Source: Registered Drug Product Database (NG) Publisher: SWISS PHARMA NIGERIA LTD, 5 Dopemu Road, Agege, Lagos, Nigeria
Flunitrazepam is a powerful hypnotic drug that is a benzodiazepine derivative. It has powerful hypnotic, sedative, anxiolytic, and skeletal muscle relaxant properties. The drug is sometimes used as a date rape drug. In the United States, the drug has not been approved by the Food and Drug Administration for medical use, and is considered to be an illegal drug. It has however been approved in the United Kingdom and other countries. Benzodiazepines bind nonspecifically to benzodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%. Benzodiazepines such as flunitrazepam are lipophilic and rapidly penetrate membranes.
Flunitrazepam has a long half-life of 18-26 hours and an active metabolite which has a half-life of 36-200 hours, which means flunitrazepam effects after nighttime administration persist throughout the next day. Residual ‘hangover’ effects after nighttime administration of flunitrazepam such as sleepiness, impaired psychomotor and cognitive may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.
Flunitrazepam is lipophilic and is metabolised hepatically via oxidative pathways. The enzyme CYP3A4 is the main enzyme in its phase 1 metabolism.
Following oral administration, flunitrazepam is almost entirely absorbed. 10-15% undergoes first-pass metabolism in the liver resulting in an absolute (vs. intravenous solution) bioavailability of 70-90%. The maximum plasma concentrations of flunitrazepam are 6-11 ng/ml and occur 0.75 -2 hours after administration of a single oral dose of 1 mg on an empty stomach. Food reduces the rate and extent of flunitrazepam absorption. The pharmacokinetics of flunitrazepam are linear in the 0.5-4 mg dose range. Repetitive daily oral administrations lead to a moderate accumulation of flunitrazepam in plasma (accumulation ratio 1.6-1.7).The steady state plasma concentration of flunitrazepam is reached after 5 days. The minimum plasma concentration of flunitrazepam at steady state is 3-4 ng/ml following multiple oral doses of 2 mg. The steady state plasma concentration of the pharmacologically active N- desmethyl metabolite is almost identical to that of the parent compound.
The distribution of flunitrazepam is rapid and extensive. The volume of distribution at steady state is 3-5 liters/kg. Flunitrazepam is 78% bound to plasma proteins. There is a rapid uptake of flunitrazepam into human cerebrospinal fluid. Flunitrazepam crosses the human placenta and blood-milk barrier slowly and to a minor extent after a single dose.
Flunitrazepam is almost completely metabolized. About 80% and 10% of the radiolabelare found in urine and faeces, respectively. The principal plasma metabolites are 7-amino-flunitrazepam and N-desmethyl-flunitrazepam. The major urinary metabolite is 7-amino-flunitrazepam. Less than 2% of a dose is excreted renally as unchanged drug and as N-desmethyl-flunitrazepam.
Pharmacologically active in man, though less than flunitrazepam, and plasma levels at steady state resulting from daily doses of 2 mg flunitrazepam are below the minimum effective concentration of the metabolite.
The elimination half-life of flunitrazepam is between 16 and 35 hours. The half-life of the active N-desmethyl-flunitrazepam is 28 hours. The total plasma clearance is 120-140 ml/min.
None stated.
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