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Bromazepam

Bromazepam (marketed under brand names Calmepam, Compendium, Creosedin, Durazanil, Lectopam, Lexaurin, Lexilium, Lexomil, Lexotan, Lexotanil, Normoc, Novepam, Somalium, Lexatin) is a drug which is a benzodiazepine derivative, developed in 1970s. It has mainly anxiolytic and at higher doses also sedative, hypnotic and skeletal muscle relaxant properties.

Pharmacology

Bromazepam is a "classical" benzodiazepine; other classical benzodiazepines include; diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, flurazepam and clorazepate. 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. 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 inhibitory effects of GABA. Other neurotransmitters are not influenced. Bromazepam is intermediate-short acting benzodiazepine and is lipophilic, is metabolised hepatically via oxidative pathways. It does not possess any antidepressant qualities.

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.

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

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. 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.

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

Tolerance, dependence and withdrawal

Bromazepam shares with other benzodiazepines the risk of abuse, misuse, psychological and/or physical dependence.

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.

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.

Indications

Short-term treatment of insomnia
Short-term treatment of anxiety or panic attacks, if a benzodiazepine is required
Alleviation of the symptoms of alcohol- and opiate-withdrawal, under close clinical supervision

Availability

Bromazepam is available as a generic in Belgium and Japan (as Lexotan), Bosnia, Bulgaria, Canada, Chile, Denmark (as Bromam), Estonia, France, Germany, Israel (Lenitin, by Teva), Italy, Kosovo province, the Republic of Macedonia, The Netherlands, Latvia, (as Lexotanil), Poland, Portugal and Switzerland. It is available as Lexaurin in Croatia. It is also available as Lexotanil in Bangladesh, Colombia, Greece, Pakistan, United Arab Emirates and Venezuela. It is available as Lexotan and Somalium in Australia, Brazil, Portugal, Singapore, and the Philippines. It is available as Lexilium in the Republic of Macedonia and Serbia (also as a generic, produced by ZORKA Pharma). Bromazepam is also available in Canada as Lectopam. Bromazepam is available in Yemen as Novepam and in Cambodia as Lexomil. And it is also available in Spain as Lexatin.

Dosage

Usually, 3 mg to 6 mg at bedtime, with additional 1.5 mg to 3 mg during the next day if needed. Malnourished patients, patients with compromised cardiovascular, liver or renal function, and elderly patients should receive lower doses. In hospitalized patients with severe agitation and/or anxiety, daily doses of up to 24 mg have been given and tolerated for a limited period of time. A 3 mg dose of bromazepam is equivalent to a 5 mg dose of diazepam.

Side-effects

All common side-effects of benzodiazepines have been noted. Consult the article under diazepam. Euphoria, leading to a high abuse potential, is quite often reported.

Bromazepam taken alone impairs learning capacities significantly in humans. In combination with alcohol the impairments of learning capacity become even more pronounced.

Impaired psychomotor performance.

Deterioration of attention capacity and impaired co-ordinative skills.

Impaired reactive and attention performance, which may impair driving skills.

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.

Contraindications

The general contraindications for benzodiazepines apply. Consult the section under diazepam.

Special Populations

In 1987, a team of scientists lead 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. The clinical consequence is that the elderly should be treated with lower doses than younger patients.