Sedative-, Hypnotic-, and Anxiolytic-Related Disorders

Abuse and Dependence Sedative-hypnotic and alcohol intoxications are similar in symptoms and complications. Because sedative-hypnotic use is so frequent in hospitalized patients, the detection of sedative abuse can be difficult. Abuse rarely starts as a result of treatment of acute anxiety or insomnia in a hospitalized patient. The risk of sedative abuse in chronically medically ill outpatients is far greater. There are three major classes of benzodiazepine abusers: polysubstance abusers, pure sedative abusers, and therapeutic users who have lost control. Individuals prone to polysubstance abuse tend to use sedatives for their calming effects (i.e., to come down after use of a stimulant such as cocaine) and for their ability to decrease dysphoric affects, including anxiety, or to potentiate euphoric effects of other drug classes (e.g., benzodiazepines in combination with methadone to boost euphoria). Pure sedative abusers usually have significant underlying psychopathological conditions, and relapse is common. In a long-term follow-up study involving subjects with primary sedative-hypnotic dependence, 46% of the subjects continued to abuse drugs after in-hospital rehabilitation treatment. Anyone can develop physiological Read more […]

Flunitrazepam: Generic and Trade Names

Synthetic substance Common generic and trade names Absint Flunitrazepam Neuraxpharm Pre-Sonil Benzosan Flunitrazepam Ratiopharm Primun B Dual N Flunizep von ct Psiconeurin Bibittoace Flupam Razepam Conexine Fluscand Rohipnol Darkene Fluserin Rohpinol Flubioquim Flutraz Rohypnol Fluminoc Hipnosedon Rohyprol Flumipam Hipnox Roipnal Fluni A1 Pharma Hypnocalm Roipnol Fluni OPT Hypnodorm Ronal Flunimerck Hypnor Rophynal Fluninoc Ipnopen Sedex Flunipam Libelius Serenil Raurich Flunita Metopram N Silece Flunitrax Narcozed Somnium Flunitrazepam Narcozep Somnubene Flunitrazepam Duncan Nitam Sylase Flunitrazepam Lando Noriel Valsera Flunitrazepam NM Pharma Parnox Vulbegal   Read more […]

Immunoassay Detection of Benzodiazepines

Benzodiazepines were first introduced in the 1960s as a safer alternative to phenobarbital. In the 1970s and mid-1980s, diazepam (Valium) was the most commonly prescribed benzodiazepine. The dose levels and excretion patterns of these first generation benzodiazepines produced concentrations in samples that made drug detection easy by immunoassay. As chemists explored structure-activity relationships of this new class of compounds, a new generation of benzodiazepines was developed that exploited substituent activation of 1,4-benzodiazepine. These new benzodiazepines were more potent; therefore, they were prescribed in lower doses. This new generation of benzodiazepines was also fast acting and had much shorter half-lives with respect to blood concentrations and excretion levels. The higher doses and longer half-lives of the diazepam-related benzodiazepines, made it possible to detect this class of drugs by immunoassay screening. After a single dose of 5 mg of Valium, immunoassay detection is possible for up to 2 wk. With the lower dose, faster clearing benzodiazepines, (alprazolam, triazolam, lorazepam, nitrazepam, flunitrazepam, and clonazepam), detection by immunoassay at historical cutoff levels was nearly impossible. Read more […]

Immunoassay of Benzodiazepines

The following is an overview of the performance of the most widely used immunoassay screening methods and the effect of hydrolysis on the sensitivity of the methods. There are several widely marketed commercial products available to screen for benzodiazepmes. Most techniques cannot reliably detect therapeutic doses of the new generation of benzodiazepmes. The difference in performance between methods is mainly due to the different calibrators used and the difference in antibody cross-reactivities. The cross-reactivity is related to the antibody’s immunoreactivity to the parent drug of each analyte as well as each metabolite present. It is important to remember that quantitative results must be interpreted with caution, as the calibrator may be a different drug than the analyte(s) detected. Table Immunoassay Sensitivity and Cutoff Immunoassay LOD Cutoff FPIA 40 ng/mL 200 ng/mL EMIT 70 ng/mL 300 ng/mL CEDIA 6.8 ng/mL 200 ng/mL CEDIA 8.3 ng/mL 300 ng/mL OnLine 5 ng/mL 100 ng/mL SBENZ 7 ng/mL 7 ng/mL The role of the calibrator on the performance of the method is related to both the cutoff and the characteristic binding curve of the analyte chosen for the calibrator. Read more […]

Flunitrazepam: Pharmacodynamics

Sites of Action γ-Aminobutyric acid (GABA) is the most widely distributed inhibitory neurotransmitter in the human brain. GABA owes its pharmacology to at least three receptor subtypes: GABA A-C. Whereas GABA A is coupled to a chloride channel, GABA B is coupled to cationic channels (K+, Ca2+) via G-proteins and second-messenger systems, and GABA C are chloride channels with totally different pharmacology than GABA A. A chloride channel allows negatively charged Cl- ions to enter the neurons and lower the resting membrane potential (hyperpolarization), resulting in a less excitable tissue and decreased neuronal function. The three GABA receptors have distinct structures, distinct functions, and different cellular localization and pharmacology. GABA A receptors are made of five subunits, and each subunit spans the neuronal membranes four times. This complex stoichiometry can clearly give rise to several subtypes of GABA A receptors: the most abundant human CNS receptor type is the α1β2γ2 isoform. Classically, GABA A receptors have modulatory (allosteric) sites for the binding of benzodiazepines, barbiturates, and neurosteroids. The functional response of the channel to both GABA and to its modulators is dependent Read more […]

Pharmacokinetics of Flunitrazepam

Absorption, Distribution, and Plasma Levels Flunitrazepam is administered orally or by intravenous or intramuscular injection in doses of 0.5-2 mg. Flunitrazepam is lipophilic at physiological pH and is absorbed very quickly and almost completely after oral administration: flunitrazepam undergoes first-pass metabolism in the liver, resulting in a systemic bioavailability of 85-90%. The onset of action is directly linked to the absorption rate from the gastrointestinal tract, a fact that holds true for all benzodiazepines. The pharmacokinetic parameters of single- and multiple-dose oral flunitrazepam are summarized in site. Flunitrazepam absorption and disposition follow first-order kinetics after single- and multiple-dose oral administration. The distribution is biphasic and lasts up to 20 h, with an initial half-life of 2-4 h. The rapid uptake into the brain is followed by a fairly rapid distribution out of the central compartment. Two-compartment models are in most cases adequate to describe the plasma concentration-time profiles of oral flunitrazepam, whereas three-compartment models are used for intravenous flunitrazepam. After a single oral dose of 2 mg, plasma peaks of 8.8 ±3.0 ng/mL flunitrazepam occur Read more […]

Pharmacology of Flunitrazepam and Other Benzodiazepines

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 Read more […]