塩酸フルラゼパム

関: flurazepam

WordNet

tranquilizer (trade name Dalmane) used to treat insomnia (同)flurazepam_hydrochloride, Dalmane
a complex consisting of an organic base in association with hydrogen chloride

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/08 14:24:09」(JST)

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Flurazepam^[1] (marketed under the brand names Dalmane and Dalmadorm) is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It produces a metabolite with a very long half-life (40–250 hours), which may stay in the bloodstream for up to four days.^[2]^{[unreliable source?]} Flurazepam is therefore unsuitable as a sleeping medication for some individuals due to next-day sedation; however, this same effect may also provide next-day anxiety relief. For this reason it is sometimes utilized to treat anxiety-induced insomnia on the night before dental visits and other medical procedures, patients are usually instructed to have someone to drive them to and from the appointment when using flurazepam in this context.

Indications

Flurazepam is officially indicated for mild to moderate insomnia and as such it is used for short-term treatment of patients with mild to moderate insomnia such as difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Flurazepam is a long-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep. Intermediate half-life benzodiazepines are also useful for patients with difficulty in maintaining sleep (e.g. loprazolam, lormetazepam, temazepam). Hypnotics should only be used on a short term basis or in those with chronic insomnia on an occasional basis.^[3]

Side effects

The most common adverse effects are dizziness, drowsiness, light-headedness, and ataxia. Flurazepam has abuse potential and should never be used with alcoholic beverages or any other substance that can cause drowsiness. Addictive and possibly fatal results may occur. Flurazepam users should only take this drug strictly as prescribed, and should only be taken directly before the user plans on sleeping a full night. Next day drowsiness is common and may increase during the initial phase of treatment as accumulation occurs until steady-state plasma levels are attained.

Tolerance, dependence and withdrawal problems

A review paper found that long term use of flurazepam is associated with drug tolerance, drug dependence, rebound insomnia and CNS related adverse effects. Flurazepam is best used for a short time period and at the lowest possible dose to avoid complications associated with long term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality.^[4] Flurazepam and other benzodiazepines such as fosazepam, and nitrazepam lost some of their effect after seven days administration in psychogeriatric patients.^[5] Flurazepam shares cross tolerance with barbiturates and barbiturates can easily be substituted by flurazepam in those who are habituated to barbiturate sedative hypnotics.^[6]

After discontinuation of flurazepam a rebound effect or benzodiazepine withdrawal syndrome may occur about four days after discontinuation of medication.^[7]

Contraindications and special caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.^[8]

Elderly

Flurazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.^[9] An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines including flurazepam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy in elderly persons. Tolerability in elderly patients, however, is improved marginally in that benzodiazepines have moderately higher risks of falls, memory problems, and disinhibition ("Paradoxical agitation") when compared to non-benzodiazepine sedatives. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Chronic use of sedative-hypnotic drugs for the management of insomnia does not have an evidence base and has been discouraged due to concerns including potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of sedative hypnotics has been determined to be no better than placebo after 3 months of therapy and worse than placebo after 6 months of therapy. (NEJM, 1983, 1994, et seq.)^[10]

Pharmacology

Flurazepam is a "classical" benzodiazepine; some other classical benzodiazepines include diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam, and clorazepate.^[11] Flurazepam generates an active metabolite with a very long elimination half-life of 40–250 hours.^[2]^{[unreliable source?]} Residual 'hangover' effects after nighttime administration of flurazepam, such as sleepiness, impaired psychomotor and cognitive functions, may persist into the next day, which may impair the ability of users to drive safely and increase risks of falls and hip fractures.^[12]

Flurazepam is lipophilic, is metabolized hepatically via oxidative pathways. The main pharmacological effect of flurazepam is to increase the effect of GABA at the GABA_A receptor via binding to the benzodiazepine site on the GABA_A receptor causing an increase influx of chloride ions into the GABA_A neuron.^[13]^[14] Flurazepam is a unique benzodiazepine in that it is a partial agonist of benzodiazepine receptors whereas other benzodiazepines are full agonists of benzodiazepine receptors.^[15]

Flurazepam is contraindicated in pregnancy. It is recommended to withdraw flurazepam during breast feeding, as flurazepam is excreted in breast milk.^[16]

Drug misuse

Flurazepam is a drug with potential for misuse. Two types of drug misuse can occur, either recreational misuse where the drug is taken to achieve a high, or when the drug is continued long term against medical advice.^[17]

Legal status

Flurazepam is a Schedule IV drug under the Convention on Psychotropic Substances.^[18]

Synthesis

Inclusion of fluorine on the pendant aromatic ring, and the basic side chain seems to emphasize/accentuate the anticonvulsant and hypnotic effects of this class of drugs.

Flurazepam synthesis:^[19] Prepn:^[20]^[21]^[22] all to Hoffmann-La Roche. Manuf process:^[23] Synthesis:^[24]

Thus alkylation of the benzodiazepam 3 (prepared from the corresponding substituted aminobenzophenone), with 2-chlorotriethylamine via its sodium salt affords Flurazepam (4).

References

^ BE 629005
^ ^a ^b "Benzodiazepine Equivalents Table - A list of Equivalent Doses of Benzodiazepines". Non-benzodiazepines.org.uk. Retrieved 2015-05-05.
^ Rickels K. (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics". Acta Psychiatrica Scandinavica Suppl. 74 (S332): 132–41. doi:10.1111/j.1600-0447.1986.tb08990.x. PMID 2883820.
^ Kirkwood CK (1999). "Management of insomnia". J Am Pharm Assoc (Wash) 39 (5): 688–96; quiz 713–4. PMID 10533351.
^ Viukari M; Linnoila M; Aalto U. (January 1978). "Efficacy and side effects of flurazepam, fosazepam, and nitrazepam as sleeping aids in psychogeriatric patients". Acta Psychiatrica Scandinavica 57 (1): 27–35. doi:10.1111/j.1600-0447.1978.tb06871.x. PMID 24980.
^ Rooke KC. (1976). "The use of flurazepam (dalmane) as a substitute for barbiturates and methaqualone/diphenhydramine (mandrax) in general practice". J Int Med Res. 4 (5): 355–9. doi:10.1177/030006057600400510. PMID 18375.
^ Hindmarch I. (November 1977). "A repeated dose comparison of three benzodiazepine derivative (nitrazepam, flurazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication". Acta Psychiatrica Scandinavica 56 (5): 373–81. doi:10.1111/j.1600-0447.1977.tb06678.x. PMID 22990.
^ 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.
^ Mets, MA.; Volkerts, ER.; Olivier, B.; Verster, JC. (Feb 2010). "Effect of hypnotic drugs on body balance and standing steadiness.". Sleep Med Rev 14 (4): 259–67. doi:10.1016/j.smrv.2009.10.008. PMID 20171127.
^ Bain KT (June 2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother 4 (2): 168–92. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264.
^ 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.
^ Vermeeren A. (2004). "Residual effects of hypnotics: epidemiology and clinical implications". CNS Drugs. 18 (5): 297–328. doi:10.2165/00023210-200418050-00003. PMID 15089115.
^ Oelschläger H. (July 4, 1989). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweiz Rundsch Med Prax. 78 (27–28): 766–72. PMID 2570451.
^ Lehoullier PF, Ticku MK (March 1987). "Benzodiazepine and beta-carboline modulation of GABA-stimulated 36Cl-influx in cultured spinal cord neurons". Eur. J. Pharmacol. 135 (2): 235–8. doi:10.1016/0014-2999(87)90617-0. PMID 3034628.
^ Chan CY; Farb DH (1 September 1985). "Modulation of neurotransmitter action: control of the gamma-aminobutyric acid response through the benzodiazepine receptor" (PDF). J Neurosci 5 (9): 2365–73. PMID 2863335.
^ Olive G; Dreux C. (January 1977). "Pharmacologic bases of use of benzodiazepines in peréinatal medicine". Arch Fr Pediatr. 34 (1): 74–89. PMID 851373.
^ Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". J Clin Psychiatry. 66 Suppl 9: 31–41. PMID 16336040.
^ [1]^{[dead link]}
^ Sternbach, L. H.; Archer, G. A.; Earley, J. V.; Fryer, R. I.; Reeder, E.; Wasyliw, N.; Randall, L. O.; Banzger, R. (1965). "Quinazolines and 1,4-Benzodiazepines. XXV.1Structure-Activity Relationships of Aminoalkyl-Substituted 1,4-Benzodiazepin-2-ones". Journal of Medicinal Chemistry 8 (6): 815. doi:10.1021/jm00330a019. PMID 5885077. edit
^ G. A. Archer et al., BE 629005 C.A. 60, 15896f (1964).
^ NL 6401335 C.A. 62, 5289a (1965).
^ G. A. Archer et al., U.S. Patent 3,299,053 (1967).
^ R. Fryer, L. H. Sternbach, U.S. Patent 3,567,710 (1971 to Hoffmann-La Roche).
^ Chemical and Pharmaceutical Bulletin; Vol. 19 (1971) No. 2 P 263-272.

External links

Rx-List – Flurazepam
Inchem – Flurazepam

UpToDate Contents

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1. 不眠症の治療 treatment of insomnia
2. 鎮静剤および催眠剤の乱用および依存：薬理学および疫学 sedatives and hypnotics abuse and dependence pharmacology and epidemiology
3. ベンゾジアゼピンの中毒および離脱 benzodiazepine poisoning and withdrawal
4. 高齢者に対する薬剤処方 drug prescribing for older adults
5. 筋萎縮性側索硬化症の症状に基づくマネージメント symptom based management of amyotrophic lateral sclerosis

English Journal

A double-blind, placebo-controlled trial of dextromethorphan combined with clonidine in the treatment of heroin withdrawal.

Lin SK1, Pan CH, Chen CH.
Journal of clinical psychopharmacology.J Clin Psychopharmacol.2014 Aug;34(4):508-12. doi: 10.1097/JCP.0000000000000144.
Dextromethorphan has been reported to ameliorate opioid withdrawal symptoms in both animal and human subjects. In the present study, we investigated the efficacy of dextromethorphan as an add-on medication in heroin detoxification treatment in a double-blind, placebo-controlled design. Sixty-five he
PMID 24875077

Synaptic GABAA receptor clustering without the γ2 subunit.

Kerti-Szigeti K1, Nusser Z2, Eyre MD2.
The Journal of neuroscience : the official journal of the Society for Neuroscience.J Neurosci.2014 Jul 30;34(31):10219-33. doi: 10.1523/JNEUROSCI.1721-14.2014.
Rapid activation of postsynaptic GABAA receptors (GABAARs) is crucial in many neuronal functions, including the synchronization of neuronal ensembles and controlling the precise timing of action potentials. Although the γ2 subunit is believed to be essential for the postsynaptic clustering of GABAA
PMID 25080584

Amatoxins (α- and β-Amanitin) and phallotoxin (Phalloidin) analyses in urines using high-resolution accurate mass LC-MS technology.

Gicquel T1, Lepage S1, Fradin M1, Tribut O2, Duretz B3, Morel I4.
Journal of analytical toxicology.J Anal Toxicol.2014 Jul-Aug;38(6):335-40. doi: 10.1093/jat/bku035. Epub 2014 Apr 28.
Mycotoxin intoxications can result from the consumption of amatoxins like α- and β-amanitin or of phallotoxin, present in several toxic mushrooms like Amanita phalloides. To identify and quantify amatoxins and phallotoidin in biological matrixes, we developed a method using liquid chromatography c
PMID 24778089

Japanese Journal

トリアゾラム錠 0.25 mg から 0.125 mg へ変更後の睡眠薬の使用動向と外来患者の反応

米澤健三,菅原泰典,大貫ひろみ,阿部順,三浦珠緒,武者栄美子,石澤文章,山口勇
病院薬学 20(4), 309-314, 1994-08-20
… The hypnotics prescribed were: triazolam, zopiclone, estazolam, brotizolam, nitrazepam, flunitrazepam and flurazepam hydrochloride. …
NAID 110001801614

トリアゾラム錠０．２５ｍｇから０．１２５ｍｇへ変更後の睡眠薬の使用動向と外来患者の反応

米澤健三,菅原泰典,大貫ひろみ,阿部順,三浦珠緒,武者栄美子,石澤文章,山口勇
病院薬学 20(4), 309-314, 1994
… The hypnotics prescribed were: triazolam, zopiclone, estazolam, brotizolam, nitrazepam, flunitrazepam and flurazepam hydrochloride.<BR>Of 91 subjects in the triazolam group, 37 were male and 54 were female. …
NAID 130004299363

Flurazepamの生体内運命その2 Flurazepamの代謝

西川隆,峯浦和幸,高平汎志
藥學雜誌 93(2), 232-238, 1973-02-25
… The metabolic fate of Flurazepam hydrochloride, 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one monohydrochloride, having a sleep-inducing effect, was examined in a rat after oral administration of this compound labeled with ^<14>C at the C-5 position. … Less than 3% of the bilary ^<14>C could be extracted with ethyl acetate at pH 9.0 and no appreciable amount of intact Flurazepam was detected in this extract. …
NAID 110003651480

Related Pictures

★リンクテーブル★

リンク元	「フルラゼパム」
関連記事	「hydrochloride」「flurazepam」

「フルラゼパム」

Flurazepam
Systematic (IUPAC) name
	7-Chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one
Clinical data
Trade names	Dalmane
AHFS/Drugs.com	monograph
MedlinePlus	a682051
Pregnancy; category	X (Contraindicated in pregnancy);
Legal status	US: Schedule IV;
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	83%
Metabolism	Hepatic
Biological half-life	40–250 hours
Excretion	Renal
Identifiers
CAS Registry Number	17617-23-1
ATC code	N05CD01
PubChem	CID: 3393
IUPHAR/BPS	7188
DrugBank	DB00690
ChemSpider	3276
UNII	IHP475989U
KEGG	D00329
ChEMBL	CHEMBL968
PDB ligand ID	FL7 (PDBe, RCSB PDB)
Chemical data
Formula	C21H23ClFN3O
Molecular mass	387.88 g/mol
	SMILES FC1=CC=CC=C1C2=NCC(N(CCN(CC)CC)C3=C2C=C(C=C3)Cl)=O ;
	InChI InChI=1S/C21H23ClFN3O/c1-3-25(4-2)11-12-26-19-10-9-15(22)13-17(19)21(24-14-20(26)27)16-7-5-6-8-18(16)23/h5-10,13H,3-4,11-12,14H2,1-2H3 ; Key:SAADBVWGJQAEFS-UHFFFAOYSA-N ;
Physical data
Melting point	79.5 °C (175.1 °F)
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　　[★]

英: flurazepam
ラ: flurazepamum
化: 塩酸フルラゼパム flurazepam hydrochloride
商: ダルメート、ベノジール、インスミン
関: 睡眠薬

「hydrochloride」

　　[★] 塩酸塩、ハイドロクロライド　

「flurazepam」

　　[★] フルラゼパム

[1] BE 629005

[non-benzodiazepines.org-2] "Benzodiazepine Equivalents Table - A list of Equivalent Doses of Benzodiazepines". Non-benzodiazepines.org.uk. Retrieved 2015-05-05.

[3] Rickels K. (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics". Acta Psychiatrica Scandinavica Suppl. 74 (S332): 132–41. doi:10.1111/j.1600-0447.1986.tb08990.x. PMID 2883820.

[4] Kirkwood CK (1999). "Management of insomnia". J Am Pharm Assoc (Wash) 39 (5): 688–96; quiz 713–4. PMID 10533351.

[5] Viukari M; Linnoila M; Aalto U. (January 1978). "Efficacy and side effects of flurazepam, fosazepam, and nitrazepam as sleeping aids in psychogeriatric patients". Acta Psychiatrica Scandinavica 57 (1): 27–35. doi:10.1111/j.1600-0447.1978.tb06871.x. PMID 24980.

[6] Rooke KC. (1976). "The use of flurazepam (dalmane) as a substitute for barbiturates and methaqualone/diphenhydramine (mandrax) in general practice". J Int Med Res. 4 (5): 355–9. doi:10.1177/030006057600400510. PMID 18375.

[7] Hindmarch I. (November 1977). "A repeated dose comparison of three benzodiazepine derivative (nitrazepam, flurazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication". Acta Psychiatrica Scandinavica 56 (5): 373–81. doi:10.1111/j.1600-0447.1977.tb06678.x. PMID 22990.

[8] 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.

[Mets-2010-9] Mets, MA.; Volkerts, ER.; Olivier, B.; Verster, JC. (Feb 2010). "Effect of hypnotic drugs on body balance and standing steadiness.". Sleep Med Rev 14 (4): 259–67. doi:10.1016/j.smrv.2009.10.008. PMID 20171127.

[10] Bain KT (June 2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother 4 (2): 168–92. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264.

[11] 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.

[12] Vermeeren A. (2004). "Residual effects of hypnotics: epidemiology and clinical implications". CNS Drugs. 18 (5): 297–328. doi:10.2165/00023210-200418050-00003. PMID 15089115.

[13] Oelschläger H. (July 4, 1989). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweiz Rundsch Med Prax. 78 (27–28): 766–72. PMID 2570451.

[14] Lehoullier PF, Ticku MK (March 1987). "Benzodiazepine and beta-carboline modulation of GABA-stimulated 36Cl-influx in cultured spinal cord neurons". Eur. J. Pharmacol. 135 (2): 235–8. doi:10.1016/0014-2999(87)90617-0. PMID 3034628.

[15] Chan CY; Farb DH (1 September 1985). "Modulation of neurotransmitter action: control of the gamma-aminobutyric acid response through the benzodiazepine receptor" (PDF). J Neurosci 5 (9): 2365–73. PMID 2863335.

[16] Olive G; Dreux C. (January 1977). "Pharmacologic bases of use of benzodiazepines in peréinatal medicine". Arch Fr Pediatr. 34 (1): 74–89. PMID 851373.

[17] Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". J Clin Psychiatry. 66 Suppl 9: 31–41. PMID 16336040.

[18] [1]^{[dead link]}

[19] Sternbach, L. H.; Archer, G. A.; Earley, J. V.; Fryer, R. I.; Reeder, E.; Wasyliw, N.; Randall, L. O.; Banzger, R. (1965). "Quinazolines and 1,4-Benzodiazepines. XXV.1Structure-Activity Relationships of Aminoalkyl-Substituted 1,4-Benzodiazepin-2-ones". Journal of Medicinal Chemistry 8 (6): 815. doi:10.1021/jm00330a019. PMID 5885077. edit

[20] G. A. Archer et al., BE 629005 C.A. 60, 15896f (1964).

[21] NL 6401335 C.A. 62, 5289a (1965).

[22] G. A. Archer et al., U.S. Patent 3,299,053 (1967).

[23] R. Fryer, L. H. Sternbach, U.S. Patent 3,567,710 (1971 to Hoffmann-La Roche).

[24] Chemical and Pharmaceutical Bulletin; Vol. 19 (1971) No. 2 P 263-272.

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flurazepam hydrochloride