Clorazepate
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| 200px | |
| Systematic (IUPAC) name | |
|---|---|
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7-chloro-2,3-dihydro-2-oxo-5-phenyl- 1H-1,4-benzodiazepine-3-carboxylic acid | |
| Clinical data | |
| Pregnancy category |
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| Routes of administration | Oral |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Bioavailability | 91% |
| Metabolism | Hepatic |
| Biological half-life | 48 hours |
| Excretion | Renal |
| Identifiers | |
| CAS Number |
23887-31-2 57109-90-7 (potassium salt) |
| ATC code | N05BA05 (WHO) |
| PubChem | CID 2809 |
| DrugBank | APRD00881 |
| ChemSpider | 10617010 |
| Chemical data | |
| Formula | C16H11ClN2O3 |
| Molar mass | 314.72[[Script error: No such module "String".]] |
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Clorazepate (marketed under the brand names Tranxene and Novo-Clopate), also known as clorazepate dipotassium, is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant properties. Clorazepate was discontinued in February 2006 in the United Kingdom.[1] Clorazepate is a prodrug for desmethyldiazepam which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.[2]
Contents
Indications
Clorazepate is used in the treatment of anxiety disorders and insomnia. It may also be prescribed as an anticonvulsant or muscle relaxant.[3] It is also used as a premedication.[4]
Clorazepate is principally prescribed in the treatment of alcohol withdrawal and epilepsy, although it is also a useful anxiolytic because of its long half-life. The normal starting dosage range of Clorazepate is 15 to 60 mg per day. The drug is to be taken two to four times per day. Dosages as high as 90 to 120 mg per day may be used in the treatment of acute alcohol withdrawal. In the United States and Canada, Clorazepate is available in 3.75, 7.5, and 15 mg capsules or tablets. In Europe, tablet formations are 5 mg, 10 mg, 20 mg and 50 mg.[5] Clorazepate SD (controlled release) is available and may have a reduced incidence in adverse effects. The sustained release formulation of clorazepate has some advantages in that if a dose is missed less profound fluctuations in blood plasma levels occur which may be helpful to some people with epilepsy who are at risk of break-through seizures.[6]
Pharmacology
Clorazepate is a "classical" benzodiazepine. Other classical benzodiazepines include alprazolam, diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam and flurazepam.[7] Clorazepate is a long acting benzodiazepine drug.[8] Clorazepate produces the active metabolite desmethyl-diazepam which is a partial agonist of the GABAA receptor and has a half life of 20 – 179 hours; a small amount of desmethyldiazepam is further metabolised into oxazepam. Clorazepate exerts its pharmacological properties via increasing the opening frequency of the chloride ion channel of GABAA receptors. This effect of benzodiazepines requires the presence of the neurotransmitter GABA and results in enhanced inhibitory effects of the neurotransmitter GABA acting on GABAA receptors.[6] Clorazepate, like other benzodiazepines, is widely distributed and is highly bound to plasma proteins; clorazepate also crosses readily over the placenta and into breast milk. Peak plasma levels of the active metabolite desmethyl-diazepam are seen between 30 minutes and 2 hours after oral administration of clorazepate. Clorazepate is completely metabolised to desmethyl-diazepam in the gastrointestinal tract and thus the pharmacological properties of clorazepate are largely due to desmethyldiazepam.[6]
Interactions
All sedatives or hypnotics eg other benzodiazepines, antiepileptic drugs, alcohol, antihistamines, opiates, neuroleptics, sleep aids are likely to magnify the effects of clorazepate on the central nervous system. Drugs which may interact with clorazepate include, digoxin, disulfiram, fluoxetine, isoniazid, ketoconazole, levodopa, metoprolol, hormonal contraceptives, probenecid, propranolol, rifampin, theophylline, valproic acid.[3] Selective serotonin reuptake inhibitors, cimetidine, macrolide antibiotics and antimycotics inhibit the metabolism of benzodiazepines and may result in increased plasma levels with resultant enhancement of adverse effects. Phenytoin, phenobarbital and carbamazepine have the opposite effect with coadministration leading to increased metabolism and decreased therapeutic effects of clorazepate.[6]
Adverse effects
Adverse effects of clorazepate include, tolerance, dependence, withdrawal reactions, cognitive impairment, confusion, anterograde amnesia, falls in the elderly, ataxia and hangover effects and drowsiness. It is unclear whether cognitive deficits resulting from the long-term use of benzodiazepines return to normal or persist indefinitely after withdrawal from benzodiazepines. Benzodiazepines are also known to cause or worsen depression. Paradoxical effects including excitement and paradoxical worsening of seizures can sometimes result from the use of benzodiazepines. Children, the elderly, individuals who have a history of alcohol abuse or a history of aggressive behavior and anger are at greater risk of developing paradoxical reactions to benzodiazepines.[6]
Tolerance, dependence and withdrawal
A benzodiazepine dependence occurs in approximately one third of patients who take benzodiazepines for longer than 4 weeks which is characterised by a withdrawal syndrome upon dose reduction. When used for seizure control tolerance may manifest itself with an increased rate of seizures as well an increased risk of withdrawal seizures. In humans tolerance to the anticonvulsant effects of clorazepate occurs frequently with regular use. Due to the development of tolerance benzodiazepines are generally not considered appropriate for the long-term management of epilepsy; increasing the dose may only result in tolerance developing to the higher dose combined with worsened adverse effects. Cross-tolerance occurs between benzodiazepines, meaning if an individual is tolerant to one benzodiazepine, they will display a tolerance to equivalent doses of other benzodiazepines. Withdrawal symptoms from benzodiazepines include a worsening of pre-existing symptoms as well as the appearance of new symptoms that were not pre-existing. The withdrawal symptoms may range from mild anxiety and insomnia to severe withdrawal symptoms such as seizures and psychosis. Withdrawal symptoms can be difficult in some cases to differentiate between pre-existing symptoms and withdrawal symptoms. Use of high doses, long-term use and abrupt or over-rapid withdrawal increases increase the severity of withdrawal syndrome.[6] However, tolerance to the active metabolite of clorazepate may occur more slowly than with other benzodiazepines.[6] Regular use of benzodiazepines causes 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 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.[9]
Contraindications and special caution
Benzodiazepines require special precaution if used in the elderly, children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.[10]
Chlorazepate if used late in pregnancy, the third trimester, causes a definite risk a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the new born may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.[11]
Special precaution is required when using clorazepate in the elderly because the elderly metabolise clorazepate more slowly which may result in excessive drug accumulation. Additionally the elderly are more sensitive to the adverse effects of benzodiazepines compared to younger individuals even when blood plasma levels are the same. Use of benzodiazepines in the elderly is only recommended for 2 weeks and it is also recommended that half of the usual daily dose is prescribed.[6]
Legal status
Clorazepate is listed under Schedule IV of the Controlled Substances Act.
See also
- Benzodiazepine
- Benzodiazepine dependence
- Benzodiazepine withdrawal syndrome
- Long term effects of benzodiazepines
References
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de:Clorazepates:Clorazepato fr:Clorazépate gl:Clorazepate nl:Clorazepinezuur ja:クロラゼプ酸 pl:Klorazepan pt:Clorazepato dipotássico
sv:Dikaliumklorazepat- ↑ National electronic Library for Medicines. "SPC (Product Licence) Changes". E-Communications Team at the London and South East Medicines Information Service based at Guy’s Hospital London. Retrieved 19 December 2008.
- ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
- ↑ 3.0 3.1 National Institutes of Health (2003). "Clorazepate". National Library of Medicine. Retrieved 19 July 2008.
- ↑ http://www.ncbi.nlm.nih.gov/pubmed/17551699
- ↑ Tranxene prescribing information in the Netherlands (Dutch language); accessed 2007-03-08
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
- ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
- ↑ The Committee on the Review of Medicines (CRM) (March 29, 1980). "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". Br Med J. 280 (6218): 910–2. doi:10.1136/bmj.280.6218.910. PMC 1601049 Freely accessible. PMID 7388368.
- ↑ Committee on the Review of Medicines (March 29, 1980). "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. doi:10.1136/bmj.280.6218.910. PMC 1601049 Freely accessible. PMID 7388368.
- ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
- ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
