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Clorazepate^[1] (marketed under the brand names Tranxene and Novo-Clopate), also known as clorazepate dipotassium, is a benzodiazepine. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. 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]

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 prescribed principally 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 of 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 at risk of break-through seizures.^[6]

Pharmacology

Clorazepate is a "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, 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 GABA_A 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 GABA_A receptors. This effect of benzodiazepines requires the presence of the neurotransmitter GABA and results in enhanced inhibitory effects of the neurotransmitter GABA acting on GABA_A 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 e.g. other benzodiazepines, antiepileptic drugs, alcohol, antihistamines, opiates, neuroleptics, sleep aids are likely to magnify the effects of clorazepate on the central nervous system. Drugs that 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, 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 with 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

Delirium has been noted from discontinuation from clorazepate^[9] 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, in general, not considered appropriate for the long-term management of epilepsy; increasing the dose may result only in the developing of tolerance to the higher dose combined with worsened adverse effects. Cross-tolerance occurs between benzodiazepines, meaning that, if individuals are 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 diarrhea.^[10]

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.^[11]

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 newborn 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.^[12]

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]

Chemistry

Chorazepate, 7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzodiazepin- 3-carboxylic acid is used in the form of a dipotassium salt.

2-Amino-5-chlorobenzonitrile is used as the initial compound, which upon reaction with phenylmagnesiumbromide is transformed into 2-amino-5-chlorbenzophenone imine.
Reacting this with aminomalonic ester gives a heterocyclization product, 7-chloro-1,3-dihydro-3-carbethoxy-5-phenyl-2H-benzodiazepin-2-one.
Upon hydrolysis using an alcoholic solution of potassium hydroxide forms a dipotassium salt, chlorazepate.

J. Schmitt, U.S. Patent 3,516,988 (1970).
J. Schmitt, DE 1518764 (1965).
J. Schmitt, P. Comoy, M. Subsequent, G. Callet, I. Le Meur, T. Clim, M. Brunaud, J. Mereir, J. Salle,

G. Siou, Chim. Ther., 4, 239 (1969).

Legal status

In the United States, clorazepate is listed under Schedule IV of the Controlled Substances Act.

References

^ US Patent 3966793
^ Ochs HR, Greenblatt DJ, Verburg-Ochs B, Locniskar A (October 1984). "Comparative single-dose kinetics of oxazolam, prazepam, and clorazepate: three precursors of desmethyldiazepam". J Clin Pharmacol 24 (10): 446–51. doi:10.1002/j.1552-4604.1984.tb01817.x. PMID 6150943.
^ ^a ^b National Institutes of Health (2003). "Clorazepate". National Library of Medicine. Archived from the original on 20 May 2008. Retrieved 19 July 2008.
^ Meybohm P, Hanss R, Bein B; et al. (September 2007). "[Comparison of premedication regimes. A randomized, controlled trial]". Anaesthesist 56 (9): 890–2, 894–6. doi:10.1007/s00101-007-1208-7. PMID 17551699.
^ Tranxene prescribing information in the Netherlands (Dutch language); accessed 2007-03-08.
^ ^a ^b ^c ^d ^e ^f ^g ^h Riss, J.; Cloyd, J.; Gates, J.; Collins, S. (Aug 2008). "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics" (PDF). Acta Neurol Scand 118 (2): 69–86. doi:10.1111/j.1600-0404.2008.01004.x. PMID 18384456.
^ Braestrup C; Squires RF. (1 April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". Eur J Pharmacol 48 (3): 263–70. doi:10.1016/0014-2999(78)90085-7. PMID 639854.
^ 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. PMID 7388368.
^ Allgulander, C,; Borg S. (1978). "Case Report: A Delirious Abstinence Syndrome Associated with Clorazepate (Tranxilen)". British Journal of Addiction 73 (2): 175–177. doi:10.1111/j.1360-0443.1978.tb00139.x. PMID 27202.
^ 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". Br Med J. 280 (6218): 910–2. doi:10.1136/bmj.280.6218.910. PMC 1601049. PMID 7388368.
^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
^ McElhatton PR. (Nov–December 1994). "The effects of benzodiazepine use during pregnancy and lactation". Reprod Toxicol. 8 (6): 461–75. doi:10.1016/0890-6238(94)90029-9. PMID 7881198. Check date values in: |date= (help)

External links

Rx-List.com - Clorazepate
Inchem.org - Clorazepate

UpToDate Contents

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Benzodiazepines increase the reward effects of buprenorphine in a conditioned place preference test in the mouse.

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Fluoxetine combined with clorazepate dipotassium and behaviour modification for treatment of anxiety-related disorders in dogs.

Pineda S1, Anzola B1, Olivares A1, Ibáñez M2.
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The effectiveness of clorazepate dipotassium combined with fluoxetine and a behaviour modification programme for the treatment of anxiety disorders in dogs was investigated. Forty dogs with anxiety disorders were initially enrolled and 36 dogs completed the trial. Dogs were classified into two behav
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Clorazepate
Systematic (IUPAC) name
	7-chloro-2,3-dihydro-2-oxo-5-phenyl-; 1H-1,4-benzodiazepine-3-carboxylic acid
Clinical data
Trade names	Tranxene
AHFS/Drugs.com	monograph
MedlinePlus	a682052
Pregnancy; category	US: D (Evidence of risk); ;
Routes of; administration	Oral
Legal status
Legal status	DE: Anlage III (Prescription only); US: Schedule IV;
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
IUPHAR/BPS	7548
DrugBank	DB00628
ChemSpider	10617010
UNII	D51WO0G0L4
KEGG	D00694
ChEMBL	CHEMBL1201305
Chemical data
Formula	C16H11ClN2O3
Molar mass	314.72 g/mol
	SMILES OC(C1N=C(C2=CC=CC=C2)C3=C(NC1(O)O)C=CC(Cl)=C3)=O ;
	InChI InChI=1S/C16H13ClN2O4/c17-10-6-7-12-11(8-10)13(9-4-2-1-3-5-9)18-14(15(20)21)16(22,23)19-12/h1-8,14,19,22-23H,(H,20,21) ; Key:DMKBGLSCDYFSGG-UHFFFAOYSA-N ;
(what is this?) (verify)

　　[★]

英: clorazepate
商: Tranxene

[1] US Patent 3966793

[2] Ochs HR, Greenblatt DJ, Verburg-Ochs B, Locniskar A (October 1984). "Comparative single-dose kinetics of oxazolam, prazepam, and clorazepate: three precursors of desmethyldiazepam". J Clin Pharmacol 24 (10): 446–51. doi:10.1002/j.1552-4604.1984.tb01817.x. PMID 6150943.

[nlmclor-3] National Institutes of Health (2003). "Clorazepate". National Library of Medicine. Archived from the original on 20 May 2008. Retrieved 19 July 2008.

[4] Meybohm P, Hanss R, Bein B; et al. (September 2007). "[Comparison of premedication regimes. A randomized, controlled trial]". Anaesthesist 56 (9): 890–2, 894–6. doi:10.1007/s00101-007-1208-7. PMID 17551699.

[5] Tranxene prescribing information in the Netherlands (Dutch language); accessed 2007-03-08.

[Riss-2008-6] ^ ^a ^b ^c ^d ^e ^f ^g ^h Riss, J.; Cloyd, J.; Gates, J.; Collins, S. (Aug 2008). "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics" (PDF). Acta Neurol Scand 118 (2): 69–86. doi:10.1111/j.1600-0404.2008.01004.x. PMID 18384456.

[7] Braestrup C; Squires RF. (1 April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". Eur J Pharmacol 48 (3): 263–70. doi:10.1016/0014-2999(78)90085-7. PMID 639854.

[8] 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. PMID 7388368.

[9] Allgulander, C,; Borg S. (1978). "Case Report: A Delirious Abstinence Syndrome Associated with Clorazepate (Tranxilen)". British Journal of Addiction 73 (2): 175–177. doi:10.1111/j.1360-0443.1978.tb00139.x. PMID 27202.

[10] 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". Br Med J. 280 (6218): 910–2. doi:10.1136/bmj.280.6218.910. PMC 1601049. PMID 7388368.

[11] Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.

[12] McElhatton PR. (Nov–December 1994). "The effects of benzodiazepine use during pregnancy and lactation". Reprod Toxicol. 8 (6): 461–75. doi:10.1016/0890-6238(94)90029-9. PMID 7881198. Check date values in: |date= (help)

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