Chlordiazepoxide
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Chlordiazepoxide
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| Systematic (IUPAC) name | |
| 7-chloro-4-hydroxy-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-imine | |
| Identifiers | |
| CAS number | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C16H14ClN3O |
| Mol. mass | 299.08 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | Hepatic |
| Half life | 5–30 hours |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. |
D(US) |
| Legal status | |
| Routes | oral intramuscular |
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.
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[edit] 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.[1]
[edit] 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.[2] Chlordiazepoxide is anticonvulsant.[3] There is preferential storage of chlordiazepoxide in some organs including the heart. Absorption 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.[4] Chlordiazepoxide also decreases prolactin release.[5] Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake.[6] Chlordiazepoxide has been found to inhibit acetylcholine release and sodium-dependent high affinity choline uptake which may play a role in chlordiazepoxide's anticonvulsant properties.[7]
[edit] 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.[8] 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.[9]
[edit] 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.[10] 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 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.[11]
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.[12]
Chlordiazepoxide taken during pregnancy can cause a postnatal benzodiazepine withdrawal syndrome.[13]
[edit] 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.[14]
[edit] Dosage
Chlordiazepoxide is available in 5mg, 10mg and 25mg strengths.
[edit] Side effects
Common side effects of chlordiazepoxide include:[15]
- 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.[16] In tests of various benzodiazepine compounds Chlordiazepoxide was found to cause the most profound reduction in the turnover of 5HT (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.[17]
[edit] 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
[edit] Interactions
Some of the major interactions involving Chlordiazepoxide are listed below.[18]
- 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 - benzodiazapines enhance effects of sodium oxybate (avoid concomitant use)
[edit] 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 LD50 of chlordiazepoxide is 537 mg/kg.
Chlordiazepoxide is a drug which is very frequently involved in drug intoxication, including overdose.[19] 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).
[edit] Abuse
Chlordiazepoxide is frequently detected in urine samples of drug abusers who have not been prescribed the drug.[20] Chlordiazepoxide in animal studies has been shown to increase reward seeking behaviours which may suggest an increased risk of addictive behavioural patterns.[21]
Legal status
Internationally, chlordiazepoxide is a Schedule IV drug under the Convention on Psychotropic Substances[1].
[edit] 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.[22]
[edit] Trade names
- Alpoxid
- Klopoxid
- Librium
- Librocol
- Librelease
- Libritabs
- Limbitrol
- Menrium
- Novo-Poxide
- Poxidium
- Risolid
- Defobin
- Elenium
[edit] Combination Drugs
- Librax - chlordiazepoxide and clidinium
[edit] External links
[edit] References
- ^ Cooper, Jack R; Floyd E. Bloom, Robert H. Roth (15). The Complete Story of the Benzodiazepines, seventh (in Eng), USA: Oxford University Press. ISBN 0195103998. Retrieved on 07.
- ^ Skerritt JH; Johnston GA. (6). "Enhancement of GABA binding by benzodiazepines and related anxiolytics.". Eur J Pharmacol. 89 (3-4): 193–8. doi:. PMID 6135616.
- ^ Chweh AY; Swinyard EA, Wolf HH, Kupferberg HJ (25). "Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines". Life Sci 36 (8): 737–44. doi:. PMID 2983169.
- ^ Olive G; Dreux C. (Jan 1977). "Pharmacologic bases of use of benzodiazepines in peréinatal medicine.". Arch Fr Pediatr. 34(1): 74–89. PMID 851373.
- ^ Grandison L (1982). "Suppression of prolactin secretion by benzodiazepines in vivo". Neuroendocrinology 34 (5): 369–73. doi:. PMID 6979001.
- ^ Taft WC; DeLorenzo RJ (May 1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations". Proc Natl Acad Sci U S A 81 (10): 3118–22. doi:. PMID 6328498.
- ^ Miller JA; Richter JA (Jan 1985). "Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes" (PDF). Br J Pharmacol 84 (1): 19–25. PMID 3978310.
- ^ Ashton CH. (April 2007). BENZODIAZEPINE EQUIVALENCY TABLE. Retrieved on Sept 23, 2007.
- ^ Vozeh S. (21). "[Pharmacokinetic of benzodiazepines in old age]". Schweiz Med Wochenschr. 111 (47): 1789–93. PMID 6118950.
- ^ Crawley JN; Marangos PJ, Stivers J, Goodwin FK (Jan 1982). "Chronic clonazepam administration induces benzodiazepine receptor subsensitivity". Neuropharmacology 21 (1): 85–9. doi:. PMID 6278355.
- ^ Committee on the Review of Medicines (29). "Systematic review of the benzodiazepines. Guidelines for data sheets on diazepam, chlordiazepoxide, medazepam, clorazepate, lorazepam, oxazepam, temazepam, triazolam, nitrazepam, and flurazepam. Committee on the Review of Medicines." (pdf). Br Med J. 280 (6218): 910–2. PMID 7388368.
- ^ MacKinnon GL; Parker WA. (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation.". The American journal of drug and alcohol abuse. 9 (1): 19–33. doi:. PMID 6133446.
- ^ Moretti M; Montali S (Sep-Oct 1982). "[Fetal defects caused by the passive consumption of drugs]". Pediatr Med Chir 4 (5): 481–90. PMID 6985425.
- ^ British National Formulary; Committee on Safety of Medicines (8). CHLORDIAZEPOXIDE HYDROCHLORIDE. BNF.org. Retrieved on 08 Apr 2008.
- ^ drugs. Chlordiazepoxide patient advice including side effects. drugs.com. Retrieved on Apr 07, 2008.
- ^ Nabeshima T; Tohyama K, Ichihara K, Kameyama T. (Nov 1990). "Effects of benzodiazepines on passive avoidance response and latent learning in mice: relationship to benzodiazepine receptors and the cholinergic neuronal system.". J Pharmacol Exp Ther. 255 (2): 789–94. PMID 2173758.
- ^ Antkiewicz-Michaluk L; Grabowska M, Baran L, Michaluk J. (1975). "Influence of benzodiazepines on turnover of serotonin in cerebral structures in normal and aggressive rats.". Arch Immunol Ther Exp (Warsz). 23 (6): 763–7. PMID 1241268.
- ^ British National Formulary. Chlordiazepoxide interactions. BNF. Retrieved on 07, 2008. Retrieved on Apr 2008.
- ^ Zevzikovas A; Kiliuviene G, Ivanauskas L, Dirse V. (2002). "[Analysis of benzodiazepine derivative mixture by gas-liquid chromatography]". Medicina (Kaunas). 38 (3): 316–20. PMID 12474705.
- ^ Garretty DJ; Wolff K, Hay AW, Raistrick D. (Jan 1997). "Benzodiazepine misuse by drug addicts.". Annals of clinical biochemistry. 34 (Pt 1): 68–73. PMID 9022890.
- ^ Thiébot MH; Le Bihan C, Soubrié P, Simon P. (1985). "Benzodiazepines reduce the tolerance to reward delay in rats.". Psychopharmacology (Berl). 86 (1-2): 147–52. doi:. PMID 2862657.
- ^ Kar RN; Das RK. (1983). "Induction of sperm head abnormalities in mice by three tranquilizers.". Cytobios. 36 (141): 45–51. PMID 6132780.
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