AMITRIPTYLINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C20H23N
Molecular Weight	277.4041
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN(C)CCC=C1c2ccccc2CCc3ccccc31

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	277.4041
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:: 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	Condition	Potency
Sodium-dependent noradrenaline transporter 38 Target ID: P23975 Gene ID: 6530 Gene Symbol: SLC6A2 Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/14744476	Inhibitor 7701	Depressive disorder	3.45000000000000018 nM [IC50]
Sodium-dependent serotonin transporter 41 Target ID: P31645 Gene ID: 6532 Gene Symbol: SLC6A4 Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/14744476	Inhibitor 7701	Depressive disorder	13.3000000000000007 nM [IC50]
5-hydroxytryptamine receptor 2A 68 Target ID: P28223 Gene ID: 3356 Gene Symbol: HTR2A Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pubmed/7855217	Antagonist 2577	Depressive disorder

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	Sodium-dependent noradrenaline transporter Sodium-dependent serotonin transporter 5-hydroxytryptamine receptor 2A	Approved 7997	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 873936000000

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 Health Status: healthy Age Group: 21 to 70 years Sex: M+F 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 Health Status: unhealthy Age Group: 57 years Sex: M 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 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 Health Status: healthy Age Group: mean age 22.1 years Sex: M+F 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 Health Status: unhealthy Age Group: mean age 43.2 years Sex: M+F 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 Health Status: unhealthy Age Group: mean age 55 years Sex: M+F 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 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 Health Status: unhealthy Age Group: mean age 60.4 years Sex: M+F 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 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 Health Status: healthy Sex: M+F 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 1470 inhibitor 1172	substrate 865	substrate 1038 inhibitor 1421	inhibitor 1360

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1215 CYP2C8 761 OCT1 473 OCT2 582	CYP1A2 892 CYP2C19 830 CYP2B6 575 UGT2B10 112 UGT1A4 295

Drug as perpetrator

Target	Modality	Activity
OCT2 583	inhibitor 2614 Sources: https://pubmed.ncbi.nlm.nih.gov/19002438/	yes [IC50 14 uM]
OCT1 488	inhibitor 2614 Sources: https://pubmed.ncbi.nlm.nih.gov/20567254/	yes [IC50 6.99 uM]
CYP3A4 1462	inhibitor 2614 Sources: https://pubmed.ncbi.nlm.nih.gov/16415122/	yes [IC50 8.8 uM]
CYP2C8 810	inhibitor 2614 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2015019/	yes [Inhibition 200 uM]
CYP2D6 1455	inhibitor 2614 Sources: https://pubmed.ncbi.nlm.nih.gov/12228186/	yes [Ki 31 uM]
CYP2C19 1277	inhibitor 2614 Sources: https://pubmed.ncbi.nlm.nih.gov/12228186/	yes [Ki 37.7 uM]

Drug as victim

Target	Modality	Activity
CYP1A2 892	substrate 2752 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042727/	no
CYP2C19 830	substrate 2752 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042727/	no
CYP2B6 575	substrate 2752 Sources: https://pubmed.ncbi.nlm.nih.gov/11259560/	yes
CYP2C9 865	substrate 2752 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042727/	yes
CYP2D6 1038	substrate 2752 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042727/	yes
CYP3A4 1470	substrate 2752 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042727/	yes
UGT1A4 295	substrate 2752 Sources: https://pubmed.ncbi.nlm.nih.gov/20133892/	yes
UGT2B10 112	substrate 2752 Sources: https://pubmed.ncbi.nlm.nih.gov/20133892/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1392	inhibitor 1374 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

PubMed

Title	Date	PubMed
Seizures during lithium-amitriptyline therapy.	1979 Sep	112590
Syncope associated with concurrent amitriptyline and fluconazole therapy.	2000 Dec	11144697
Fatal cholestatic jaundice associated with amitriptyline.	2000 Jul-Aug	11092117
Amitriptyline and somnambulism.	2000 Oct	11054994
Near fatal case of atrio-ventricular block induced by amitriptyline at therapeutic dose.	2000 Sep	11089775
A randomized trial of fluoxetine versus amitriptyline in musculo-skeletal pain.	2001	11475920
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
Involvement of potassium channels in amitriptyline and clomipramine analgesia.	2001	11077073
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
Noradrenergic dysfunction and antidepressant treatment response.	2001 Apr	11313162
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
Controlling phantom limb pain in Sierra Leone.	2001 Apr 21	11418165
Combined pharmacotherapy for nocturnal enuresis.	2001 Aug	11519898
Interaction of psychotropic drugs with monoamine oxidase in rat brain.	2001 Aug	11518022
Serum levels and cardiovascular effects of tricyclic antidepressants and selective serotonin reuptake inhibitors in depressed patients.	2001 Aug	11477329
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
Capillary electrochromatography of hydrophobic amines on continuous beds.	2001 Feb	11258763
Antidepressant treatment and global tests of coagulation and fibrinolysis.	2001 Feb	11247103
Transplacental transfer of amitriptyline and nortriptyline in isolated perfused human placenta.	2001 Feb	11243492
Prolonged coma and loss of brainstem reflexes following amitriptyline overdose.	2001 Feb	11205078
Cromolyn cream for recalcitrant idiopathic vulvar vestibulitis: results of a placebo controlled study.	2001 Feb	11158692
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
Amitriptyline enhances the central component of physiological tremor.	2001 Jan	11118252
Mirtazepine: heir apparent to amitriptyline?	2001 Jan-Feb	11406877
Isolated sural neuropathy presenting as lateral ankle pain.	2001 Jul	11421525
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
The effect of amitriptyline on pain intensity and perception of stress in bruxers.	2001 Jun	11512111
Acute eosinophilic pneumonia associated with amitriptyline in a hemodialysis patient.	2001 Jun	11456405
Involvement of adenosine in the effect of antidepressants on glutamate and aspartate release in the rat prefrontal cortex.	2001 Jun	11414661
Pharmacological modulation of SK3 channels.	2001 Jun	11378158
Corticotropin-releasing hormone perturbations in interstitial cystitis patients: evidence for abnormal sympathetic activity.	2001 Jun	11378124
Ring flexibility within tricyclic antidepressant drugs.	2001 Jun	11357174
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
Patterns of response to repeated total sleep deprivations in depression.	2001 May	11313092
Combining psychotherapy and antidepressants in the treatment of depression.	2001 May	11313088
[St. John's wort: a pharmaceutical with potentially dangerous interactions].	2001 May 10	11407242
Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial.	2001 May 2	11325322
Efficacy of spinal manipulation for chronic headache: a systematic review.	2001 Sep	11562654
Drug use and five-year incidence of age-related cataracts: The Beaver Dam Eye Study.	2001 Sep	11535471
Antidepressants as risk factor for ischaemic heart disease: case-control study in primary care.	2001 Sep 22	11566831

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 `Sat Jun 26 09:26:22 UTC 2021` Edited by `admin` on `Sat Jun 26 09:26:22 UTC 2021`
Record UNII	1806D8D52K
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AMITRIPTYLINE

Official Name

English

AMITRIPTYLINE [USP]

Common 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

NORTRIPTYLINE HYDROCHLORIDE IMPURITY F [EP]

Common Name

English

AMITRIPTYLINE [MI]

Common Name

English

AMITRIPTYLINE [VANDF]

Common Name

English

AMITRIPTYLINE [INN]

Common Name

English

AMITRIPTYLINE [MART.]

Common Name

English

SEROTEN

Common Name

English

AMITRIPTYLINE [WHO-DD]

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