Chlordiazepoxide

Source: Wikipedia, the free encyclopedia.
Chlordiazepoxide
Clinical data
Pronunciation/ˌklɔːrdaɪ.əzɪˈpɒksaɪd/
Trade namesLibrium, others
AHFS/Drugs.comMonograph
MedlinePlusa682078
Dependence
liability		High[1]
Routes of
administration		By mouth
intramuscular
Drug classBenzodiazepine
ATC code
Legal status
Legal status
desmethyldiazepam 36–200 hours: other active metabolites include oxazepam)
ExcretionKidney
Identifiers
  • 7-Chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide
JSmol)
  • ClC1=CC2=C(N=C(NC)C[N+]([O-])=C2C3=CC=CC=C3)C=C1
  • 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) checkY
  • Key:ANTSCNMPPGJYLG-UHFFFAOYSA-N checkY
  (verify)

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs.

Chlordiazepoxide has a medium to long

skeletal muscle relaxant properties.[3]

Chlordiazepoxide was patented in 1958 and approved for medical use in 1960.[4] It was the first benzodiazepine to be synthesized and the discovery of chlordiazepoxide was by pure chance.[5] Chlordiazepoxide and other benzodiazepines were initially accepted with widespread public approval but were followed with widespread public disapproval and recommendations for more restrictive medical guidelines for its use.[6]

Medical uses

Chlordiazepoxide is indicated for the short-term (2–4 weeks) treatment of anxiety that is severe and disabling or subjecting the person to unacceptable distress. It is also indicated as a treatment for the management of acute alcohol withdrawal syndrome.[7]

It can sometimes be prescribed to ease symptoms of

Librax.[8]

Contraindications

Use of chlordiazepoxide should be avoided in individuals with the following conditions:

Chlordiazepoxide is generally considered an inappropriate benzodiazepine for the elderly due to its long

psychiatric disorders.[10]

Pregnancy

The research into the safety of benzodiazepines during pregnancy is limited and it is recommended that use of benzodiazepines during pregnancy should be based on whether the benefits outweigh the risks. If chlordiazepoxide is used during pregnancy the risks can be reduced via using the lowest effective dose and for the shortest time possible. Benzodiazepines should generally be avoided during the

breast feeding as chlordiazepoxide passes into breast milk.[11][12]

Adverse effects

Sedative drugs and sleeping pills, including chlordiazepoxide, have been associated with an increased risk of death.[13] The studies had many limitations: possibly tending to overestimate risk, such as possible confounding by indication with other risk factors; confusing hypnotics with drugs having other indications;

Common side-effects of chlordiazepoxide include:[14]

Chlordiazepoxide in laboratory mice studies impairs latent learning. Benzodiazepines impair learning and memory via their action on benzodiazepine receptors, which causes a dysfunction in the cholinergic neuronal system in mice.

GABA activity (and that benzodiazepines were not associated with the cholinergic system).[16] In tests of various benzodiazepine compounds, chlordiazepoxide was found to cause the most profound reduction in the turnover of 5HT (serotonin) in rats. Serotonin is closely involved in regulating mood and may be one of the causes of feelings of depression in rats using chlordiazepoxide or other benzodiazepines.[17]

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.[18]

Tolerance and dependence

Tolerance

Chronic use of benzodiazepines, such as chlordiazepoxide, leads to the development of tolerance, with a decrease in number of benzodiazepine binding sites in mice forebrains.

Institute of Medicine and the conclusions of a study carried out by the White House Office of Drug Policy and the US National Institute on Drug Abuse—that there was little evidence that long-term use of benzodiazepines was beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep-promoting properties within 3 to 14 days of continuous use, and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after four months' continuous use due to the development of tolerance.[20]

Dependence

Chlordiazepoxide can cause

barbiturates. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can, however, occur at standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible through a slow and gradual dose-reduction regime.[21]

Chlordiazepoxide taken during pregnancy can cause a

postnatal benzodiazepine withdrawal syndrome.[22]

Overdose

See also: Benzodiazepine overdose

An individual who has consumed excess chlordiazepoxide may display some of the following symptoms:

Chlordiazepoxide is a drug that is very frequently involved in drug intoxication, including overdose.[23] Chlordiazepoxide overdose is considered a medical emergency and, in general, requires the immediate attention of medical personnel. The antidote for an overdose of chlordiazepoxide (or any other benzodiazepine) is flumazenil. Flumazenil should be given with caution as it may precipitate severe withdrawal symptoms in benzodiazepine-dependent individuals.

Pharmacology

Chlordiazepoxide acts on

benzodiazepines.[24] Chlordiazepoxide is an anticonvulsant.[25]

There is preferential storage of chlordiazepoxide in some organs including the heart of the neonate. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate. The withdrawal of chlordiazepoxide during pregnancy and breast feeding is recommended, as chlordiazepoxide rapidly crosses the placenta and also is excreted in breast milk.

Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in animal nerve terminal preparations.[28] Chlordiazepoxide inhibits acetylcholine release in mouse hippocampal synaptosomes in vivo. This has been found by measuring sodium-dependent high affinity choline uptake in vitro after pretreatment of the mice in vivo with chlordiazepoxide. This may play a role in chlordiazepoxide's anticonvulsant properties.[29]

Pharmacokinetics

Chlordiazepoxide is a long-acting benzodiazepine drug. The half-life of chlordiazepoxide is from 5 to 30 hours but has an active benzodiazepine metabolite,

nordiazepam, which has a half-life of 36 to 200 hours.[30] The half-life of chlordiazepoxide increases significantly in the elderly, which may result in prolonged action as well as accumulation of the drug during repeated administration. Delayed body clearance of the long half-life active metabolite also occurs in those over 60 years of age, which further prolongs the effects of the drugs with additional accumulation after repeated dosing.[31]

Despite its name, chlordiazepoxide is not an epoxide.

History

Chlordiazepoxide (initially called methaminodiazepoxide) was the first benzodiazepine to be synthesized in the mid-1950s. The synthesis was derived from work on a class of dyes, quinazolone-3-oxides.[citation needed] It was discovered by accident when in 1957 tests revealed that the compound had hypnotic, anxiolytic, and muscle relaxant effects. "The story of the chemical development of Librium and Valium was told by Sternbach. The serendipity involved in the invention of this class of compounds was matched by the trials and errors of the pharmacologists in the discovery of the tranquilizing activity of the benzodiazepines. The discovery of Librium in 1957 was due largely to the dedicated work and observational ability of a gifted technician, Beryl Kappell. For some seven years she had been screening compounds by simple animal tests for muscle relaxant activity using myanesin as a standard and then meprobamate and chlorpromazine when they became available. All compounds submitted by the chemical staff for central nervous activity were screened. It was this battery of tests that picked out RO 5-0690 (Librium, chlordiazepoxide) as being similar but more potent than meprobamate."[32] Three years later chlordiazepoxide was marketed as a therapeutic benzodiazepine medication under the brand name Librium. Following chlordiazepoxide, in 1963 diazepam hit the market under the brand name Valium—and was followed by many further benzodiazepine compounds over the subsequent years and decades.[33]

In 1959 it was used by over 2,000 physicians and more than 20,000 patients. It was described as "chemically and clinically different from any of the tranquilizers, psychic energizers or other psychotherapeutic drugs now available." During studies, chlordiazepoxide induced muscle relaxation and a quieting effect on laboratory animals like mice,

alcoholic patients. It was reported that ulcers and dermatologic problems, both of which involved emotional factors, were reduced by chlordiazepoxide.[34]

In 1963, approval for use was given to diazepam (Valium), a "simplified" version of chlordiazepoxide, primarily to counteract anxiety symptoms. Sleep-related problems were treated with nitrazepam (Mogadon), which was introduced in 1972, temazepam (Restoril), which was introduced in 1979, and flurazepam (Dalmane), which was introduced in 1975.[35]

Recreational use

See also:
Benzodiazepine drug misuse

In 1963, Carl F. Essig of the

barbiturates, whose habit-forming qualities were more widely known. He mentioned a 90-day study of chlordiazepoxide, which concluded that the automobile accident rate among 68 users was 10 times higher than normal. Participants' daily dosage ranged from 5 to 100 milligrams.[36]

Chlordiazepoxide is a drug of potential

misuse and is frequently detected in urine samples of drug users who have not been prescribed the drug.[37]

Legal status

Internationally, chlordiazepoxide is a Schedule IV controlled drug under the Convention on Psychotropic Substances.[38]

Toxicity

Animal

Laboratory tests assessing the toxicity of chlordiazepoxide,

spermatozoa found that chlordiazepoxide produced toxicities in sperm including abnormalities involving both the shape and size of the sperm head. Nitrazepam, however, caused more profound abnormalities than chlordiazepoxide.[39]

Availability

Chlordiazepoxide is available in various dosage forms, alone or in combination with other drugs, worldwide. In combination with

Clidinium as NORMAXIN-CC and in combination with dicyclomine as NORMAXIN for IBS, and with the anti-depressant amitriptyline as Limbitrol.[40]

See also

References

  1. ISBN 9780323087902
    .
  2. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  3. PMID 42628
    .
  4. ISBN 9783527607495
    .
  5. PMID 17117615
    .
  6. PMID 19524858
    .
  7. ^ "Chlordiazepoxide 10mg Capsules - Summary of Product Characteristics". UK Electronic Medicines Compendium. 19 December 2012. Archived from the original on 23 April 2017. Retrieved 23 April 2017.
  8. ^ "Chlordiazepoxide". MedlinePlus Drug Information. February 15, 2017.
  9. PMID 12482007
    .
  10. PMID 19900604
    .
  11. PMID 12802839
    .
  12. PMID 11773648
    .
  13. S2CID 7946506
    .
  14. ^ drugs. "Chlordiazepoxide patient advice including side-effects". drugs.com. Retrieved April 7, 2008.
  15. PMID 2173758
    .
  16. S2CID 42752576
    .
  17. PMID 1241268
    .
  18. ^ "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". U.S. Food and Drug Administration (FDA). 23 September 2020. Retrieved 23 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  19. S2CID 24771398
    .
  20. PMID 7388368
    .
  21. PMID 6133446
    .
  22. PMID 6985425
    .
  23. PMID 12474705
    .
  24. PMID 6135616
    .
  25. PMID 2983169
    .
  26. PMID 851373
    .
  27. PMID 6979001
    .
  28. PMID 6328498
    .
  29. PMID 3978310
    .
  30. ^ Ashton CH. (April 2007). "Benzodiazepine equivalency table". Archived from the original on September 28, 2007. Retrieved September 23, 2007.
  31. PMID 6118950
    .
  32. ^ "Pharmacological and clinical-studies on valium: a new psychotherapeutic agent of the benzodiazepine class" (PDF). 1980-11-24. Retrieved 2019-05-23.
  33. ISBN 0-19-510399-8. Archived from the original
    on 2008-03-15. Retrieved 7 Apr 2008.
  34. ^ The New York Times (28 February 1960). "Help For Mental Ills (Reports on Tests of Synthetic Drug Say The Results are Positive)". The New York Times. USA. p. E9.
  35. S2CID 26923026
    .
  36. ^ The New York Times (30 December 1963). "Warning Is Issued On Tranquilizers". The New York Times. USA. p. 23.
  37. S2CID 42665843
    .
  38. ISBN 978-92-1-048165-6
    .
  39. PMID 6132780
    .
  40. ^ Drugs.com Drugs.com: International availability of chlordiazepoxide Page accessed April 24, 2015

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Chlordiazepoxide&oldid=1215923233"