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Bromazepam
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| Systematic (IUPAC) name | |
| 9-bromo-6-pyridin-2-yl- 2,5-diazabicyclo[5.4.0]undeca-5,8,10,12-tetraen-3-one |
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| Identifiers | |
| CAS number | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| ChemSpider | |
| Chemical data | |
| Formula | C14H10BrN3O |
| Mol. mass | 316.2 |
| Pharmacokinetic data | |
| Bioavailability | 84% |
| Metabolism | Hepatic |
| Half life | 12-20 hours |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. |
D (USA) |
| Legal status |
Schedule IV(US) |
| Routes | Oral |
Bromazepam (marketed under brand names Calmepam, Compendium, Creosedin, Durazanil, Lectopam, Lexaurin, Lexilium, Lexomil, Lexotan, Lexotanil, Normoc, Novepam, Somalium, Lexatin)1 is a drug which is a benzodiazepine derivative, developed in 1970s.2 It has mainly anxiolytic and at higher doses also sedative, hypnotic and skeletal muscle relaxant properties.3
Contents |
Pharmacology
Bromazepam is a "classical" benzodiazepine; other classical benzodiazepines include; diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, flurazepam and clorazepate.4 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.5 It is a 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 GABAA, 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.6 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.7
Bromazepam alters electrical status of the brain causing an increased beta activity and a decrease in alpha activity in the EEG recordings.8
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.9 In 1995, J. van Harten at 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.10
The active metabolite of bromazepam is hydroxybromazepam, which has half life approximately equal to bromazepam.
Tolerance, dependence and withdrawal
Bromazepam shares with other benzodiazepines the risk of abuse, misuse, psychological and/or physical dependence.1112
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.13
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.14
Indications
- Short-term treatment of insomnia
- Short-term treatment of anxiety or panic attacks, 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 and Japan (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 available as Lexaurin in Croatia. 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 and Bosnia (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.15
Impaired psychomotor performance.16
Deterioration of attention capacity and impaired co-ordinative skills.17
Impaired reactive and attention performance, which may impair driving skills.18
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 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.
Special Populations
In 1987, a team of scientists lead by Ochs reported that the elimination half-life, peak serum concentration, and serum free fraction are significantly elevated and the oral clearance and volume of distribution significantly lowered in elderly subjects.19 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.20
References
- ^ PubChem Substance: Bromazepam National Center of Biotechnology Information.
- ^ "Bromazepam, a new anxiolytic: a comparative study with diazepam in general practice".
- ^ "Bromazepam prescribing information (Roche)".
- ^ Braestrup C; Squires RF. (1 April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". Eur J Pharmacol 48 (3): 263–70. doi:. PMID 639854.
- ^ Bromazepam Eutimia.com - Salud Mental. © 1999-2002.
- ^ Oelschläger H. (4 July 1989). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweiz Rundsch Med Prax. 78 (27-28): 766–72. PMID 2570451.
- ^ Stacher G; Stärker D (February 1974). "Inhibitory effect of bromazepam on basal and betazole-stimulated gastric acid secretion in man". Gut 15 (2): 116–20. doi:. PMID 4820635, http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1412901&blobtype=pdf.
- ^ Fink M; Weinfeld RE, Schwartz MA, Conney AH (August 1976). "Blood levels and electroencephalographic effects of diazepam and bromazepam". Clin Pharmacol Ther 20 (2): 184–91. PMID 7375.
- ^ 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 English Fulltext (registration required) Japanese Fulltext (PDF, no registration)
- ^ van Harten J. "Overview of the pharmacokinetics of fluvoxamine." Clinical Pharmacokinetics. 1995;29 Suppl 1:1-9. PMID 8846617
- ^ Rastogi RB; Lapierre YD, Singhal RL (1978). "Some neurochemical correlates of "rebound" phenomenon observed during withdrawal after long-term exposure to 1, 4-benzodiazepines". Prog Neuropsychopharmacol 2 (1): 43–54. doi:. PMID 31644.
- ^ Laux G (May 1979). "[A case of Lexotanil dependence. Case report on tranquilizer abuse]". Nervenarzt 50 (5): 326–7. PMID 37451.
- ^ Chouinard G; Labonte A, Fontaine R, Annable L (1983). "New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines". Prog Neuropsychopharmacol Biol Psychiatry 7 (4-6): 669–73. doi:. PMID 6141609.
- ^ Agarwal RA; Lapierre YD, Rastogi RB, Singhal RL (May 1977). "Alterations in brain 5-hydroxytryptamine metabolism during the 'withdrawal' phase after chronic treatment with diazepam and bromazepam". Br J Pharmacol 60 (1): 3–9. PMID 18243, http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1667179&blobtype=pdf.
- ^ Liljequist R; Linnoila M, Mattila MJ, Saario I, Seppälä T (October 1975). "Effect of two weeks' treatment with thioridazine, chlorpromazine, sulpiride and bromazepam, alone or in combination with alcohol, on learning and memory in man". Psychopharmacologia 44 (2): 205–8. doi:. PMID 710.
- ^ Stacher G; Bauer P, Brunner H, Grünberger J (January 1976). "Gastric acid secretion, serum-gastrin levels and psychomotor function under the influence of placebo, insulin-hypoglycemia, and/or bromazepam". Int J Clin Pharmacol Biopharm 13 (1): 1–10. PMID 2560.
- ^ Saario I (April 1976). "Psychomotor skills during subacute treatment with thioridazine and bromazepam, and their combined effects with alcohol". Ann Clin Res 8 (2): 117–23. PMID 7178.
- ^ Seppälä T; Saario I, Mattila MJ (1976). "Two weeks' treatment with chlorpromazine, thioridazine, sulpiride, or bromazepam: actions and interactions with alcohol on psychomotor skills related to driving". Mod Probl Pharmacopsychiatry 11: 85–90. PMID 9581.
- ^ 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
- ^ List of psychotropic substances under international control (PDF). International Narcotics Control Board.
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- This page was last modified on 24 November 2008, at 00:39.
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