potassium clorazepate

クロラゼプ酸カリウム

関

clorazepate、clorazepate dipotassium、clorazepate monopotassium

WordNet

1. a light soft silver-white metallic element of the alkali metal group; oxidizes rapidly in air and reacts violently with water; is abundant in nature in combined forms occurring in sea water and in carnallite and kainite and sylvite (同)K, atomic number 19

PrepTutorEJDIC

1. ポタシウム,カリウム(金属元素;化学記号はK)

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/10/24 03:57:13」(JST)

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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 cat.	D (US)
Legal status	Schedule IV(US)
Routes	Oral
Pharmacokinetic data
Bioavailability	91%
Metabolism	Hepatic
Half-life	48 hours
Excretion	Renal
Identifiers
CAS number	23887-31-2 Y 57109-90-7 (potassium salt)
ATC code	N05BA05
PubChem	CID 2809
DrugBank	DB00628
ChemSpider	10617010 Y
UNII	D51WO0G0L4 Y
KEGG	D00694 Y
ChEMBL	CHEMBL1201305 N
Chemical data
Formula	C16H11ClN2O3
Mol. 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) Y Key:DMKBGLSCDYFSGG-UHFFFAOYSA-N Y
N (what is this?)  (verify)

Clorazepate (marketed under the brand names Tranxene and Novo-Clopate), also known as clorazepate dipotassium, is a drug that is a benzodiazepine derivative. 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.

Indications

Clorazepate is used in the treatment of anxiety disorders and insomnia. It may also be prescribed as an anticonvulsant or muscle relaxant. It is also used as a premedication.

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. 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 at risk of break-through seizures.

Pharmacology

Clorazepate is a "classical" benzodiazepine. Other classical benzodiazepines include diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam and flurazepam. Clorazepate is a long-acting benzodiazepine drug. 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. 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.

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. 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.

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.

Tolerance, dependence and withdrawal

Main article: Benzodiazepine withdrawal syndrome

Delirium has been noted from discontinuation from chorazepate 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. However, tolerance to the active metabolite of clorazepate may occur more slowly than with other benzodiazepines. 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.

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.

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.

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.

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.

1. 2-Amino-5-chlorobenzonitrile is used as the initial compound, which upon reaction with phenylmagnesiumbromide is transformed into 2-amino-5-chlorbenzophenone imine.
2. Reacting this with aminomalonic ester gives a heterocyclization product, 7-chloro-1,3-dihydro-3-carbethoxy-5-phenyl-2H-benzodiazepin-2-one.
3. 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.

See also

• Benzodiazepine
• Benzodiazepine dependence
• Benzodiazepine withdrawal syndrome
• Long term effects of benzodiazepines

References

External links

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

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

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• 4. 低カリウム血症の臨床症状および治療 clinical manifestations and treatment of hypokalemia
• 5. Chapter 12B：腎臓のカリウム排泄 chapter 12b renal potassium excretion

English Journal

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

• Ma LL1, Freret T, Lange M, Bourgine J, Coquerel A, Lelong-Boulouard V.Author information 1Normandie University, Caen, France; UCBN, COMETE, Caen, France; Inserm, U 1075 COMETE, Caen, France.AbstractBuprenorphine (BPN) is widely used as a substitution treatment for opioid addiction. Some cases of abuse and misuse, especially associated with various benzodiazepines (BZDs), have been described, and a previous study has shown that BZDs increase the sedative effect of BPN and decrease its anxiogenic properties. To investigate the reward effect that may lead to the abusive combination of BPN and BZD, we studied the influence of different doses of three BZDs extensively used with BPN by drug addicts on conditioned place preference behavior in mice BPN (0.3, 1, 3 mg/kg) was injected subcutaneously into male mice alone or in combination with a BZD administered intraperitoneally: dipotassium clorazepate (CRZ; 1, 4, 16 mg/kg), diazepam (DAZ; 0.5, 1, 5 mg/kg), or bromazepam (BMZ; 0.5, 1, 3 mg/kg). Amphetamine (8 mg/kg) was used as a reference drug. Reward effects of BPN alone or in combination were measured in a conditioned place preference paradigm using an unbiased procedure Our results showed that groups treated with BPN associated with different doses of diazepam and clorazepate, but not bromazepam, spent significantly more time in the drug-paired compartment compared to the group treated with BPN alone Our study shows that joint consumption of diazepam and clorazepate, but not bromazepam, can increase the reward properties of BPN alone in mice. These results could help to explain the use of this type of drug combination in the drug addict population This article is protected by copyright. All rights reserved.
• Fundamental & clinical pharmacology.Fundam Clin Pharmacol.2014 Mar 12. doi: 10.1111/fcp.12072. [Epub ahead of print]
• Buprenorphine (BPN) is widely used as a substitution treatment for opioid addiction. Some cases of abuse and misuse, especially associated with various benzodiazepines (BZDs), have been described, and a previous study has shown that BZDs increase the sedative effect of BPN and decrease its anxiogeni
• PMID 24617653

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

• Pineda S1, Anzola B1, Olivares A1, Ibáñez M2.Author information 1Universidad Complutense de Madrid, Facultad de Veterinaria, Clínica de Comportamiento Animal, Departamento de Producción Animal, Ciudad Universitaria, 28040 Madrid, Spain.2Universidad Complutense de Madrid, Facultad de Veterinaria, Clínica de Comportamiento Animal, Departamento de Producción Animal, Ciudad Universitaria, 28040 Madrid, Spain. Electronic address: mibanez@vet.ucm.es.AbstractThe 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 behavioural categories (anxious dogs with aggression and anxious dogs without aggression) according to their presenting complaints, and were also subdivided into males, females, juveniles and adults. The dog owners were provided with a behaviour modification plan for their dogs to be commenced in the first week of therapy. Clorazepate dipotassium was administered PO at 1.0mg/kg every 24h for 4weeks, and fluoxetine was administered PO at 1.0mg/kg every 24h for 10weeks. Therapy with both drugs was initiated simultaneously. Improvement was reported in 25/36 dogs. Significant differences in treatment effects were observed between anxious dogs with aggression and anxious dogs without aggression (P<0.05). Positive correlations between owner compliance with the treatment plan and reported improvement achieved during three periods of study were also noted.
• Veterinary journal (London, England : 1997).Vet J.2014 Mar;199(3):387-91. doi: 10.1016/j.tvjl.2013.11.021. Epub 2013 Dec 1.
• 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
• PMID 24439470

• A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy.

• Ishii A1, Shioda M, Okumura A, Kidokoro H, Sakauchi M, Shimada S, Shimizu T, Osawa M, Hirose S, Yamamoto T.Author information 1Department of Pediatrics, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. Electronic address: ishii@fukuoka-u.ac.jp.AbstractWe performed analysis of KCNT1 in two unrelated patients with malignant migrating partial seizures in infancy. Both patients had intractable focal seizures since two months of age. Their seizures were characterized by a shift of epileptic focus during a single seizure and were resistant to most antiepileptic drugs but responded to vagus nerve stimulation in one and clorazepate in the other. Bidirectional sequencing for KCNT1 was analyzed by standard Sanger sequencing method. A de novo c.862G>A (p.Gly288Ser) missense mutation was identified at the pore region of KCNT1 channel in both patients, whereas all KCNT1 mutations in the previous reports were identified mostly in the intracellular C-terminal region. Computational analysis suggested possible changes in the molecular structure and the ion channel property induced by the Gly288Ser mutation. Because the G-to-A transition was located at CG dinucleotide sequences as previously reported for KCNT1 mutations, the recurrent occurrence of de novo KCNT1 mutations indicated the hot spots of these locations.
• Gene.Gene.2013 Dec 1;531(2):467-71. doi: 10.1016/j.gene.2013.08.096. Epub 2013 Sep 10.
• We performed analysis of KCNT1 in two unrelated patients with malignant migrating partial seizures in infancy. Both patients had intractable focal seizures since two months of age. Their seizures were characterized by a shift of epileptic focus during a single seizure and were resistant to most anti
• PMID 24029078

Related Links

• Potassium clorazepate - definition of Potassium clorazepate ...

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• Potassium clorazepate | Online references | cyclopaedia.net

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リンク元	「クロラゼプ酸」「クロラゼプ酸カリウム」「clorazepate dipotassium」「clorazepate monopotassium」

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英

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クロラゼプ酸カリウム、クロラゼプ酸二カリウム、クロラゼプ酸一カリウム

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英

potassium clorazepate、clorazepate dipotassium、clorazepate monopotassium

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クロラゼプ酸、クロラゼプ酸二カリウム、クロラゼプ酸一カリウム

「clorazepate dipotassium」

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• クロラゼプ酸二カリウム、クロラゼプ酸カリウム

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clorazepate、clorazepate monopotassium、potassium clorazepate

「clorazepate monopotassium」

　　[★]

• クロラゼプ酸一カリウム、クロラゼプ酸カリウム

関

clorazepate、clorazepate dipotassium、potassium clorazepate