Estazolam Explained

Watchedfields:changed
Verifiedrevid:457289200
Width:170
Width2:170
Tradename:Prosom, Esilgan, Eurodin, Nuctalon, others
Dailymedid:Estazolam
Pregnancy Us:X
Pregnancy Us Comment:[1]
Legal Br:B1
Legal Br Comment:[2]
Legal Ca:Schedule IV
Legal De:Rx-only/Anlage III
Legal Uk:Class C
Legal Us:Schedule IV
Routes Of Administration:By mouth
Atc Prefix:N05
Atc Suffix:CD04
Bioavailability:93%
Metabolism:Liver
Elimination Half-Life:10–24 hours
Excretion:Kidney
Iuphar Ligand:7550
Cas Number:29975-16-4
Pubchem:3261
Drugbank:DB01215
Chemspiderid:3146
Unii:36S3EQV54C
Kegg:D00311
Chebi:4858
Chembl:285674
Synonyms:Desmethylalprazolam
Iupac Name:8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
C:16
H:11
Cl:1
N:4
Smiles:ClC1=CC2=C(C=C1)N3C=NN=C3CN=C2C4=CC=CC=C4
Stdinchi: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
Stdinchikey:CDCHDCWJMGXXRH-UHFFFAOYSA-N

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.[3]

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.[4] [5] 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.[6] Estazolam also has anxiolytic properties and due to its long half life can be an effective short-term treatment for insomnia associated with anxiety.[7]

Side effects

A hang-over effect commonly occurs with next day impairments of mental and physical performance.[8] Other side effects of estazolam include somnolence, dizziness, hypokinesia, and abnormal coordination.[9]

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.[10]

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.[11] [12] 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.[13]

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.[14]

Pharmacology

Estazolam is classed as a "triazolo" benzodiazepine drug.[15] Estazolam exerts its therapeutic effects via its benzodiazepines receptor agonist properties.[16] Estazolam at high doses decreases histamine turnover via its action at the benzodiazepine-GABA receptor complex in mouse brains.[17]

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.[18] [19] The major metabolite of estazolam is 4-hydroxyestazolam.[20] Other identified metabolites include 1-oxo-estazolam, 4'-hydroxy-estazolam, and benzophenone.[21]

Interactions

Alcohol enhances the sedative hypnotic properties of estazolam.[22] 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.[23]

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.[24]

Abuse

See also: Benzodiazepine drug misuse. A primate study found that estazolam has abuse potential.[25] 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.[26] 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.[27] In 2007, a Canadian product called Sleepees was recalled after it was found to contain undeclared estazolam.[28] [29]

See also

External links

Notes and References

  1. Web site: Estazolam (Prosom) Use During Pregnancy . Drugs.com . 18 September 2020 . 25 October 2020.
  2. Web site: Anvisa . Brazilian Health Regulatory Agency . 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. live . https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 . 2023-08-03 . 2023-08-16 . . pt-BR . 2023-04-04.
  3. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006 . John Wiley & Sons . 9783527607495 . 538 . en.
  4. Roehrs T, Zorick F, Lord N, Koshorek GL, Roth T . Dose-related effects of estazolam on sleep of patients with insomnia . Journal of Clinical Psychopharmacology . 3 . 3 . 152–156 . June 1983 . 6135720 . 10.1097/00004714-198306000-00002 . 9143614 .
  5. Rosen RC, Lewin DS, Goldberg L, Woolfolk RL . Psychophysiological insomnia: combined effects of pharmacotherapy and relaxation-based treatments . Sleep Medicine . 1 . 4 . 279–288 . October 2000 . 11040460 . 10.1016/S1389-9457(00)00042-3 .
  6. Mauro C, Sperlongano P . [Controlled clinical evaluation of 2 hypnotic triazole benzodiazepines, estazolam and triazolam, used the night before surgical interventions] . it . Minerva Medica . 78 . 18 . 1381–1384 . September 1987 . 2889169 .
  7. Post GL, Patrick RO, Crowder JE, Houston J, Ferguson JM, Bielski RJ, Bailey L, Pearlman HG, Shu VS, Pierce MW . 6 . Estazolam treatment of insomnia in generalized anxiety disorder: a placebo-controlled study . Journal of Clinical Psychopharmacology . 11 . 4 . 249–253 . August 1991 . 1918423 . 10.1097/00004714-199108000-00005 . 7890993 .
  8. Müller KW, Müller-Limmroth W, Strasser H . [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)] . de . Arzneimittel-Forschung . 32 . 4 . 456–460 . 1982 . 6125155 .
  9. Pierce MW, Shu VS, Groves LJ . Safety of estazolam. The United States clinical experience . The American Journal of Medicine . 88 . 3A . 12S-17S . March 1990 . 1968713 . 10.1016/0002-9343(90)90280-Q .
  10. Web site: FDA expands Boxed Warning to improve safe use of benzodiazepine drug . U.S. Food and Drug Administration (FDA) . 23 September 2020 . 23 September 2020.
  11. Kirkwood CK . Management of insomnia . Journal of the American Pharmaceutical Association . 39 . 5 . 688–96; quiz 713–4 . 1999 . 10533351 . 10.1016/S1086-5802(15)30354-5 .
  12. Lee YJ . Overview of the therapeutic management of insomnia with zolpidem . CNS Drugs . 18 . Suppl 1 . 17–23; discussion 41, 43–5 . 2004 . 15291010 . 10.2165/00023210-200418001-00005 . 7936406 .
  13. Grad RM . Benzodiazepines for insomnia in community-dwelling elderly: a review of benefit and risk . The Journal of Family Practice . 41 . 5 . 473–481 . November 1995 . 7595266 .
  14. Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, Vennat B, Llorca PM, Eschalier A . 6 . Benzodiazepine dependence: focus on withdrawal syndrome . Annales Pharmaceutiques Françaises . 67 . 6 . 408–413 . November 2009 . 19900604 . 10.1016/j.pharma.2009.07.001 .
  15. Braestrup C, Squires RF . Pharmacological characterization of benzodiazepine receptors in the brain . European Journal of Pharmacology . 48 . 3 . 263–270 . April 1978 . 639854 . 10.1016/0014-2999(78)90085-7 .
  16. Akbarzadeh T, Tabatabai SA, Khoshnoud MJ, Shafaghi B, Shafiee A . 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 . March 2003 . 12538007 . 10.1016/S0968-0896(02)00469-8 .
  17. Oishi R, Nishibori M, Itoh Y, Saeki K . Diazepam-induced decrease in histamine turnover in mouse brain . European Journal of Pharmacology . 124 . 3 . 337–342 . May 1986 . 3089825 . 10.1016/0014-2999(86)90236-0 .
  18. Allen MD, Greenblatt DJ, Arnold JD . Single- and multiple-dose kinetics of estazolam, a triazolo benzodiazepine . Psychopharmacology . 66 . 3 . 267–274 . 1979 . 43552 . 10.1007/BF00428318 . 23882114 .
  19. Mancinelli A, Guiso G, Garattini S, Urso R, Caccia S . Kinetic and pharmacological studies on estazolam in mice and man . Xenobiotica; The Fate of Foreign Compounds in Biological Systems . 15 . 3 . 257–265 . March 1985 . 2862746 . 10.3109/00498258509045357 .
  20. Miura M, Otani K, Ohkubo T . 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 . May 2005 . 16012077 . 10.1080/00498250500111612 . 10576075 .
  21. Web site: Estazolam tablet . DailyMed . 30 September 2020 . 25 October 2020.
  22. Wang JS, DeVane CL . Pharmacokinetics and drug interactions of the sedative hypnotics . Psychopharmacology Bulletin . 37 . 1 . 10–29 . 2003 . 14561946 . 10.1007/BF01990373 . dead . 1543185 . https://web.archive.org/web/20070709230745/http://www.medworksmedia.com/psychopharmbulletin/pdf/12/010-029_PB%20W03_Wang_final.pdf . 2007-07-09 .
  23. Miura M, Ohkubo T, Sugawara K, Okuyama N, Otani K . Determination of estazolam in plasma by high-performance liquid chromatography with solid-phase extraction . Analytical Sciences . 18 . 5 . 525–528 . May 2002 . 12036118 . 10.2116/analsci.18.525 . PDF . free .
  24. Watanabe S, Ohta H, Sakurai Y, Takao K, Ueki S . [Electroencephalographic effects of 450191-S and its metabolites in rabbits with chronic electrode implants] . Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica . 88 . 1 . 19–32 . July 1986 . 3758874 . 10.1254/fpj.88.19 . free .
  25. Johanson CE . Benzodiazepine self-administration in rhesus monkeys: estazolam, flurazepam and lorazepam . Pharmacology, Biochemistry, and Behavior . 26 . 3 . 521–526 . March 1987 . 2883668 . 10.1016/0091-3057(87)90159-6 . 21917850 .
  26. Griffiths RR, Johnson MW . 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 . 2005 . 16336040 .
  27. Web site: FDA WARNS CONSUMERS AGAINST TAKING DIETARY SUPPLEMENT "SLEEPING BUDDHA" . 21 December 2008 . Food and Drug Administration . Food and Drug Administration . U.S. Department of Health and Human Services . 10 March 1998 . FDA . https://web.archive.org/web/20081006134201/https://www.fda.gov/bbs/topics/NEWS/NEW00625.html . October 6, 2008.
  28. News: Feb 23, 2007. Potentially habit-forming herbal sleep aid recalled. CBC News. 2020-07-03.
  29. News: André P . Aug 14, 2007. Losing sleep over 'natural' aids. The Globe and Mail. 2020-07-03.

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