Lexotan Mechanism of Action

Therapeutic/Pharmacologic Class of Drug: Anxiolytic. ATC code: N05BA08.
Pharmacology: Pharmacodynamics: Mechanism of Action: The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines, the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.
At low dosage, Bromazepam (Lexotan) selectively reduces tension and anxiety. At high dosage, sedative and muscle-relaxant properties appear.
Pharmacokinetics: Absorption: Bromazepam is absorbed quickly and reaches peak plasma concentrations within 2 hours after oral administration. The absolute bioavailability of bromazepam from the tablet is 60%.
Food may decrease the bioavailability of bromazepam, however, the clinical relevance of this has not been established. During multiple dosing of bromazepam the extent of absorption remains constant; predictable steady-state concentrations are observed and confirm linear kinetics for the drug. Steady state plasma concentrations are reached in around 5-9 days. Following multiple oral doses of 3 mg given three times daily, the average maximum concentration of bromazepam at steady-state was 120 mg/mL (9) which is 3- to 4-fold higher than that observed after a single 3-mg dose.
Distribution: After absorption, bromazepam is rapidly distributed in the body. On average, 70% of bromazepam is bound by hydrophobic interaction to plasma proteins; binding partners are albumin and α1-acid glycoprotein.
The volume of distribution is around 50 liters.
Metabolism: Bromazepam is extensively metabolized in the liver. No metabolites with a half-life longer than that of the parent drug are formed.
Quantitatively, two metabolites dominate: 3-hydroxy-bromazepam (less active than bromazepam) and 2-(2-amino-5-bromo-3-hydroxybenzoyl) pyridine (inactive).
Bromazepam is metabolized, at least in part, through cytochrome P450 (CYP450).
However, the specific CYP isozymes involved have not been identified. Nevertheless, the observations that a strong CYP3A4 inhibitor (itraconazole) and a moderate CYP2C9 inhibitor (fluconazole) had no effect on the pharmacokinetics of bromazepam suggest that these isozymes are not involved to a major extent. The pronounced interaction with fluvoxamine (see Pharmacokinetic drug-drug interaction under Interactions) points to involvement of CYP1A2.
Elimination: Bromazepam has an elimination half-life of about 20 hours and an elimination clearance of around 40 mL/min.
Metabolism is the key elimination pathway for the drug. The urinary recovery of intact bromazepam is only 2% and of the glucuronide conjugates of 3-hydroxy-bromazepam and 2-(-2-amino-5-bromo-3-hydroxybenzoyl) pyridine are 27% and 40% of the administered dose respectively.
Pharmacokinetics in Special Populations: Geriatric Population: Elderly patients may have significantly higher peak concentrations, a smaller volume of distribution, increased serum free fraction, lower clearance and hence also a prolonged elimination half-life. This indicates that steady-state concentrations of bromazepam at any given dosing rate will be on average nearly twice as high in an elderly subject as compared to a younger individual (see Special dosage instructions under Dosage & Administration).
Renal impairment: No formal pharmacokinetic study has been conducted and no population PK data was collected in patients with renal impairment.
Hepatic impairment: No formal pharmacokinetic study has been conducted and no population PK data was collected in patients with hepatic impairment.
Toxicology: Nonclinical Safety: Carcinogenicity: Carcinogenicity studies conducted in rats did not reveal any evidence of a carcinogenic potential for bromazepam.
Genotoxicity: Bromazepam was not genotoxic in in vitro and in vivo tests.
Impairment of Fertility: Daily oral administration of bromazepam did not have any effect on the fertility and general reproductive performance of rats.
Reproductive Toxicity: Increases in fetal mortality, an increase in the stillbirth rate and a reduction in pup survival have been observed when bromazepam was given to pregnant rats. In studies on embryotoxicity/teratogenicity no teratogenic effect was detected up to a dosage of 125 mg/kg/day.
Following oral administration with doses of up to 50 mg/kg/day to pregnant rabbits a reduction in maternal weight gain, a reduction in fetal weight and an increase in the incidence of resorptions have been observed.