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Bromazepam (marketed under several brand names, including Lectopam, Lexotan, Lexilium, Lexaurin, Brazepam, Rekotnil, Bromaze, Somalium and Lexotanil)^[1] is a benzodiazepine derivative drug, patented by Roche in 1963^[2] and developed clinically in the 1970s.^[3]^[4] 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.^[5] 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.

Indications

Short-term treatment of anxiety or panic attacks, if a benzodiazepine is required.^[6]
Premedication to alleviate anxiety before surgery.^[7]

Side-effects

Bromazepam is similar in side effects to other benzodiazepines. The most common side effects reported are drowsiness, sedation, ataxia, memory impairment, and dizziness.^[8] Impairments to memory functions are common with bromazepam and include a reduced working memory and reduced ability to process environmental information.^[9]^[10]^[11] 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.^[12] Various studies report impaired memory, visual information processing and sensory data and impaired psychomotor performance;^[13]^[14]^[15] deterioration of cognition including attention capacity and impaired co-ordinative skills;^[16]^[17] impaired reactive and attention performance, which can impair driving skills;^[18] drowsiness and decrease in libido.^[19]^[20]Unsteadiness after taking bromazepam is, however, less pronounced than other benzodiazepines such as lorazepam.^[21]

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.^[22]

Very rarely, dystonia can develop.^[23]

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.^[24]^[25] 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.^[26]

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.^[27] 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.^[28]^[29]^[30]

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.^[31] 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.^[32]^[33]

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.^[34]

Special populations

In 1987, a team of scientists led 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.^[35] The clinical consequence is that the elderly should be treated with lower doses than younger patients.
Bromazepam may affect driving and ability to operate machinery.^[36]
Bromazepam is pregnancy category D, a classification that means that bromazepam has been shown to cause harm to the unborn child. The Hoffman LaRoche product information leaflet warns against breast feeding while taking bromazepam. There has been at least one report of sudden infant death syndrome linked to breast feeding while consuming bromazepam.^[37]^[38]

Interactions

Cimetidine, fluvoxamine and propranolol causes a marked increase in the elimination half-life of bromazepam leading to increased accumulation of bromazepam.^[39]^[40]^[41]

Pharmacology

50 Pills of Lexotanil (containing 6 mg of Bromezepam apiece) as sold by Hoffmann-La Roche in Germany

Bromazepam is a "classical" benzodiazepine; other classical benzodiazepines include; diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, flurazepam, and clorazepate.^[42] 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.^[43] 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 GABA_A, 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.^[44] It does not possess any antidepressant or antipsychotic qualities.^[45]

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.^[46]

Bromazepam alters the electrical status of the brain causing an increase in beta activity and a decrease in alpha activity in EEG recordings.^[47]

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, a member of the Cytochrome P450 family, was not the responsible enzyme since itraconazole, a known inhibitor of CYP3A4, did not affect its metabolism.^[48] 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.^[41]

The active metabolite of bromazepam is hydroxybromazepam, which has a half-life approximately equal to that of bromazepam.^{[citation needed]}

Overdose

Bromazepam is commonly involved in drug overdoses.^[49] A severe bromazepam benzodiazepine overdose may result in an alpha pattern coma type.^[50] The toxicity of bromazepam in overdosage increases when combined with other CNS depressant drugs such as alcohol or sedative hypnotic drugs.^[51] Bromazepam is the most common benzodiazepine involved in intentional overdoses in France.^[52] 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.^[53]

Drug misuse

Bromazepam has a similar misuse risk as other benzodiazepines such as diazepam.^[54] 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.^[55] Bromazepam has also been used for serious criminal offences including robbery, homicide, and sexual assault.^[56]^[57]^[58]

Legal status

Bromazepam is a Schedule IV drug under the Convention on Psychotropic Substances.^[59]

Synthesis

anthranilamide + P4O10 Phosphorus pentoxide → anthranilonitrile + 2-pyridyllithium → 2-(2-Aminobenzoyl)pyridine.

Bromazepam synthesis.^[60]

References

^ "Benzodiazepine Names". non-benzodiazepines.org.uk. 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.
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^ "LECTOPAM®". RxMed. RxMed. Retrieved 23 March 2014.
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^ 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.
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^ 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. 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; Gatti; Spina (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. 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.
^ Gandolfi E, Andrade Mda G; Andrade Mda (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; Mégarbane; Pirnay; Rhaoui; Thuong (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; Theil; Candella (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.
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^ 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.
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^ List of psychotropic substances under international control (PDF). International Narcotics Control Board.
^ http://drugsynthesis.blogspot.co.uk/2012/01/laboratory-synthesis-of-bromazepam.html

External links

Bromazepam drug information from Lexi-Comp. Includes dosage information and a comprehensive list of international brand names.
Inchem - Bromazepam
LEXOTAN product information leaflet from Roche Pharmaceuticals

English Journal

Development of CT-guided biopsy sampling for time-dependent postmortem redistribution investigations in blood and alternative matrices-proof of concept and application on two cases.

Staeheli SN1, Gascho D2, Fornaro J2, Laberke P2, Ebert LC2, Martinez RM2, Thali MJ2, Kraemer T1, Steuer AE3.
Analytical and bioanalytical chemistry.Anal Bioanal Chem.2016 Feb;408(4):1249-58. doi: 10.1007/s00216-015-9234-9. Epub 2015 Dec 16.
The postmortem redistribution (PMR) phenomenon complicates interpretation in forensic toxicology. Human data on time-dependent PMR are rare and only exist for blood so far. A new method for investigation of time-dependent PMR in blood as well as in alternative body fluids and tissues was developed a
PMID 26677021

[Consumption of anxiolytic benzodiazepines: a correlation between SNGPC data and sociodemographic indicators in Brazilian capitals].

Azevedo ÂJ1, Araújo AA2, Ferreira MÂ1.
Ciência & saúde coletiva.Cien Saude Colet.2016 Jan;21(1):83-90. doi: 10.1590/1413-81232015211.15532014.
The scope of this article is to determine the distribution and frequency of consumption of anxiolytic benzodiazepines and the correlation between consumption and demographic, epidemiological, economic and social characteristics. It is an ecological study with a sample of 27 state capitals. Data coll
PMID 26816166

Alpha power oscillation in the frontal cortex under Bromazepam and Modafinil effects.

Aprigio D1, Adolfo W1, Bittencourt J1, Gongora M2, Teixeira S3, Basile LF4, Budde H5, Cagy M6, Ribeiro P2, Velasques B1.
Arquivos de neuro-psiquiatria.Arq Neuropsiquiatr.2015 Nov;73(11):918-23. doi: 10.1590/0004-282X20150140.
OBJECTIVE: Our aim was to investigate and compare the neuromodulatory effects of bromazepam (6 mg) and modafinil (200 mg) during a sensorimotor task analyzing the changes produced in the absolute alpha power.METHOD: The sample was composed of 15 healthy individuals exposed to three experimental cond
PMID 26517214

Japanese Journal

Benzodiazepines Inhibit the Acetylcholine Receptor-Operated Potassium Current (IK.ACh) by Different Mechanisms in Guinea-pig Atrial Myocytes

OKADA Muneyoshi,MIZUNO Wataru,NAKARAI Ryu [他],MATADA Takashi,YAMAWAKI Hideyuki,HARA Yukio
Journal of Veterinary Medical Science 74(7), 879-884, 2012
… The anticholinergic effects of 7 benzodiazepines, bromazepam, camazepam, chlordiazepoxide, diazepam, lorazepam, medazepam and triazolam, were compared by examining their inhibitory effects on the acetylcholine receptor-operated potassium current (IK.ACh) in guinea-pig atrial myocytes. … medazepam, diazepam, camazepam, triazolam, bromazepam, lorazepam and chlordiazepoxide (>300 μM). …
NAID 130001879781

Determination of Bromazepam in Pharmaceutical Formulations Using Fluorescence Enhancement by Surfactants

Al-Kindy Salma M. Z.,Suliman Fakhr Eldin O.,Aoudia Mohamed
Journal of flow injection analysis 21(1), 33-36, 2004-06
NAID 40006895447

Pharmacokinetics of bromazepam in 57 patients with acute drug intoxication

KOYAMA K.
Chudoku Kenkyu 16(1), 51-56, 2003
NAID 80015772839

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「ブロマゼパム」

Bromazepam
Systematic (IUPAC) name
	7-bromo-5-(pyridin-2-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one
Clinical data
Trade names	Lexotan, Lexotanil
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy; category	D (USA);
Routes of; administration	Oral (tablets)
Legal status
Legal status	CA: Schedule IV; DE: Anlage III (Prescription only); US: Schedule IV;
Pharmacokinetic data
Bioavailability	84%
Metabolism	Hepatic
Biological half-life	12–20 hours
Excretion	Renal
Identifiers
CAS Number	1812-30-2
ATC code	N05BA08 (WHO)
PubChem	CID 2441
DrugBank	DB01558
ChemSpider	2347
UNII	X015L14V0O
KEGG	D01245
ChEMBL	CHEMBL277062
Chemical data
Formula	C14H10BrN3O
Molar mass	316.2
	SMILES BrC1=CC2=C(C=C1)NC(CN=C2C3=CC=CC=N3)=O ;
	InChI InChI=1S/C14H10BrN3O/c15-9-4-5-11-10(7-9)14(17-8-13(19)18-11)12-3-1-2-6-16-12/h1-7H,8H2,(H,18,19) ; Key:VMIYHDSEFNYJSL-UHFFFAOYSA-N ;
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　　[★]

英: bromazepam
商: セニラン、レキソタン

[1] "Benzodiazepine Names". non-benzodiazepines.org.uk. Retrieved 2008-10-31.

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[60] ttp://drugsynthesis.blogspot.co.uk/2012/01/laboratory-synthesis-of-bromazepam.html

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