AMITRIPTYLINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H23N
Molecular Weight	277.4033
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN(C)CCC=C1C2=C(CCC3=C1C=CC=C3)C=CC=C2

InChI

InChIKey=KRMDCWKBEZIMAB-UHFFFAOYSA-N

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

HIDE SMILES / InChI

Molecular Formula	C20H23N
Molecular Weight	277.4033
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.emedexpert.com/facts/amitriptyline-facts.shtml
Curator's Comment: description was created based on several sources, including http://www.rxlist.com/elavil-drug.htm https://www.ncbi.nlm.nih.gov/pubmed/23235671; https://www.ncbi.nlm.nih.gov/pubmed/11157426; http://www.ncbi.nlm.nih.gov/pubmed/16871467; http://www.ncbi.nlm.nih.gov/pubmed/2578912; http://www.ncbi.nlm.nih.gov/pubmed/?term=15943846

Amitriptyline is a derivative of dibenzocycloheptadiene and a tricyclic antidepressant (TCA) and is mainly used to treat symptoms of depression. It works on the central nervous system (CNS) by inhibiting the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Amitriptyline has been frequently used as an active comparator in clinical trials on newer antidepressants. It is rarely used as a first-line antidepressant nowadays due to its high degree of toxicity in overdose and generally poorer tolerability than the newer antidepressants.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Sodium-dependent noradrenaline transporter 38 Target ID: P23975 Gene ID: 6530.0 Gene Symbol: SLC6A2 Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/14744476	Inhibitor 8228	3.45 nM [IC50]
Sodium-dependent serotonin transporter 40 Target ID: P31645 Gene ID: 6532.0 Gene Symbol: SLC6A4 Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/14744476	Inhibitor 8228	13.3 nM [IC50]
5-hydroxytryptamine receptor 2A 69 Target ID: P28223 Gene ID: 3356.0 Gene Symbol: HTR2A Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/7855217	Antagonist 2760

Conditions

Condition	Modality	Targets	Highest Phase	Product
Depressive disorder 4 Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1e6d2c80-fbc8-444e-bdd3-6a91fe1b95bd	Preventing		Approved 8360	AMITRIPTYLINE HYDROCHLORIDE Approved Use For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than are other depressive states. Launch Date 8.7393599E11

C_max

Value	Dose	Co-administered	Analyte	Population
15.3 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10383563	75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered:		AMITRIPTYLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
593 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10383563	75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered:		AMITRIPTYLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
20.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10383563	75 mg single, oral dose: 75 mg route of administration: Oral experiment type: SINGLE co-administered:		AMITRIPTYLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
7.7% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/6125396	150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:		AMITRIPTYLINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
100 mg 1 times / day single, intravenous Studied dose Dose: 100 mg, 1 times / day Route: intravenous Route: single Dose: 100 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17512256/	healthy, 21 to 70 years n = 5 Health Status: healthy Age Group: 21 to 70 years Sex: M+F Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/17512256/	Disc. AE: Bradycardia... Other AEs: Agitation, Dry mouth... AEs leading to discontinuation/dose reduction: Bradycardia (grade 3, 20%) Other AEs: Agitation (20%) Dry mouth (20%) Drowsiness (20%) Language disorder (20%) Sources: https://pubmed.ncbi.nlm.nih.gov/17512256/
10 % 1 times / day single, topical Highest studied dose Dose: 10 %, 1 times / day Route: topical Route: single Dose: 10 %, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/21676162/	unhealthy, 57 years n = 1 Health Status: unhealthy Condition: pain Age Group: 57 years Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/21676162/	Other AEs: Thought disorder, Mental concentration difficult... Other AEs: Thought disorder Mental concentration difficult Sources: https://pubmed.ncbi.nlm.nih.gov/21676162/
520.3 mg 1 times / day single, oral (mean) Studied dose Dose: 520.3 mg, 1 times / day Route: oral Route: single Dose: 520.3 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20923818/	healthy, mean age 22.1 years n = 96 Health Status: healthy Age Group: mean age 22.1 years Sex: M+F Population Size: 96 Sources: https://pubmed.ncbi.nlm.nih.gov/20923818/	Other AEs: Mental status changes... Other AEs: Mental status changes Sources: https://pubmed.ncbi.nlm.nih.gov/20923818/
25 mg 1 times / day multiple, oral Studied dose Dose: 25 mg, 1 times / day Route: oral Route: multiple Dose: 25 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/24259978/	unhealthy, mean age 43.2 years n = 16 Health Status: unhealthy Condition: globus pharyngeus Age Group: mean age 43.2 years Sex: M+F Population Size: 16 Sources: https://pubmed.ncbi.nlm.nih.gov/24259978/	Other AEs: Dry mouth, Sleepiness... Other AEs: Dry mouth (75%) Sleepiness (68.8%) Dizziness (25%) Constipation (18.8%) Palpitations (6.3%) Malaise (6.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/24259978/
75 mg 1 times / day multiple, oral Recommended Dose: 75 mg, 1 times / day Route: oral Route: multiple Dose: 75 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/8494126/	unhealthy, mean age 55 years n = 27 Health Status: unhealthy Condition: chronic pain Age Group: mean age 55 years Sex: M+F Population Size: 27 Sources: https://pubmed.ncbi.nlm.nih.gov/8494126/	Disc. AE: Drowsiness, Dry mouth... Other AEs: Drowsiness, Nausea... AEs leading to discontinuation/dose reduction: Drowsiness (10%) Dry mouth (10%) Other AEs: Drowsiness (51.8%) Nausea (7.4%) Headache (7.4%) Dry mouth (63%) Thirst (7.4%) Tiredness (7.4%) Bad taste (18.5%) Attention concentration difficulty (7.4%) Hyperglycaemia (3.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/8494126/
59 mg 1 times / day multiple, oral (mean) Studied dose Dose: 59 mg, 1 times / day Route: oral Route: multiple Dose: 59 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/10493324/	unhealthy, mean age 60.4 years n = 25 Health Status: unhealthy Condition: diabetic peripheral neuropathy pain Age Group: mean age 60.4 years Sex: M+F Population Size: 25 Sources: https://pubmed.ncbi.nlm.nih.gov/10493324/	Disc. AE: Ankle edema, Dizziness... Other AEs: Sedation, Dry mouth... AEs leading to discontinuation/dose reduction: Ankle edema (4%) Dizziness (4%) Other AEs: Sedation (32%) Dry mouth (32%) Postural hypotension (20%) Weight gain (24%) Ataxia (8%) Constipation (12%) Lethargy (20%) Edema (8%) Headache (12%) Pruritus (12%) Bad taste (4%) Nausea (4%) Diarrhea (4%) Blurred vision (8%) Sources: https://pubmed.ncbi.nlm.nih.gov/10493324/
520.3 mg 1 times / day single, oral (mean) Studied dose Dose: 520.3 mg, 1 times / day Route: oral Route: single Dose: 520.3 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20923818/	healthy n = 96 Health Status: healthy Sex: M+F Population Size: 96 Sources: https://pubmed.ncbi.nlm.nih.gov/20923818/	Other AEs: Tachycardia... Other AEs: Tachycardia Sources: https://pubmed.ncbi.nlm.nih.gov/20923818/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1709 inhibitor 1579	substrate 1010	substrate 1193 inhibitor 1837	inhibitor 1599

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1463 CYP2C8 901 OCT1 506 OCT2 638	CYP1A2 1032 CYP2C19 985 CYP2B6 660 UGT2B10 127 UGT1A4 347

Drug as perpetrator

Target	Modality	Activity
OCT2 639	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/19002438/	yes [IC50 14 uM]
OCT1 523	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/20567254/	yes [IC50 6.99 uM]
CYP3A4 1909	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/16415122/	yes [IC50 8.8 uM]
CYP2C8 955	inhibitor 3240 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2015019/	yes [Inhibition 200 uM]
CYP2D6 1875	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/12228186/	yes [Ki 31 uM]
CYP2C19 1537	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/12228186/	yes [Ki 37.7 uM]

Drug as victim

Target	Modality	Activity
CYP1A2 1032	substrate 3326 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042727/	no
CYP2C19 985	substrate 3326 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042727/	no
CYP2B6 660	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/11259560/	yes
CYP2C9 1010	substrate 3326 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042727/	yes
CYP2D6 1193	substrate 3326 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042727/	yes
CYP3A4 1709	substrate 3326 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042727/	yes
UGT1A4 347	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/20133892/	yes
UGT2B10 127	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/20133892/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1632	inhibitor 1613 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1571977/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:2666	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:2666
MolPort	MolPort-001-662-651	https://www.molport.com/shop/molecule-link/MolPort-001-662-651
ZINC	ZINC000000968257	http://zinc15.docking.org/substances/ZINC000000968257
eMolecules	739635	https://www.emolecules.com/cgi-bin/more?vid=739635

PubMed

Title	Date	PubMed
[Cardiac arrest following amitriptylin and adrenaline].	1975 Jun 16	1145841
Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdr1a P-glycoprotein gene disruption.	2000 Apr	10700657
Antidepressants upregulate messenger RNA levels of the neuroprotective enzyme superoxide dismutase (SOD1).	2000 Jan	10721683
Block of rat brain recombinant SK channels by tricyclic antidepressants and related compounds.	2000 Jul 28	10915830
Prolonged QT interval and torsades de pointes caused by the combination of fluconazole and amitriptyline.	2000 Mar	10750939
Potent synergism of the combination of fluconazole and cyclosporine in Candida albicans.	2000 Sep	10952582
Activation of cytochrome P450 gene expression in the rat brain by phenobarbital-like inducers.	2000 Sep	10945841
Gender differences in depression associated with neurologic illness: clinical correlates and pharmacologic response.	2001	11480103
A randomized trial of fluoxetine versus amitriptyline in musculo-skeletal pain.	2001	11475920
Tianeptine: a review of its use in depressive disorders.	2001	11463130
Long-term effects of tricyclic antidepressants on norepinephrine kinetics in humans.	2001	11341486
The concentration of three anti-seizure medications in hair: the effects of hair color, controlling for dose and age.	2001	11339881
Dopaminergic activity in transgenic mice underexpressing glucocorticoid receptors: effect of antidepressants.	2001	11226678
Amitriptyline versus bupivacaine in rat sciatic nerve blockade.	2001 Apr	11379688
Evidence for the use of gabapentin in the treatment of diabetic peripheral neuropathy.	2001 Apr	11354388
The effects of amitriptyline, citalopram and reboxetine on autonomic nervous system. A randomised placebo-controlled study on healthy volunteers.	2001 Apr	11349386
Antidepressive treatment with amitriptyline and paroxetine: comparable effects on heart rate variability.	2001 Apr	11270923
Changes in quantitatively assessed tremor during treatment of major depression with lithium augmented by paroxetine or amitriptyline.	2001 Apr	11270916
[Sensory neuropathy in HIV infection: pathogenesis and therapy].	2001 Apr 14	11332255
Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram.	2001 Aug	11532381
Interaction of psychotropic drugs with monoamine oxidase in rat brain.	2001 Aug	11518022
Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates.	2001 Aug	11505218
Regional potassium distribution in the brain in forensic relevant types of intoxication preliminary morphometric evaluation using a histochemical method.	2001 Feb	11307856
Preventive therapy in pediatric migraine.	2001 Feb	11292228
Antidepressant treatment and global tests of coagulation and fibrinolysis.	2001 Feb	11247103
Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomised controlled trials.	2001 Feb	11157426
The effect of polyelectrolyte counterion specificity, charge density, and conformation on polyelectrolyte-amphiphile interaction: the carrageenan/furcellaran-amitriptyline system.	2001 Feb	11093117
Salmon calcitonin potentiates the analgesia induced by antidepressants.	2001 Jan	11274717
Serum levels of amitriptyline and therapeutic effect in non-delusional moderately to severely depressed in-patients: a therapeutic window relationship.	2001 Jan	11229620
The effects of antidepressants on obstructed and unobstructed gait in healthy elderly people.	2001 Jan	11193231
Amitriptyline enhances the central component of physiological tremor.	2001 Jan	11118252
Late-onset GM2 gangliosidosis presenting as burning dysesthesias.	2001 Jul	11483398
Antinociception by tricyclic antidepressants in the rat formalin test: differential effects on different behaviours following systemic and spinal administration.	2001 Jul	11406338
[Ciguatera: clinical relevance of a marine neurotoxin].	2001 Jul 13	11499263
Assessment of DNA damage in C6 glioma cells after antidepressant treatment using an alkaline comet assay.	2001 Jun	11482523
Involvement of adenosine in the effect of antidepressants on glutamate and aspartate release in the rat prefrontal cortex.	2001 Jun	11414661
Ring flexibility within tricyclic antidepressant drugs.	2001 Jun	11357174
In vitro reaction of formaldehyde with fenfluramine: conversion to N-methyl fenfluramine.	2001 Mar	11300512
Cyclobenzaprine hydrochloride is a commonly prescribed centrally acting muscle relaxant, which is structurally similar to tricyclic antidepressants (TCAs) and differs from amitriptyline by only one double bond.	2001 Mar	11289081
[Comparative studies of adverse effects in patients with refractory depression treated with amitryptyline, mianserin and unilateral ECT].	2001 Mar-Apr	11490887
Antidepressant drugs in dermatology.	2001 May	11438813
Bipolar disorder after mefloquine treatment.	2001 May	11394195
Treatment of neuropathic pain with venlafaxine.	2001 May	11346061
Advances in the management of neuropathic pain.	2001 May	11345017
Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine(2C) receptor.	2001 Oct	11561066
Efficacy of spinal manipulation for chronic headache: a systematic review.	2001 Sep	11562654
Antidepressants as risk factor for ischaemic heart disease: case-control study in primary care.	2001 Sep 22	11566831
Intersegmental vessel formation in zebrafish: requirement for VEGF but not BMP signalling revealed by selective and non-selective BMP antagonists.	2010 Sep	20718746

Patents

Sample Use Guides

In Vivo Use Guide

For outpatients, 75 mg of amitriptyline HCl a day in divided doses. If necessary, this may be increased to a total of 150 mg per day. An alternate method of initiating therapy in outpatients is to begin with 50 to 100 mg amitriptyline HCl at bedtime. This may be increased by 25 or 50 mg as necessary in the bedtime dose to a total of 150 mg per day. Hospitalized patients may require 100 mg a day initially. This can be increased gradually to 200 mg a day if necessary up to 300 mg a day. Not recommended for patients under 12 years of age

Route of Administration: Oral

In Vitro Use Guide

Amitriptyline was used at 40 uM in isolated rat hepatocytes for 60,120,180 min.

Substance Class	Chemical Created by `admin` on `Thu Jul 06 23:19:45 UTC 2023` Edited by `admin` on `Thu Jul 06 23:19:45 UTC 2023`
Record UNII	1806D8D52K
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AMITRIPTYLINE

Official Name

English

1-PROPANAMINE, 3-(10,11-DIHYDRO-5H-DIBENZO(A,D)CYCLOHEPTEN-5-YLIDENE)-N,N-DIMETHYL-

Systematic Name

English

LAROXYL

Brand Name

English

3-(10,11-DIHYDRO-5H-DIBENZO(A,D)CYCLOHEPTEN-5-YLIDENE)-N,N-DIMETHYL-1-PROPANAMINE

Systematic Name

English

AMITRIPTYLINE [USP IMPURITY]

Common Name

English

AMITRIPTYLINE [MI]

Common Name

English

AMITRIPTYLINE [VANDF]

Common Name

English

amitriptyline [INN]

Common Name

English

NORTRIPTYLINE HYDROCHLORIDE IMPURITY F [EP IMPURITY]

Common Name

English

Amitriptyline [WHO-DD]

Common Name

English

AMITRIPTYLINE [MART.]

Common Name

English

SEROTEN

Common Name

English

PROHEPTADIENE

Common Name

English

TRIPTANOL

Common Name

English

DAMITRIPTYLINE

Common Name

English

FLAVYL

Common Name

English

Classification Tree Code System Code

WHO-ATC

N06CA01