kow of 4.92(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC).
(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 167 (1995)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 9, 2016: https://www2.epa.gov/tsca-screening-tools
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.8 Soil Adsorption / Mobility

A log Koc of 3.56 (Kd = 138 L/kg), corresponding to a Koc of 3530, was measured using an agricultural soil (pH 6.3) from Corrstown, Co Dublin, Ireland(1). According to a classification scheme(2), this Koc value suggests that amitriptyline is expected to be immobile in soil. The estimated pKa of amitriptyline is 9.76(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). A sorption isotherm Kd of 2.8X10+3 has been reported using secondary sludge from the Klagshamn waste water treatment plant in Malmo City, Sweden(5). A Kd value of 1049 L/kg was measured using a digester sludge from wastewater treatment plant, Dublin Ireland (pH 6.3)(1).
(1) Barron L et al; Analyst 134: 663-670 (2009)
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) ChemSpider; Nortriptyline. (72-69-5). London, UK: Royal Chemical Society. Available from, as of Feb 18, 2016: https://www.chemspider.com/Search.aspx
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(5) Horsing M et al; Water Res 45: 4470-82 (2011)

12.2.9 Volatilization from Water / Soil

An estimated pKa of 9.76(1) indicates amitriptyline will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water of moist soil surfaces is not expected to be an important fate process. Amitriptyline is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.6X10-7 mm Hg(SRC), determined from a fragment constant method(2).
(1) ChemSpider; Nortriptyline. (72-69-5). London, UK: Royal Chemical Society. Available from, as of Feb 18, 2016: https://www.chemspider.com/Search.aspx
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 2, 2016: https://www2.epa.gov/tsca-screening-tools

12.2.10 Environmental Water Concentrations

GROUNDWATER: Amitriptyline was not detected in well water samples from the Herault River watershed, south of France, sampled in 2003; detection limit = 0.7 ng/L(1).
(1) Rabiet M et al; Environ Sci Technol 40: 5282-88 (2006)
DRINKING WATER: Amitriptyline was tested for but not detected in tap water samples from the Madrid region, Spain, sampled between October 25 and 30, 2007; quantification limit = 1 ug/L(1).
(1) Valcarcel Y et al; Chemosphere 84(10): 1336-48 (2011)
SURFACE WATER: Amitriptyline was detected at a range of <0.5-30 ng/L with a maximum of 72 ng/L in unspecified surface water samples(1). The compound was not detected in water samples from the Herault River watershed, south of France, sampled in 2003; detection limit = 2.2 ng/L(2). Amitriptyline median concentration was <1 ng/L (quantitation limit) in surface water samples downstream from sewage treatment plants in the Madrid region, Spain, sampled between October 25 and 30, 2007; rivers sampled were: Jarama, Manzanares, Guadarrama, Henares, and the Tagus(3).
(1) Petrie B et al; Water Res 72: 3-27 (2015)
(2) Rabiet M et al; Environ Sci Technol 40: 5282-88 (2006)
(3) Valcarcel Y et al; Chemosphere 84(10): 1336-48 (2011)

12.2.11 Effluent Concentrations

Amitriptyline was detected in 2% of samples from 90 EU wastewater treatment plant effluents, at an average concentration of 0.3 ng/L and a maximum concentration of 14.6 ng/L. Sampling was conducted in 2010; detection limit = 5 ng/L(1). The compound was reported in influent at a range of 106-2,092 ng/L and in the final effluent 66-207 ng/L, with 50-80% removal (secondary treatment). The primary breakdown products are metabolites notriptyline and 10-hydroxyamitriptyline(2). Amitriptyline was detected at a concentration of 6.0 ng/L in effluent samples entering the Herault River from the Lodeve waste water treatment plant on the Lergue River, south of France, sampled in 2003; detection limit = 3.4 ng/L(3).
(1) Loos R et al; Water Res 47(17): 6475-87 (2013)
(2) Petrie B et al; Water Res 72: 3-27 (2015)
(3) Rabiet M et al; Environ Sci Technol 40: 5282-88 (2006)

12.2.12 Sediment / Soil Concentrations

Amitriptyline was detected, not quantified in 39 of 40 the marine sediment locations throughout Puget Sound, Washington, USA, sampled during April and June, 2010. It was detected in one sample at 0.45 ng/g dry wt; minimum reporting limit = 0.23-2.45 ng/g dry wt(1).
(1) Long ER et al; Environ Toxicol Chem 32(8): 1701-1710 (2013)

12.2.13 Milk Concentrations

Amitriptyline and its active metabolite, nortriptyline, are distributed into milk. Amitriptyline and nortriptyline concentrations in milk appear to be similar to or slightly greater than those present in maternal serum. It is estimated that a nursing infant would ingest less than 1% of the daily maternal dose of amitriptyline ... .
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2399

12.2.14 Probable Routes of Human Exposure

NIOSH (NOES Survey 1981-1983) has statistically estimated that 3,157 workers (1,154 of these are female) were potentially exposed to amitriptyline in the US(1). Occupational exposure to amitriptyline may occur through inhalation and dermal contact with this compound at workplaces where amitriptyline is produced or used. Limited monitoring data indicate that the general population may be exposed to amitriptyline via ingestion of contaminated drinking water. Use data indicate that some of the general public are likely to be exposed to amitriptyline by direct medical treatment(SRC).
(1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available from, as of Feb 2, 2016: https://www.cdc.gov/noes/

12.2.15 Body Burden

Amitriptyline and its active metabolite, nortriptyline, are distributed into milk. Amitriptyline and nortriptyline concentrations in milk appear to be similar to or slightly greater than those present in maternal serum. It is estimated that a nursing infant would ingest less than 1% of the daily maternal dose of amitriptyline ... .
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 2169
Amitriptyline is extensively excreted in sweat (0.78-0.2 mg/L) after cases of severe poisoning(1).
(1) Daughton CG, Ruhoy IS; Environ Toxicol Chem 28(12): 2495-2521 (2009)
2% Amitriptyline is excreted unchanged(1).
(1) Petrie B et al; Water Res 72: 3-27 (2015)

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Chemical Co-Occurrences in Literature

14.7 Chemical-Gene Co-Occurrences in Literature

14.8 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

16.4 Drug-Food Interactions

  • Avoid alcohol.
  • Avoid St. John's Wort.
  • Limit caffeine intake.
  • Take with food. Food reduces irritation.

17 Biological Test Results

17.1 BioAssay Results

18 Taxonomy

19 Classification

19.1 MeSH Tree

19.2 NCI Thesaurus Tree

19.3 ChEBI Ontology

19.4 KEGG: ATC

19.5 KEGG: Target-based Classification of Drugs

19.6 KEGG: Drug Groups

19.7 WHO ATC Classification System

19.8 FDA Pharm Classes

19.9 ChemIDplus

19.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

19.11 ChEMBL Target Tree

19.12 UN GHS Classification

19.13 NORMAN Suspect List Exchange Classification

19.14 CCSBase Classification

19.15 EPA DSSTox Classification

19.16 EPA Substance Registry Services Tree

19.17 MolGenie Organic Chemistry Ontology

20 Information Sources

  1. CAS Common Chemistry
    LICENSE
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    https://creativecommons.org/licenses/by-nc/4.0/
  2. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  4. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
  6. FDA Global Substance Registration System (GSRS)
    LICENSE
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  7. Hazardous Substances Data Bank (HSDB)
  8. Human Metabolome Database (HMDB)
    LICENSE
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    http://www.hmdb.ca/citing
  9. New Zealand Environmental Protection Authority (EPA)
    LICENSE
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    https://www.epa.govt.nz/about-this-site/general-copyright-statement/
  10. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  11. ChEBI
  12. FDA Pharm Classes
    LICENSE
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  13. LiverTox
  14. NCI Thesaurus (NCIt)
    LICENSE
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    https://www.cancer.gov/policies/copyright-reuse
  15. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  16. Toxin and Toxin Target Database (T3DB)
    LICENSE
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    http://www.t3db.ca/downloads
  17. ChEMBL
    LICENSE
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    http://www.ebi.ac.uk/Information/termsofuse.html
  18. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    AMITRIPTYLINE
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  19. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  20. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
    N4-PHENYLETHOXYCYTIDINE-5'-TRIPHOSPHATE
    https://www.dgidb.org/drugs/iuphar.ligand:6200
  21. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  22. Therapeutic Target Database (TTD)
  23. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  24. Drugs and Lactation Database (LactMed)
  25. Mother To Baby Fact Sheets
    LICENSE
    Copyright by OTIS. This work is available under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported license (CC BY-NC-ND 3.0).
    https://www.ncbi.nlm.nih.gov/books/about/copyright/
  26. WHO Model Lists of Essential Medicines
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license.
    https://www.who.int/about/policies/publishing/copyright
  27. EU Clinical Trials Register
  28. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  29. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  30. SpectraBase
  31. Japan Chemical Substance Dictionary (Nikkaji)
  32. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  33. Kruve Lab, Ionization & Mass Spectrometry, Stockholm University
    amitriptyline
  34. MassBank Europe
  35. Metabolomics Workbench
  36. Natural Product Activity and Species Source (NPASS)
  37. NIPH Clinical Trials Search of Japan
  38. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  39. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  40. PharmGKB
    LICENSE
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    https://www.pharmgkb.org/page/policies
  41. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  42. Protein Data Bank in Europe (PDBe)
  43. RCSB Protein Data Bank (RCSB PDB)
    LICENSE
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    https://www.rcsb.org/pages/policies
  44. Springer Nature
  45. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  46. USGS Health-Based Screening Levels for Evaluating Water-Quality Data
  47. Wikidata
  48. Wikipedia
  49. Wiley
  50. Medical Subject Headings (MeSH)
    LICENSE
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    https://www.nlm.nih.gov/copyright.html
    Adrenergic Uptake Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68018759
    Antidepressive Agents, Tricyclic
    https://www.ncbi.nlm.nih.gov/mesh/68000929
  51. PubChem
  52. GHS Classification (UNECE)
  53. EPA Substance Registry Services
  54. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  55. PATENTSCOPE (WIPO)
  56. NCBI
CONTENTS