Bromazepam

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Bromazepam
Bromazepam.svg
Bromazepam-from-xtal-3D-balls.png
Clinical data
Trade namesLexotan, Lexotanil, others
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • AU: C
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability84%
MetabolismLiver
Elimination half-life12–20 hours (avg. 17hr)[1]
ExcretionKidney
Identifiers
  • 7-bromo-5-(pyridin-2-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.015.748 Edit this at Wikidata
Chemical and physical data
FormulaC14H10BrN3O
Molar mass316.158 g·mol−1
3D model (JSmol)
  • BrC1=CC2=C(C=C1)NC(CN=C2C3=CC=CC=N3)=O
  • 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) checkY
  • Key:VMIYHDSEFNYJSL-UHFFFAOYSA-N checkY
  (verify)

Bromazepam, sold under many brand names, is a benzodiazepine. 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.[2]

It was patented in 1961 by Roche and approved for medical use in 1974.[3]

Medical uses[edit]

Members of its class are used for treatment of anxiety.[4] Despite certain side effects and the emergence of alternative products (e.g pregabalin), benzodiazepines remain an effective way of reducing problematic symptoms and are typically deemed effective by patients[5][6] and medical professionals.[7][8][9] Similarly to other intermediate-acting depressants, it may be used as a hypnotic[10] or to mitigate withdrawal from alcohol consumption.[11][12][13]

Pharmacology[edit]

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

Bromazepam is a "classical" benzodiazepine, as are diazepam, clonazepam, oxazepam, lorazepam, chlordiazepoxide, nitrazepam, flurazepam, and clorazepate.[14] Its molecular structure is a diazepine connected to a benzene ring and a pyridine ring. The benzene ring has a single nitrogen atom replacing one of the carbon atoms.[15] It is a 1,4-benzodiazepine, which means that the nitrogens are in the 1 and 4 positions.

Bromazepam binds to the GABAA receptor, causing a conformational change and increasing the inhibitory effects of GABA. It acts as a positive modulator, increasing the response when activated by GABA itself or an agonist (such as alcohol). As opposed to barbital, BZDs are not GABA-receptor activators and rely on increasing the neurotransmitter's natural activity.[16] Bromazepam is an intermediate-acting benzodiazepine, is moderately lipophilic compared to other substances of its class,[17] and metabolized hepatically via oxidative pathways.[18] It does not possess any antidepressant or antipsychotic qualities.[19]

After nighttime administration of bromazepam, a highly significant reduction of gastric acid secretion occurs during sleep followed by a highly significant rebound the following day.[20]

Bromazepam alters the electrical status of the brain by causing an increase in beta wave and a decrease in alpha wave activity in EEG recordings.[21]

Pharmacokinetics[edit]

Bromazepam is reported to be metabolized by a hepatic enzyme belonging to the cytochrome P450 family of enzymes. In 2003, a team led by 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.[22] In 1995, J. van Harten at the Solvay Pharmaceutical Department of Clinical Pharmacology in Weesp reported that fluvoxamine (a potent inhibitor of CYP1A2, a less potent CYP3A4 inhibitor, and a negligible inhibitor of CYP2D6) does inhibit its metabolism.[23]

The major metabolite of bromazepam is hydroxybromazepam,[22] an active agent itself with a half-life approximately equal to that of bromazepam.[citation needed]

Side-effects[edit]

Bromazepam is similar in side effects to other benzodiazepines. The most common side effects reported are drowsiness, sedation, ataxia, memory impairment, and dizziness.[24] Impaired memory is common with bromazepam, including reduced working memory and processing of environmental information.[25][26][27] 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 three times daily for two weeks impaired learning capacity significantly. In combination with alcohol, this impairment was even more pronounced.[28] Various studies report impaired memory; visual and sensory data processing; and psychomotor performance.[29][30][31] Deterioration of cognition including attention capacity and impaired co-ordinative skills;[32][33] impaired reactive and attention performance;[34] drowsiness; and decrease in libido were also noted.[35][36] Unsteadiness after taking bromazepam is less pronounced than other benzodiazepines.[37]

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 higher doses.[38] Very rarely, dystonia can develop.[39]

Up to 30% treated on a long-term basis develop dependence.

Leukopenia and cholestatic liver damage with or without jaundice (icterus) have been reported; its original manufacturer, Roche, recommends regular laboratory surveillance.

Ambulatory patients should be warned that it may impair the ability to drive vehicles and to operate machinery, further worsened by the consumption of alcohol since both are central nervous system depressants. During the course of therapy, tolerance to the sedative effect usually develops.

Frequency and seriousness of adverse effects[edit]

As with all medication, the frequency and seriousness of side-effects vary greatly by the quantity consumed.[40][41] In a study about bromazepam's negative effects on psychomotor skills and driving ability, it was noted that 3 mg doses caused minimal impairment.[42] It also appeared that impairment may be tied to methods of testing more so than the drug's activity.[43]

Moreover, side-effects other than drowsiness, dizziness, and ataxia seem to be rare.[44] The use of comparable medication seems to display an identically moderate side-effect profile.[45]'[46]'[47]

Tolerance, dependence and withdrawal[edit]

Prolonged use of bromazepam can cause tolerance and may lead to both physical and psychological dependence on the drug; as a result, it is a controlled medication by international law. It is nonetheless important to note that dependence and long-term misuse occur in a minority of cases[48][49][50] and are not representative of most patients' experience with this type of medication.[51]'[52]

It shares with other benzodiazepines the risks of non-medical use, psychological dependence, and physical dependence.[53][54] A withdrawal study demonstrated both psychological and physical dependence including marked rebound anxiety after four weeks of use. Those whose dose was gradually reduced experienced no withdrawal.[55]

Patients treated with bromazepam for generalized anxiety disorder were found to experience withdrawal symptoms with sudden discontinuation.[56] Abrupt or rapid withdrawal from bromazepam after chronic use even at therapeutic doses can lead to a severe withdrawal symptoms including status epilepticus and a condition resembling delerium tremens.[57][58][59]

Animal studies have shown that chronic administration of benzodiazepines causes a decrease in spontaneous locomotor activity; decreased turnover of noradrenaline, dopamine, and serotonin; increased activity of tyrosine hydroxylase; and increased levels of catecholamines. During withdrawal, a fall in tryptophan and serotonin levels[60] 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.[61][62]

Overdose[edit]

Bromazepam is commonly involved in drug overdoses.[63] A severe bromazepam overdose may result in alpha pattern coma.[64] The toxicity of bromazepam in overdoses increases when combined with other CNS depressant drugs such as alcohol or sedative hypnotics.[65] Similar to other benzodiazepines, being a positive modulator of certain neuroreceptors and not an agonist, the drug has reduced overdose potential compared to older products of the barbiturate class. Its consumption alone is very seldom fatal in healthy adults.[66][67]

Bromazepam was the most common benzodiazepine involved in intentional overdoses in France in 2005.[68] It has also been responsible for accidental poisonings in companion animals. A review of such poisonings in cats and dogs from 1991-1994 found it to be the most frequently associated benzodiazepine.[69]

Contraindications[edit]

Special populations[edit]

  • Globally, 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 use disorders, and children.
  • 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.[70] 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.[71]
  • 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.[72][73]

Interactions[edit]

Cimetidine, fluvoxamine, and propranolol causes a marked increase in the elimination half-life of bromazepam leading to its increased accumulation.[74][75][23]

Society and culture[edit]

Drug misuse[edit]

Bromazepam has a similar misuse risk as other benzodiazepines.[76] In France, car accidents involving psychotropic drugs in combination with alcohol 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.[77] Bromazepam has also been attributed to criminal offenses including robbery, homicide, and sexual assault.[78][79][80]

Brand names[edit]

It is marketed under many brand names, including Lectopam, Lexatín, Lexomil, Lexotan, and Lexotanil.[81]

Legal status[edit]

Bromazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[82]

Synthesis[edit]

Bromazepam synthesis.[83]

See also[edit]

References[edit]

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External links[edit]

  • "Bromazepam". Drug Information Portal. U.S. National Library of Medicine.