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=CC=C(Cl)C=C2C(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

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 186	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 186	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 186	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 186	368.0 nM [Ki]
GABA-A receptor; anion channel 203 Target ID: CHEMBL2093872 Sources: https://www.ncbi.nlm.nih.gov/pubmed/6135616	Positive Allosteric Modulator 186

Conditions

Condition	Modality	Highest Phase	Product
Anxiety 275 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	Primary	Approved 8583	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 8583	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 179 Sources: https://clinicaltrials.gov/ct2/show/NCT01109030	Primary	Phase III 665	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
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
0.86 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
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
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
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

T_1/2

Value	Dose	Analyte	Population
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
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

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 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	unhealthy, adult Health Status: unhealthy 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 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	unhealthy, adult Health Status: unhealthy 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 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	unhealthy, adult Health Status: unhealthy 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 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf	unhealthy, adult Health Status: unhealthy Age Group: adult Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/012249s049lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inducer 1087		substrate 1388 inhibitor 2507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
Ca2+ channels 59	P-gp 2052 CYP1A2 1197	CYP1A2 832

Drug as perpetrator

Target	Modality	Activity
CYP2D6 2546	inhibitor 4027 Sources: https://www.jstage.jst.go.jp/article/cpb/59/2/59_2_249/_article/-char/ja/ Page: 251.0	likely
CYP1A2 2333	inducer 1966 Sources: https://www.sciencedirect.com/science/article/pii/S0378427410000184?casa_token=tnbKlh7mxs0AAAAA:rpzG86vMq1DWoibDepNBY9FsqNcI_RYU0qRjzYokbv1b1L5jPrgCcywgCpM8wxqUty9BCRiEtg78 Page: abstract	no
CYP3A4 2633	inducer 1966 Sources: https://www.sciencedirect.com/science/article/pii/S0378427410000184?casa_token=tnbKlh7mxs0AAAAA:rpzG86vMq1DWoibDepNBY9FsqNcI_RYU0qRjzYokbv1b1L5jPrgCcywgCpM8wxqUty9BCRiEtg78 Page: abstract	no
Ca2+ channels 62	inhibitor 4027 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 1388	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/071297s030lbl.pdf Page: 1.0	likely
CYP3A4 1946	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/27317413/ Page: 1476.0	major
CYP1A2 1197	substrate 4014 Sources: https://europepmc.org/article/med/18646550 Page: 311.0	yes
P-gp 2052	substrate 4014 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
eMolecules	901620	https://www.emolecules.com/cgi-bin/more?vid=901620
ZINC	ZINC000019632917	http://zinc15.docking.org/substances/ZINC000019632917

PubMed

Title	Date	PubMed
Hydroxyzine for generalised anxiety disorder.	2010-12-08	21154375
Acute liver failure after administration of paracetamol at the maximum recommended daily dose in adults.	2010-12-02	21127120
Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development.	2010-12	20829430
A dopaminergic gene cluster in the prefrontal cortex predicts performance indicative of general intelligence in genetically heterogeneous mice.	2010-11-17	21103339
A transposon in Comt generates mRNA variants and causes widespread expression and behavioral differences among mice.	2010-08-17	20808911
Relations between open-field, elevated plus-maze, and emergence tests in C57BL/6J and BALB/c mice injected with GABA- and 5HT-anxiolytic agents.	2010-06	19735300
Effects of neuronal Kv7 potassium channel activators on hyperactivity in a rodent model of mania.	2009-03-17	19162078
Repeated antipsychotic treatment progressively potentiates inhibition on phencyclidine-induced hyperlocomotion, but attenuates inhibition on amphetamine-induced hyperlocomotion: relevance to animal models of antipsychotic drugs.	2009-01-14	19059234
Palmar-plantar erythrodysesthesia caused by mercaptopurine and mesalamine.	2008-08	18711101
Overlapping and distinct brain regions associated with the anxiolytic effects of chlordiazepoxide and chronic fluoxetine.	2008-08	17987061
Emerging synergisms between drugs and physiologically-patterned weak magnetic fields: implications for neuropharmacology and the human population in the twenty-first century.	2007-12	19305744
Pharmacological modulation of stress reactivity dissociates general learning ability from the propensity for exploration.	2007-10	17907827
Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic effects of predator stress.	2007-05-16	17335916
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
The attenuation of suppression of motility by triazolam in the conditioned fear stress task is exacerbated by ethanol in mice.	1995	7637548
Magnesium valproate attenuates hyperactivity induced by dexamphetamine-chlordiazepoxide mixture in rodents.	1993-06-24	8103460
Transdermal clonidine versus chlordiazepoxide in alcohol withdrawal: a randomized, controlled clinical trial.	1991-03	2000517
Prenatal oxazepam enhances mouse maternal aggression in the offspring, without modifying acute chlordiazepoxide effects.	1991-01-01	1646381
Expression cloning of a cDNA encoding the mouse pituitary thyrotropin-releasing hormone receptor.	1990-12	2175902
Absence of tumor initiating effect in the liver of rats treated with chlordiazepoxide plus sodium nitrite.	1990-09-01	2097634
Effects of DM-9384, a pyrrolidone derivative, on alcohol- and chlordiazepoxide-induced amnesia in mice.	1990-06	2113296
Inhibition by antimanic drugs of hyperactivity induced by methamphetamine-chlordiazepoxide mixture in mice.	1990-04	2345763
Evidence that the increased anxiety detected in the elevated plus-maze during chlordiazepoxide withdrawal is not due to enhanced noradrenergic activity.	1989-12	2623049
Chlordiazepoxide metabolite accumulation in liver disease.	1989-01-01	2710011
Caffeine-induced anxiogenesis: the role of adenosine, benzodiazepine and noradrenergic receptors.	1989-01	2543990
Use of receptor antagonist in elucidating the mechanism of action of TRH in GH3 cells.	1989	2566295
Anticonvulsive and convulsive effects of lidocaine: comparison with those of phenytoin, and implications for mechanism of action concepts.	1988-09	2905779
Inhibition of the binding and the behavioral effects of thyrotropin-releasing hormone (TRH) by the triazolobenzodiazepines.	1988-05	2845442
Reversal of increased anxiety during benzodiazepine withdrawal: evidence for an anxiogenic endogenous ligand for the benzodiazepine receptor.	1988-05	2838131
The effects of lindane, DDT, and chlordecone on avoidance responding and seizure activity.	1987-03-30	2436354
Hyperactivity induced by dexamphetamine/chlordiazepoxide mixtures in rats and its attenuation by lithium pretreatment: a role for dopamine?	1987	3107031
Antagonism of drug-induced yawning and penile erections in rats.	1986-03-18	2872065
Chlordiazepoxide enhances the anxiogenic action of CGS 8216 in the social interaction test: evidence for benzodiazepine withdrawal?	1985-07	3929278
Incidence and potentiation of external and internal fetal anomalies resulting from chlordiazepoxide and amitriptyline alone and in combination.	1984-08	6435276
Acute lithium-induced tremor.	1983-07	6411158
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
Differential diagnosis of cimetidine-induced delirium.	1981-03	7220787
Neuroleptic-induced acute dyskinesias in rhesus monkeys.	1981	6117919
Cataleptic and anticataleptic effects of muscimol and gabaculine injected into globus pallidus and substantia nigra, and interactions with haloperidol or benzodiazepines.	1978-12	33340
The antinicotinic effects of drugs with clinically useful sedative-antianxiety properties.	1975	1803
Disulfiram hypersensitivity hepatitis.	1974-10-21	4479092
Clinical toxicity of chlordiazepoxide and diazepam in relation to serum albumin concentration: a report from the Boston Collaborative Drug Surveillance Program.	1974-07-26	4851053
Letter: Psychotic symptoms due to meperidine intoxication.	1974-06-08	4834427
Bromazepam, medazepam, chlordiazepoxide in treatment of neurotic anxiety.	1974-05	4836379
Clinical electronystagmography.	1971-01	5547475
Hypotensive effects of chlordiazepoxide, amobarbital and chlorpromazine on behaviorally induced elevated arterial blood pressure in the squirrel monkey.	1970-06	4988497
Unusual effect of fenfluramine.	1969-11-29	5354861
Chlordiazepoxide and hallucinations. Report of cases.	1968-09	5667241
Cholestatic jaundice associated with chlordiazepoxide hydrochloride (Librium) therapy. Report of a case and review of the literature.	1967-08	4952749

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.

Name

Type

Language

CHLORDIAZEPOXIDE CIV

Preferred Name

English

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

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

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 [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