Bromazepam

Last updated
Bromazepam
Bromazepam.svg
Bromazepam-from-xtal-3D-balls.png
Clinical data
Trade names Lexotan, Lexotanil, others
AHFS/Drugs.com Micromedex Detailed Consumer Information
Addiction
liability 		High [1]
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 84%
Protein binding 70%
Metabolism Liver: P450
Metabolites 3-hydroxybromazepam
Elimination half-life 12–20 hours (avg. 17hr) [3]
Excretion Urine 69%, as metabolites [1]
Identifiers
  • 7-bromo-5-(pyridin-2-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.015.748 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H10BrN3O
Molar mass 316.158 g·mol−1
3D model (JSmol)
  • 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) Yes check.svgY
  • Key:VMIYHDSEFNYJSL-UHFFFAOYSA-N Yes check.svgY
   (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 3 mg and 6 mg tablets. [4]

Contents

It was patented in 1961 by Roche and approved for medical use in 1974. [5]

Medical uses

Lexotan medicine package from 2006 Lexotan.jpg
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

50 Pills of Lexotanil (containing 6 mg of Bromazepam apiece) as sold by Hoffmann-La Roche in Germany Lexotanil 6 mg.png
50 Pills of Lexotanil (containing 6 mg of Bromazepam 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. [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 GABA receptor GABAA, causing a conformational change and increasing the inhibitory effects of GABA. It acts as a positive modulator, increasing the receptors' 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. [18] Bromazepam is an intermediate-acting benzodiazepine, is moderately 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 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. [24] In 1995, J. van Harten at 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, ataxia, memory impairment, and dizziness. [26] Impairments to memory functions are common with bromazepam and include a reduced working memory and reduced ability to process environmental information. [27] [28] [29] 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. [30] Various studies report impaired memory, visual information processing and sensory data and impaired psychomotor performance; [31] [32] [33] deterioration of cognition including attention capacity and impaired co-ordinative skills; [34] [35] impaired reactive and attention performance, which can impair driving skills; [36] 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 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. [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.

Leukopenia and liver-damage of the cholestatic 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.

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, psychological dependence or physical dependence. [55] [56] 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. [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. [58] 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. [59] [60] [61]

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. [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

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 comorbid 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

Bromazepam has a similar misuse risk as other benzodiazepines such as diazepam. [78] 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. [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. Bromazepam synthesis.png
Bromazepam synthesis.

See also

Related Research Articles

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

Benzodiazepines, colloquially known as "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was made available in 1960 by Hoffmann–La Roche, which followed with the development of diazepam (Valium) three years later, in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

<span class="mw-page-title-main">Diazepam</span> Benzodiazepine sedative

Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally, as a suppository inserted into the rectum, intramuscularly, intravenously or used as a nasal spray. When injected intravenously, effects begin in one to five minutes and last up to an hour. When taken by mouth, effects begin after 15 to 60 minutes.

<span class="mw-page-title-main">Temazepam</span> Insomnia medication

Temazepam, sold under the brand name Restoril among others, is a medication of the benzodiazepine class which is generally used to treat severe or debilitating insomnia. It is taken by mouth. Temazepam is rapidly absorbed, and significant hypnotic effects begin in less than 30 minutes and can last for up to eight hours. Prescriptions for hypnotics such as temazepam have seen a dramatic decrease since 2010, while anxiolytics such as alprazolam, clonazepam, and lorazepam have increased or remained stable. Temazepam and similar hypnotics, such as triazolam (Halcion) are generally reserved for severe and debilitating insomnia. They have largely been replaced by z-drugs and atypical antidepressants as first line treatment for insomnia.

<span class="mw-page-title-main">Alprazolam</span> Benzodiazepine medication

Alprazolam, sold under the brand name Xanax and others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines. Alprazolam is most commonly prescribed in the management of anxiety disorders, especially panic disorder and generalized anxiety disorder (GAD). Other uses include the treatment of chemotherapy-induced nausea, together with other treatments. GAD improvement occurs generally within a week. Alprazolam is generally taken orally.

<span class="mw-page-title-main">Lorazepam</span> Benzodiazepine medication

Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and chemotherapy-induced nausea and vomiting. It is also used during surgery to interfere with memory formation and to sedate those who are being mechanically ventilated. It is also used, along with other treatments, for acute coronary syndrome due to cocaine use. It can be given orally, transdermally, intravenously (IV), or intramuscularly When given by injection, onset of effects is between one and thirty minutes and effects last for up to a day.

<span class="mw-page-title-main">Triazolam</span> Triazolobenzodiazepine class medication

Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties, triazolam's amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced as well.

<span class="mw-page-title-main">Nitrazepam</span> Benzodiazepine sedative

Nitrazepam, sold under the brand name Mogadon among others, is a hypnotic drug of the benzodiazepine class used for short-term relief from severe, disabling anxiety and insomnia. It also has sedative (calming) properties, as well as amnestic, anticonvulsant, and skeletal muscle relaxant effects.

<span class="mw-page-title-main">Flurazepam</span> Hypnotic medication

Flurazepam is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It produces a metabolite with a long half-life, which may stay in the bloodstream for days. Flurazepam was patented in 1968 and came into medical use the same year. Flurazepam, developed by Roche Pharmaceuticals, was one of the first benzodiazepine hypnotic medications to be marketed.

<span class="mw-page-title-main">Oxazepam</span> Benzodiazepine medication

Oxazepam is a short-to-intermediate-acting benzodiazepine. Oxazepam is used for the treatment of anxiety, insomnia, and to control symptoms of alcohol withdrawal syndrome.

<span class="mw-page-title-main">Nordazepam</span> Benzodiazepine derivative medication

Nordazepam is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has amnesic, anticonvulsant, anxiolytic, muscle relaxant, and sedative properties. However, it is used primarily in the treatment of anxiety disorders. It is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, pinazepam, and medazepam.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.

<span class="mw-page-title-main">Loprazolam</span> Benzodiazepine

Loprazolam (triazulenone) marketed under many brand names is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It is licensed and marketed for the short-term treatment of moderately-severe insomnia.

<span class="mw-page-title-main">Prazepam</span> Benzodiazepine drug

Prazepam is a benzodiazepine derivative drug developed by Warner-Lambert in the 1960s. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. Prazepam is a prodrug for desmethyldiazepam which is responsible for the therapeutic effects of prazepam.

<span class="mw-page-title-main">Tofisopam</span> Anxiolytic medication

Tofisopam is an anxiolytic that is marketed in several European countries. Chemically, it is a 2,3-benzodiazepine. Unlike other anxiolytic benzodiazepines however, tofisopam does not have anticonvulsant, sedative, skeletal muscle relaxant, motor skill-impairing or amnestic properties. While it may not be an anticonvulsant in and of itself, it has been shown to enhance the anticonvulsant action of classical 1,4-benzodiazepines and muscimol, but not sodium valproate, carbamazepine, phenobarbital, or phenytoin. Tofisopam is indicated for the treatment of anxiety and alcohol withdrawal, and is prescribed in a dosage of 50–300 mg per day divided into three doses. Peak plasma levels are attained two hours after an oral dose. Tofisopam is not reported as causing dependence to the same extent as other benzodiazepines, but is still recommended to be prescribed for a maximum of 12 weeks.

<span class="mw-page-title-main">Chlordiazepoxide</span> Benzodiazepine class sedative and hypnotic medication

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol, benzodiazepines, and other drugs.

<span class="mw-page-title-main">Delorazepam</span> Benzodiazepine medication

Delorazepam, also known by the synonyms chlordesmethyldiazepam and nordiclazepam, is a drug which is a benzodiazepine and a derivative of desmethyldiazepam. It is marketed in Italy, where it is available under the trade name EN and Dadumir. Delorazepam (chlordesmethyldiazepam) is also an active metabolite of the benzodiazepine drugs diclazepam and cloxazolam. Adverse effects may include hangover type effects, drowsiness, behavioural impairments and short-term memory impairments. Similar to other benzodiazepines delorazepam has anxiolytic, skeletal muscle relaxant, hypnotic and anticonvulsant properties.

<span class="mw-page-title-main">Fosazepam</span> Benzodiazepam

Fosazepam is a drug which belonging to the benzodiazepine class of drugs, which are primarily anti-anxiety and sedative-hypnotic agents. It is a water soluble derivative of diazepam which has been substituted with a dimethylphosphoryl group to improve solubility in water. At equipotent doses, it possesses sedative and anxiolytic properties that are qualitatively and quantitatively similar to the effects of diazepam, with equal sedative-hypnotic, anti-convulsive, and muscle relaxant effects. In comparison to an equipotent dose of nitrazepam ,, its effects tended to be of noticeably milder magnitude.

<span class="mw-page-title-main">Premazepam</span> Chemical compound

Premazepam is a Pyrrolodiazepine class of drug. It is a partial agonist of benzodiazepine receptors and was shown in 1984 to possess both anxiolytic and sedative properties in humans but was never marketed.

<span class="mw-page-title-main">Benzodiazepine use disorder</span> Medical condition

Benzodiazepine use disorder (BUD), also called misuse or abuse, is the use of benzodiazepines without a prescription and/or for recreational purposes, which poses risks of dependence, withdrawal and other long-term effects. Benzodiazepines are one of the more common prescription drugs used recreationally. When used recreationally benzodiazepines are usually administered orally but sometimes they are taken intranasally or intravenously. Recreational use produces effects similar to alcohol intoxication.

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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  25. 1 2 van Harten J (1995). "Overview of the pharmacokinetics of fluvoxamine". Clinical Pharmacokinetics. 29 (Suppl 1): 1–9. doi:10.2165/00003088-199500291-00003. PMID   8846617. S2CID   71812133.
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