Estazolam

Estazolam
Clinical data
Trade names	Prosom, Esilgan, Eurodin, Nuctalon, others
Other names	Desmethylalprazolam
AHFS/Drugs.com	Monograph
MedlinePlus	a691003
License data	US DailyMed: Estazolam;
Routes of; administration	By mouth
ATC code	N05CD04 (WHO) ;
Legal status
Legal status	BR: Class B1 (Psychoactive drugs); CA: Schedule IV; DE: Prescription only (Anlage III for higher doses); UK: Class C; US: WARNINGSchedule IV;
Pharmacokinetic data
Bioavailability	93%
Metabolism	Liver
Elimination half-life	10–24 hours
Excretion	Kidney
Identifiers
	IUPAC name 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;
CAS Number	29975-16-4 ;
PubChem CID	3261;
IUPHAR/BPS	7550;
DrugBank	DB01215 ;
ChemSpider	3146 ;
UNII	36S3EQV54C;
KEGG	D00311 ;
ChEBI	CHEBI:4858 ;
ChEMBL	ChEMBL285674 ;
CompTox Dashboard (EPA)	DTXSID5020572 ;
ECHA InfoCard	100.045.424
Chemical and physical data
Formula	C16H11ClN4
Molar mass	294.74 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES ClC1=CC2=C(C=C1)N3C=NN=C3CN=C2C4=CC=CC=C4;
	InChI InChI=1S/C16H11ClN4/c17-12-6-7-14-13(8-12)16(11-4-2-1-3-5-11)18-9-15-20-19-10-21(14)15/h1-8,10H,9H2 ; Key:CDCHDCWJMGXXRH-UHFFFAOYSA-N ;
	(verify)

Estazolam, sold under the brand name Prosom among others, is a tranquilizer medication of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. Estazolam is an intermediate-acting oral benzodiazepine. It is used for short-term treatment of insomnia.

It was patented in 1968 and came into medical use in 1975.^[5]

Medical uses

Estazolam is prescribed for the short-term treatment of certain sleep disorders. It is an effective hypnotic drug showing efficacy in increasing the time spent asleep as well as reducing awakenings during the night. Combination with non-pharmacological options for sleep management results in long-term improvements in sleep quality after discontinuation of short-term estazolam therapy.^[6]^[7] Estazolam is also sometimes used as a preoperative sleep aid. It was found to be superior to triazolam in side effect profile in preoperative patients in a trial.^[8] Estazolam also has anxiolytic properties and due to its long half life can be an effective short-term treatment for insomnia associated with anxiety.^[9]

Side effects

A hang-over effect commonly occurs with next day impairments of mental and physical performance.^[10] Other side effects of estazolam include somnolence, dizziness, hypokinesia, and abnormal coordination.^[11]

In September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.^[12]

Tolerance and dependence

The main safety concern of benzodiazepines such as estazolam is a benzodiazepine dependence and the subsequent benzodiazepine withdrawal syndrome which can occur upon discontinuation of the estazolam. A review of the literature found that long-term use of benzodiazepines such as estazolam is associated with drug tolerance, drug dependence, rebound insomnia and CNS related adverse effects. Estazolam should only be used short term and at the lowest effective dose to avoid complications related to long-term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality.^[13]^[14] The short-term benefits of benzodiazepines on sleep begin to reduce after a few days due to tolerance to the hypnotic effects of benzodiazepines in the elderly.^[15]

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.^[16]

Pharmacology

Estazolam is classed as a "triazolo" benzodiazepine drug.^[17] Estazolam exerts its therapeutic effects via its benzodiazepines receptor agonist properties.^[18] Estazolam at high doses decreases histamine turnover via its action at the benzodiazepine-GABA receptor complex in mouse brains.^[19]

Pharmacokinetics

Peak plasma levels are achieved within 1–6 hours. Estazolam is an intermediate acting benzodiazepine. The elimination half life of estazolam is an average of 19 hours, with a range of 8–31 hours.^[20]^[21] The major metabolite of estazolam is 4-hydroxyestazolam.^[22] Other identified metabolites include 1-oxo-estazolam, 4'-hydroxy-estazolam, and benzophenone.^[3]

Interactions

Alcohol enhances the sedative hypnotic properties of estazolam.^[23] In package inserts, the manufacturer clearly warns about an interaction with ritonavir, and although clinical interactions of ritonavir with estazolam have not yet been described, the lack of clinical descriptions of the interactions does not negate the seriousness of the interaction.^[24]

EEG effects in rabbits

An animal study in rabbits demonstrated that estazolam induces a drowsy pattern of spontaneous EEG including high voltage slow waves and spindle bursts increase in the cortex and amygdala, while the hippocampal theta rhythm is desynchronized. Also low voltage fast waves occur particularly in the cortical EEG. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus is significantly suppressed. The photic driving response elicited by a flash light in the visual cortex is significantly suppressed by estazolam.^[25]

Abuse

A primate study found that estazolam has abuse potential.^[26] Two types of drug misuse can occur; recreational misuse, where the drug is taken to achieve a high or when the drug is continued long term against medical advice.^[27] Estazolam became notorious in 1998 when a large amount of an 'herbal sleeping mix' called Sleeping Buddha was recalled from the shelves after the FDA discovered that it contained estazolam.^[28] In 2007, a Canadian product called Sleepees was recalled after it was found to contain undeclared estazolam.^[29]^[30]

References

^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
^ ^a ^b "Estazolam tablet". DailyMed. 30 September 2020. Retrieved 25 October 2020.
^ "Estazolam (Prosom) Use During Pregnancy". Drugs.com. 18 September 2020. Retrieved 25 October 2020.
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 538. ISBN 9783527607495.
^ Roehrs T, Zorick F, Lord N, Koshorek GL, Roth T (June 1983). "Dose-related effects of estazolam on sleep of patients with insomnia". Journal of Clinical Psychopharmacology. 3 (3): 152–156. doi:10.1097/00004714-198306000-00002. PMID 6135720. S2CID 9143614.
^ Rosen RC, Lewin DS, Goldberg L, Woolfolk RL (October 2000). "Psychophysiological insomnia: combined effects of pharmacotherapy and relaxation-based treatments". Sleep Medicine. 1 (4): 279–288. doi:10.1016/S1389-9457(00)00042-3. PMID 11040460.
^ Mauro C, Sperlongano P (September 1987). "[Controlled clinical evaluation of 2 hypnotic triazole benzodiazepines, estazolam and triazolam, used the night before surgical interventions]". Minerva Medica (in Italian). 78 (18): 1381–1384. PMID 2889169.
^ Post GL, Patrick RO, Crowder JE, Houston J, Ferguson JM, Bielski RJ, et al. (August 1991). "Estazolam treatment of insomnia in generalized anxiety disorder: a placebo-controlled study". Journal of Clinical Psychopharmacology. 11 (4): 249–253. doi:10.1097/00004714-199108000-00005. PMID 1918423. S2CID 7890993.
^ Müller KW, Müller-Limmroth W, Strasser H (1982). "[Alterations of sleep stage pattern in human beings and hang-over effects under the influence of estazolam/2nd Comm.: Studies on the hang-over effect in psycho-physiological performance (author's transl)]". Arzneimittel-Forschung (in German). 32 (4): 456–460. PMID 6125155.
^ Pierce MW, Shu VS, Groves LJ (March 1990). "Safety of estazolam. The United States clinical experience". The American Journal of Medicine. 88 (3A): 12S–17S. doi:10.1016/0002-9343(90)90280-Q. PMID 1968713.
^ "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". U.S. Food and Drug Administration (FDA). 23 September 2020. Retrieved 23 September 2020. This article incorporates text from this source, which is in the public domain.
^ Kirkwood CK (1999). "Management of insomnia". Journal of the American Pharmaceutical Association. 39 (5): 688–96, quiz 713–4. doi:10.1016/S1086-5802(15)30354-5. PMID 10533351.
^ Lee YJ (2004). "Overview of the therapeutic management of insomnia with zolpidem". CNS Drugs. 18 (Suppl 1): 17–23, discussion 41, 43–5. doi:10.2165/00023210-200418001-00005. PMID 15291010. S2CID 7936406.
^ Grad RM (November 1995). "Benzodiazepines for insomnia in community-dwelling elderly: a review of benefit and risk". The Journal of Family Practice. 41 (5): 473–481. PMID 7595266.
^ Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Annales Pharmaceutiques Françaises. 67 (6): 408–413. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
^ Braestrup C, Squires RF (April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". European Journal of Pharmacology. 48 (3): 263–270. doi:10.1016/0014-2999(78)90085-7. PMID 639854.
^ Akbarzadeh T, Tabatabai SA, Khoshnoud MJ, Shafaghi B, Shafiee A (March 2003). "Design and synthesis of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole derivatives as benzodiazepine receptor agonists". Bioorganic & Medicinal Chemistry. 11 (5): 769–773. doi:10.1016/S0968-0896(02)00469-8. PMID 12538007.
^ Oishi R, Nishibori M, Itoh Y, Saeki K (May 1986). "Diazepam-induced decrease in histamine turnover in mouse brain". European Journal of Pharmacology. 124 (3): 337–342. doi:10.1016/0014-2999(86)90236-0. PMID 3089825.
^ Allen MD, Greenblatt DJ, Arnold JD (1979). "Single- and multiple-dose kinetics of estazolam, a triazolo benzodiazepine". Psychopharmacology. 66 (3): 267–274. doi:10.1007/BF00428318. PMID 43552. S2CID 23882114.
^ Mancinelli A, Guiso G, Garattini S, Urso R, Caccia S (March 1985). "Kinetic and pharmacological studies on estazolam in mice and man". Xenobiotica; The Fate of Foreign Compounds in Biological Systems. 15 (3): 257–265. doi:10.3109/00498258509045357. PMID 2862746.
^ Miura M, Otani K, Ohkubo T (May 2005). "Identification of human cytochrome P450 enzymes involved in the formation of 4-hydroxyestazolam from estazolam". Xenobiotica; The Fate of Foreign Compounds in Biological Systems. 35 (5): 455–465. doi:10.1080/00498250500111612. PMID 16012077. S2CID 10576075.
^ Wang JS, DeVane CL (2003). "Pharmacokinetics and drug interactions of the sedative hypnotics" (PDF). Psychopharmacology Bulletin. 37 (1): 10–29. doi:10.1007/BF01990373. PMID 14561946. S2CID 1543185. Archived from the original (PDF) on 2007-07-09.
^ Miura M, Ohkubo T, Sugawara K, Okuyama N, Otani K (May 2002). "Determination of estazolam in plasma by high-performance liquid chromatography with solid-phase extraction" (PDF). Analytical Sciences. 18 (5): 525–528. doi:10.2116/analsci.18.525. PMID 12036118.
^ Watanabe S, Ohta H, Sakurai Y, Takao K, Ueki S (July 1986). "[Electroencephalographic effects of 450191-S and its metabolites in rabbits with chronic electrode implants]". Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica. 88 (1): 19–32. doi:10.1254/fpj.88.19. PMID 3758874.
^ Johanson CE (March 1987). "Benzodiazepine self-administration in rhesus monkeys: estazolam, flurazepam and lorazepam". Pharmacology, Biochemistry, and Behavior. 26 (3): 521–526. doi:10.1016/0091-3057(87)90159-6. PMID 2883668. S2CID 21917850.
^ Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". The Journal of Clinical Psychiatry. 66 (Suppl 9): 31–41. PMID 16336040.
^ Food and Drug Administration; U.S. Department of Health and Human Services (10 March 1998). "FDA WARNS CONSUMERS AGAINST TAKING DIETARY SUPPLEMENT "SLEEPING BUDDHA"". FDA. Archived from the original on October 6, 2008. Retrieved 21 December 2008.
^ "Potentially habit-forming herbal sleep aid recalled". CBC News. Feb 23, 2007. Retrieved 2020-07-03.
^ André P (Aug 14, 2007). "Losing sleep over 'natural' aids". The Globe and Mail. Retrieved 2020-07-03.

External links

"Estazolam". Drug Information Portal. U.S. National Library of Medicine.

[FDA-AllBoxedWarnings-1] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.

[2] Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.

[Estazolam_FDA_label-3] "Estazolam tablet". DailyMed. 30 September 2020. Retrieved 25 October 2020.

[Drugs.com_pregnancy-4] "Estazolam (Prosom) Use During Pregnancy". Drugs.com. 18 September 2020. Retrieved 25 October 2020.

[Fis2006-5] Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 538. ISBN 9783527607495.

[6] Roehrs T, Zorick F, Lord N, Koshorek GL, Roth T (June 1983). "Dose-related effects of estazolam on sleep of patients with insomnia". Journal of Clinical Psychopharmacology. 3 (3): 152–156. doi:10.1097/00004714-198306000-00002. PMID 6135720. S2CID 9143614.

[7] Rosen RC, Lewin DS, Goldberg L, Woolfolk RL (October 2000). "Psychophysiological insomnia: combined effects of pharmacotherapy and relaxation-based treatments". Sleep Medicine. 1 (4): 279–288. doi:10.1016/S1389-9457(00)00042-3. PMID 11040460.

[8] Mauro C, Sperlongano P (September 1987). "[Controlled clinical evaluation of 2 hypnotic triazole benzodiazepines, estazolam and triazolam, used the night before surgical interventions]". Minerva Medica (in Italian). 78 (18): 1381–1384. PMID 2889169.

[9] Post GL, Patrick RO, Crowder JE, Houston J, Ferguson JM, Bielski RJ, et al. (August 1991). "Estazolam treatment of insomnia in generalized anxiety disorder: a placebo-controlled study". Journal of Clinical Psychopharmacology. 11 (4): 249–253. doi:10.1097/00004714-199108000-00005. PMID 1918423. S2CID 7890993.

[10] Müller KW, Müller-Limmroth W, Strasser H (1982). "[Alterations of sleep stage pattern in human beings and hang-over effects under the influence of estazolam/2nd Comm.: Studies on the hang-over effect in psycho-physiological performance (author's transl)]". Arzneimittel-Forschung (in German). 32 (4): 456–460. PMID 6125155.

[11] Pierce MW, Shu VS, Groves LJ (March 1990). "Safety of estazolam. The United States clinical experience". The American Journal of Medicine. 88 (3A): 12S–17S. doi:10.1016/0002-9343(90)90280-Q. PMID 1968713.

[12] "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". U.S. Food and Drug Administration (FDA). 23 September 2020. Retrieved 23 September 2020. This article incorporates text from this source, which is in the public domain.

[13] Kirkwood CK (1999). "Management of insomnia". Journal of the American Pharmaceutical Association. 39 (5): 688–96, quiz 713–4. doi:10.1016/S1086-5802(15)30354-5. PMID 10533351.

[14] Lee YJ (2004). "Overview of the therapeutic management of insomnia with zolpidem". CNS Drugs. 18 (Suppl 1): 17–23, discussion 41, 43–5. doi:10.2165/00023210-200418001-00005. PMID 15291010. S2CID 7936406.

[15] Grad RM (November 1995). "Benzodiazepines for insomnia in community-dwelling elderly: a review of benefit and risk". The Journal of Family Practice. 41 (5): 473–481. PMID 7595266.

[16] Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Annales Pharmaceutiques Françaises. 67 (6): 408–413. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.

[17] Braestrup C, Squires RF (April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". European Journal of Pharmacology. 48 (3): 263–270. doi:10.1016/0014-2999(78)90085-7. PMID 639854.

[18] Akbarzadeh T, Tabatabai SA, Khoshnoud MJ, Shafaghi B, Shafiee A (March 2003). "Design and synthesis of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole derivatives as benzodiazepine receptor agonists". Bioorganic & Medicinal Chemistry. 11 (5): 769–773. doi:10.1016/S0968-0896(02)00469-8. PMID 12538007.

[19] Oishi R, Nishibori M, Itoh Y, Saeki K (May 1986). "Diazepam-induced decrease in histamine turnover in mouse brain". European Journal of Pharmacology. 124 (3): 337–342. doi:10.1016/0014-2999(86)90236-0. PMID 3089825.

[20] Allen MD, Greenblatt DJ, Arnold JD (1979). "Single- and multiple-dose kinetics of estazolam, a triazolo benzodiazepine". Psychopharmacology. 66 (3): 267–274. doi:10.1007/BF00428318. PMID 43552. S2CID 23882114.

[21] Mancinelli A, Guiso G, Garattini S, Urso R, Caccia S (March 1985). "Kinetic and pharmacological studies on estazolam in mice and man". Xenobiotica; The Fate of Foreign Compounds in Biological Systems. 15 (3): 257–265. doi:10.3109/00498258509045357. PMID 2862746.

[22] Miura M, Otani K, Ohkubo T (May 2005). "Identification of human cytochrome P450 enzymes involved in the formation of 4-hydroxyestazolam from estazolam". Xenobiotica; The Fate of Foreign Compounds in Biological Systems. 35 (5): 455–465. doi:10.1080/00498250500111612. PMID 16012077. S2CID 10576075.

[23] Wang JS, DeVane CL (2003). "Pharmacokinetics and drug interactions of the sedative hypnotics" (PDF). Psychopharmacology Bulletin. 37 (1): 10–29. doi:10.1007/BF01990373. PMID 14561946. S2CID 1543185. Archived from the original (PDF) on 2007-07-09.

[24] Miura M, Ohkubo T, Sugawara K, Okuyama N, Otani K (May 2002). "Determination of estazolam in plasma by high-performance liquid chromatography with solid-phase extraction" (PDF). Analytical Sciences. 18 (5): 525–528. doi:10.2116/analsci.18.525. PMID 12036118.

[25] Watanabe S, Ohta H, Sakurai Y, Takao K, Ueki S (July 1986). "[Electroencephalographic effects of 450191-S and its metabolites in rabbits with chronic electrode implants]". Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica. 88 (1): 19–32. doi:10.1254/fpj.88.19. PMID 3758874.

[26] Johanson CE (March 1987). "Benzodiazepine self-administration in rhesus monkeys: estazolam, flurazepam and lorazepam". Pharmacology, Biochemistry, and Behavior. 26 (3): 521–526. doi:10.1016/0091-3057(87)90159-6. PMID 2883668. S2CID 21917850.

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

[28] Food and Drug Administration; U.S. Department of Health and Human Services (10 March 1998). "FDA WARNS CONSUMERS AGAINST TAKING DIETARY SUPPLEMENT "SLEEPING BUDDHA"". FDA. Archived from the original on October 6, 2008. Retrieved 21 December 2008.

[29] "Potentially habit-forming herbal sleep aid recalled". CBC News. Feb 23, 2007. Retrieved 2020-07-03.

[30] André P (Aug 14, 2007). "Losing sleep over 'natural' aids". The Globe and Mail. Retrieved 2020-07-03.

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Estazolam

Medical uses

Side effects

Tolerance and dependence

Contraindications and special caution

Pharmacology

Pharmacokinetics

Interactions

EEG effects in rabbits

Abuse

See also

References

External links

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