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Quazepam (marketed under brand names Doral, Dormalin) is a benzodiazepine derivative drug developed by the Schering Corporation in the 1970s.^[1] Quazepam is indicated for the treatment of insomnia including sleep induction and sleep maintenance.^[2] Quazepam induces impairment of motor function and has hypnotic and anticonvulsant properties with less overdose potential than other benzodiazepines.^[3]^[4] Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.^[5] Quazepam is a trifluoroalkyl type of benzodiazepine, like fletazepam, halazepam, triflubazam and triflunordazepam. Quazepam is unique amongst benzodiazepines in that it selectively targets the GABA_A α₁ subunit receptors which are responsible for inducing sleep. Its mechanism of action is very similar to zolpidem and zaleplon in its pharmacology and can successfully substitute for zolpidem and zaleplon in animal studies.^[6]^[7]^[8]

Indications

Quazepam is used for short-term treatment of insomnia related to sleep induction or sleep maintenance problems and has demonstrated superiority over other benzodiazepines such as temazepam. It had a fewer incidence of side effects than temazepam, including less sedation, amnesia, and less motor-impairment.^[9]^[10]^[11]^[12] Usual dosage is 7.5 to 15 mg orally at bedtime.^[13]

Quazepam is effective as a premedication prior to surgery.^[14]

Side effects

Quazepam has fewer side effects than other benzodiazepines and less potential to induce tolerance and rebound effects.^[15]^[16] There is significantly less potential for quazepam to induce respiratory depression or to adversely affect motor coordination than other benzodiazepines.^[17] The different side effect profile of quazepam may be due to its more selective binding profile to type 1 benzodiazepine receptors.^[18]^[19]

Ataxia^[20]
Daytime somnolence^[21]
Hypokinesia^[22]
Cognitive and performance impairments^[23]

Tolerance and dependence

Tolerance may occur to quazepam but more slowly than seen with other benzodiazepines such as triazolam.^[24] However, quazepam causes significantly less drug tolerance and less withdrawal symptoms including less rebound insomnia upon discontinuation compared to other benzodiazepines.^[25]^[26]^[27]^[28] Quazepam may cause less rebound effects than other type1 benzodiazepine receptor selective nonbenzodiazepine drugs due to its longer half-life.^[29] Short-acting hypnotics often cause next day rebound anxiety. Quazepam due to its pharmacological profile does not cause next day rebound withdrawal effects during treatment.^[30]

No firm conclusions can be drawn, however, whether long-term use of quazepam does not produce tolerance as few, if any, long-term clinical trials extending beyond 4 weeks of chronic use have been conducted.^[31] Quazepam should be withdrawn gradually if used beyond 4 weeks of use to avoid the risk of a severe benzodiazepine withdrawal syndrome developing. Very high dosage administration over prolonged periods of time, up to 52 weeks, of quazepam in animal studies provoked severe withdrawal symptoms upon abrupt discontinuation, including excitability, hyperactivity, convulsions and the death of two of the monkeys due to withdrawal-related convulsions. More monkeys died however, in the diazepam-treated monkeys.^[32] In addition it has now been documented in the medical literature that one of the major metabolites of quazepam, N-desalkyl-2-oxoquazepam (N-desalkylflurazepam), which is long-acting and prone to accumulation, binds unselectively to benzodiazepine receptors, thus quazepam may not differ all that much pharmacologically from other benzodiazepines.^[33]

Special precautions

Benzodiazepines require special precaution if used in the during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.^[34]

Quazepam and its active metabolites are excreted into breast milk.^[35]

Accumulation of one of the active metabolites of quazepam, N-desalkylflurazepam, may occur in the elderly. A lower dose may be required in the elderly.^[36]

Elderly

Quazepam is more tolerable for elderly patients compared to flurazepam due to its reduced next day impairments.^[37] However, another study showed marked next day impairments after repeated administration due to accumulation of quazepam and its long-acting metabolites. Thus the medical literature shows conflicts on quazepam's side effect profile.^[38] A further study showed significant balance impairments combined with an unstable posture after administration of quazepam in test subjects.^[39] 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 quazepam, the nonbenzodiazepine sedative/hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. 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. Long-term use of sedative/hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such 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 these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.^[40]

Pharmacology

Quazepam is selective for type I benzodiazepine receptors containing the α₁ subunit, similar to other drugs such as zaleplon and zolpidem. As a result, quazepam has little or no muscle relaxant properties. Most other benzodiazepines are unselective and bind to type1 GABA_A receptors and type2 GABA_A receptors. Type1 GABA_A receptors include the α₁ subunit containing GABA_A receptors which are responsible for hypnotic properties of the drug. Type 2 receptors include the α₂, α₃ and α₅ subunits which are responsible for anxiolytic action, amnesia and muscle relaxant properties.^[41]^[42] Thus quazepam may have less side effects than other benzodiazepines but, it has a very long half-life of 25 hours which reduces its benefits as a hypnotic due to likely next day sedation. It also has two active metabolites with half-lives of 28 and 79 hours. Quazepam may also cause less drug tolerance than other benzodiazepines such as temazepam and triazolam perhaps due to its subtype selectivity.^[43]^[44]^[45]^[46] The longer half-life of quazepam may have the advantage however, of causing less rebound insomnia than shorter acting subtype selective nonbenzodiazepines.^[10]^[29] However, one of the major metabolites of quazepam, the N-desmethyl-2-oxoquazepam (aka N-desalkylflurazepam), binds unselectively to both type1 and type2 GABA_A receptors. The N-desmethyl-2-oxoquazepam metabolite also has a very long half-life and likely contributes to the pharmacological effects of quazepam.^[47]

Pharmacokinetics

2-Oxoquazepam, a major active quazepam metabolite.

Quazepam has an absorption half-life of 0.4 hours with a peak in plasma levels after 1.75 hours. It is eliminated both renally and through feces.^[48] The active metabolites of quazepam are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. The N-desalkyl-2-oxoquazepam metabolite has only limited pharmacological activity compared to the parent compound quazepam and the active metabolite 2-oxoquazepam. Quazepam and its major active metabolite 2-oxoquazepam both show high selectivity for the type1 GABA_A receptors.^[49]^[50]^[51]^[52] The elimination half-life range of quazepam is between 27 and 41 hours.^[31]

Interactions

The absorption rate is likely to be significantly reduced if quazepam is taken in the fasted state reducing the hypnotic effect of quazepam. If 3 or more hours have passed since eating food then some food should be eaten before taking quazepam.^[53]^[54]

Mechanism of action

Quazepam modulates specific GABA_A receptors via the benzodiazepine site on the GABA_A receptor. This modulation enhances the actions of GABA, causing an increase in opening frequency of the chloride ion channel which results in an increased influx of chloride ions into the GABA_A receptors. Quazepam, unique amongst benzodiazepine drugs selectively targets type1 benzodiazepine receptors which results reduced sleep latency in promotion of sleep.^[55]^[56]^[57] Quazepam also has some anticonvulsant properties.^[58]

EEG and sleep

Quazepam has potent sleep inducing and sleep maintaining properties.^[59]^[60] Studies in both animals and humans have demonstrated that EEG changes induced by quazepam resemble normal sleep patterns whereas other benzodiazepines disrupt normal sleep. Quazepam promotes slow wave sleep.^[61]^[62] This positive effect of quazepam on sleep architecture may be due to its high selectivity for type1 benzodiazepine receptors as demonstrated in animal and human studies. This makes quazepam unique in the benzodiazepine family of drugs.^[63]^[64]

Drug misuse

Quazepam is a drug with the potential for misuse. Two types of drug misuse can occur either recreational misuse is where the drug is taken to achieve a high or when the drug is continued long term against medical advice.^[65]

References

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External links

Inchem.org - Quazepam

UpToDate Contents

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1. 不眠症の治療 treatment of insomnia
2. 患者情報：不眠症の治療（詳細） insomnia treatments beyond the basics

English Journal

Quantitative analysis of quazepam and its metabolites in human blood, urine, and bile by liquid chromatography-tandem mass spectrometry.

Zhou J1, Yamaguchi K2, Ohno Y3.
Forensic science international.Forensic Sci Int.2014 May 5. pii: S0379-0738(14)00180-7. doi: 10.1016/j.forsciint.2014.04.027. [Epub ahead of print]
Quazepam (QZP), which is a long-acting benzodiazepine-type hypnotic, and its 4 metabolites, 2-oxoquazepam, N-desalkyl-2-oxoquazepam (DOQ), 3-hydroxy-2-oxoquazepam (HOQ), and 3-hydroxy-N-desalkyl-2-oxoquazepam, in human blood, urine, and bile were quantitatively analyzed by liquid chromatography-tand
PMID 24856286

National use of prescription medications for insomnia: NHANES 1999-2010.

Bertisch SM1, Herzig SJ2, Winkelman JW3, Buettner C2.
Sleep.Sleep.2014 Feb 1;37(2):343-9. doi: 10.5665/sleep.3410.
STUDY OBJECTIVES: To determine current patterns and predictors of use of prescription medications commonly used for insomnia (MCUFI) in the U.S.DESIGN: Cross-sectional study.SETTING: National Health and Nutrition Examination Survey, 1999-2010.PARTICIPANTS: 32,328 noninstitutionalized community-dwell
PMID 24497662

Analysis of quazepam and its metabolites in human urine by gas chromatography-mass spectrometry: application to a forensic case.

Terada M1, Shinozuka T, Hasegawa C, Tanaka E, Hayashida M, Ohno Y, Kurosaki K.
Forensic science international.Forensic Sci Int.2013 Apr 10;227(1-3):95-9. doi: 10.1016/j.forsciint.2012.11.017. Epub 2013 Jan 3.
A sensitive method for the simultaneous determination of quazepam and two of its metabolites, 2-oxoquazepam and 3-hydroxy-2-oxoquazepam, in human urine was developed using gas chromatography-mass spectrometry (GC/MS) with an Rtx-5MS capillary column. The quazepam and its metabolites were extracted f
PMID 23290298

Japanese Journal

向精神薬と転倒·転落の関係に関する研究

医療薬学 37(1), 49-55, 2011
NAID 130004502652

Quazepam Improves Health-related Quality of Life and Nocturia in Elderly Japanese Patients with Chronic Insomnia

Journal of rural medicine : JRM 4(1), 1-6, 2009-06-01
NAID 10025614932

Comparison of Short- and Long-Acting Benzodiazepine-Receptor Agonists With Different Receptor Selectivity on Motor Coordination and Muscle Relaxation Following Thiopental-Induced Anesthesia in Mice

Journal of pharmacological sciences 107(3), 277-284, 2008-07-20
NAID 10024321336

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リンク元

「クアゼパム」

Quazepam
Systematic (IUPAC) name
	7-chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-3H-1,4-benzodiazepine-2-thione
Clinical data
Trade names	Doral
AHFS/Drugs.com	Consumer Drug Information
MedlinePlus	a684001
Pregnancy; category	AU: D; US: X (Contraindicated); ;
Routes of; administration	Oral
Legal status
Legal status	CA: Schedule IV; US: Schedule IV;
Pharmacokinetic data
Bioavailability	29–35%
Metabolism	Hepatic
Biological half-life	39 hours
Excretion	Renal
Identifiers
CAS Number	36735-22-5
ATC code	N05CD10 (WHO)
PubChem	CID 4999
IUPHAR/BPS	7288
DrugBank	DB01589
ChemSpider	4825
UNII	JF8V0828ZI
KEGG	D00457
ChEMBL	CHEMBL1200472
Chemical data
Formula	C17H11ClF4N2S
Molar mass	386.795 g/mol
	SMILES FC(F)(F)CN1C(=S)C/N=C(\c2cc(Cl)ccc12)c3ccccc3F ;
	InChI InChI=1S/C17H11ClF4N2S/c18-10-5-6-14-12(7-10)16(11-3-1-2-4-13(11)19)23-8-15(25)24(14)9-17(20,21)22/h1-7H,8-9H2 ; Key:IKMPWMZBZSAONZ-UHFFFAOYSA-N ;
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　　[★]

英: quazepam
商: ドラール

睡眠薬;長時間作用型;ベンゾジアゼピン系

[1] US Patent 3845039

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v t e Benzodiazepines

1,4-Benzodiazepines	2-Oxoquazepam 3-Hydroxyphenazepam Bromazepam Camazepam Carburazepam Chlordiazepoxide Cinazepam Cinolazepam Clonazepam Clorazepate Cyprazepam Delorazepam Demoxepam Desmethylflunitrazepam Devazepide* Diazepam Diclazepam Doxefazepam Elfazepam Ethyl carfluzepate Ethyl dirazepate Ethyl loflazepate Flubromazepam Fletazepam Fludiazepam Flunitrazepam Flurazepam Flutemazepam Flutoprazepam Fosazepam Gidazepam Halazepam Iclazepam Irazepine Kenazepine Ketazolam Lorazepam Lormetazepam Lufuradom* Meclonazepam Medazepam Menitrazepam Metaclazepam Motrazepam N-Desalkylflurazepam Nifoxipam Nimetazepam Nitrazepam Nitrazepate Nordazepam Nortetrazepam Oxazepam Phenazepam Pinazepam Pivoxazepam Prazepam Proflazepam Quazepam QH-II-66 Reclazepam RO4491533* Ro5-4864* Sulazepam Temazepam Tetrazepam Tifluadom* Tolufazepam Triflunordazepam Tuclazepam Uldazepam

1,5-Benzodiazepines	Arfendazam Clobazam CP-1414S Lofendazam Triflubazam

2,3-Benzodiazepines*	Girisopam GYKI-52466 GYKI-52895 Nerisopam Talampanel Tofisopam

Triazolobenzodiazepines	Adinazolam Alprazolam Clonazolam Estazolam Flubromazolam Nitrazolam Pyrazolam Triazolam

Imidazobenzodiazepines	Bretazenil Climazolam EVT-201 FG-8205 Flumazenil Imidazenil ¹²³I-Iomazenil L-655,708 Loprazolam Midazolam PWZ-029 Remimazolam Ro15-4513 Ro48-6791 Ro48-8684 Ro4938581 Sarmazenil SH-053-R-CH3-2′F

Oxazolobenzodiazepines	Cloxazolam Flutazolam Haloxazolam Mexazolam Oxazolam

Thienodiazepines	Bentazepam Clotiazepam

Thienotriazolodiazepines	Brotizolam Ciclotizolam Deschloroetizolam Etizolam Israpafant* JQ1* Metizolam

Thienobenzodiazepines*	Olanzapine Telenzepine

Pyridodiazepines	Lopirazepam

Pyridotriazolodiazepines	Zapizolam

Pyrazolodiazepines	Razobazam* Ripazepam Zolazepam Zomebazam Zometapine*

Pyrrolodiazepines	Premazepam

Tetrahydroisoquinobenzodiazepines	Clazolam

Pyrrolobenzodiazepines*	Anthramycin

Benzodiazepine prodrugs	Avizafone Rilmazafone

* atypical activity profile (not GABA_A receptor ligands)

v t e GABA_A receptor positive allosteric modulators

Alcohols	Brometone Butanol Chloralodol Chlorobutanol (cloretone) Ethanol (drinking alcohol) Ethchlorvynol Isobutanol Isopropanol Menthol Methanol Methylpentynol Pentanol Petrichloral Propanol tert-Butanol (2M2P) tert-Pentanol (2M2B) Tribromoethanol Trichloroethanol Triclofos Trifluoroethanol

Barbiturates	(-)-DMBB Allobarbital Alphenal Amobarbital Aprobarbital Barbexaclone Barbital Benzobarbital Benzylbutylbarbiturate Brallobarbital Brophebarbital Butabarbital/Secbutabarbital Butalbital Buthalital Butobarbital Butallylonal Carbubarb CP-1414S Crotylbarbital Cyclobarbital Cyclopentobarbital Difebarbamate Enallylpropymal Ethallobarbital Eterobarb Febarbamate Heptabarb Heptobarbital Hexethal Hexobarbital Metharbital Methitural Methohexital Methylphenobarbital Narcobarbital Nealbarbital Pentobarbital Phenallymal Phenobarbital Phetharbital Primidone Probarbital Propallylonal Propylbarbital Proxibarbital Reposal Secobarbital Sigmodal Spirobarbital Talbutal Tetrabamate Tetrabarbital Thialbarbital Thiamylal Thiobarbital Thiobutabarbital Thiopental Thiotetrabarbital Valofane Vinbarbital Vinylbital

Benzodiazepines	2-Oxoquazepam 3-Hydroxyphenazepam Adinazolam Alprazolam Arfendazam Avizafone Bentazepam Bretazenil Bromazepam Brotizolam Camazepam Carburazepam Chlordiazepoxide Ciclotizolam Cinazepam Cinolazepam Clazolam Climazolam Clobazam Clonazepam Clonazolam Clorazepate Clotiazepam Cloxazolam Cyprazepam Delorazepam Demoxepam Diazepam Diclazepam Doxefazepam Elfazepam Estazolam Ethyl carfluzepate Ethyl dirazepate Ethyl loflazepate Etizolam EVT-201 FG-8205 Fletazepam Flubromazepam Flubromazolam Fludiazepam Flunitrazepam Flurazepam Flutazolam Flutemazepam Flutoprazepam Fosazepam Gidazepam Halazepam Haloxazolam Iclazepam Imidazenil Irazepine Ketazolam Lofendazam Lopirazepam Loprazolam Lorazepam Lormetazepam Meclonazepam Medazepam Menitrazepam Metaclazepam Mexazolam Midazolam Motrazepam N-Desalkylflurazepam Nifoxipam Nimetazepam Nitrazepam Nitrazepate Nitrazolam Nordazepam Nortetrazepam Oxazepam Oxazolam Phenazepam Pinazepam Pivoxazepam Prazepam Premazepam Proflazepam Pyrazolam QH-II-66 Quazepam Reclazepam Remimazolam Rilmazafone Ripazepam Ro48-6791 Ro48-8684 SH-053-R-CH3-2′F Sulazepam Temazepam Tetrazepam Tolufazepam Triazolam Triflubazam Triflunordazepam (Ro5-2904) Tuclazepam Uldazepam Zapizolam Zolazepam Zomebazam

Carbamates	Carisbamate Carisoprodol Clocental Cyclarbamate Difebarbamate Emylcamate Ethinamate Febarbamate Felbamate Hexapropymate Lorbamate Mebutamate Meprobamate Nisobamate Pentabamate Phenprobamate Procymate Styramate Tetrabamate Tybamate

Flavonoids	6-Methylapigenin Ampelopsin (dihydromyricetin) Apigenin Baicalein Baicalin Catechin EGC EGCG Hispidulin Linarin Luteolin Rc-OMe Skullcap constituents (e.g., baicalin) Wogonin

Imidazoles	Etomidate Metomidate Propoxate

Kava constituents	10-Methoxyyangonin 11-Methoxyyangonin 11-Hydroxyyangonin Desmethoxyyangonin 11-Methoxy-12-hydroxydehydrokavain 7,8-Dihydroyangonin Kavain 5-Hydroxykavain 5,6-Dihydroyangonin 7,8-Dihydrokavain 5,6,7,8-Tetrahydroyangonin 5,6-Dehydromethysticin Methysticin 7,8-Dihydromethysticin Yangonin

Monoureides	Acecarbromal Apronal (apronalide) Bromisoval Carbromal Capuride Ectylurea

Neuroactive steroids	Acebrochol Allopregnanolone (SAGE-547) Alfadolone Alfaxalone Anabolic steroids 3α-Androstanediol Androstenol Androsterone Cholesterol DHDOC 3α-DHP 5α-DHP 5β-DHP DHT Etiocholanolone Ganaxolone Hydroxydione Minaxolone Org 20599 Org 21465 Pregnanolone (eltanolone) Progesterone Quingestrone Renanolone SAGE-105 SAGE-217 SAGE-324 SAGE-516 SAGE-689 SAGE-872 Testosterone THDOC

Nonbenzodiazepines	β-Carbolines: Abecarnil Gedocarnil Harmane SL-651,498 ZK-93423; Cyclopyrrolones: Eszopiclone Pagoclone Pazinaclone Suproclone Suriclone Zopiclone; Imidazopyridines: Alpidem DS-1 Necopidem Saripidem Zolpidem; Pyrazolopyrimidines: Divaplon Fasiplon Indiplon Lorediplon Ocinaplon Panadiplon Taniplon Zaleplon; Others: Adipiplon CGS-8216 CGS-9896 CGS-13767 CGS-20625 CL-218,872 CP-615,003 CTP-354 ELB-139 GBLD-345 JM-1232 L-838,417 Lirequinil (Ro41-3696) NS-2664 NS-2710 NS-11394 Pipequaline ROD-188 RWJ-51204 SB-205,384 SX-3228 TGSC01AA TP-003 TPA-023 TP-13 U-89843A U-90042 Viqualine Y-23684

Phenols	Fospropofol Propofol Thymol

Piperidinediones	Glutethimide Methyprylon Piperidione Pyrithyldione

Pyrazolopyridines	Cartazolate Etazolate ICI-190,622 Tracazolate

Quinazolinones	Afloqualone Cloroqualone Diproqualone Etaqualone Mebroqualone Mecloqualone Methaqualone Methylmethaqualone Nitromethaqualone SL-164

Volatiles/gases	Acetone Acetophenone Acetylglycinamide chloral hydrate Aliflurane Benzene Butane Butylene Centalun Chloral Chloral betaine Chloral hydrate Chloroform Cryofluorane Desflurane Dichloralphenazone Dichloromethane Diethyl ether Enflurane Ethyl chloride Ethylene Fluroxene Gasoline Halopropane Halothane Isoflurane Kerosine Methoxyflurane Methoxypropane Nitric oxide Nitrogen Nitrous oxide Norflurane Paraldehyde Propane Propylene Roflurane Sevoflurane Synthane Teflurane Toluene Trichloroethane (methyl chloroform) Trichloroethylene Vinyl ether

Others/unsorted	3-Hydroxybutanal α-EMTBL AA-29504 Avermectins (e.g., ivermectin) Bromide compounds (e.g., lithium bromide, potassium bromide, sodium bromide) Carbamazepine Chloralose Chlormezanone Clomethiazole DEABL Dihydroergolines (e.g., dihydroergocryptine, dihydroergosine, dihydroergotamine, ergoloid (dihydroergotoxine)) DS2 Efavirenz Etazepine Etifoxine Fenamates (e.g., flufenamic acid, mefenamic acid, niflumic acid, tolfenamic acid) Fluoxetine Flupirtine Hopantenic acid Lanthanum Lavender oil Lignans (e.g., 4-O-methylhonokiol, honokiol, magnolol, obovatol) Loreclezole Menthyl isovalerate (validolum) Monastrol Niacin Nicotinamide (niacinamide) Org 25,435 Phenytoin Propanidid Retigabine (ezogabine) Safranal Seproxetine Stiripentol Sulfonylalkanes (e.g., sulfonmethane (sulfonal), tetronal, trional) Terpenoids (e.g., borneol) Topiramate Valerian constituents (e.g., isovaleric acid, isovaleramide, valerenic acid, valerenol) Unsorted benzodiazepine site PAMs: MRK-409 (MK-0343) TCS-1105 TCS-1205

See also: GABAergics

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