Bromazepam (marketed under several brand names, including Lectopam, Lexotan, Lexilium, Lexaurin, Brazepam, Rekotnil, Bromaze, Somalium, Lexatin and Lexotanil) is a benzodiazepine derivative drug, patented by Roche in 1963 and developed clinically in the 1970s. It is mainly an anti-anxiety agent with similar side effects to diazepam (Valium). In addition to being used to treat anxiety or panic states, bromazepam may be used as a premedicant prior to minor surgery. Bromazepam typically comes in doses of 3 mg and 6 mg tablets. Bromazepam is contraindicated and should be used with caution in women who are pregnant, the elderly, patients with a history of alcohol or other substance abuse disorders and children. Prolonged use of bromazepam causes tolerance and may lead to both physical and psychological dependence on the drug, and as a result, it is a medication which is controlled by international law.
Bromazepam is similar in side effects to other benzodiazepines. The most common side effects reported are drowsiness, sedation, ataxia, memory impairment, and dizziness. Impairments to memory functions are common with bromazepam and include a reduced working memory and reduced ability to process environmental information. A 1975 experiment on healthy, male college students exploring the effects of four different drugs on learning capacity observed that taking bromazepam alone at 6 mg 3 times daily for 2 weeks impaired learning capacities significantly. In combination with alcohol, impairments in learning capacity became even more pronounced. Various studies report impaired memory, visual information processing and sensory data and impaired psychomotor performance; deterioration of cognition including attention capacity and impaired co-ordinative skills; impaired reactive and attention performance, which can impair driving skills; drowsiness and decrease in libido. Unsteadiness after taking bromazepam is, however, less pronounced than other benzodiazepines such as lorazepam.
On occasion, benzodiazepines can induce extreme alterations in memory such as anterograde amnesia and amnesic automatism, which may have medico-legal consequences. Such reactions occur usually only at the higher dose end of the prescribing spectrum.
Very rarely, dystonia can develop.
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.
Tolerance, dependence and withdrawal
Bromazepam shares with other benzodiazepines the risk of abuse, misuse, psychological dependence or physical dependence. A withdrawal study demonstrated both psychological dependence and physical dependence on bromazepam including marked rebound anxiety after 4 weeks chronic use. Those whose dose was gradually reduced experienced no 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 bromazepam. Abrupt or over rapid withdrawal from bromazepam after chronic use even at therapeutic prescribed doses can lead to a severe withdrawal syndrome including status epilepticus and a condition resembling delerium tremens.
Animal studies have shown that chronic administration of diazepam or bromazepam causes a decrease in spontaneous locomotor activity, decreased turnover of noradrenaline and dopamine and serotonin, increased activity of tyrosine hydroxylase and increased levels of the catecholamines. During withdrawal of bromazepam or diazepam a fall in tryptophan, serotonin levels occurs as part of the benzodiazepine withdrawal syndrome. Changes in the levels of these chemicals in the brain can cause headaches, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, dysphoria, dizziness, derealization, depersonalization, numbness/tingling of extremities, hypersensitivity to light, sound, and smell, perceptual distortions, nausea, vomiting, diarrhea, appetite loss, hallucinations, delirium, seizures, tremor, stomach cramps, myalgia, agitation, palpitations, tachycardia, panic attacks, short-term memory loss, and hyperthermia.
Contraindications and special precautions
Benzodiazepines require special precaution if used in elderly, pregnant, child, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.
Cimetidine, fluvoxamine and propranolol causes a marked increase in the elimination half-life of bromazepam leading to increased accumulation of bromazepam.
Bromazepam is a "classical" benzodiazepine; other classical benzodiazepines include; diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, flurazepam, and clorazepate. Its molecular structure is composed of a diazepine connected to a benzene ring and a pyridine ring, the benzene ring having a single nitrogen atom that replaces one of the carbon atoms in the ring structure. 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 the inhibitory effects of GABA. Bromazepam is a long-acting benzodiazepine and is lipophilic and metabolised hepatically via oxidative pathways. It does not possess any antidepressant or antipsychotic 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.
Bromazepam alters the electrical status of the brain causing an increase in beta activity and a decrease in alpha activity in EEG recordings.
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, a member of the Cytochrome P450 family, was not the responsible enzyme since itraconazole, a known inhibitor of CYP3A4, did not affect its metabolism. 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.
The active metabolite of bromazepam is hydroxybromazepam, which has a half-life approximately equal to that of bromazepam.
Bromazepam is commonly involved in drug overdoses. A severe bromazepam benzodiazepine overdose may result in an alpha pattern coma type. The toxicity of bromazepam in overdosage increases when combined with other CNS depressant drugs such as alcohol or sedative hypnotic drugs. Bromazepam is the most common benzodiazepine involved in intentional overdoses in France. Bromazepam has also been responsible for accidental poisonings in companion animals. A review of benzodiazepine poisonings in cats and dogs from 1991-1994 found bromazepam to be responsible for significantly more poisonings than any other benzodiazepine.
Bromazepam has a similar misuse risk as other benzodiazepines such as diazepam. In France car accidents involving psychotropic drugs in combination with alcohol (itself a major contributor) found benzodiazepines, mainly diazepam, nordiazepam, and bromazepam, to be the most common drug present in the blood stream, almost twice that of the next-most-common drug cannabis. Bromazepam has also been used in serious criminal offences including robbery, homicide, and sexual assault.
Bromazepam is a Schedule IV drug under the Convention on Psychotropic Substances.
- ^ "Benzodiazepine Names". non-benzodiazepines.org.uk. Archived from the original on 2008-12-08. Retrieved 2008-10-31.
- ^ US patent 3100770, Rodney Ian Friar, "5-PYRIDYL-1,4-Benzodiazepine Compounds", published 1961-11-7, issued 1963-13-7
- ^ "Bromazepam, a new anxiolytic: a comparative study with diazepam in general practice. Royal College of General Practitioners Medicines Surveillance Organisation". J R Coll Gen Pract. 34 (266): 509–12. September 1984. PMC 1959670 . PMID 6147412.
- ^ Fontaine, R; Annable, L; Beaudry, P; Mercier, P; Chouinard, G (1985). "Efficacy and withdrawal of two potent benzodiazepines: bromazepam and lorazepam". Psychopharmacology bulletin. 21 (1): 91–2. ISSN 0048-5764. PMID 2858908.
- ^ "Bromazepam". Pharmaceutical Benefits Scheme (PBS). Australian Government - Department of Health. Retrieved 23 March 2014.
- ^ "Content Not Available". www.uptodate.com. Retrieved 2017-09-07.
- ^ "LECTOPAM®". RxMed. RxMed. Retrieved 23 March 2014.
- ^ Münte TF, Gehde E, Johannes S, Seewald M, Heinze HJ (1996). "Effects of alprazolam and bromazepam on visual search and verbal recognition memory in humans: a study with event-related brain potentials". Neuropsychobiology. 34 (1): 49–56. doi:10.1159/000119291. PMID 8884760.
- ^ Montenegro M, Veiga H, Deslandes A, et al. (June 2005). "[Neuromodulatory effects of caffeine and bromazepam on visual event-related potential (P300): a comparative study.]". Arq Neuropsiquiatr. 63 (2B): 410–5. doi:10.1590/S0004-282X2005000300009. PMID 16059590.
- ^ Cunha M, Portela C, Bastos VH, et al. (December 2008). "Responsiveness of sensorimotor cortex during pharmacological intervention with bromazepam". Neurosci. Lett. 448 (1): 33–6. doi:10.1016/j.neulet.2008.10.024. PMID 18938214.
- ^ 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:10.1007/BF00421011. 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.
- ^ Bourin M, Auget JL, Colombel MC, Larousse C (1989). "Effects of single oral doses of bromazepam, buspirone and clobazam on performance tasks and memory". Neuropsychobiology. 22 (3): 141–5. doi:10.1159/000118609. PMID 2577220.
- ^ Puga F, Sampaio I, Veiga H, et al. (December 2007). "The effects of bromazepam on the early stage of visual information processing (P100)". Arq Neuropsiquiatr. 65 (4A): 955–9. doi:10.1590/s0004-282x2007000600006. PMID 18094853.
- ^ 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.
- ^ Jansen, AA; Verbaten, MN; Slangen, JL (1988). "Acute effects of bromazepam on signal detection performance, digit symbol substitution test and smooth pursuit eye movements". Neuropsychobiology. 20 (2): 91–5. doi:10.1159/000118481. PMID 2908134.
- ^ 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.
- ^ Horseau, C; Brion, S (May 1982). "Clinical trial of bromazepam. Thirty-four cases (author's transl)". La Nouvelle presse médicale. 11 (22): 1741–3. ISSN 0301-1518. PMID 6124948.
- ^ Perret, J; Zagala, A; Gaio, Jm; Hommel, M; Meaulle, F; Pellat, J; Pollak, P (May 1982). "Bromazepam in anxiety. Clinical evaluation (author's transl)". La Nouvelle presse médicale. 11 (22): 1722–4. ISSN 0301-1518. PMID 6124942.
- ^ Patat A, Foulhoux P (July 1985). "Effect on postural sway of various benzodiazepine tranquillizers". Br J Clin Pharmacol. 20 (1): 9–16. doi:10.1111/j.1365-2125.1985.tb02792.x. PMC 1400619 . PMID 2862898.
- ^ Rager, P; Bénézech, M (Jan 1986). "Memory gaps and hypercomplex automatisms after a single oral dose of benzodiazepines: clinical and medico-legal aspects". Annales medico-psychologiques. 144 (1): 102–9. ISSN 0003-4487. PMID 2876672.
- ^ Pérez Trullen JM, Modrego Pardo PJ, Vázquez André M, López Lozano JJ (1992). "Bromazepam-induced dystonia". Biomed. Pharmacother. 46 (8): 375–6. doi:10.1016/0753-3322(92)90306-R. PMID 1292648.
- ^ 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:10.1016/0364-7722(78)90021-8. PMID 31644.
- ^ Laux G (May 1979). "[A case of Lexotanil dependence. Case report on tranquilizer abuse]". Nervenarzt. 50 (5): 326–7. PMID 37451.
- ^ Fontaine, R; Chouinard, G; Annable, L (Jul 1984). "Rebound anxiety in anxious patients after abrupt withdrawal of benzodiazepine treatment". The American Journal of Psychiatry. 141 (7): 848–52. doi:10.1176/ajp.141.7.848. ISSN 0002-953X. PMID 6145363.
- ^ 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:10.1016/0278-5846(83)90043-X. PMID 6141609.
- ^ Böning, J (May 1981). "Bromazepam withdrawal delirium - a psychopharmacological contribution to clinical withdrawal syndromes (author's transl)". Der Nervenarzt. 52 (5): 293–7. ISSN 0028-2804. PMID 6113557.
- ^ Thomas P, Lebrun C, Chatel M (1993). "De novo absence status epilepticus as a benzodiazepine withdrawal syndrome". Epilepsia. 34 (2): 355–8. doi:10.1111/j.1528-1157.1993.tb02421.x. PMID 8384109.
- ^ Fukuda M, Nakajima N, Tomita M (January 1999). "Generalized tonic-clonic seizures following withdrawal of therapeutic dose of bromazepam". Pharmacopsychiatry. 32 (1): 42–3. doi:10.1055/s-2007-979188. PMID 10071183.
- ^ 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. doi:10.1111/j.1476-5381.1977.tb16740.x. PMC 1667179 . PMID 18243.
- ^ Professor Heather Ashton (2002). "Benzodiazepines: How They Work and How to Withdraw".
- ^ O'Connor, RD (1993). "Benzodiazepine dependence--a treatment perspective and an advocacy for control". NIDA research monograph. 131: 266–9. PMID 8105385.
- ^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr. 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
- ^ Ochs, HR; Greenblatt, DJ; Friedman, H; Burstein, ES; Locniskar, A; Harmatz, JS; Shader, RI. (May 1987). "Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol". Clinical Pharmacology & Therapeutics. 41 (5): 562–70. doi:10.1038/clpt.1987.72. PMID 2882883.
- ^ Hobi, V; Kielholz, P; Dubach, Uc (Oct 1981). "The effect of bromazepam on fitness to drive (author's transl)". MMW, Munchener medizinische Wochenschrift. 123 (42): 1585–8. ISSN 0341-3098. PMID 6118830.
- ^ Hoffman LaRoche Pharmaceuticals (3 April 2008). "NAME OF THE MEDICINE LEXOTAN". Australia: roche-australia.com. Archived from the original (PDF) on 19 July 2008. Retrieved 16 December 2008.
- ^ Martens PR (June 1994). "A sudden infant death like syndrome possibly induced by a benzodiazepine in breast-feeding". Eur J Emerg Med. 1 (2): 86–7. doi:10.1097/00063110-199406000-00008. PMID 9422145.
- ^ Ochs HR, Greenblatt DJ, Friedman H, et al. (May 1987). "Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine, and propranolol". Clin. Pharmacol. Ther. 41 (5): 562–70. doi:10.1038/clpt.1987.72. PMID 2882883.
- ^ Perucca E, Gatti G, Spina E (September 1994). "Clinical pharmacokinetics of fluvoxamine". Clin Pharmacokinet. 27 (3): 175–90. doi:10.2165/00003088-199427030-00002. PMID 7988100.
- ^ a b van Harten J (1995). "Overview of the pharmacokinetics of fluvoxamine". Clin Pharmacokinet. 29 (Suppl 1): 1–9. doi:10.2165/00003088-199500291-00003. PMID 8846617.
- ^ Braestrup C; Squires RF. (1 April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". Eur J Pharmacol. 48 (3): 263–70. doi:10.1016/0014-2999(78)90085-7. 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.
- ^ Amphoux, G; Agussol, P; Girard, J (May 1982). "The action of bromazepam on anxiety (author's transl)". La Nouvelle presse médicale. 11 (22): 1738–40. ISSN 0301-1518. PMID 6124947.
- ^ 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:10.1136/gut.15.2.116. PMC 1412901 . PMID 4820635.
- ^ 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. doi:10.1002/cpt1976202184. PMID 7375.
- ^ Oda, M; Kotegawa, T; Tsutsumi, K; Ohtani, Y; Kuwatani, K; Nakano, S (Nov 2003). "The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers" (PDF). European Journal of Clinical Pharmacology. 59 (8-9): 615–9. doi:10.1007/s00228-003-0681-4. PMID 14517708. Archived from the original (PDF) on 2005-08-20.
- ^ Gandolfi E, Andrade Mda G (December 2006). "[Drug-related toxic events in the state of São Paulo, Brazil]". Rev Saude Publica (in Portuguese). 40 (6): 1056–64. PMID 17173163.
- ^ Pasinato, E; Franciosi, A; De Vanna, M (Apr 1983). ""Alpha pattern coma" after poisoning with flunitrazepam and bromazepam. Case description". Minerva psichiatrica. 24 (2): 69–74. ISSN 0374-9320. PMID 6140613.
- ^ Marrache F, Mégarbane B, Pirnay S, Rhaoui A, Thuong M (October 2004). "Difficulties in assessing brain death in a case of benzodiazepine poisoning with persistent cerebral blood flow". Hum Exp Toxicol. 23 (10): 503–5. doi:10.1191/0960327104ht478cr. PMID 15553176.
- ^ Staikowsky F, Theil F, Candella S (July 2005). "[Trends in the pharmaceutical profile of intentional drug overdoses seen in the emergency room]". Presse Med (in French). 34 (12): 842–6. PMID 16097205.
- ^ Bertini, S; Buronfosse F; Pineau X; Berny P; Lorgue G. (Dec 1995). "Benzodiazepine poisoning in companion animals". Vet Hum Toxicol. 37 (6): 559–62. PMID 8588297.
- ^ Woods, Jh (Mar 1984). "Progress report on the stimulant-depressant abuse liability evaluation project". NIDA research monograph. 49: 59–62. ISSN 1046-9516. PMID 6148695.
- ^ Staub C, Lacalle H, Fryc O (1994). "[Presence of psychotropic drugs in the blood of drivers responsible for car accidents, and who consumed alcohol at the same time]". Soz Praventivmed (in French). 39 (3): 143–9. PMID 8048274.
- ^ Brinkmann, B; Fechner, G; Püschel, K (Dec 1984). "Identification of mechanical asphyxiation in cases of attempted masking of the homicide". Forensic Science International. 26 (4): 235–45. doi:10.1016/0379-0738(84)90028-8. ISSN 0379-0738. PMID 6519613.
- ^ de Boisjolly JM, Rougé-Maillart C, Roy PM, Roussel B, Turcant A, Delhumeau A (August 2003). "[Chemical submission]". Presse Med (in French). 32 (26): 1216–8. PMID 14506459.
- ^ Djezzar S, Questel F, Burin E, Dally S (October 2008). French Network of Centers for Evaluation Information on Pharmacodependence. "Chemical submission: results of 4-year French inquiry" (PDF). Int. J. Legal Med. 123 (3): 213–9. doi:10.1007/s00414-008-0291-x. PMID 18925406.
- ^ List of psychotropic substances under international control Archived December 5, 2005, at the Wayback Machine. (PDF). International Narcotics Control Board.
- ^ [drugsynthesis.blogspot.co.uk]