CHLORDIAZEPOXIDE

First approved in 1960

Details

Stereochemistry	ACHIRAL
Molecular Formula	C16H14ClN3O
Molecular Weight	299.755
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CNC1=NC2=C(C=C(Cl)C=C2)C(C3=CC=CC=C3)=[N+]([O-])C1

InChI

InChIKey=ANTSCNMPPGJYLG-UHFFFAOYSA-N

InChI=1S/C16H14ClN3O/c1-18-15-10-20(21)16(11-5-3-2-4-6-11)13-9-12(17)7-8-14(13)19-15/h2-9H,10H2,1H3,(H,18,19)

HIDE SMILES / InChI

Molecular Formula	C16H14ClN3O
Molecular Weight	299.755
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/2016/012249s049lbl.pdf
Curator's Comment: description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT00136617 | https://www.drugs.com/pro/chlordiazepoxide.html | https://clinicaltrials.gov/ct2/show/NCT03012815 | https://www.ncbi.nlm.nih.gov/pubmed/6135616 | https://www.ncbi.nlm.nih.gov/pubmed/6304314

Chlordiazepoxide (trade name Librium) is a sedative and hypnotic medication of the benzodiazepine class. Chlordiazepoxide is indicated for the management of anxiety disorders or for the short-term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of Librium in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. Chlordiazepoxide acts on benzodiazepine allosteric sites that are part of the GABAA receptor/ion-channel complex and this results in an increased binding of the inhibitory neurotransmitter GABA to the GABAA receptor thereby producing inhibitory effects on the central nervous system and body similar to the effects of other benzodiazepines. Chlordiazepoxide act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in animal nerve terminal preparations. The withdrawal of chlordiazepoxide during pregnancy and breastfeeding is recommended, as chlordiazepoxide rapidly crosses the placenta and also is excreted in breast milk. Chlordiazepoxide is a long-acting benzodiazepine drug. The half-life of Chlordiazepoxide is 5 – 30 hours but has an active benzodiazepine metabolite (desmethyldiazepam), which has a half-life of 36 – 200 hours. The necessity of discontinuing therapy because of undesirable effects has been rare. Drowsiness, ataxia and confusion have been reported in some patients — particularly the elderly and debilitated. While these effects can be avoided in almost all instances by proper dosage adjustment, they have occasionally been observed at the lower dosage ranges. In a few instances syncope has been reported.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
GABA-A receptor; alpha-1/beta-3/gamma-2 16 Target ID: CHEMBL2094121 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15537339	Positive Allosteric Modulator 179	605.0 nM [Ki]
GABA-A receptor; alpha-2/beta-3/gamma-2 12 Target ID: CHEMBL2094130 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15537339	Positive Allosteric Modulator 179	392.0 nM [Ki]
GABA-A receptor; alpha-3/beta-3/gamma-2 11 Target ID: CHEMBL2094120 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15537339	Positive Allosteric Modulator 179	471.0 nM [Ki]
GABA-A receptor; alpha-5/beta-3/gamma-2 14 Target ID: CHEMBL2094122 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15537339	Positive Allosteric Modulator 179	368.0 nM [Ki]
GABA-A receptor; anion channel 202 Target ID: CHEMBL2093872 Sources: https://www.ncbi.nlm.nih.gov/pubmed/6135616	Positive Allosteric Modulator 179

Conditions

Condition	Modality	Highest Phase	Product
Anxiety 267 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	Primary	Approved 8429	LIBRELEASE Approved Use Chlordiazepoxide HCl capsules USP are indicated for the management of anxiety disorders or for the short term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of chlordiazepoxide HCl capsules USP in long term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient. Launch Date 1983
Withdrawal symptoms of acute alcoholism 2 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	Primary	Approved 8429	LIBRELEASE Approved Use Chlordiazepoxide HCl capsules USP are indicated for the management of anxiety disorders or for the short term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of chlordiazepoxide HCl capsules USP in long term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient. Launch Date 1983
Major depressive disorder 173 Sources: https://clinicaltrials.gov/ct2/show/NCT01109030	Primary	Phase III 656	LIBRELEASE Approved Use Chlordiazepoxide HCl capsules USP are indicated for the management of anxiety disorders or for the short term relief of symptoms of anxiety, withdrawal symptoms of acute alcoholism, and preoperative apprehension and anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of chlordiazepoxide HCl capsules USP in long term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient. Launch Date 1983

C_max

Value	Dose	Analyte	Population
0.86 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/359214	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:	CHLORDIAZEPOXIDE blood	Homo sapiens population: UNKNOWN age: ADULT sex: MALE food status: UNKNOWN
1.65 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/359214	50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered:	CHLORDIAZEPOXIDE blood	Homo sapiens population: UNKNOWN age: ADULT sex: FEMALE / MALE food status: UNKNOWN
0.84 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7286030	25 mg single, intramuscular dose: 25 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	CHLORDIAZEPOXIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
0.69 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7286030	25 mg single, intramuscular dose: 25 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	CHLORDIAZEPOXIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
7.16 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/770046	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:	CHLORDIAZEPOXIDE blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
26.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7286030	25 mg single, intramuscular dose: 25 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	CHLORDIAZEPOXIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
53.6 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7286030	25 mg single, intramuscular dose: 25 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	CHLORDIAZEPOXIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
8.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/770046	25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered:	CHLORDIAZEPOXIDE blood	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
16.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7286030	25 mg single, intramuscular dose: 25 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	CHLORDIAZEPOXIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
40.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7286030	25 mg single, intramuscular dose: 25 mg route of administration: Intramuscular experiment type: SINGLE co-administered:	CHLORDIAZEPOXIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
95.5% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/359214			CHLORDIAZEPOXIDE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
200 mg single, oral Highest studied dose Dose: 200 mg Route: oral Route: single Dose: 200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/413145	unhealthy, 24-74 years Health Status: unhealthy Age Group: 24-74 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/413145	Sources: https://pubmed.ncbi.nlm.nih.gov/413145
20 mg 3 times / day multiple, oral Studied dose Dose: 20 mg, 3 times / day Route: oral Route: multiple Dose: 20 mg, 3 times / day Co-administed with:: opioids Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	unhealthy, adult Health Status: unhealthy Condition: Severe Anxiety Disorders Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	Disc. AE: Sedation, Coma... AEs leading to discontinuation/dose reduction: Sedation Coma Respiratory depression Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf

AEs

AE	Significance	Dose	Population
Coma	Disc. AE	20 mg 3 times / day multiple, oral Studied dose Dose: 20 mg, 3 times / day Route: oral Route: multiple Dose: 20 mg, 3 times / day Co-administed with:: opioids Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	unhealthy, adult Health Status: unhealthy Condition: Severe Anxiety Disorders Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf
Respiratory depression	Disc. AE	20 mg 3 times / day multiple, oral Studied dose Dose: 20 mg, 3 times / day Route: oral Route: multiple Dose: 20 mg, 3 times / day Co-administed with:: opioids Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	unhealthy, adult Health Status: unhealthy Condition: Severe Anxiety Disorders Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf
Sedation	Disc. AE	20 mg 3 times / day multiple, oral Studied dose Dose: 20 mg, 3 times / day Route: oral Route: multiple Dose: 20 mg, 3 times / day Co-administed with:: opioids Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	unhealthy, adult Health Status: unhealthy Condition: Severe Anxiety Disorders Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737 inducer 781		substrate 1217 inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
Ca2+ channels 57	P-gp 1537 CYP1A2 1054	CYP1A2 701

Drug as perpetrator

Target	Modality	Activity
CYP2D6 1891	inhibitor 3277 Sources: https://www.jstage.jst.go.jp/article/cpb/59/2/59_2_249/_article/-char/ja/ Page: 251.0	likely
CYP1A2 1692	inducer 1573 Sources: https://www.sciencedirect.com/science/article/pii/S0378427410000184?casa_token=tnbKlh7mxs0AAAAA:rpzG86vMq1DWoibDepNBY9FsqNcI_RYU0qRjzYokbv1b1L5jPrgCcywgCpM8wxqUty9BCRiEtg78 Page: abstract	no
CYP3A4 1925	inducer 1573 Sources: https://www.sciencedirect.com/science/article/pii/S0378427410000184?casa_token=tnbKlh7mxs0AAAAA:rpzG86vMq1DWoibDepNBY9FsqNcI_RYU0qRjzYokbv1b1L5jPrgCcywgCpM8wxqUty9BCRiEtg78 Page: abstract	no
Ca2+ channels 60	inhibitor 3277 Sources: https://www.jstage.jst.go.jp/article/jjp/85/4/85_4_339/_article/-char/ja/ Page: 344.0	yes [IC50 300 uM]

Drug as victim

Target	Modality	Activity
CYP2D6 1217	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/071297s030lbl.pdf Page: 1.0	likely
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27317413/ Page: 1476.0	major
CYP1A2 1054	substrate 3367 Sources: https://europepmc.org/article/med/18646550 Page: 311.0	yes
P-gp 1537	substrate 3367 Sources: https://search.proquest.com/openview/de75715c450da33296c5455f6717b9ab/1?pq-origsite=gscholar&cbl=43703 Page: 136.0	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:3611	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3611
ZINC	ZINC000019632917	http://zinc15.docking.org/substances/ZINC000019632917
eMolecules	901620	https://www.emolecules.com/cgi-bin/more?vid=901620

PubMed

Title	Date	PubMed
Cholestatic jaundice associated with chlordiazepoxide hydrochloride (Librium) therapy. Report of a case and review of the literature.	1967 Aug	4952749
Hypotensive effects of chlordiazepoxide, amobarbital and chlorpromazine on behaviorally induced elevated arterial blood pressure in the squirrel monkey.	1970 Jun	4988497
Clinical electronystagmography.	1971 Jan	5547475
Clinical toxicity of chlordiazepoxide and diazepam in relation to serum albumin concentration: a report from the Boston Collaborative Drug Surveillance Program.	1974 Jul 26	4851053
Disulfiram hypersensitivity hepatitis.	1974 Oct 21	4479092
Hiccups following ingestion of oral chlordiazepoxide.	1976 Jun	1275106
Cataleptic and anticataleptic effects of muscimol and gabaculine injected into globus pallidus and substantia nigra, and interactions with haloperidol or benzodiazepines.	1978 Dec	33340
Differential diagnosis of cimetidine-induced delirium.	1981 Mar	7220787
Opposite effects of chlordiazepoxide and serotonin receptor antagonists on morphine-induced locomotor stimulation in mice.	1982	6815697
Effect of benzodiazepines on the central action of narcotic analgesics.	1982	6132369
Acute lithium-induced tremor.	1983 Jul	6411158
Incidence and potentiation of external and internal fetal anomalies resulting from chlordiazepoxide and amitriptyline alone and in combination.	1984 Aug	6435276
Inhibition of the binding and the behavioral effects of thyrotropin-releasing hormone (TRH) by the triazolobenzodiazepines.	1988 May	2845442
Reversal of increased anxiety during benzodiazepine withdrawal: evidence for an anxiogenic endogenous ligand for the benzodiazepine receptor.	1988 May	2838131
Evidence that the increased anxiety detected in the elevated plus-maze during chlordiazepoxide withdrawal is not due to enhanced noradrenergic activity.	1989 Dec	2623049
Chlordiazepoxide metabolite accumulation in liver disease.	1989 Jan-Feb	2710011
Expression cloning of a cDNA encoding the mouse pituitary thyrotropin-releasing hormone receptor.	1990 Dec	2175902
Effects of DM-9384, a pyrrolidone derivative, on alcohol- and chlordiazepoxide-induced amnesia in mice.	1990 Jun	2113296
Anxiogenic effects of acute and chronic cocaine administration: neurochemical and behavioral studies.	1992 Mar	1584846
Magnesium valproate attenuates hyperactivity induced by dexamphetamine-chlordiazepoxide mixture in rodents.	1993 Jun 24	8103460
The attenuation of suppression of motility by triazolam in the conditioned fear stress task is exacerbated by ethanol in mice.	1995	7637548
GABA(A) receptor epsilon-subunit may confer benzodiazepine insensitivity to the caudal aspect of the nucleus tractus solitarii of the rat.	2001 Nov 1	11691872
Spasmocanulase in irritable bowel syndrome.	2002 Sep	12370715
Anxiolytic effects of the novel anti-epileptic drug levetiracetam in the elevated plus-maze test in the rat.	2003 Nov 14	14637176
Evaluation of the effects of lamotrigine, valproate and carbamazepine in a rodent model of mania.	2005 Mar 7	15680200
Microinfusion of pituitary adenylate cyclase-activating polypeptide into the central nucleus of amygdala of the rat produces a shift from an active to passive mode of coping in the shock-probe fear/defensive burying test.	2007	17641738
Pharmacological modulation of stress reactivity dissociates general learning ability from the propensity for exploration.	2007 Oct	17907827
Palmar-plantar erythrodysesthesia caused by mercaptopurine and mesalamine.	2008 Aug	18711101
Effects of neuronal Kv7 potassium channel activators on hyperactivity in a rodent model of mania.	2009 Mar 17	19162078
Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development.	2010 Dec	20829430
Hydroxyzine for generalised anxiety disorder.	2010 Dec 8	21154375
Relations between open-field, elevated plus-maze, and emergence tests in C57BL/6J and BALB/c mice injected with GABA- and 5HT-anxiolytic agents.	2010 Jun	19735300

Patents

Sample Use Guides

In Vivo Use Guide

Relief of Mild and Moderate Anxiety Disorders and Symptoms of Anxiety: 5 mg or 10 mg, 3 or 4 times daily Relief of Severe Anxiety Disorders and Symptoms of Anxiety: 20 mg or 25 mg, 3 or 4 times daily Geriatric Patients, or in the presence of debilitating disease: 5 mg, 2 to 4 times daily

Route of Administration: Oral

In Vitro Use Guide

Eight concentrations of Chlordiazepoxide were added to tubes containing rat brain membranes and [3H]diazepam at a final concentration of 4 mkM. After incubation at 30 C for 10 min, followed by 4 C for 20 min, reactions were terminated by vacuum filtration through Whatman GF/C glass-fiber filters. Nonspecific binding was determined in the presence of 4 mkM unlabeled diazepam. The IC50 of a compound was that concentration resulting in 50% inhibition of [3H]diazepam binding to the membrane fraction.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:20:53 GMT 2023` Edited by `admin` on `Fri Dec 15 15:20:53 GMT 2023`
Record UNII	6RZ6XEZ3CR
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

CHLORDIAZEPOXIDE

Official Name

English

chlordiazepoxide [INN]

Common Name

English

LIMBITROL DS COMPONENT CHLORDIAZEPOXIDE

Common Name

English

3H-1,4-BENZODIAZEPIN-2-AMINE, 7-CHLORO-N-METHYL-5-PHENYL-, 4-OXIDE

Systematic Name

English

CHLORDIAZEPOXIDE COMPONENT OF LIMBITROL DS

Common Name

English

7-CHLORO-2-METHYLAMINO-5-PHENYL-3H-1,4-BENZODIAZEPINE-4-OXIDE

Systematic Name

English

CHLORDIAZEPOXIDE [MART.]

Common Name

English

CHLORDIAZEPOXIDE [JAN]

Common Name

English

CHLORDIAZEPOXIDE [ORANGE BOOK]

Common Name

English

CHLORDIAZEPOXIDE COMPONENT OF LIMBITROL

Common Name

English

CHLORDIAZEPOXIDE CIV

Common Name

English

7-Chloro-2-(methylamino)-5-phenyl-3H-1,4-benzodiazepine 4-oxide

Systematic Name

English

CHLORDIAZEPOXIDE [USP MONOGRAPH]

Common Name

English

CHLORDIAZEPOXIDE [MI]

Common Name

English

Chlordiazepoxide [WHO-DD]

Common Name

English

CHLORDIAZEPOXIDE CIV [USP-RS]

Common Name

English

CHLORDIAZEPOXIDE [EP MONOGRAPH]

Common Name

English

CHLORDIAZEPOXIDE [HSDB]

Common Name

English

LIMBITROL COMPONENT CHLORDIAZEPOXIDE

Common Name

English

CHLORDIAZEPOXIDE COMPONENT OF MENRIUM

Common Name

English

CHLORDIAZEPOXIDE [VANDF]

Common Name

English

LIBRITABS

Brand Name

English

LIBRELEASE

Brand Name

English

MENRIUM COMPONENT CHLORDIAZEPOXIDE

Common Name

English

Classification Tree Code System Code

WHO-VATC

QN05BA02