Pharmacology of Flunitrazepam and Other Benzodiazepines

2012

Benzodiazepines, therapeutically used as tranquilizers, hypnotics, anticonvulsants, and centrally acting muscle relaxants, rank among the most frequently prescribed drugs. Since Sternbach’s synthesis in 1955 of the first benzodiazepine by unexpected ring extension of a quinazoline-S-N-oxide derivative, a number of structurally similar compounds have been marketed by drug companies. Chlordiazepoxide (Librium®) was the first medical benzodiazepine, introduced in 1960, followed in 1963 by diazepam(Valium®) and in 1965 by oxazepam (Serax®). More than 50 of these drugs are presently marketed for clinical use throughout the world; 35 are subject to international control under the 1971 Convention on Psychotropic Substances. From International Narcotic Control Board (INCB) statistics, the most significant benzodiazepines in the last decade have been diazepam, lorazepam, alprazolam, temazepam, chlordiazepoxide, nitrazepam, triazolam, flunitrazepam, and lormetazepam.

In this post dealing with the chemistry, pharmacokinetics, and pharmacodynamics of benzodiazepines, we focus mainly on flunitrazepam (). Flunitrazepam was first introduced on the market in 1975, in Switzerland, under the trade name of Rohypnol®. It is indicated to treat insomnia and as a preoperative anesthetic. International sales data indicate that, over the past 10 yr, flunitrazepam has accounted for an average of 6-7% of sales of sedative-hypnotics in 20 countries, including the major European markets, Japan, Australia, South Africa, Brazil, Venezuela, and Mexico, among others. It has estimated worldwide sales of 2.3 million doses a day but is not approved by the Food and Drug Administration (FDA) for use in the United States.

In recent years, the drug has been smuggled into the United States from Mexico and central and southern America for illegal use. The first reported police seizure of flunitrazepam was on June 15, 1989 in Miami, Florida. In 1983, flunitrazepam was classified as a Schedule IV drug by the U.N. Convention on Psychotropic Substances. Despite little evidence of abuse, it was the first benzodiazepine to be moved in March 1995 to Schedule III by the World Health Organization (WHO). This scheduling requires more rigid controls, and was based largely on reports that flunitrazepam was involved in a high incidence of illicit activities and that it was widely abused by opioid addicts. Its ability to cause euphoria and a drunk-like “high” is the likely reason for the increasing abuse of flunitrazepam in recent years at parties, night clubs, and rave dances. Street names are numerous and include the following: roofies, rophies, rophynol, ruffles, roche, roches, roach, ropes, rib, reyna, the date-rape drug, and the forget pill. In the United States it has also become a tool in drug-facilitated rapes. Mixture with alcoholic beverages results in unconsciousness, hypnosis, and amnesia of the rape victims. In Europe the abuse of flunitrazepam by ingestion, smoking, injection, or intranasal application is popular among heroin addicts. The rapid onset of sedation (“slowing down”, “to be turned off) can ameliorate symptoms of opiate withdrawal, reducing stress, anxiety, or depression and can also enhance the effects of alcohol and cannabis. There have been reports of abuse of flunitrazepam in Florida, Texas, and other states.

Those who have used lysergic acid diethylamide (LSD) or marijuana in the past or who have a peer or partner who used this drug appear to be at greater risk of abuse. Doses and frequency of use vary from 1 to 15 tablets once or occasionnally twice a week. Habitual users frequently report ingesting flunitrazepam with alcohol or in combination with cannabis. In 1996, Customs regulations were changed, making it illegal to bring the medication across the U.S. border, and some states (like Florida, Oklahoma) have already classified flunitrazepam as a Schedule I drug.

Flunitrazepam: Chemistry

The classical benzodiazepines are based on a 5-aryl-l,4-benzodiazepine structure in which the benzene ring is linked to the 6-7 bond of the 1,4-diazepine. The aryl substituent at position 5 is usually phenyl (e.g., oxazepam) or 2′-halophenyl (e.g., 2-fluorophenyl for flunitrazepam or 2-chlorophenyl for lorazepam). The more recently introduced benzodiazepines include variations such as an imidazole (1,3-diazole) ring fused to the 1-2 bond of the 1,4-diazepine, that is, the imidazolobenzodiazepines, for example, midazolam or loprazolam. In a similar way, the triazolobenzodiazepines have a 1,2,4-triazole ring instead of the imidazole. Examples are alprazolam, estazolam andtriazolam. Other structural modifications include annelation of heterocyclic rings at the 4-5 bond, for example, haloxazolam, ketazolam, and oxazolam or replacement of the benzene ring by a thienyl ring (clotiazepam). Many benzodiazepines are hydrolyzed in acid solutions to form the corresponding benzophenone derivatives which can be used for analytical purposes. In the free base/acid form, benzodiazepines are generally soluble in most organic solvents such as ethyl ether, ethyl acetate, chloroform, and methanol, but are practically insoluble in water.

See also:

Pharmacokinetics of Flunitrazepam

Flunitrazepam: Pharmacodynamics