NORTRIPTYLINE

First approved in 1964

Details

Stereochemistry	ACHIRAL
Molecular Formula	C19H21N
Molecular Weight	263.3767
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CNCCC=C1C2=C(CCC3=C1C=CC=C3)C=CC=C2

InChI

InChIKey=PHVGLTMQBUFIQQ-UHFFFAOYSA-N

InChI=1S/C19H21N/c1-20-14-6-11-19-17-9-4-2-7-15(17)12-13-16-8-3-5-10-18(16)19/h2-5,7-11,20H,6,12-14H2,1H3

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018013s063lbl.pdf

Nortriptyline is a second-generation tricyclic antidepressant (TCA) marketed as the hydrochloride salt under the trade names Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen. Nortriptyline is used in the treatment of depression and childhood nocturnal enuresis. Its off-label uses include treatment of postherpetic neuralgia, angioedema and smoking Cessation, and attention deficit hyperactivity disorder in some neurological disorders. It is believed that nortriptyline either inhibits the reuptake of the neurotransmitter serotonin at the neuronal membrane or acts at beta-adrenergic receptors. Nortriptyline is US FDA-approved for the treatment of major depression. In the United Kingdom, it may also be used for treating nocturnal enuresis, with courses of treatment lasting no more than three months. The most common side effects include dry mouth, sedation, constipation, and increased appetite, mild blurred vision, tinnitus, occasionally hypomania or mania. An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects. However, fewer and milder side effects occur with nortriptyline than tertiary tricyclic antidepressants such as imipramine and amitriptyline. For this reason, nortriptyline is preferred to other tricyclic antidepressants, particularly with older adults, which also improves compliance.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Norepinephrine transporter 190 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10715164	Inhibitor 8228		6.3 nM [Ki]
Alpha-1a adrenergic receptor 66 Target ID: CHEMBL229 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10447960	Antagonist 2760		0.04 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Depression 233 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018013s063lbl.pdf	Preventing	Approved 8360	AVENTYL HYDROCHLORIDE Approved Use Nortriptyline hydrochloride capsules are indicated for the relief of symptoms of depression. Endogenous depressions are more likely to be alleviated than are other depressive states. Launch Date -1.62604794E11
Plaque psoriasis 16 Sources: https://clinicaltrials.gov/ct2/show/NCT00557739	Primary	Phase II 1144	AVENTYL HYDROCHLORIDE Approved Use Nortriptyline hydrochloride capsules are indicated for the relief of symptoms of depression. Endogenous depressions are more likely to be alleviated than are other depressive states. Launch Date -1.62604794E11
Gastroesophageal reflux disease 60 Sources: https://clinicaltrials.gov/ct2/show/NCT00539240	Primary	Phase III 663	AVENTYL HYDROCHLORIDE Approved Use Nortriptyline hydrochloride capsules are indicated for the relief of symptoms of depression. Endogenous depressions are more likely to be alleviated than are other depressive states. Launch Date -1.62604794E11

C_max

Value	Dose	Co-administered	Analyte	Population
36 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12814461	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:		NORTRIPTYLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
16.91 ng/mL OTHER GOV https://pdf.hres.ca/dpd_pm/00001266.PDF	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:		NORTRIPTYLINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
1591 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12814461	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:		NORTRIPTYLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
767.28 ng × h/mL OTHER GOV https://pdf.hres.ca/dpd_pm/00001266.PDF	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:		NORTRIPTYLINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
29.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12814461	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:		NORTRIPTYLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
32.75 h OTHER GOV https://pdf.hres.ca/dpd_pm/00001266.PDF	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:		NORTRIPTYLINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
8.35% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7094510			NORTRIPTYLINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1709		substrate 1193	inhibitor 1599

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2E1 876	CYP2C19 985 CYP1A2 1032

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2E1 964	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/9574817/ Page: 7.0	yes [Ki 450 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2D6 1193	substrate 3326 Sources: https://dmd.aspetjournals.org/content/25/6/740; https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018012s031lbl.pdf#page=18	major	likely (co-administration study) Comment: 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 Sources: https://dmd.aspetjournals.org/content/25/6/740; https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018012s031lbl.pdf#page=18
CYP1A2 1032	substrate 3326 Sources: https://dmd.aspetjournals.org/content/25/6/740	minor
CYP2C19 985	substrate 3326 Sources: https://dmd.aspetjournals.org/content/25/6/740	minor
CYP3A4 1709	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/10354960/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1632	inhibitor 1613 Sources: https://pubmed.ncbi.nlm.nih.gov/21262863/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:7640	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:7640
ChemicalBook	CB1317147	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1317147
ZINC	ZINC000001530741	http://zinc15.docking.org/substances/ZINC000001530741

PubMed

Title	Date	PubMed

Ophthalmological effects of nortriptyline--relationship to plasma level.	1972	4566251
Hoarseness and aphonia as a side effect of tricyclic antidepressants.	1979 Dec	507219
Hoarseness and tricyclic antidepressants.	1980 May	7369424
Comparison of imipramine- and nortriptyline-induced orthostatic hypotension: a meaningful difference.	1981 Sep	6277997
The clinical efficacy and side-effects of mianserin and nortriptyline in depressed out-patients: a double-blind randomized trial.	1982	6759061
The effects of mood changes and antidepressants on the cognitive capacity of elderly depressed patients.	1989 Fall	2491140
Tryptophan antagonism of stimulant-induced tics.	1989 Feb	2708560
Treatment-emergent depression with antidepressants in panic disorder.	1989 May-Jun	2731426
Myoclonus caused by a tricyclic antidepressant.	1990 Apr	2181694
Simulated home treatment of depression with nortriptyline.	1991	2008540
Tricyclics and heart failure.	1991 Nov	1928479
Left bundle branch block developing in a patient with sub-therapeutic nortriptyline levels: a case report.	1991 Oct	1918772
Cognitive decline with nortriptyline use in a patient with dementia of the Alzheimer's type.	1992 Jan	1734612
Drug-induced Creutzfeldt-Jakob like syndrome.	1992 Sep	1390620
Midodrine for TCA-induced orthostatic hypotension.	1993 Nov	7507712
Sleep in bereavement-related depression during and after pharmacotherapy with nortriptyline.	1994 Apr-Jun	8204191
The cardiovascular effects of bupropion and nortriptyline in depressed outpatients.	1994 Jun	7804386
Nortriptyline-induced fulminant hepatic failure.	1995 Jan	7884180
Nortriptyline-induced hepatic failure.	1996 Feb	8848811
A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression.	2002	12082591
Risk factors for falls during treatment of late-life depression.	2002 Oct	12416604
Effect of nortriptyline and paroxetine on measures of chaos of heart rate time series in patients with panic disorder.	2003 Dec	14642980
Age-dependent antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and G protein beta3 subunit as predictors of response to fluoxetine and nortriptyline.	2003 Dec	14604448
The promises and pitfalls of reboxetine.	2003 Winter	14647527
Drug analysis in blowfly larvae and in human tissues: a comparative study.	2004 Aug	15106008
Mechanism-based inactivation of human cytochrome P4502C8 by drugs in vitro.	2004 Dec	15304522
Spasmodic dysphonia, a rare form of tardive dystonia, induced by low-dose risperidone?	2004 Mar	14961937
Efficacy of antidepressants in substance use disorders with and without comorbid depression. A systematic review and meta-analysis.	2005 Apr 4	15769553
Interactions of cyclobenzaprine and tricyclic antidepressants.	2005 Jan	15669899
Determination of the dissociation constants (pKa) of secondary and tertiary amines in organic media by capillary electrophoresis and their role in the electrophoretic mobility order inversion.	2005 Mar 11	15844547
The adsorption mechanism of nortryptiline on C18-bonded Discovery.	2005 Nov 18	16275280
[A case of Brugada syndrome with convulsive seizure during antidepressant administration: relation of antidepressant agents and arrhythmia leading to sudden death].	2006	17089931
Gabapentin versus nortriptyline in post-herpetic neuralgia patients: a randomized, double-blind clinical trial--the GONIP Trial.	2006 Aug	16961166
[Trazodone for the treatment of behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease: a retrospective study focused on the aggression and negativism in caregiving situations].	2006 Jun	16856516
Photoinduced chemiluminescence of pharmaceuticals.	2006 May 3	16413738
Monoamine transporter gene polymorphisms and antidepressant response in koreans with late-life depression.	2006 Oct 4	17018806
Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17.	2007 Aug	17470523
Inhibition of astroglial inwardly rectifying Kir4.1 channels by a tricyclic antidepressant, nortriptyline.	2007 Feb	17071817
In silico prediction of pregnane X receptor activators by machine learning approaches.	2007 Jan	17003167
Bioactivation of the tricyclic antidepressant amitriptyline and its metabolite nortriptyline to arene oxide intermediates in human liver microsomes and recombinant P450s.	2008 May 9	18359012
Citalopram associated with complex visual hallucination: a case report.	2009 Apr 30	19439248
Trifluoperazine: a rynodine receptor agonist.	2009 Aug	19277699
Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity.	2009 Jun 15	19362101
Adverse reactions to antidepressants.	2009 Sep	19721108
Early-life stress and antidepressants modulate peripheral biomarkers in a gene-environment rat model of depression.	2010 Aug 16	20580919
Identification of human Ether-à-go-go related gene modulators by three screening platforms in an academic drug-discovery setting.	2010 Dec	21158687
Current treatment options in smoking cessation.	2010 Feb	20469625
Which xenobiotic(s) could be responsible for the radiologic findings below? Answer: any proconvulsant xenobiotic, in this case tramadol, bupropion, and nortriptyline.	2010 Mar	20306168
Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.	2011 Jul 14	21599003

Patents

Sample Use Guides

In Vivo Use Guide

25mg PO q6-8hr. No more than 150 mg/day

Route of Administration: Oral

In Vitro Use Guide

Two cell lines and eight primary cell cultures from metastatic melanoma deposits were exposed to three tricyclic drugs, amitriptyline, nortriptyline and clomipramine, at concentrations ranging from 200 to 6.25 µmol/l in the ATP-based tumour chemosensitivity assay. All three drugs showed activity, although nortriptyline was more active than clomipramine or amitriptyline in both cell lines and primary cell cultures, with an IC50 of 9, 27 and 33 µmol/l, respectively.

Name

Type

Language

NORTRIPTYLINE

Official Name

English

NORAMITRIPTYLINE

Common Name

English

NSC-757234

Code

English

SESAVAL

Common Name

English

NORTRIPTYLINE [VANDF]

Common Name

English

3-(10,11-DIHYDRO-5H-DIBENZO(A,D)(7)ANNULEN-5-YLIDENE)-N-METHYLPROPAN-1-AMINE

Common Name

English

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

Systematic Name

English

LUMBECK

Common Name

English

AVENTYL

Brand Name

English

Nortriptyline [WHO-DD]

Common Name

English

nortriptyline [INN]

Common Name

English

AMITRIPTYLINE HYDROCHLORIDE IMPURITY C [EP IMPURITY]

Common Name

English

NORTRIPTYLINE [MI]

Common Name

English

NCI-169453

Code

English

NORTRILEN

Brand Name

English

DESITRIPTILINA

Common Name

English

10,11-DIHYDRO-N-METHYL-5H-DIBENZO(A,D)CYCLOHEPTENE-D(SUP5,.GAMMA.)-PROPYLAMINE

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C94727