Estazolam

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.

Estazolam
Clinical data
Trade namesProsom, Esilgan, Eurodin, Nuctalon, others
Other namesDesmethylalprazolam
AHFS/Drugs.comMonograph
MedlinePlusa691003
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability93%
MetabolismLiver
Elimination half-life10–24 hours
ExcretionKidney
Identifiers
IUPAC name
  • 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.045.424
Chemical and physical data
FormulaC16H11ClN4
Molar mass294.74 g·mol−1
3D model (JSmol)
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 Y
  • Key:CDCHDCWJMGXXRH-UHFFFAOYSA-N Y
  (verify)

It was patented in 1968 and came into medical use in 1975.[2]

Medical uses
Estazolam 1mg pills, sold as Eurodin, from Japan.
From United States, sold as ProSom (2MG)

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.[3][4] 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.[5] Estazolam also has anxiolytic properties and due to its long half life can be an effective short-term treatment for insomnia associated with anxiety.[6]

Side effects

A hang-over effect commonly occurs with next day impairments of mental and physical performance.[7] Other side effects of estazolam include somnolence, dizziness, hypokinesia, and abnormal coordination.[8]

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.[9]

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.[10][11] 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.[12]

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.[13]

Elderly

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 estazolam, 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.[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.[1]

Interactions

Alcohol enhances the sedative hypnotic properties of estazolam.[21] 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.[22]

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.[23]

Abuse
See also: Benzodiazepine drug misuse

A primate study found that estazolam has abuse potential.[24] Estazolam is a drug with the potential for misuse. 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.[25] 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.[26] In 2007, a Canadian product called Sleepees was recalled after it was found to contain undeclared estazolam.[27][28]

See also

References
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  2. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 538. ISBN 9783527607495.
  3. Roehrs T, Zorick F, Lord N, Koshorek GL, Roth T (June 1983). "Dose-related effects of estazolam on sleep of patients with insomnia". J Clin Psychopharmacol. 3 (3): 152–6. doi:10.1097/00004714-198306000-00002. PMID 6135720. S2CID 9143614.
  4. Rosen RC, Lewin DS, Goldberg L, Woolfolk RL (October 2000). "Psychophysiological insomnia: combined effects of pharmacotherapy and relaxation-based treatments". Sleep Med. 1 (4): 279–288. doi:10.1016/S1389-9457(00)00042-3. PMID 11040460.
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  7. 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)]". Arzneimittelforschung (in German). 32 (4): 456–60. PMID 6125155.
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  9. "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.
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  16. 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". Bioorg. Med. Chem. 11 (5): 769–73. doi:10.1016/S0968-0896(02)00469-8. PMID 12538007.
  17. Oishi R; Nishibori M; Itoh Y; Saeki K (May 27, 1986). "Diazepam-induced decrease in histamine turnover in mouse brain". Eur J Pharmacol. 124 (3): 337–42. doi:10.1016/0014-2999(86)90236-0. PMID 3089825.
  18. Allen MD, Greenblatt DJ, Arnold JD (1979). "Single- and multiple-dose kinetics of estazolam, a triazolo benzodiazepine". Psychopharmacology. 66 (3): 267–74. doi:10.1007/BF00428318. PMID 43552. S2CID 23882114.
  19. Mancinelli A, Guiso G, Garattini S, Urso R, Caccia S (March 1985). "Kinetic and pharmacological studies on estazolam in mice and man". Xenobiotica. 15 (3): 257–65. doi:10.3109/00498258509045357. PMID 2862746.
  20. Miura M, Otani K, Ohkubo T (May 2005). "Identification of human cytochrome P450 enzymes involved in the formation of 4-hydroxyestazolam from estazolam". Xenobiotica. 35 (5): 455–65. doi:10.1080/00498250500111612. PMID 16012077. S2CID 10576075.
  21. Wang JS, DeVane CL (2003). "Pharmacokinetics and drug interactions of the sedative hypnotics" (PDF). Psychopharmacol Bull. 37 (1): 10–29. doi:10.1007/BF01990373. PMID 14561946. S2CID 1543185. Archived from the original (PDF) on 2007-07-09.
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  27. "Potentially habit-forming herbal sleep aid recalled". CBC News. Feb 23, 2007. Retrieved 2020-07-03.
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  • "Estazolam". Drug Information Portal. U.S. National Library of Medicine.
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