Chlordiazepoxide hydrochloride, sold under the brand nameLibrium, is asedative andhypnotic medication of thebenzodiazepine class. It is used to treatanxiety,insomnia, and symptoms ofwithdrawal fromalcohol,benzodiazepines, and other drugs. It is also used to discontinue long-term use of other, shorter-acting benzodiazepines due to its long half-life.
Chlordiazepoxide has a medium to longhalf-life, while itsactive metabolite has a very long half-life. The drug hasamnesic,anticonvulsant,anxiolytic,hypnotic,sedative, andskeletal muscle relaxant properties.[4]
Chlordiazepoxide was patented in 1958 and approved for medical use in 1960.[5] It was the first benzodiazepine to be synthesized, and the discovery of chlordiazepoxide was by pure chance.[6] 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.[7]
Chlordiazepoxide hydrochloride is indicated for the short-term (2–4 weeks) treatment ofanxiety that is severe and disabling or subjecting the person to uncomfortable distress. It is also indicated as a treatment for the management of acutealcohol withdrawal syndrome.[8]
Chlordiazepoxide hydrochloride may be used in chronic benzodiazepine users to discontinue benzodiazepine use. The long half-life means that the patient’s final dose will last several days, making the likelihood of withdrawal symptoms low. Tapering can last months to years.
It can sometimes be prescribed to ease symptoms ofirritable bowel syndrome (IBS) combined withclidinium bromide as a fixed dose medication,Librax.[9]
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 longelimination half-life and the risks of accumulation.[10] Benzodiazepines require special precaution if used in the elderly, pregnancy, children, alcohol- or drug-dependent individuals and individuals withcomorbidpsychiatric disorders.[11]
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 thefirst trimester of pregnancy. Chlordiazepoxide anddiazepam are considered to be among the safer benzodiazepines to use during pregnancy in comparison to other benzodiazepines. Possible adverse effects from benzodiazepine use during pregnancy includemiscarriage,malformation,intrauterine growth retardation, functional deficits,carcinogenesis andmutagenesis. Caution is also advised duringbreast feeding as chlordiazepoxide passes into breast milk.[12][13]
Sedative drugs and sleeping pills, including chlordiazepoxide, have been associated with an increased risk of death.[14] The studies had many limitations, such as possible tendency to overestimate risk, possible confounding by indication with other risk factors and confusing hypnotics with drugs having other indications.
Common side-effects of chlordiazepoxide include:[15]
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.[16] It was later found that impairment in learning was caused by an increase in benzodiazepine/GABA activity (and that benzodiazepines were not associated with the cholinergic system).[17] 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.[18]
In September 2020, the USFood and Drug Administration (FDA) required theboxed warning for all benzodiazepine medicines to be updated to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.[19]
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.[20] The Committee of Review of Medicines, who carried out an extensive review of benzodiazepines including chlordiazepoxide, found—and were in agreement with the USInstitute of Medicine and the conclusions of a study carried out by the White House Office of Drug Policy and the USNational 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.[21]
Chlordiazepoxide can causephysical dependence and what is known as thebenzodiazepine withdrawal syndrome. Withdrawal from chlordiazepoxide or other benzodiazepines often leads to withdrawal symptoms that are similar to those seen with alcohol andbarbiturates. The higher the dose and the longer the drug is taken, the risk of experiencing unpleasant withdrawal symptoms becomes greater. 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.[22]
Chlordiazepoxide taken during pregnancy can cause apostnatalbenzodiazepine withdrawal syndrome.[23]
An individual who has consumed excess chlordiazepoxide may display some of the following symptoms:
Chlordiazepoxide is typically used under controlled conditions for specific syndromes and sees far less frequent usage when compared to newer drugs of the same class and thus is unlikely to be encountered in a clinical emergency setting as a stand-alone drug causing life-threatening concern. Like other drugs in its class, chlordiazepoxide alongside benzodiazepines as a whole have a lowered potential to cause life-threatening injury - though this does not preclude their common co-contaminant discovery with other depressant drugs of abuse, nor their ability to contribute to an already potentially fatal episode of drug-induced respiratory depression. In cases of suspected overdose, supportive care and observation are most often indicated and provided incrementally in relation to severity and duration of symptoms.Flumazenil is uniquely poised as an "antidote" that specifically counteracts damagingcentral nervous system affect induced via benzodiazepine mechanism of action - though is not generally indicated in relation to the severity of symptoms where other treatment options exist, and often has numerous damaging consequences that must be carefully weighted before any potential administration.[24]
Chlordiazepoxide acts onbenzodiazepine allosteric sites that are part of the GABAA receptor/ion-channel complex and this results in an increased binding of the inhibitory neurotransmitterGABA to the GABAA receptor thereby producing inhibitory effects on thecentral nervous system and body similar to the effects of otherbenzodiazepines.[25] Chlordiazepoxide is ananticonvulsant.[26]
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.[27] Chlordiazepoxide also decreases prolactin release in rats.[28] Benzodiazepines act viamicromolar benzodiazepine binding sites asCa2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in animal nerve terminal preparations.[29] Chlordiazepoxide inhibitsacetylcholine release in mouse hippocampal synaptosomes in vivo. This has been found by measuring sodium-dependent high affinitycholine uptake in vitro after pretreatment of the mice in vivo with chlordiazepoxide. This may play a role in chlordiazepoxide's anticonvulsant properties.[30]
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.[31] 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.[32]
Despite its name, chlordiazepoxide is not anepoxide.
Chlordiazepoxide (initially calledmethaminodiazepoxide) 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.[33] It was discovered by accident when in 1957 tests revealed that the compound hadhypnotic,anxiolytic, andmuscle relaxant effects. "The story of the chemical development of Librium and Valium was told bySternbach. 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 usingmyanesin as a standard and thenmeprobamate andchlorpromazine 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."[34] Three years later chlordiazepoxide was marketed as a therapeutic benzodiazepine medication under the brand name Librium. Following chlordiazepoxide, in 1963diazepam hit the market under the brand name Valium—and was followed by many further benzodiazepine compounds over the subsequent years and decades.[35]
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, anddogs. Fear and aggression were eliminated in much smaller doses than those necessary to produce hypnosis. Chlordiazepoxide is similar tophenobarbital in itsanticonvulsant properties. However, it lacks the hypnotic effects ofbarbiturates. Animal tests were conducted in theBoston Zoo and theSan Diego Zoo. Forty-two hospital patients admitted for acute and chronic alcoholism, and variouspsychoses andneuroses were treated with chlordiazepoxide. In a majority of the patients,anxiety,tension, and motor excitement were "effectively reduced." The most positive results were observed amongalcoholic patients. It was reported thatulcers anddermatologic problems, both of which involved emotional factors, were reduced by chlordiazepoxide.[36]
In 1963, approval for use was given todiazepam (Valium), a "simplified" version of chlordiazepoxide, primarily to counteract anxiety symptoms. Sleep-related problems were treated withnitrazepam (Mogadon), which was introduced in 1972,temazepam (Restoril), which was introduced in 1979, andflurazepam (Dalmane), which was introduced in 1975.[37]
In 1963, Carl F. Essig of theAddiction Research Center of theNational Institute of Mental Health stated thatmeprobamate,glutethimide,ethinamate,ethchlorvynol,methyprylon and chlordiazepoxide were drugs whose usefulness “can hardly be questioned.” However, Essig labeled these “newer products” as “drugs of addiction,” likebarbiturates, 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.[38]
Chlordiazepoxide is a drug of potentialmisuse and is frequently detected in urine samples of drug users who have not been prescribed the drug.[39]
Internationally, chlordiazepoxide is aSchedule IV controlled drug under theConvention on Psychotropic Substances.[40]
Laboratory tests assessing the toxicity of chlordiazepoxide,nitrazepam anddiazepam on micespermatozoa 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.[41]
Chlordiazepoxide is the drug referenced in the Netflix series "The Queen's Gambit," under the commercial name Librium.[42] It also appears prominently in the HBO series "The Pitt."
Chlordiazepoxide is available in various dosage forms, alone or in combination with other drugs, worldwide. In combination withclidinium as NORMAXIN-CC and in combination withdicycloverine as NORMAXIN for IBS, and with the anti-depressantamitriptyline as Limbitrol.[43]
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