Chlordiazepoxide

Effects

AnxiolyticSedativeMuscle RelaxantAmnesiaDystaxiaHypnotic TS

Overview

Chlordiazepoxide, a medium-acting benzodiazepine drug prescribed mostly for sleep purposes. Sedative and hypnotic, it may cause lowered inhibitions and amnesia in high doses.[1] TS

Chlordiazepoxide hydrochloride, sold under the brand name Librium, is a sedative and hypnotic medication of the benzodiazepine class. It is used to treat anxiety, insomnia, and symptoms of withdrawal from alcohol, benzodiazepines, and other drugs. It is also used to discontinue long-term use of other, shorter-acting benzodiazepines due to its long half-life. WP

Chlordiazepoxide has a medium to long half-life, while its active metabolite has a very long half-life. The drug has amnesic, anticonvulsant, anxiolytic, hypnotic, sedative, and skeletal muscle relaxant properties.[2] WP

Chlordiazepoxide was patented in 1958 and approved for medical use in 1960. It was the first benzodiazepine to be synthesized, and the discovery of chlordiazepoxide was by pure chance. 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.[3][4][5] WP

History

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, quinazoline-3-oxides. 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." 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.[6][7][8] WP

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, rats, cats, and dogs. Fear and aggression were eliminated in much smaller doses than those necessary to produce hypnosis. Chlordiazepoxide is similar to phenobarbital in its anticonvulsant properties. However, it lacks the hypnotic effects of barbiturates. Animal tests were conducted in the Boston Zoo and the San Diego Zoo. Forty-two hospital patients admitted for acute and chronic alcoholism, and various psychoses and neuroses were treated with chlordiazepoxide. In a majority of the patients, anxiety, tension, and motor excitement were "effectively reduced." The most positive results were observed among alcoholic patients. It was reported that ulcers and dermatologic problems, both of which involved emotional factors, were reduced by chlordiazepoxide.[9] WP

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.[6] WP

Legal status

Legal status

Internationally, chlordiazepoxide is a Schedule IV controlled drug under the Convention on Psychotropic Substances.[10] WP

Society and culture

Chlordiazepoxide is the drug referenced in the Netflix series "The Queen's Gambit," under the commercial name Librium. It also appears prominently in the HBO series "The Pitt." In “Infinite Jest”, by David Foster Wallace, a nurse “negotiated a trade of shoes for Librium” with the character Tiny Ewell. In the first episode of Yes, Minister, Jim Hacker tells his wife Annie to take a Librium when she couldn't find a cigarette.[11] WP

Pharmacology

Pharmacology

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 is an anticonvulsant.[12][13] WP

Chlordiazepoxide is preferentially stored in some organs including the hearts of neonates. Absorption by any administered route and the risk of accumulation is significantly higher in neonates. The withdrawal of chlordiazepoxide during pregnancy and breast feeding is recommended, as chlordiazepoxide rapidly crosses the placenta and also is excreted in breast milk. Chlordiazepoxide also decreases prolactin release in rats. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in animal nerve terminal preparations. 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.[14–17] WP

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. 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.[18][19] WP

Despite its name, chlordiazepoxide is not an epoxide. WP

Chemistry

Formula

C16H14ClN3O PC

CAS number

58-25-3 PC

Molar mass (g/mol)

299.75 PC

IUPAC name (computed by PubChem)

7-chloro-4-hydroxy-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-imine PC

SMILES

CN=C1CN(C(=C2C=C(C=CC2=N1)Cl)C3=CC=CC=C3)O PC

InChIKey

BUCORZSTKDOEKQ-UHFFFAOYSA-N PC

PubChem CID

2712

Pop culture

No references added yet.

References

1. Journal / agency Alcohol and benzodiazepines in fatal poisonings
2. Journal / agency Liljequist R, Palva E, Linnoila M. Effects on learning and memory of 2-week treatments with chlordiazepoxide lactam, N-desmethyldiazepam, oxazepam and methyloxazepam, alone or in combination with alcohol. International Pharmacopsychiatry. 1979. doi:10.1159/000468381 · PMID 42628
3. Other Fischer J, Ganellin CR. Analogue-based Drug Discovery. 2006
4. Journal / agency Ban TA. The role of serendipity in drug discovery. Dialogues in Clinical Neuroscience. 2006. doi:10.31887/DCNS.2006.8.3/tban · PMID 17117615 · PMC3181823
5. Journal / agency Marshall KP, Georgievskava Z, Georgievsky I. Social reactions to Valium and Prozac: a cultural lag perspective of drug diffusion and adoption. Research in Social & Administrative Pharmacy. June 2009. doi:10.1016/j.sapharm.2008.06.005 · PMID 19524858
6. Journal / agency Sternbach LH. The discovery of librium. Agents and Actions. June 1972. doi:10.1007/BF01965860 · PMID 4557348
7. Other Pharmacological and clinical-studies on valium: a new psychotherapeutic agent of the benzodiazepine class. 1980-11-24
8. Other Cooper JR, Bloom FE, Roth RH. The Complete Story of the Benzodiazepines. January 15, 1996
9. Other The New York Times. Help For Mental Ills (Reports on Tests of Synthetic Drug Say The Results are Positive). 28 February 1960
10. Other Psychotropic Substances. 2016
11. Other The Frightening True Story Behind Those Green "Tranquility" Pills in 'The Queen's Gambit'. 4 November 2020
12. Journal / agency Skerritt JH, Johnston GA. Enhancement of GABA binding by benzodiazepines and related anxiolytics. European Journal of Pharmacology. May 1983. doi:10.1016/0014-2999(83)90494-6 · PMID 6135616
13. Journal / agency Chweh AY, Swinyard EA, Wolf HH, Kupferberg HJ. Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines. Life Sciences. February 1985. doi:10.1016/0024-3205(85)90193-6 · PMID 2983169
14. Journal / agency Olive G, Dreux C. Pharmacologic bases of use of benzodiazepines in peréinatal medicine. Archives Françaises de Pédiatrie. January 1977. PMID 851373
15. Journal / agency Grandison L. Suppression of prolactin secretion by benzodiazepines in vivo. Neuroendocrinology. 1982. doi:10.1159/000123330 · PMID 6979001
16. Journal / agency Taft WC, DeLorenzo RJ. Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations. Proceedings of the National Academy of Sciences of the United States of America. May 1984. doi:10.1073/pnas.81.10.3118 · PMID 6328498 · PMC345232
17. Journal / agency Miller JA, Richter JA. Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes. British Journal of Pharmacology. January 1985. doi:10.1111/j.1476-5381.1985.tb17368.x · PMID 3978310 · PMC1987204
18. Other Ashton CH. Benzodiazepine equivalency table. April 2007
19. Journal / agency Vozeh S. Pharmacokinetic of benzodiazepines in old age. Schweizerische Medizinische Wochenschrift. November 1981. PMID 6118950

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