Bromazepam
1120701
224396322
2008-07-08T17:48:30Z
BOT-Superzerocool
338065
robot Adding: [[es:Bromazepam]]
{{Drugbox|
|IUPAC_name = 9-bromo-6-pyridin-2-yl-<br>2,5-diazabicyclo[5.4.0]undeca-5,8,10,12-tetraen-3-one
| image=Bromazepam.svg
| image2 = Bromazepam 3D.png
| CAS_number=1812-30-2
| ATC_prefix=N05
| ATC_suffix=BA08
| ATC_supplemental=
| PubChem=2441
| DrugBank=?
| C=14 | H=10 | Br=1 | N=3 | O=1
| molecular_weight = 316.2
| bioavailability= 84%
| metabolism = [[Liver|Hepatic]]
| elimination_half-life= 12-20 hours
| excretion = [[Kidney|Renal]]
| pregnancy_category = D ([[United States|USA]])
| legal_status = [[Schedule IV controlled substance|Schedule IV]](US)
| routes_of_administration= Oral
}}
'''Bromazepam''' (marketed under brand names Calmepam, Compendium, Creosedin, Durazanil, Lectopam, Lexaurin, Lexilium, Lexomil, Lexotan, Lexotanil, Normoc, Novepam, Somalium, Lexatin)<ref name="brandnames">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pcsubstance_mesh&from_uid=2908134 PubChem Substance: Bromazepam] National Center of Biotechnology Information.</ref> is a drug which is a [[benzodiazepine]] derivative. It has mainly [[anxiolytic]] and at higher doses also [[sedative]], [[hypnotic]] and [[skeletal muscle relaxant]] properties (see P.I. information on links).
==Pharmacology==
Bromazepam is a "classical" benzodiazepine; other classical benzodiazepines include; [[diazepam]], [[clonazepam]], [[oxazepam]], [[lorazepam]], [[nitrazepam]], [[flurazepam]] and [[clorazepate]].<ref>{{cite journal | author = Braestrup C | coauthors = Squires RF. | year = 1978 | month = Apr | day = 1 | 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> Its molecular structure is composed of a [[diazepine]] connected to a [[benzene]] ring and a [[pyridine]] ring, the benzene ring having a [[bromine]] atom attached to it.<ref name="bromazepamstructure">[http://www.eutimia.com/psicofarmacos/ansioliticos/bromazepam.htm Bromazepam] Eutimia.com - Salud Mental. © 1999-2002.</ref> It is a [[benzodiazepine|1,4-benzodiazepine]], which means that the nitrogens on the seven-sided diazepine ring are in the 1 and 4 positions.
Bromazepam binds to the [[GABA]] receptor [[GABA A receptor|GABA<sub>A</sub>]], causing a conformational change and increasing inhibitory effects of GABA. Other neurotransmitters are not influenced. Bromazepam is intermediate-short acting benzodiazepine and is [[lipophilic]], is metabolised hepatically via oxidative pathways.<ref>{{cite journal | author = Oelschläger H. | coauthors = | year = 1989 | month = Jul | date = 4 | title = [Chemical and pharmacologic aspects of benzodiazepines] | journal = Schweiz Rundsch Med Prax. | volume = 78 | issue = 27-28 | pages = 766–72 | pmid = 2570451 }}</ref> It does not possess any antidepressant qualities.
After night time administration of bromazepam a highly significant reduction of gastric acid secretion occurs during sleep followed by a highly significant rebound in gastric acid production the following day.<ref>{{cite journal | author = Stacher G | coauthors = Stärker D | year = 1974 | month = Feb | title =Inhibitory effect of bromazepam on basal and betazole-stimulated gastric acid secretion in man | journal = Gut | volume = 15 | issue = 2 | pages = 116–20 | pmid = 4820635 | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1412901&blobtype=pdf | type = PDF | doi = 10.1136/gut.15.2.116}}</ref>
Bromazepam alters electrical status of the brain causing an increased beta activity and a decrease in alpha activity in the EEG recordings.<ref>{{cite journal | journal = Clin Pharmacol Ther | year = 1976 | month = Aug | volume = 20 |issue=2 | pages = 184–91 | title =Blood levels and electroencephalographic effects of diazepam and bromazepam | author = Fink M | coauthors = Weinfeld RE, Schwartz MA, Conney AH | pmid = 7375}}</ref>
==Pharmacokinetics==
Bromazepam is reported to be metabolized by a hepatic enzyme belonging to the [[Cytochrome P450]] family of enzymes. In 2003, a team led by Dr. Oda Manami at Oita Medical University reported that [[CYP3A4]] was not the responsible enzyme, seeing as [[itraconazole]], a known inhibitor of [[CYP3A4]], did not effect its metabolism.<ref name="itraconazole">Oda M, Kotegawa T, Tsutsumi K, Ohtani Y, Kuwatani K, Nakano S. "The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers." ''European Journal of Clinical Pharmacology.'' 2003 Nov;59(8-9):615-9. Epub 2003 Sep 27. PMID 14517708 [http://dx.doi.org/10.1007/s00228-003-0681-4 English Fulltext (registration required)] [http://www.oita-u.ac.jp/gakui/ik-307.pdf Japanese Fulltext (PDF, no registration)]</ref> In [[1995]], J. van Harten at [[Solvay Pharmaceuticals B.V.|Solvay Duphar B.V.]]'s Department of Clinical Pharmacology in [[Weesp]] reported that [[fluvoxamine]], which is a potent inhibitor of CYP1A2, a less potent [[CYP3A4]] inhibitor, and a negligible inhibitor of [[CYP2D6]], does inhibit its metabolism.<ref name="fluvoxamine">van Harten J. "Overview of the pharmacokinetics of fluvoxamine." ''Clinical Pharmacokinetics.'' 1995;29 Suppl 1:1-9. PMID 8846617</ref>
The active metabolite of bromazepam is hydroxybromazepam, which has half life approximately equal to bromazepam.
==Tolerance, dependence and withdrawal==
Patients treated with bromazepam for generalised anxiety disorder were found to experience withdrawal symptoms such as a worsening of anxiety, as well as the development of physical withdrawal symptoms when abruptly withdrawn from bromazepam.<ref>{{cite journal |author=Chouinard G |coauthors=Labonte A, Fontaine R, Annable L |year=1983 |title=New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines |volume=7 |issue=4-6 |pages=669–73 |pmid=6141609 |journal=Prog Neuropsychopharmacol Biol Psychiatry |doi=10.1016/0278-5846(83)90043-X}}</ref>
Animal studies have shown that chronic administration of [[diazepam]] or bromazepam causes a decrease in spontaneous locomotor activity and the turnover of noradrenaline and dopamine and serotonin, decreased activity of tyrosine hydroxylase and increased levels of the catecholamines. During withdrawal of bromazepam or diazepam a fall in tryptophan, 5-hydroxytryptamine levels occurs as part of the [[benzodiazepine withdrawal syndrome]].<ref>{{cite journal | journal = Br J Pharmacol | year = 1977 | month = May | volume = 60 |issue=1 | pages = 3–9 | title =Alterations in brain 5-hydroxytryptamine metabolism during the 'withdrawal' phase after chronic treatment with diazepam and bromazepam | author = Agarwal RA | coauthors = Lapierre YD, Rastogi RB, Singhal RL | pmid = 18243 | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1667179&blobtype=pdf}}</ref>
Bromazepam shares with other benzodiazepines the risk of abuse, misuse, psychological and/or physical dependence. According to many psychiatric experts Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. Due to its relatively short halflife and duration of action (8 to 12 hours), withdrawal symptoms may be more severe and more frequently encountered than with long acting benzodiazepines.
==Indications==
* Short-term treatment of [[insomnia]]
* Short-term treatment of [[anxiety]] or [[panic attack]]s, if a benzodiazepine is required
* Alleviation of the symptoms of alcohol- and opiate-withdrawal, under close [[clinical supervision]]
===Availability===
Bromazepam is available as a generic in Belgium (as Lexotan), Bosnia, Bulgaria, Canada, Chile, Denmark (as Bromam), Estonia, France, Germany, Israel (Lenitin, by Teva), Italy, Kosovo province, the Republic of Macedonia, The Netherlands, Latvia, (as Lexotanil), Poland, Portugal and Switzerland.
It is also available as Lexotanil in Bangladesh, Colombia, Greece, Pakistan, United Arab Emirates and Venezuela.
It is available as Lexotan and Somalium in Australia, Brazil, Portugal, Singapore, and the Philippines.
It is available as Lexilium in the Republic of Macedonia and Serbia (also as a generic, produced by ZORKA Pharma).
Bromazepam is also available in Canada as Lectopam.
Bromazepam is available in Yemen as Novepam and in Cambodia as Lexomil.
And it is also available in Spain as Lexatin.
==Dosage==
Usually, 3 mg to 6 mg at bedtime, with additional 1.5 mg to 3 mg during the next day if needed. Malnourished patients, patients with compromised cardiovascular, liver or renal function, and elderly patients should receive lower doses. In hospitalized patients with severe agitation and/or anxiety, daily doses of up to 24 mg have been given and tolerated for a limited period of time. A 3 mg dose of bromazepam is equivalent to a 5 mg dose of [[diazepam]].
==Side-effects==
All common side-effects of benzodiazepines have been noted. Consult the article under [[Diazepam]]. Euphoria, leading to a high abuse potential, is quite often reported.
Bromazepam taken alone impairs learning capacities significantly in humans. In combination with alcohol the impairments of learning capacity become even more pronounced.<ref>{{cite journal | journal = Psychopharmacologia | author = Liljequist R | coauthors = Linnoila M, Mattila MJ, Saario I, Seppälä T | year = 1975 | month = Oct | title =Effect of two weeks' treatment with thioridazine, chlorpromazine, sulpiride and bromazepam, alone or in combination with alcohol, on learning and memory in man | volume = 44 | issue = 2 | pages = 205–8 | pmid = 710 | doi = 10.1007/BF00421011}}</ref>
Impaired psychomotor performance.<ref>{{cite journal | journal = Int J Clin Pharmacol Biopharm | author = Stacher G | coauthors = Bauer P, Brunner H, Grünberger J | year = 1976 | month = Jan | volume = 13 | issue = 1 | pages = 1–10 | title =Gastric acid secretion, serum-gastrin levels and psychomotor function under the influence of placebo, insulin-hypoglycemia, and/or bromazepam | pmid = 2560}}</ref>
Deterioration of attention capacity and impaired co-ordinative skills.<ref>{{cite journal | journal = Ann Clin Res | year = 1976 | month = Apr | volume = 8 |issue=2 | pages = 117–23 | title =Psychomotor skills during subacute treatment with thioridazine and bromazepam, and their combined effects with alcohol | author = Saario I | pmid = 7178}}</ref>
Impaired reactive and attention performance, which may impair driving skills.<ref>{{cite journal | journal = Mod Probl Pharmacopsychiatry | year = 1976 | volume = 11 | pages = 85–90 | title =Two weeks' treatment with chlorpromazine, thioridazine, sulpiride, or bromazepam: actions and interactions with alcohol on psychomotor skills related to driving | author = Seppälä T | coauthors = Saario I, Mattila MJ | pmid = 9581}}</ref>
Up to 30% treated on a long-term basis develop a form of dependence, i.e. these patients cannot stop the medication without experiencing physical and/or psychological [[benzodiazepine withdrawal symptoms]].
Leukopenia and liver-damage of the cholostatic type with or without jaundice (icterus) have additionally been seen; the original manufacturer [[Hoffmann-La Roche|Roche]] recommends regular laboratory examinations to be performed routinely.
Ambulatory patients should be warned that Bromazepam may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. During the course of therapy, tolerance to the sedative effect usually develops.
==Contraindications==
The general contraindications for benzodiazepines apply. Consult the section under [[Diazepam#Contraindications|Diazepam]].
===Special Populations===
In 1987, a team of scientists lead by Ochs reported that the elimination half-life, peak [[Wiktionary:serum concentration|serum concentration]], and [[Wiktionary:serum free fraction|serum free fraction]] are significantly elevated and the [[Wiktionary:oral clearance|oral clearance]] and [[volume of distribution]] significantly lowered in elderly subjects.<ref name="bromazepamold">Ochs HR, Greenblatt DJ, Friedman H, Burstein ES, Locniskar A, Harmatz JS, Shader RI. "Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol." ''Clinical Pharmacology & Therapeutics.'' 1987 May;41(5):562-70. PMID 2882883</ref> The clinical consequence is that the elderly should be treated with lower doses than younger patients.
==Legal Status==
Bromazepam is a [[Schedule IV]] drug under the [[Convention on Psychotropic Substances]].<ref name="schedule4">[http://www.incb.org/pdf/e/list/green.pdf List of psychotropic substances under international control] (PDF). International Narcotics Control Board.</ref>
==References==
{{reflist}}
==External links==
* [http://www.pbs.gov.au/pi/roplexot10207.pdf Lexotan P.I.]
* [http://www.inchem.org/documents/pims/pharm/pim281.htm Inchem - Bromazepam]
* [http://www.pharmamotion.com.ar/animation-benzodiazepines-diazepam-lorazepam-alprazolam.html Flash animation about how bromazepam works (mechanism of action)]
{{Benzodiazepines}}
{{Anxiolytics}}
[[Category:Benzodiazepines]]
[[Category:Hypnotics]]
[[Category:Bromine compounds]]
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