Bromazepam

Source: Wikipedia, the free encyclopedia.
Bromazepam
Clinical data
Trade namesLexotan, Lexotanil, others
AHFS/Drugs.comMicromedex Detailed Consumer Information
Addiction
liability		High[1]
Routes of
administration		By mouth
ATC code
Legal status
Legal status
P450
Metabolites3-hydroxybromazepam
Elimination half-life12–20 hours (avg. 17hr)[3]
ExcretionUrine 69%, as metabolites[1]
Identifiers
  • 7-bromo-5-(pyridin-2-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one
JSmol)
SMILES
  • C1C(=O)NC2=C(C=C(C=C2)Br)C(=N1)C3=CC=CC=N3
  • 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. 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 1.5 mg, 3 mg and 6 mg tablets.[4]

It was patented in 1961 by

Roche and approved for medical use in 1974.[5]

Medical uses

Lexotan medicine package
Lexotan medicine package from 2006

Medical uses include treatment of severe anxiety.[6] Despite certain side effects and the emergence of alternative products (e.g. pregabalin), benzodiazepine medication remains an effective way of reducing problematic symptoms, and is typically deemed effective by patients[7][8] and medical professionals.[9][10][11] Similarly to other intermediate-acting

depressants, it may be used as hypnotic medication[12] or in order to mitigate withdrawal effects of alcohol consumption.[13][14][15]

Pharmacology

Hoffmann-La Roche in Germany

Bromazepam is a "classical" benzodiazepine; other classical benzodiazepines include: diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, flurazepam, and clorazepate.[16] 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.[17] 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

lipophilic compared to other substances of its class[19] and metabolised hepatically via oxidative pathways.[20] It does not possess any antidepressant or antipsychotic qualities.[21]

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.[22]

Bromazepam alters the electrical status of the brain causing an increase in beta activity and a decrease in alpha activity in EEG recordings.[23]

Pharmacokinetics

Bromazepam is reported to be metabolized by a hepatic enzyme belonging to the

Solvay Pharmaceutical 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.[25]

The major metabolite of bromazepam is hydroxybromazepam,[24] which is an active agent too and has a half-life approximately equal to that of bromazepam.[citation needed]

Side-effects

Bromazepam is similar in side effects to other benzodiazepines. The most common side effects reported are drowsiness, sedation,

drowsiness and decrease in libido.[37][38] Unsteadiness after taking bromazepam is, however, less pronounced than other benzodiazepines such as lorazepam.[39]

On occasion, benzodiazepines can induce extreme alterations in memory such as

amnesic automatism, which may have medico-legal consequences. Such reactions occur usually only at the higher dose end of the prescribing spectrum.[40]

Very rarely, dystonia can develop.[41]

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
.

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.

Frequency and seriousness of adverse effects

As with all medication, the frequency and seriousness of side-effects varies greatly depending on quantities consumed.[42][43] In a study about bromazepam's negative effects on psychomotor skills and driving ability, it was noted that 3 mg doses caused minimal impairment.[44] It also appeared that impairment may be tied to methods of testing more so than on the product's intrinsic activity.[45]

Moreover, side-effects other than drowsiness, dizziness and ataxia seem to be rare[46] and not experienced by more than a few percent of users. The use of other, comparable medication seems to display an identically moderate side-effect profile.[47][48][49]

Tolerance, dependence and withdrawal

Prolonged use of bromazepam can cause 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. It is nonetheless important to note that dependence, long-term use and misuse occur in a minority of cases[50][51][52] and are not representative of most patients' experience with this type of medication.[53][54]

It shares with other benzodiazepines the risk of abuse, misuse,

rebound anxiety after 4 weeks chronic use. Those whose dose was gradually reduced experienced no withdrawal.[57]

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.

delerium tremens.[59][60][61]

Animal studies have shown that chronic administration 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.[62] 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.[63][64]

Overdose

Main article: Benzodiazepine overdose

Bromazepam is commonly involved in drug overdoses.[65] A severe bromazepam benzodiazepine overdose may result in an alpha pattern coma type.[66] The toxicity of bromazepam in overdosage increases when combined with other CNS depressant drugs such as alcohol or sedative hypnotic drugs.[67] Similarly to other benzodiazepines however, being a positive modulator of certain neuroreceptors and not an agonist, the product has reduced overdose potential compared to older products of the barbiturate class. Its consumption alone is very seldom fatal in healthy adults.[68][69]

Bromazepam was in 2005 the most common benzodiazepine involved in intentional overdoses in France.[70] Bromazepam has also been responsible for accidental poisonings in companion animals. A review of benzodiazepine poisonings in cats and dogs from 1991 to 1994 found bromazepam to be responsible for significantly more poisonings than any other benzodiazepine.[71]

Contraindications

Benzodiazepines require special precaution if used in elderly, pregnant, child, alcohol- or drug-dependent individuals and individuals with

psychiatric disorders.[72]

Special populations

Interactions

Cimetidine, fluvoxamine and propranolol causes a marked increase in the elimination half-life of bromazepam leading to increased accumulation of bromazepam.[73][77][25]

Society and culture

Drug misuse

See also: Benzodiazepine use disorder

Bromazepam has a similar misuse risk as other benzodiazepines such as

nordiazepam, and bromazepam, to be the most common drug present in the blood stream, almost twice that of the next-most-common drug cannabis.[79] Bromazepam has also been used in serious criminal offences including robbery, homicide, and sexual assault.[80][81][82]

Brand names

It is marketed under several brand names, including, Brozam, Lectopam, Lexomil, Lexotan, Lexilium, Lexaurin, Brazepam, Rekotnil, Bromaze, Somalium, Lexatin, Calmepam, Zepam and Lexotanil.[83]

Bromazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[84]

Synthesis

Bromazepam synthesis.[85]

See also

References

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  2. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
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