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

Molecular Formula	C19H21N
Molecular Weight	263.3767
Charge	0
Count

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

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
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
Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs.	1976 Feb	2004
[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
Comparison of imipramine- and nortriptyline-induced orthostatic hypotension: a meaningful difference.	1981 Sep	6277997
Marked sinus tachycardia resulting from the synergistic effects of marijuana and nortriptyline.	1983 May	6303138
A placebo-controlled comparison of the effect of nortriptyline and phenelzine on orthostatic hypotension in elderly depressed patients.	1987 Dec	3323263
Tryptophan antagonism of stimulant-induced tics.	1989 Feb	2708560
Treatment-emergent depression with antidepressants in panic disorder.	1989 May-Jun	2731426
Naproxen reversal of nortriptyline-induced orthostatic hypotension.	1989 Sep	2768204
Simulated home treatment of depression with nortriptyline.	1991	2008540
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
High initial nortriptyline doses in the treatment of depression.	1993 Feb	8444823
Sleep in bereavement-related depression during and after pharmacotherapy with nortriptyline.	1994 Apr-Jun	8204191
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
Extrapyramidal symptoms associated with the adjunct of nortriptyline to a venlafaxine-valproic acid combination.	1999 May	10435776
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
Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test.	2001 Oct	11673748
Risk factors for falls during treatment of late-life depression.	2002 Oct	12416604
The promises and pitfalls of reboxetine.	2003 Winter	14647527
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
Monoamine transporter gene polymorphisms and antidepressant response in koreans with late-life depression.	2006 Oct 4	17018806
In silico prediction of pregnane X receptor activators by machine learning approaches.	2007 Jan	17003167
Tobacco smoking cessation management: integrating varenicline in current practice.	2008	19066000
Nortriptyline protects mitochondria and reduces cerebral ischemia/hypoxia injury.	2008 Feb	18174477
Tako-tsubo syndrome following nortriptyline overdose.	2008 Jun	18568805
Possession states precipitated by nortriptyline.	2008 May	18499931
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
Community-based randomised controlled trial evaluating falls and osteoporosis risk management strategies.	2008 Nov 4	18983670
Trifluoperazine: a rynodine receptor agonist.	2009 Aug	19277699
Spontaneous hypothermia on intensive care unit admission is a predictor of unfavorable neurological outcome in patients after resuscitation: an observational cohort study.	2010	20573203
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
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
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.

Substance Class	Chemical Created by `admin` on `Thu Jul 06 21:58:24 UTC 2023` Edited by `admin` on `Thu Jul 06 21:58:24 UTC 2023`
Record UNII	BL03SY4LXB
Record Status	`Validated (UNII)`
Record Version

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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