Estazolam: Difference between revisions

{{Drugbox

| verifiedrevid = 443736153

| IUPAC_name = 8-Chloro-6-phenyl-<BR>4''H''-1,2,4-triazolo(4,3-''a'')-<BR>1,4-benzodiazepine

| width = 180

| tradename =

| pregnancy_category = ? ([[United States|USA]])

| routes_of_administration = Oral

| metabolism = [[Liver|Hepatic]]

| elimination_half-life = 10-24 hours

| excretion = [[Kidney|Renal]]

| CASNo_Ref = {{cascite|correct|CAS}}

| ATC_prefix = N05

| ATC_suffix = CD04

| ATC_supplemental =

| C=16 | H=11 | Cl=1 | N=4

| molecular_weight = 294.7

| smiles = Clc3cc2\C(=N/Cc1nncn1c2cc3)c4ccccc4

| InChI = 1/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

| InChIKey = CDCHDCWJMGXXRH-UHFFFAOYAH

'''Estazolam''' (marketed under the brand names '''ProSom''', '''Eurodin''') is a [[benzodiazepine]] [[derivative (chemistry)|derivative]] drug developed by Upjohn in the 1970s<ref>US Patent 3701782 - 1-CARBOLOWER ALKOXY-6-PHENYL-4H-S-TRIAZOLO(1,4)BENZODIAZEPINE COMPOUNDS</ref>. 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 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.<ref>{{cite journal |author=Roehrs T, Zorick F, Lord N, Koshorek GL, Roth T |title=Dose-related effects of estazolam on sleep of patients with insomnia |journal=J Clin Psychopharmacol |volume=3 |issue=3 |pages=152–6 |year=1983 |month=June |pmid=6135720 |doi= 10.1097/00004714-198306000-00002|url=}}</ref><ref>{{cite journal |author=Rosen RC, Lewin DS, Goldberg L, Woolfolk RL |title=Psychophysiological insomnia: combined effects of pharmacotherapy and relaxation-based treatments |journal=Sleep Med. |volume=1 |issue=4 |pages=279–288 |year=2000 |month=October |pmid=11040460 |doi= 10.1016/S1389-9457(00)00042-3|url=}}</ref> 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.<ref>{{cite journal |author=Mauro C, Sperlongano P |title=[Controlled clinical evaluation of 2 hypnotic triazole benzodiazepines, estazolam and triazolam, used the night before surgical interventions] |language=Italian |journal=Minerva Med. |volume=78 |issue=18 |pages=1381–4 |year=1987 |month=September |pmid=2889169 |doi= |url=}}</ref> Estazolam also has [[anxiolytic]] properties and due to its long half life can be an effective short term treatment for insomnia associated with [[anxiety]].<ref>{{cite journal |author=Post GL, Patrick RO, Crowder JE, ''et al.'' |title=Estazolam treatment of insomnia in generalized anxiety disorder: a placebo-controlled study |journal=J Clin Psychopharmacol |volume=11 |issue=4 |pages=249–53 |year=1991 |month=August |pmid=1918423 |doi= 10.1097/00004714-199108000-00005|url=}}</ref>

A hang-over effect commonly occurs with next day impairments of mental and physical performance impairments.<ref>{{cite journal |author=Müller KW, Müller-Limmroth W, Strasser H |title=[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)] |language=German |journal=Arzneimittelforschung |volume=32 |issue=4 |pages=456–60 |year=1982 |pmid=6125155 |doi= |url=}}</ref> Other side effects of estazolam include [[somnolence]], [[dizziness]], [[hypokinesia]], and abnormal [[motor coordination|coordination]].<ref>{{cite journal |author=Pierce MW, Shu VS, Groves LJ |title=Safety of estazolam. The United States clinical experience |journal=Am. J. Med. |volume=88 |issue=3A |pages=12S–17S |year=1990 |month=March |pmid=1968713 |doi= 10.1016/0002-9343(90)90280-Q|url=}}</ref>

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.<ref>{{cite journal |author=Kirkwood CK |title=Management of insomnia |journal=J Am Pharm Assoc (Wash) |volume=39 |issue=5 |pages=688–96; quiz 713–4 |year=1999 |pmid=10533351 |doi= |url=}}</ref><ref>{{cite journal |author=Lee YJ |title=Overview of the therapeutic management of insomnia with zolpidem |journal=CNS Drugs |volume=18 Suppl 1 |issue= |pages=17–23; discussion 41, 43–5 |year=2004 |pmid=15291010 |doi= 10.2165/00023210-200418001-00005|url=}}</ref> The short term benefits of benzodiazepines on sleep begin to reduce after a few days due to [[Drug tolerance|tolerance]] to the hypnotic effects of benzodiazepines in the elderly.<ref>{{cite journal |author=Grad RM |title=Benzodiazepines for insomnia in community-dwelling elderly: a review of benefit and risk |journal=J Fam Pract |volume=41 |issue=5 |pages=473–81 |year=1995 |month=November |pmid=7595266 |doi= |url=}}</ref>

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with [[comorbid]] [[psychiatric disorders]].<ref>{{Cite journal | last1 = Authier | first1 = N. | last2 = Balayssac | first2 = D. | last3 = Sautereau | first3 = M. | last4 = Zangarelli | first4 = A. | last5 = Courty | first5 = P. | last6 = Somogyi | first6 = AA. | last7 = Vennat | first7 = B. | last8 = Llorca | first8 = PM. | last9 = Eschalier | first9 = A. | title = Benzodiazepine dependence: focus on withdrawal syndrome. | journal = Ann Pharm Fr | volume = 67 | issue = 6 | pages = 408–13 | month= November| year = 2009 | doi = 10.1016/j.pharma.2009.07.001 | pmid = 19900604 }}</ref>

==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.<ref>{{cite journal | journal = Am J Geriatr Pharmacother | year = 2006 | month = June | volume = 4 | issue = 2 | pages = 168–92 | title = Management of chronic insomnia in elderly persons | author = Bain KT | pmid = 16860264 | doi = 10.1016/j.amjopharm.2006.06.006}}</ref>

Estazolam is classed as a "triazolo" benzodiazepine drug.<ref>{{cite journal | author = Braestrup C | coauthors = Squires RF. | date=1 April 1978| title = Pharmacological characterization of benzodiazepine receptors in the brain | journal = Eur J Pharmacol | volume = 48 | issue = 3 | pages = 263–70 | pmid = 639854 | doi = 10.1016/0014-2999(78)90085-7 }}</ref> Estazolam exerts its therapeutic effects via its benzodiazepines receptor agonist properties.<ref>{{cite journal |author=Akbarzadeh T, Tabatabai SA, Khoshnoud MJ, Shafaghi B, Shafiee A |title=Design and synthesis of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole derivatives as benzodiazepine receptor agonists |journal=Bioorg. Med. Chem. |volume=11 |issue=5 |pages=769–73 |year=2003 |month=March |pmid=12538007 |doi= 10.1016/S0968-0896(02)00469-8|url=http://linkinghub.elsevier.com/retrieve/pii/S0968089602004698}}</ref> Estazolam at high doses decreases histamine turnover via its action at the benzodiazepine-GABA receptor complex in mouse brains.<ref>{{cite journal | author = Oishi R | coauthors = Nishibori M, Itoh Y, Saeki K. | date= May 27, 1986 | title = Diazepam-induced decrease in histamine turnover in mouse brain | journal = Eur J Pharmacol. | volume = 124 | issue = 3 | pages = 337–42 | pmid = 3089825 | doi = 10.1016/0014-2999(86)90236-0 }}</ref>

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.<ref>{{cite journal |author=Allen MD, Greenblatt DJ, Arnold JD |title=Single- and multiple-dose kinetics of estazolam, a triazolo benzodiazepine |journal=Psychopharmacology (Berl.) |volume=66 |issue=3 |pages=267–74 |year=1979 |pmid=43552 |doi= 10.1007/BF00428318|url=}}</ref><ref>{{cite journal |author=Mancinelli A, Guiso G, Garattini S, Urso R, Caccia S |title=Kinetic and pharmacological studies on estazolam in mice and man |journal=Xenobiotica |volume=15 |issue=3 |pages=257–65 |year=1985 |month=March |pmid=2862746 |doi= 10.3109/00498258509045357|url=}}</ref> The major metabolite of estazolam is 4-hydroxyestazolam.<ref>{{cite journal |author=Miura M, Otani K, Ohkubo T |title=Identification of human cytochrome P450 enzymes involved in the formation of 4-hydroxyestazolam from estazolam |journal=Xenobiotica |volume=35 |issue=5 |pages=455–65 |year=2005 |month=May |pmid=16012077 |doi= 10.1080/00498250500111612|url=}}</ref>

==Interactions==

[[Ethanol|Alcohol]] enhances the [[sedative]] [[hypnotic]] properties of estazolam.<ref>{{cite journal |author=Wang JS, DeVane CL |title=Pharmacokinetics and drug interactions of the sedative hypnotics |journal=Psychopharmacol Bull |volume=37 |issue=1 |pages=10–29 |year=2003 |pmid=14561946 |doi= 10.1007/BF01990373|url=http://www.medworksmedia.com/psychopharmbulletin/pdf/12/010-029_PB%20W03_Wang_final.pdf |format=PDF}}</ref> Manufacturers warn in package inserts about an interaction with [[Ritonavir]], but clinical interactions of Ritonavir with estazolam have not yet been described.<ref>{{cite journal |author=Miura M, Ohkubo T, Sugawara K, Okuyama N, Otani K |title=Determination of estazolam in plasma by high-performance liquid chromatography with solid-phase extraction |journal=Anal Sci |volume=18 |issue=5 |pages=525–8 |year=2002 |month=May |pmid=12036118 |doi= 10.2116/analsci.18.525|url=http://www.jstage.jst.go.jp/article/analsci/18/5/525/_pdf |format=PDF}}</ref>

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 [[Cerebral cortex|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 [[Sound|auditory]] stimulation and to electric stimulation of the mesencephalic reticular formation, [[Posterior (anatomy)|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.<ref>{{cite journal | author = Watanabe S | coauthors = Ohta H, Sakurai Y, Takao K, Ueki S. | year = 1986 | month = July | title = [Electroencephalographic effects of 450191-S and its metabolites in rabbits with chronic electrode implants] | journal = Nippon Yakurigaku Zasshi. | volume = 88 | issue = 1 | pages = 19–32 | pmid = 3758874 | doi=10.1254/fpj.88.19}}</ref>

A primate study found that estazolam has abuse potential.<ref>{{cite journal |author=Johanson CE |title=Benzodiazepine self-administration in rhesus monkeys: estazolam, flurazepam and lorazepam |journal=Pharmacol. Biochem. Behav. |volume=26 |issue=3 |pages=521–6 |year=1987 |month=March |pmid=2883668 |doi= 10.1016/0091-3057(87)90159-6|url=http://linkinghub.elsevier.com/retrieve/pii/0091-3057(87)90159-6}}</ref> 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.<ref>{{cite journal |author=Griffiths RR, Johnson MW |title=Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds |journal=J Clin Psychiatry |volume=66 Suppl 9 |issue= |pages=31–41 |year=2005 |pmid=16336040 |doi= |url=}}</ref>

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.<ref>{{Cite web | url = http://www.fda.gov/bbs/topics/NEWS/NEW00625.html | title = FDA WARNS CONSUMERS AGAINST TAKING DIETARY SUPPLEMENT "SLEEPING BUDDHA" | accessdate = 21 December 2008 | author = Food and Drug Administration | authorlink = Food and Drug Administration | coauthors = U.S. Department of Health and Human Services | date = 10 March 1998 | publisher = FDA | location = USA}} {{Dead link|date=October 2010|bot=H3llBot}}</ref>

==See also==

*[[Long term effects of benzodiazepines]]

==References==

{{Reflist|2}}

==External links==

* [http://www.rxlist.com/cgi/generic2/estaz.htm Rx-List - Estazolam]

* [http://www.inchem.org/documents/pims/pharm/pim925.htm Inchem - Estazolam]

[[Category:Organochlorides]]

[[fr:Estazolam]]

[[ja:エスタゾラム]]

[[pl:Estazolam]]

[[pt:Estazolam]]

[[sv:Estazolam]]

[[zh:艾司唑侖]]