| Revision as of 03:51, 31 March 2008 edit70.137.178.160 (talk) removed relation to quinazolines and hapten. this is bull.← Previous edit | Revision as of 21:56, 31 March 2008 edit undo70.137.178.160 (talk) removed speculative results from mouse cell and angry rat experiments, irrelevant to human pharmacology.Next edit → | ||
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| ==Pharmacology== | ==Pharmacology== | ||
| Chlordiazepoxide acts on benzodiazepine subreceptors of the main GABA<sub>A</sub> receptor and this results in an increased binding of the inhibitory neurotransmitter ] to the GABA<sub>A</sub> receptor thereby producing inhibitory effects on the ] and body similar to the effects of other ].<ref>{{cite journal | author = Skerritt JH | coauthors = Johnston GA. | year = 1983 | month = May | date = 6 | title = Enhancement of GABA binding by benzodiazepines and related anxiolytics. | journal = Eur J Pharmacol. | volume = 89 | issue = 3-4 | pages = 193-8 | pmid = 6135616 }}</ref> Chlordiazepoxide is ]. |
Chlordiazepoxide acts on benzodiazepine subreceptors of the main GABA<sub>A</sub> receptor and this results in an increased binding of the inhibitory neurotransmitter ] to the GABA<sub>A</sub> receptor thereby producing inhibitory effects on the ] and body similar to the effects of other ].<ref>{{cite journal | author = Skerritt JH | coauthors = Johnston GA. | year = 1983 | month = May | date = 6 | title = Enhancement of GABA binding by benzodiazepines and related anxiolytics. | journal = Eur J Pharmacol. | volume = 89 | issue = 3-4 | pages = 193-8 | pmid = 6135616 }}</ref> Chlordiazepoxide is ]. | ||
| 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.<ref>{{cite journal | author = Olive G | coauthors = Dreux C. | year = 1977 | month = Jan | title = Pharmacologic bases of use of benzodiazepines in peréinatal medicine. | journal = Arch Fr Pediatr. | volume = 34(1) | pages = 74-89 | pmid = 851373 }}</ref> | |||
| | pages = 337-42 | pmid = 3089825 }}</ref> | |||
| 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.<ref>{{cite journal | author = Olive G | coauthors = Dreux C. | year = 1977 | month = Jan | title = Pharmacologic bases of use of benzodiazepines in peréinatal medicine. | journal = Arch Fr Pediatr. | volume = 34(1) | pages = 74-89 | pmid = 851373 }}</ref> Chlordiazepoxide induces ] in ] cells via binding to high affinity sites and modulating cell differentiation.<ref>{{cite journal |author=Matthew E |coauthors=Laskin JD, Zimmerman EA, Weinstein IB, Hsu KC, Engelhardt DL |year=1981 |month=Jun |title=Benzodiazepines have high-affinity binding sites and induce melanogenesis in B16/C3 melanoma cells |journal=Proc Natl Acad Sci U S A |volume=78 |issue=6 |pages=3935-9 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=319688&blobtype=pdf |pmid=6267610}}</ref> Chlordiazepoxide also decreases prolactin release.<ref>{{cite journal |author=Grandison L |year=1982 |title=Suppression of prolactin secretion by benzodiazepines in vivo |journal=Neuroendocrinology |volume=34 |issue=5 |pages=369-73 |pmid=6979001}}</ref> Benzodiazepines act via ] benzodiazepine binding sites as ] channel blockers and significantly inhibit depolarization-sensitive Calcium uptake.<ref>{{cite journal | journal = Proc Natl Acad Sci U S A | year = 1984 | month = May | volume = 81 | issue = 10 | pages = 3118-22 | url = http://www.pnas.org/cgi/reprint/81/10/3118.pdf | type = PDF | title = Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations | author = Taft WC |coauthors = DeLorenzo RJ | pmid = 6328498}}</ref> Chlordiazepoxide has been found to inhibit ] release and sodium-dependent high affinity ] uptake which may play a role in chlordiazepoxide's ] properties.<ref>{{cite journal | journal = Br J Pharmacol | year = 1985 | month = Jan | volume = 84 | issue = 1 | pages = 19-25 | title = Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes | author = Miller JA | coauthors = Richter JA | pmid = 3978310 | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1987204&blobtype=pdf| format = PDF }}</ref> | |||
| 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.<ref>{{cite web | url = http://www.bcnc.org.uk/equivalence.html | title = BENZODIAZEPINE EQUIVALENCY TABLE | accessmonthday = Sept 23 | accessyear = 2007 | author = Ashton CH. | year = 2007 | month = April }}</ref> 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.<ref>{{cite journal | author = Vozeh S. | coauthors = | year = 1981 | month = Nov | date = 21 | title = | journal = Schweiz Med Wochenschr. | volume = 111 | issue = 47 | pages = 1789-93 | pmid = 6118950 }}</ref> | 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.<ref>{{cite web | url = http://www.bcnc.org.uk/equivalence.html | title = BENZODIAZEPINE EQUIVALENCY TABLE | accessmonthday = Sept 23 | accessyear = 2007 | author = Ashton CH. | year = 2007 | month = April }}</ref> 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.<ref>{{cite journal | author = Vozeh S. | coauthors = | year = 1981 | month = Nov | date = 21 | title = | journal = Schweiz Med Wochenschr. | volume = 111 | issue = 47 | pages = 1789-93 | pmid = 6118950 }}</ref> | ||
| ==Tolerance== | |||
| Chronic use of benzodiazepines, such as chlordiazepoxide leads to the development of tolerance with a decrease in number of benzodiazepine binding sites.<ref>{{cite journal |author=Crawley JN |coauthors=Marangos PJ, Stivers J, Goodwin FK |year=1982 |month=Jan |title=Chronic clonazepam administration induces benzodiazepine receptor subsensitivity |volume=21 |issue=1 |pages=85-9 |pmid=6278355 |journal=Neuropharmacology}}</ref>Tolerance to the ] effects develops rapidly and a stimulating effect develops after repeated daily administration.<ref>{{cite journal | author = Nowakowska E | coauthors = Chodera A, Cenajek-Musiał D, Szczawińska K. | year = 1987 | month = May-Jun | title = Differences in the development of tolerance to various benzodiazepines. | journal = Pol J Pharmacol Pharm. | volume = 39 | issue = 3 | pages = 245-52 | pmid = 2894019 }}</ref> 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.<ref>{{cite journal | author = Garratt JC | coauthors = Gent JP, Feely M, Haigh JR. | year = 1988 | month = Jan | date = 5 | title = Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential? | journal = Eur J Pharmacol. | volume = 145 | issue = 1 | pages = 75-80 | pmid = 2894998 }}</ref> | |||
| ==Dependence== | ==Dependence== | ||
| Line 47: | Line 43: | ||
| ==Abuse Potential== | ==Abuse Potential== | ||
| Chlordiazepoxide has a moderate abuse potential, as indicated by placement into Schedule IV. | |||
| Chlordiazepoxide is frequently detected in urine samples of drug abusers who have not been prescribed the drug suggesting a high misuse potential for chlordiazepoxide.<ref>{{cite journal | author = Garretty DJ | coauthors = Wolff K, Hay AW, Raistrick D. | year = 1997 | month = Jan | title = Benzodiazepine misuse by drug addicts. | journal = Annals of clinical biochemistry. | volume = 34 | issue = Pt 1 | pages = 68-73 | pmid = 9022890 }}</ref> | |||
| Chlordiazepoxide in animal studies has been shown to increase reward seeking behaviours which may suggest an increased risk of addictive behavioural patterns.<ref>{{cite journal | author = Thiébot MH | coauthors = Le Bihan C, Soubrié P, Simon P. | year = 1985 | month = | title = Benzodiazepines reduce the tolerance to reward delay in rats. | volume = 86 | issue = 1-2 | pages = 147-52 | pmid = 2862657 | journal = Psychopharmacology (Berl).}}</ref> | |||
| ==Indications== | ==Indications== | ||
| Line 67: | Line 62: | ||
| * ] (especially pronounced in higher doses) | * ] (especially pronounced in higher doses) | ||
| * Impaired learning | * Impaired learning | ||
| Chlordiazepoxide 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.<ref>{{cite journal | author = Nabeshima T | coauthors = Tohyama K, Ichihara K, Kameyama T. | year = 1990 | month = Nov | title = Effects of benzodiazepines on passive avoidance response and latent learning in mice: relationship to benzodiazepine receptors and the cholinergic neuronal system. | journal = J Pharmacol Exp Ther. | volume = 255 | issue = 2 | pages = 789-94 | pmid = 2173758 }}</ref> In tests of various benzodiazepine compounds Chlordiazepoxide was found to cause the most profound reduction in the turnover of 5HT (]). 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.<ref>{{cite journal | author = Antkiewicz-Michaluk L | coauthors = Grabowska M, Baran L, Michaluk J. | year = 1975 | month = | title = Influence of benzodiazepines on turnover of serotonin in cerebral structures in normal and aggressive rats. | journal = Arch Immunol Ther Exp (Warsz). | volume = 23 | issue = 6 | pages = 763-7 | pmid = 1241268 }}</ref> | |||
| ] | ] | ||
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| * Severe ] | * Severe ] | ||
| * Hypersensitivity or allergy to any drug in the ] class | * Hypersensitivity or allergy to any drug in the ] class | ||
| ==Interactions== | |||
| Oral contraceptive pills, reduce the clearance of chlordiazepoxide which may lead to increased plasma levels of chlordiazepoxide and accumulation.<ref>{{cite journal | author = Back DJ | coauthors = Orme ML. | year = 1990 | month = Jun | title = Pharmacokinetic drug interactions with oral contraceptives. | journal = Clin Pharmacokinet. | volume = 18 | issue = 6 | pages = 472-84 | pmid = 2191822 }}</ref> Chlordiazepoxide interacts with contraceptives resulting in increased bleeding.<ref>{{cite journal |author=Somos P. |coauthors= |title= Interaction between certain psychopharmaca and low-dose oral contraceptives. |volume=38 |issue=1 |pages=37-40 |year=1990 |pmid=1971733 }}</ref> | |||
| ] a drug with anticonvulsant properties, reduces the anticonvulsant protency of chlordiazepoxide.<ref>{{cite journal | author = Consroe P | coauthors = Wolkin A. | year = 1977 | month = Apr | title = Cannabidiol--antiepileptic drug comparisons and interactions in experimentally induced seizures in rats. | journal = J Pharmacol Exp Ther. | volume = 201 | issue = 1 | pages = 26-32 | pmid = 850145 }}</ref> | |||
| ==Overdose== | ==Overdose== | ||
| Line 108: | Line 96: | ||
| ==Legal status== | ==Legal status== | ||
| Internationally, chlordiazepoxide is a Schedule IV drug under the ]. | Internationally, chlordiazepoxide is a Schedule IV drug under the ]. | ||
| ==Toxicity== | |||
| Laboratory tests assessing the toxicity of chlordiazepoxide, ] and ] on mice ] 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.<ref>{{cite journal | author = Kar RN | coauthors = Das RK. | year = 1983 | month = | title = Induction of sperm head abnormalities in mice by three tranquilizers. | journal = Cytobios. | volume = 36 | issue = 141 | pages = 45-51 | pmid = 6132780 }}</ref> | |||
| ==Trade names== | ==Trade names== | ||
Revision as of 21:56, 31 March 2008
Pharmaceutical compound| File:Chlordiazepoxide.png | |
 | |
| Clinical data | |
|---|---|
| Routes of administration | oral intramuscular |
| ATC code | |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | well absorbed |
| Metabolism | Hepatic |
| Elimination half-life | 5-30 hours |
| Excretion | Renal |
| Identifiers | |
IUPAC name
| |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.000.337  |
| Chemical and physical data | |
| Formula | C16H14ClN3O |
| Molar mass | 299.8 g·mol |
Chlordiazepoxide (pronounced , 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.
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 is anticonvulsant. 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.
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.
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. 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 upon cessation of short acting; and 3 - 10 days after cessation of longer acting benzodiazepines. 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 diarrhea.
Abuse Potential
Chlordiazepoxide has a moderate abuse potential, as indicated by placement into Schedule IV.
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
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
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.
Trade names
- Alpoxid
- Klopoxid
- Librium
- Librocol
- Librelease
- Libritabs
- Limbitrol
- Menrium
- Novo-Poxide
- Poxidium
- Risolid
- Defobin
- Elenium
Combination Drugs
- Librax - chlordiazepoxide and clidinium
External links
References
- Skerritt JH (6). "Enhancement of GABA binding by benzodiazepines and related anxiolytics". Eur J Pharmacol. 89 (3–4): 193–8. PMID 6135616.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - Olive G (1977). "Pharmacologic bases of use of benzodiazepines in peréinatal medicine". Arch Fr Pediatr. 34(1): 74–89. PMID 851373.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - Ashton CH. (2007). "BENZODIAZEPINE EQUIVALENCY TABLE".
{{cite web}}: Unknown parameter|accessmonthday=ignored (help); Unknown parameter|accessyear=ignored (|access-date=suggested) (help); Unknown parameter|month=ignored (help) - Vozeh S. (21). "". Schweiz Med Wochenschr. 111 (47): 1789–93. PMID 6118950.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Cite has empty unknown parameter:|coauthors=(help); Unknown parameter|month=ignored (help) - MacKinnon GL (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation". The American journal of drug and alcohol abuse. 9 (1): 19–33. PMID 6133446.
{{cite journal}}: Cite has empty unknown parameter:|month=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help) - 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.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - Zevzikovas A (2002). "". Medicina (Kaunas). 38 (3): 316–20. PMID 12474705.
{{cite journal}}: Cite has empty unknown parameter:|month=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help)