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===Special Populations===
===Special Populations===
====Elderly====
====Elderly====
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.
In 1987, a team of scientists led 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.


====Driving====
====Driving====

Revision as of 02:24, 1 March 2010

Bromazepam
Clinical data
Pregnancy
category
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability84%
MetabolismHepatic
Elimination half-life12-20 hours
ExcretionRenal
Identifiers
  • 9-bromo-6-pyridin-2-yl- 2,5-diazabicyclo [5.4.0]undeca- 5,8,10,12-tetraen- 3-one
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.015.748 Edit this at Wikidata
Chemical and physical data
FormulaC14H10BrN3O
Molar mass316.2 g·mol−1
3D model (JSmol)
  • Brc3cc\1c(NC(=O)C/N=C/1c2ncccc2)cc3
  (verify)

Bromazepam (marketed under several brand names, including Lexotan, lexilium, Lexaurin, Brazepam, Bromaze, Lexotanil, and Lectopam)[1] is a benzodiazepine derivative drug, developed in the 1970s.[2][3] It has mainly anxiolytic and at higher doses also sedative, hypnotic and skeletal muscle relaxant properties.[4]

Indications

Side-effects

All common side-effects of benzodiazepines have been noted. Consult the article under diazepam. Bromazepam 3 times 6 mg daily for 2 weeks taken alone impaired learning capacities significantly in humans in an experiment. In combination with alcohol the impairments of learning capacity became even more pronounced.[7] Impairments to memory functions are common with bromazepam and include a reduced working memory and reduced ability to process environmental information.[8][9][10] Impaired memory, visual information processing and sensory data and impaired psychomotor performance.[11][12][13] Deterioration of cognition including attention capacity and impaired co-ordinative skills.[14][15] Unsteadiness after taking bromazepam is however less pronounced than other benzodiazepines such as lorazepam.[16] Impaired reactive and attention performance, which may impair driving skills.[17]

Drowsiness and decrease in libido.[18][19] Occasionally benzodiazepines can induce extreme alterations in memory such as anterograde amnesia and amnesic automatism which may have medico-legal consequences. Such reactions usually only occur at the higher dose end of the prescribing spectrum.[20]

Very rarely dystonia can develop.[21]

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 and/or physical dependence.[22][23] 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.[24]

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.[25] Abrupt or over rapid withdrawal from bromazepam after chronic use even at therapeutic prescribed doses may lead to a severe withdrawal syndrome including status epilepticus and a condition resembling delerium tremens.[26][27][28]

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.[29]

Contraindications and special precautions

Benzodiazepines require special precaution if used in the elderly, pregnancy, children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.[30]

Special Populations

Elderly

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.[31] The clinical consequence is that the elderly should be treated with lower doses than younger patients.

Driving

Bromazepam may affect driving and ability to operate machinery.[32]

Pregnancy and breast feeding

Bromazepam is pregnancy category D, a classification which 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.[33][34]

Interactions

Cimetidine, fluvoxamine and propranolol causes a marked increase in the half life of bromazepam leading to increased accumulation of bromazepam.[35][36][37]

Pharmacology

Bromazepam is a "classical" benzodiazepine; other classical benzodiazepines include; diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, flurazepam and clorazepate.[38] 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.[39] 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.[40] It does not possess any antidepressant or antipsychotic qualities.[41]

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.[42]

Bromazepam alters electrical status of the brain causing an increased beta activity and a decrease in alpha activity in the EEG recordings.[43]

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.[44] 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.[45]

The active metabolite of bromazepam is hydroxybromazepam, which has half life approximately equal to bromazepam.[citation needed]

Overdose

Main article: Benzodiazepine overdose

Bromazepam is commonly involved in drug overdoses.[46] Bromazepam is a drug sometimes used in suicide attempts.[47] A severe bromazepam benzodiazepine overdose may result in a alpha pattern coma type.[48] The toxicity of bromazepam in overdosage increases when combined with other CNS depressant drugs such as alcohol or sedative hypnotic drugs.[49] Bromazepam is the most common benzodiazepine involved in intentional overdoses in France.[50]

Drug misuse

See also: Benzodiazepine drug misuse

Bromazepam has a similar misuse risk as other benzodiazepines such as diazepam.[51] In France car accidents involving psychotropic drugs in combination found benzodiazepines, mainly diazepam, nordiazepam, and bromazepam, to be the most common drug, almost twice that of the next most common drug cannabis.[52] Bromazepam has been also been used for serious criminal offences including, robbery, homicide and to carry out sexual assaults.[53][54][55]

Bromazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[56]

See also

References

  1. ^ "Benzodiazepine Names". non-benzodiazepines.org.uk. Retrieved 2008-10-31.
  2. ^ "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. 1984. PMC 1959670. PMID 6147412. {{cite journal}}: Unknown parameter |month= ignored (help)
  3. ^ 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. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
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  27. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  30. ^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr. 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. {{cite journal}}: Unknown parameter |month= ignored (help)
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