Chlordiazepoxide

[klawr-dahy-az-uh-pok-sahyd, klohr-]

Chlordiazepoxide (pronounced [ˈklɔːrˌdaɪəzepˈoksaɪd]), is a sedative/hypnotic drug which is a benzodiazepine derivative and is marketed under the trade name Librium. It has a medium to long half life but its active metabolite has a very long half life. Chlordiazepoxide has amnestic, anxiolytic, hypnotic and skeletal muscle relaxant properties.

History

Chlordiazepoxide, initially called methaminodiazepoxide was the first benzodiazepine discovered being synthesised in the mid 1950's. Chlordiazepoxide was synthesised from work on a chemical dye, quinazolone-3-oxides. It was discovered by accident when in 1957 tests revealed that the compound had hypnotic, anxiolytic and muscle relaxant effects. 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 followed by many further benzodiazepine compounds which were introduced over the subsequent years and decades.

Pharmacology

Chlordiazepoxide acts on benzodiazepine subreceptors of the main GABA_A receptor and this results in an increased binding of the inhibitory neurotransmitter GABA to the GABA_A receptor thereby producing inhibitory effects on the central nervous system and body similar to the effects of other benzodiazepines. Chlordiazepoxide is anticonvulsant. 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. 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.

Pharmacokinetics

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 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 mouse forebrain. The Committee of Review of Medicines who carried out an extensive review of benzodiazepines including chlordiazepoxide found and were 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 benzodiazepines were beneficial 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.

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.

Chlordiazepoxide taken during pregnancy can cause a postnatal benzodiazepine withdrawal syndrome.

Indications

Chlordiazepoxide is indicated for the short term (2–4 weeks) treatment of anxiety which 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.

Dosage

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

Side effects

Common side effects of chlordiazepoxide include:

Confusion
constipation
drowsiness
fainting
increased or decreased sex drive
liver problems
lack of muscle coordination
minor menstrual irregularities
nausea
skin rash or eruptions
swelling due to fluid retention
yellow eyes and skin

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. 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.

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

Some of the major interactions involving Chlordiazepoxide are listed below.

ACE inhibitors, Adrenergic neurone blockers, Angiotensin II receptor antagonists, Beta blockers, Calcium channel blockers, Clonidine, Diazoxide, Diuretics, Hydralazine, Methyldopa, Minoxidil, Nitrates, Sodium Nitroprusside - enhanced hypotensive effect
Alcohol, barbiturates, opiates, antihistamines, antipsychotics - increased sedative effect in combination with benzodiazapines.
Cimetidine - metabolism of benzodiazepines inhibited by cimetidine (increased plasma concentration)
Disulfiram - metabolism of benzodiazepines inhibited by disulfiram (increased sedative effects)
Fluvoxamine - plasma concentration of some benzodiazepines increased by fluvoxamine
Levodopa - benzodiazepines possibly antagonise effects of levodopa
Moxonidine - sedative effects possibly increased when benzodiazepines given with moxonidine
Olanzapine - increased risk of hypotension, bradycardia and respiratory depression when parenteral benzodiazepines given with intramuscular olanzapine
Phenytoin - benzodiazepines possibly increase or decrease plasma concentration of phenytoin
Rifampicin - metabolism of benzodiazepines possibly accelerated by rifampicin (reduced plasma concentration)
Sodium Oxybate - benzodiazepines enhance effects of sodium oxybate (avoid concomitant use)

Overdose

An individual who has consumed excess chlordiazepoxide may display some 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 median lethal dose 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).

Abuse

Chlordiazepoxide is frequently detected in urine samples of drug abusers who have not been prescribed the drug. Chlordiazepoxide in animal studies has been shown to increase reward seeking behaviours which may suggest an increased risk of addictive behavioural patterns.

Legal status

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

Toxicity

Animal

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.