Chlordiazepoxide (original) (raw)

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Summary

Chlordiazepoxide is a benzodiazepine used to treat the withdrawal symptoms of acute alcoholism, to treat preoperative anxiety, and to treat anxiety over a short term period.

Brand Names

Chlorax, Librax

Generic Name

Chlordiazepoxide

DrugBank Accession Number

DB00475

Background

An anxiolytic benzodiazepine derivative with anticonvulsant, sedative, and amnesic properties. It has also been used in the symptomatic treatment of alcohol withdrawal.

Type

Small Molecule

Groups

Approved, Illicit, Investigational

Structure

Weight

Average: 299.755
Monoisotopic: 299.082539792

Chemical Formula

C16H14ClN3O

Synonyms

• 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepin-4-oxide
• CDP
• Chloradiazepoxide
• Chlordiazepoxide
• Chlordiazepoxidum
• Clopoxide
• Clordiazepóxido
• Methaminodiazepoxide

Indication

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.8

In combination with amitriptyline, chlordiazepoxide is indicated for the treatment of moderate to severe depression.7 In combination with clidinium, chlordiazepoxide is indicated to control emotional and somatic factors in gastrointestinal disorders, and is used as adjunctive therapy in the treatment of peptic ulcer, irritable bowel syndrome and acute enterocolitis.6

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Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Chlordiazepoxide has antianxiety, sedative, appetite-stimulating and weak analgesic actions. The drug seems to block EEG arousal from stimulation in the brain stem reticular formation. The drug has been studied extensively in many species of animals and these studies are suggestive of action on the limbic system of the brain, which recent evidence indicates is involved in emotional responses. Hostile monkeys were made tame by oral drug doses which did not cause sedation. Chlordiazepoxide revealed a "taming" action with the elimination of fear and aggression. The taming effect of chlordiazepoxide was further demonstrated in rats made vicious by lesions in the septal area of the brain. The drug dosage which effectively blocked the vicious reaction was well below the dose which caused sedation in these animals.

Mechanism of action

Chlordiazepoxide binds to stereospecific benzodiazepine (BZD) binding sites on GABA (A) receptor complexes at several sites within the central nervous system, including the limbic system and reticular formation. This results in an increased binding of the inhibitory neurotransmitter GABA to the GABA(A) receptor. BZDs, therefore, enhance GABA-mediated chloride influx through GABA receptor channels, causing membrane hyperpolarization. The net neuro-inhibitory effects result in the observed sedative, hypnotic, anxiolytic, and muscle relaxant properties.

Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Hepatic.

Route of elimination

Chlordiazepoxide is excreted in the urine, with 1% to 2% unchanged and 3% to 6% as conjugate.

Half-life

24-48 hours

Clearance

Not Available

Adverse Effects

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Toxicity

LD50=537 mg/kg (Orally in rats). Signs of overdose include respiratory depression, muscle weakness, somnolence (general depressed activity).

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Food Interactions

• Avoid alcohol.
• Take with or without food. The absorption is unaffected by food.

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Product Ingredients

Product Images

International/Other Brands

Angirex / Elenium (Polfa Tarchomin) / Helogaphen / Klopoxid (Nycomed) / Libritabs / Multum / Napoton / Radepur (AWD) / Risolid (Actavis) / Silibrin / Sonimen / Tropium

Brand Name Prescription Products

Generic Prescription Products

Mixture Products

Unapproved/Other Products

ATC Codes

N05BA02 — Chlordiazepoxide

• N05BA — Benzodiazepine derivatives
• N05B — ANXIOLYTICS
• N05 — PSYCHOLEPTICS
• N — NERVOUS SYSTEM

Drug Categories

• Adjuvants, Anesthesia
• Anti-Anxiety Agents
• Benzazepines
• Benzodiazepines and benzodiazepine derivatives
• Central Nervous System Agents
• Central Nervous System Depressants
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A4 Substrates (strength unknown)
• Cytochrome P-450 Substrates
• Cytosine Nucleotides
• GABA Agents
• GABA Modulators
• Heterocyclic Compounds, Fused-Ring
• Hypnotics and Sedatives
• Nervous System
• Neurotransmitter Agents
• Nucleic Acids, Nucleotides, and Nucleosides
• Nucleotides
• Psycholeptics
• Psychotropic Drugs
• Pyrimidine Nucleotides
• Pyrimidines
• Ribonucleotides
• Tranquilizing Agents

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as 1,4-benzodiazepines. These are organic compounds containing a benzene ring fused to a 1,4-azepine.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Benzodiazepines

Sub Class

1,4-benzodiazepines

Direct Parent

1,4-benzodiazepines

Alternative Parents

Imidolactams / Benzene and substituted derivatives / Aryl chlorides / Nitrones / Propargyl-type 1,3-dipolar organic compounds / Carboxamidines / Azacyclic compounds / Organopnictogen compounds / Organochlorides / Organic zwitterions / Organic oxides / Hydrocarbon derivatives show 2 more

Substituents

1,4-benzodiazepine / Allyl-type 1,3-dipolar organic compound / Amidine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carboxylic acid amidine / Hydrocarbon derivative / Imidolactam / Monocyclic benzene moiety / Nitrone / Organic 1,3-dipolar compound / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organic zwitterion / Organochloride / Organohalogen compound / Organonitrogen compound / Organopnictogen compound / Propargyl-type 1,3-dipolar organic compound show 13 more

Molecular Framework

Aromatic heteropolycyclic compounds

External Descriptors

organochlorine compound, secondary amino compound, N-oxide, benzodiazepine (CHEBI:3611)

Affected organisms

• Humans and other mammals

UNII

6RZ6XEZ3CR

CAS number

58-25-3

InChI Key

ANTSCNMPPGJYLG-UHFFFAOYSA-N

InChI

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)

IUPAC Name

7-chloro-2-(methylamino)-5-phenyl-3H-1,4-benzodiazepin-4-ium-4-olate

SMILES

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

Synthesis Reference

Sternbach, L.H.; US. Patent 2,893,992; July 7,1959; assigned to Hoffmann-LaRoche, Inc.

General References

1. Skerritt JH, Johnston GA: Enhancement of GABA binding by benzodiazepines and related anxiolytics. Eur J Pharmacol. 1983 May 6;89(3-4):193-8. [Article]
2. Oishi R, Nishibori M, Itoh Y, Saeki K: Diazepam-induced decrease in histamine turnover in mouse brain. Eur J Pharmacol. 1986 May 27;124(3):337-42. [Article]
3. Earley JV, Fryer RI, Ning RY: Quinazolines and 1,4-benzodiazepines. LXXXIX: Haptens useful in benzodiazepine immunoassay development. J Pharm Sci. 1979 Jul;68(7):845-50. [Article]
4. Olive G, Dreux C: [Pharmacologic bases of use of benzodiazepines in pereinatal medicine]. Arch Fr Pediatr. 1977 Jan;34(1):74-89. [Article]
5. Vozeh S: [Pharmacokinetic of benzodiazepines in old age]. Schweiz Med Wochenschr. 1981 Nov 21;111(47):1789-93. [Article]
6. FDA Approved Drug Products: Librax (chlordiazepoxide hydrochloride and clidinium bromide) capsules for oral use [Link]
7. FDA Approved Drug Products: LIMBITROL (chlordiazepoxide and amitriptyline HCI) double strength tablets [Link]
8. DailyMed Label: Chlordiazepoxide hydrochloride Oral Capsules [Link]

External Links

Human Metabolome Database

HMDB0014618

KEGG Drug

D00267

PubChem Compound

2712

PubChem Substance

46505044

ChemSpider

10248513

BindingDB

50007664

RxNav

2356

ChEBI

3611

ChEMBL

CHEMBL451

ZINC

ZINC000019632917

Therapeutic Targets Database

DAP000084

PharmGKB

PA448932

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

PDRhealth

PDRhealth Drug Page

Wikipedia

Chlordiazepoxide

MSDS

Clinical Trials

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Manufacturers

• Valeant pharmaceuticals international
• Abbott laboratories pharmaceutical products div
• Rachelle laboratories inc
• Ascot hosp pharmaceuticals inc div travenol laboratories inc
• Barr laboratories inc
• John j ferrante
• Halsey drug co inc
• Impax laboratories inc
• Ivax pharmaceuticals inc sub teva pharmaceuticals usa
• Lederle laboratories div american cyanamid co
• Mm mast and co
• Mylan pharmaceuticals inc
• Parke davis div warner lambert co
• Pioneer pharmaceuticals inc
• Purepac pharmaceutical co
• Roxane laboratories inc
• Sandoz inc
• Superpharm corp
• Teva pharmaceuticals usa inc
• Usl pharma inc
• Vangard laboratories inc div midway medical co
• Watson laboratories inc
• West ward pharmaceutical corp
• Alra laboratories inc

Packagers

• A-S Medication Solutions LLC
• Barr Pharmaceuticals
• Cardinal Health
• Coupler Enterprises Inc.
• Direct Dispensing Inc.
• Dispensing Solutions
• Diversified Healthcare Services Inc.
• H and H Laboratories
• Heartland Repack Services LLC
• Innoviant Pharmacy Inc.
• Kaiser Foundation Hospital
• Legacy Pharmaceuticals Packaging LLC
• Liberty Pharmaceuticals
• Major Pharmaceuticals
• Merrell Pharmaceuticals Inc.
• Murfreesboro Pharmaceutical Nursing Supply
• Mylan
• Nucare Pharmaceuticals Inc.
• Palmetto Pharmaceuticals Inc.
• Par Pharmaceuticals
• Patheon Inc.
• PCA LLC
• PD-Rx Pharmaceuticals Inc.
• Pharmedix
• Physicians Total Care Inc.
• Prepackage Specialists
• Prepak Systems Inc.
• Qualitest
• Remedy Repack
• Sandhills Packaging Inc.
• Solco Healthcare US LLC
• Southwood Pharmaceuticals
• Stat Rx Usa
• UDL Laboratories
• Va Cmop Dallas
• Valeant Ltd.

Dosage Forms

Prices

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Not Available

State

Solid

Experimental Properties

Predicted Properties

Predicted ADMET Features

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Mass Spec (NIST)

Not Available

Spectra

Chromatographic Properties

Collision Cross Sections (CCS)

Targets

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Kind

Protein group

Organism

Humans

Pharmacological action

Yes

Actions

Positive allosteric modulator

The GABA(A) receptor is pentameric (i.e. comprising 5 subunit proteins) and therefore has a multitude of potential isoforms. The above target is a collection of all possible GABA(A) subunits that may participate in the formation of the pentameric receptor and is not meant to imply direct a drug-protein interaction for each individual subunit.

General Function

Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:23909897, PubMed:25489750, PubMed:29950725, PubMed:30602789). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (PubMed:29950725, PubMed:30602789). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient (PubMed:23909897, PubMed:29950725, PubMed:30602789). Alpha-1/GABRA1-containing GABAARs are largely synaptic (By similarity). Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission (By similarity). GABAARs containing alpha-1 and beta-2 or -3 subunits exhibit synaptogenic activity; the gamma-2 subunit being necessary but not sufficient to induce rapid synaptic contacts formation (PubMed:23909897, PubMed:25489750). GABAARs function also as histamine receptor where histamine binds at the interface of two neighboring beta subunits and potentiates GABA response (By similarity). GABAARs containing alpha, beta and epsilon subunits also permit spontaneous chloride channel activity while preserving the structural information required for GABA-gated openings (By similarity). Alpha-1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (By similarity). Together with rho subunits, may also control neuronal and glial GABAergic transmission in the cerebellum (By similarity).

Specific Function

GABA-A receptor activity

Components:

References

1. Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [Article]
2. Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [Article]

Kind

Protein group

Organism

Humans

Pharmacological action

Yes

Actions

Ligand

Benzodiazepines modulate GABA(A) function by binding at the interface between alpha (α) and gamma (γ) subunits. Of the 6 α-subunits, only 4 (α-1, -2, -3, and -5) participate in the formation of this binding site. The above target is a collection of all α- and γ-subunits that are known to participate in the formation of the benzodiazepine binding site.

General Function

Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain (PubMed:23909897, PubMed:25489750, PubMed:29950725, PubMed:30602789). GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (PubMed:29950725, PubMed:30602789). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient (PubMed:23909897, PubMed:29950725, PubMed:30602789). Alpha-1/GABRA1-containing GABAARs are largely synaptic (By similarity). Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission (By similarity). GABAARs containing alpha-1 and beta-2 or -3 subunits exhibit synaptogenic activity; the gamma-2 subunit being necessary but not sufficient to induce rapid synaptic contacts formation (PubMed:23909897, PubMed:25489750). GABAARs function also as histamine receptor where histamine binds at the interface of two neighboring beta subunits and potentiates GABA response (By similarity). GABAARs containing alpha, beta and epsilon subunits also permit spontaneous chloride channel activity while preserving the structural information required for GABA-gated openings (By similarity). Alpha-1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (By similarity). Together with rho subunits, may also control neuronal and glial GABAergic transmission in the cerebellum (By similarity).

Specific Function

GABA-A receptor activity

Components:

References

1. Sigel E, Steinmann ME: Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012 Nov 23;287(48):40224-31. doi: 10.1074/jbc.R112.386664. Epub 2012 Oct 4. [Article]
2. Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE: Structure of a human synaptic GABAA receptor. Nature. 2018 Jul;559(7712):67-72. doi: 10.1038/s41586-018-0255-3. Epub 2018 Jun 27. [Article]

Enzymes

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Substrate

General Function

A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981).

Specific Function

1,8-cineole 2-exo-monooxygenase activity

Gene Name

CYP3A4

Uniprot ID

P08684

Uniprot Name

Cytochrome P450 3A4

Molecular Weight

57342.67 Da

References

1. Stolbach A, Paziana K, Heverling H, Pham P: A Review of the Toxicity of HIV Medications II: Interactions with Drugs and Complementary and Alternative Medicine Products. J Med Toxicol. 2015 Sep;11(3):326-41. doi: 10.1007/s13181-015-0465-0. [Article]

Drug created at June 13, 2005 13:24 / Updated at October 01, 2024 12:45