Estazolam

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Estazolam
Estazolam.svg
Estazolam3d.png
Systematic (IUPAC) name
8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Clinical data
Trade names ProSom
AHFS/Drugs.com monograph
MedlinePlus a691003
Pregnancy
category
  • US: X (Contraindicated)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability 93%
Metabolism Hepatic
Biological half-life 10–24 hours
Excretion Renal
Identifiers
CAS Number 29975-16-4 YesY
ATC code N05CD04 (WHO)
PubChem CID: 3261
IUPHAR/BPS 7550
DrugBank DB01215 YesY
ChemSpider 3146 YesY
UNII 36S3EQV54C YesY
KEGG D00311 YesY
ChEBI CHEBI:4858 YesY
ChEMBL CHEMBL285674 YesY
Chemical data
Formula C16H11ClN4
Molecular mass 294.7
  • ClC1=CC2=C(C=C1)N3C=NN=C3CN=C2C4=CC=CC=C4
  • 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 YesY
  • Key:CDCHDCWJMGXXRH-UHFFFAOYSA-N YesY
  (verify)

Estazolam[1] (marketed under the brand names ProSom, Eurodin) is a benzodiazepine derivative drug developed by Upjohn in the 1970s.[2] It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. Estazolam is an intermediate-acting oral benzodiazepine.

It is commonly prescribed for short-term treatment of insomnia.

Indications

Estazolam 1mg pills, sold as Eurodin, from Japan.

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]

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.[9][10] 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.[11]

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.[12]

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.[13]

Pharmacology

Estazolam is classed as a "triazolo" benzodiazepine drug.[14] Estazolam exerts its therapeutic effects via its benzodiazepines receptor agonist properties.[15] Estazolam at high doses decreases histamine turnover via its action at the benzodiazepine-GABA receptor complex in mouse brains.[16]

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.[17][18] The major metabolite of estazolam is 4-hydroxyestazolam.[19]

Interactions

Alcohol enhances the sedative hypnotic properties of estazolam.[20] Manufacturers warn in package inserts about an interaction with Ritonavir, but clinical interactions of Ritonavir with estazolam have not yet been described.[21]

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.[22]

Abuse

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See also: Benzodiazepine drug misuse

A primate study found that estazolam has abuse potential.[23] Estazolam 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.[24] Estazolam became notorious in 1998 when a large amount of a 'herbal sleeping mix' called Sleeping Buddha was recalled from the shelves after the FDA discovered that it contained estazolam.[25]

See also

References

  1. ↑ US Patent 4116956
  2. ↑ US Patent 3701782 - 1-CARBOLOWER ALKOXY-6-PHENYL-4H-S-TRIAZOLO(1,4)BENZODIAZEPINE COMPOUNDS
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External links

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