NORTRIPTYLINE

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=CC=CC=C2CCC3=CC=CC=C13

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 197 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10715164	Inhibitor 8504		6.3 nM [Ki]
Alpha-1a adrenergic receptor 67 Target ID: CHEMBL229 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10447960	Antagonist 2849		0.04 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Depression 240 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018013s063lbl.pdf	Preventing	Approved 8583	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 1964
Plaque psoriasis 17 Sources: https://clinicaltrials.gov/ct2/show/NCT00557739	Primary	Phase II 1147	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 1964
Gastroesophageal reflux disease 68 Sources: https://clinicaltrials.gov/ct2/show/NCT00539240	Primary	Phase III 665	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 1964

C_max

Value	Dose	Co-administered	Analyte	Population
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
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

AUC

Value	Dose	Co-administered	Analyte	Population
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
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

T_1/2

Value	Dose	Co-administered	Analyte	Population
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
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

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 1946		substrate 1388	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2E1 1060	CYP2C19 1119 CYP1A2 1197

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2E1 1146	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/9574817/ Page: 7.0	yes [Ki 450 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2D6 1388	substrate 4014 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 1197	substrate 4014 Sources: https://dmd.aspetjournals.org/content/25/6/740	minor
CYP2C19 1119	substrate 4014 Sources: https://dmd.aspetjournals.org/content/25/6/740	minor
CYP3A4 1946	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/10354960/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 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
Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease.	2012-10	22700542
Genetic variants in the serotonin transporter influence the efficacy of bupropion and nortriptyline in smoking cessation.	2012-01	21658141
Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.	2011-07-14	21599003
Development of a list of potentially inappropriate drugs for the korean elderly using the delphi method.	2010-12	21818443
Identification of human Ether-à-go-go related gene modulators by three screening platforms in an academic drug-discovery setting.	2010-12	21158687
Early-life stress and antidepressants modulate peripheral biomarkers in a gene-environment rat model of depression.	2010-08-16	20580919
Which xenobiotic(s) could be responsible for the radiologic findings below? Answer: any proconvulsant xenobiotic, in this case tramadol, bupropion, and nortriptyline.	2010-03	20306168
Current treatment options in smoking cessation.	2010-02	20469625
An overview of Indian research in anxiety disorders.	2010-01	21836680
A new strategy for antidepressant prescription.	2010	21151361
Spontaneous hypothermia on intensive care unit admission is a predictor of unfavorable neurological outcome in patients after resuscitation: an observational cohort study.	2010	20573203
3D-QSAR design of new escitalopram derivatives for the treatment of major depressive disorders.	2009-12-21	21179345
Nortriptyline-induced hepatic failure.	1996-02	8848811
Depression following smoking cessation in women.	1996	8743774
Mixed mania: apparent induction by a tricyclic antidepressant in five consecutively treated patients with bipolar depression.	1995-01-01	7893862
Nortriptyline-induced fulminant hepatic failure.	1995-01	7884180
Recurrent hypotension immediately after seizures in nortriptyline overdose.	1994-07	8031432
The cardiovascular effects of bupropion and nortriptyline in depressed outpatients.	1994-06	7804386
Sleep in bereavement-related depression during and after pharmacotherapy with nortriptyline.	1994-04-01	8204191
Midodrine for TCA-induced orthostatic hypotension.	1993-11	7507712
High initial nortriptyline doses in the treatment of depression.	1993-02	8444823
Downregulation of serotonin receptor subtypes by nortriptyline and adinazolam in major depressive disorder: neuroendocrine and platelet markers.	1993	8131152
Simulated home treatment of depression with nortriptyline.	1991	2008540
Myoclonus caused by a tricyclic antidepressant.	1990-04	2181694
Naproxen reversal of nortriptyline-induced orthostatic hypotension.	1989-09	2768204
Treatment-emergent depression with antidepressants in panic disorder.	1989-05-01	2731426
Tryptophan antagonism of stimulant-induced tics.	1989-02	2708560
Use of yohimbine to counteract nortriptyline-induced orthostatic hypotension.	1989-02	2708559
The effects of mood changes and antidepressants on the cognitive capacity of elderly depressed patients.	1989	2491140
A placebo-controlled comparison of the effect of nortriptyline and phenelzine on orthostatic hypotension in elderly depressed patients.	1987-12	3323263
Occurrence of myoclonus in patients treated with cyclic antidepressants.	1987-03	3827519
Comparative efficacy and safety of MAOIs versus TCAs in treating depression in the elderly.	1986-10	3756264
The antiarrhythmic effect of nortriptyline in cardiac patients with ventricular premature depolarizations.	1986-06	3711494
Psychosis after discontinuation of nortriptyline.	1984-04	6707238
Marked sinus tachycardia resulting from the synergistic effects of marijuana and nortriptyline.	1983-05	6303138
The clinical efficacy and side-effects of mianserin and nortriptyline in depressed out-patients: a double-blind randomized trial.	1982	6759061
Atrial flutter with amoxapine: a case report.	1981-11	7294224
Comparison of imipramine- and nortriptyline-induced orthostatic hypotension: a meaningful difference.	1981-09	6277997
Hoarseness and tricyclic antidepressants.	1980-05	7369424
Slow tricyclic antidepressant metabolism, polypharmacy, and cardiac arrest.	1980-01	7352543
Hoarseness and aphonia as a side effect of tricyclic antidepressants.	1979-12	507219
Cardiovascular side effects of long-term therapy with tricyclic antidepressants in the aged.	1979-05	429744
[Double blind clinical study of mianserin and nortriptyline (author's transl)].	1978-09-01	375687
[The extrapyramidal symptoms in the combination of lithium long-term lithium therapy with nortriptyline. A case report on the formation of a pathogenesis hypothesis].	1976-01	2889
Urinary retention in a neonate secondary to maternal ingestion of nortriptyline.	1972-09	5049831
Ototoxic reaction associated with use of nortriptyline hydrochloride: case report.	1972-06	5026029
Ophthalmological effects of nortriptyline--relationship to plasma level.	1972	4566251
Tricyclic antidepressants and monoamine oxidase inhibitors.	1971-06	5578096
Correlation of subjective side effects with plasma concentrations of nortriptyline.	1970-10-03	5470429
Amitriptyline and heart block.	1967-07-29	6028741

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

NORTRILEN

Preferred 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

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