Chlordiazepoxide

Chlordiazepoxide (pronounced [ˈklɔːrˌdaɪəzepˈoksaɪd], marketed under the trade name Librium®) is a sedative/hypnotic drug which is a benzodiazepine derivative. It has a medium to long half life.

History
See the main article benzodiazepine for the history of Librium.

The correct IUPAC name is: 7-chloro-2(methylamine)-5-phenyl-3H-1,4-benzodiazepine-4-oxide-hydrochloride and you have to include HCL

Pharmacology
Chlordiazepoxide acts on benzodiazepine subreceptors of the main GABAA receptor 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 at high doses decreases histamine turnover via it's action at the benzodiazepine-GABA receptor complex. Chlordiazepoxide is molecularly related to quinazolines and is a hapten. There is preferential storage of chlordiazepoxide in some organs including the heart. Absortion by any administered route and the risk of accumulation is significantly increased in the neonate and there are clinical justification to recommend the withdrawal of chlordiazepoxide during pregnancy and breast feeding 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 which has a half life of 36 - 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.

Tolerance
Tolerance to the anxiolytic effects develops rapidly and a stimulating effect develops after repeated daily administration. In mice tolerance to the anticonvulsant properties of chlordiazepoxide developed slowly over 15 days, although some anticonvulsant effects were still apparent after 15 days of continued administration.

Dependence
Chlordiazepoxide can cause physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from chlordiazepoxide or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen with alcohol and 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 via a slow and gradual dose reduction regime.

The Committee on the Review of Medicines
The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence and benzodiazepine withdrawal problems and other adverse effects. The committee found that benzodiazepines do not have any antidepressant or analgesic properties and are therefore unsuitable treatments for conditions such as depression, tension headaches and dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis due to a lack of efficacy. The committee also recommended against benzodiazepines being used in the treatment of anxiety or insomnia in children. The committee was in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA) that there was little evidence that long term use of benzodiazepine hypnotics were benefitial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep promoting properties within 3 - 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 4 months continuous use due to the development of tolerance. The committee found that the regular use of benzodiazepines caused the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours on the cessation of a short acting benzodiazepine and within 3 - 10 days after the cessation of a more short acting benzodiazepine. Withdrawal effects could occur after treatment lasting only 2 weeks at therapeutic dose levels however withdrawal effects tended to occur with habitual use beyond 2 weeks and were more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition. The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short term use only. It was noted in the review that alcohol can potentiate the central nervous system depressant effects of benzodiazepines and should be avoided. The central nervous system depressant effects of benzodiazepines may make driving or operating machinery dangerous and the elderly are more prone to these adverse effects. In the neonate high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hypothermia in the neonate and irregularities in the fetal heart. Benzodiazepines should be avoided in lactation. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhoea.

Abuse Potential
Chlordiazepoxide is frequently detected in urine samples of drug abusers who have not been prescribed the drug suggesting a high misuse potential for chlordiazepoxide. Chlordiazepoxide in animal studies has been shown to increase reward seeking behaviours which may suggest an increased risk of addictive behavioural patterns.

Indications
Chlordiazepoxide is indicated for the short term (2 - 4 weeks) treatment of severe and distressing insomnia, anxiety and panic attacks. It has also been used as a treatment for acute alcohol or opiate withdrawal, as well as relief from Crohn's and ulcerative colitis.

Dosage
Chlordiazepoxide is available in 5mg, 10mg and 25mg strengths.

Side effects
Common side effects of chlordiazepoxide include:
 * Drowsiness
 * Depression
 * Impaired motor function
 * Impaired coordination
 * Impaired balance
 * Dizziness
 * Nervousness
 * Anterograde amnesia (especially pronounced in higher doses)
 * Impaired learning

Chloridazepoxide in laboratory 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 tests of various benzodiazepine compounds Chlordiazepoxide was found to cause the most profound reduction in the turn over of 5HT which is the building block of serotonin. Serotonin is closely involved in regulating mood and may be one of the causes of feelings of depression in users of Chlordiazepoxide or other benzodiazepines.



Contraindications
Use of chlordiazepoxide should be avoided in individuals with the following conditions:
 * Myasthenia gravis
 * Acute intoxication with alcohol, narcotics, or other psychoactive substances
 * Ataxia
 * Severe hypoventilation
 * Acute narrow-angle glaucoma
 * Severe liver deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of 2)
 * Severe sleep apnea
 * Hypersensitivity or allergy to any drug in the benzodiazepine class

Interactions
Oral contraceptive pills, reduce the clearance of chlordiazepoxide which may lead to increased plasma levels of chlordiazepoxide and accumulation. Chlordiazepoxide interacts with contraceptives resulting in increased bleeding.

Overdose
An individual who has consumed too much chlordiazepoxide will display one or more of the following symptoms:
 * Somnolence (difficulty staying awake)
 * Mental confusion
 * Hypotension
 * Hypoventilation
 * Impaired motor functions
 * Impaired reflexes
 * Impaired coordination
 * Impaired balance
 * Dizziness
 * Muscle Weakness
 * Coma

In animal models, the oral LD50 of chlordiazepoxide is 537 mg/kg.

Chlordiazepoxide is a drug which is very frequently involved in drug intoxication, including overdose. Chlordiazepoxide overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of chlordiazepoxide (or any other benzodiazepine) is flumazenil (Anexate®).

Legal status
Internationally, chlordiazepoxide is a Schedule IV drug under the Convention on Psychotropic Substances.

Toxicity
Laboratory tests assessing the toxicity of chlordiazepoxide, nitrazepam and diazepam on mice 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.

Alternative trade names

 * Librocol
 * Librelease
 * Libritabs
 * Limbitrol
 * Menrium
 * Novo-Poxide
 * Poxidium
 * Risolid
 * Defobin

Combination Drugs

 * Librax - chlordiazepoxide and clidinium