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=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 191 Target ID: CHEMBL222 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10715164	Inhibitor 8297		6.3 nM [Ki]
Alpha-1a adrenergic receptor 66 Target ID: CHEMBL229 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10447960	Antagonist 2778		0.04 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Depression 235 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/018013s063lbl.pdf	Preventing	Approved 8429	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 16 Sources: https://clinicaltrials.gov/ct2/show/NCT00557739	Primary	Phase II 1132	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 59 Sources: https://clinicaltrials.gov/ct2/show/NCT00539240	Primary	Phase III 656	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
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 1737		substrate 1217	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2E1 882	CYP2C19 991 CYP1A2 1054

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2E1 970	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9574817/ Page: 7.0	yes [Ki 450 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP2D6 1217	substrate 3367 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 1054	substrate 3367 Sources: https://dmd.aspetjournals.org/content/25/6/740	minor
CYP2C19 991	substrate 3367 Sources: https://dmd.aspetjournals.org/content/25/6/740	minor
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/10354960/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 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
Amitriptyline and heart block.	1967 Jul 29	6028741
Correlation of subjective side effects with plasma concentrations of nortriptyline.	1970 Oct 3	5470429
Tricyclic antidepressants and monoamine oxidase inhibitors.	1971 Jun	5578096
Ophthalmological effects of nortriptyline--relationship to plasma level.	1972	4566251
Ototoxic reaction associated with use of nortriptyline hydrochloride: case report.	1972 Jun	5026029
Urinary retention in a neonate secondary to maternal ingestion of nortriptyline.	1972 Sep	5049831
[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 Jan	2889
[Double blind clinical study of mianserin and nortriptyline (author's transl)].	1978 Sep-Oct	375687
Hoarseness and aphonia as a side effect of tricyclic antidepressants.	1979 Dec	507219
Cardiovascular side effects of long-term therapy with tricyclic antidepressants in the aged.	1979 May	429744
Slow tricyclic antidepressant metabolism, polypharmacy, and cardiac arrest.	1980 Jan	7352543
Hoarseness and tricyclic antidepressants.	1980 May	7369424
Atrial flutter with amoxapine: a case report.	1981 Nov	7294224
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
Marked sinus tachycardia resulting from the synergistic effects of marijuana and nortriptyline.	1983 May	6303138
Psychosis after discontinuation of nortriptyline.	1984 Apr	6707238
The antiarrhythmic effect of nortriptyline in cardiac patients with ventricular premature depolarizations.	1986 Jun	3711494
Comparative efficacy and safety of MAOIs versus TCAs in treating depression in the elderly.	1986 Oct	3756264
A placebo-controlled comparison of the effect of nortriptyline and phenelzine on orthostatic hypotension in elderly depressed patients.	1987 Dec	3323263
Occurrence of myoclonus in patients treated with cyclic antidepressants.	1987 Mar	3827519
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
Use of yohimbine to counteract nortriptyline-induced orthostatic hypotension.	1989 Feb	2708559
Treatment-emergent depression with antidepressants in panic disorder.	1989 May-Jun	2731426
Naproxen reversal of nortriptyline-induced orthostatic hypotension.	1989 Sep	2768204
Myoclonus caused by a tricyclic antidepressant.	1990 Apr	2181694
Simulated home treatment of depression with nortriptyline.	1991	2008540
Downregulation of serotonin receptor subtypes by nortriptyline and adinazolam in major depressive disorder: neuroendocrine and platelet markers.	1993	8131152
High initial nortriptyline doses in the treatment of depression.	1993 Feb	8444823
Midodrine for TCA-induced orthostatic hypotension.	1993 Nov	7507712
Sleep in bereavement-related depression during and after pharmacotherapy with nortriptyline.	1994 Apr-Jun	8204191
Recurrent hypotension immediately after seizures in nortriptyline overdose.	1994 Jul	8031432
The cardiovascular effects of bupropion and nortriptyline in depressed outpatients.	1994 Jun	7804386
Nortriptyline-induced fulminant hepatic failure.	1995 Jan	7884180
Mixed mania: apparent induction by a tricyclic antidepressant in five consecutively treated patients with bipolar depression.	1995 Jan 1	7893862
Depression following smoking cessation in women.	1996	8743774
Nortriptyline-induced hepatic failure.	1996 Feb	8848811
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.	2010 Apr-Jun	21179345
Early-life stress and antidepressants modulate peripheral biomarkers in a gene-environment rat model of depression.	2010 Aug 16	20580919
Development of a list of potentially inappropriate drugs for the korean elderly using the delphi method.	2010 Dec	21818443
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
An overview of Indian research in anxiety disorders.	2010 Jan	21836680
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
Genetic variants in the serotonin transporter influence the efficacy of bupropion and nortriptyline in smoking cessation.	2012 Jan	21658141
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 Oct	22700542

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