Siemens Healthcare Diagnostics, the leading clinical diagnostics company, is committed to providing clinicians with the vital information they need for the accurate diagnosis, treatment and monitoring of patients. Our comprehensive portfolio of performance-driven systems, unmatched menu offering and IT solutions, in conjunction with highly responsive service, is designed to streamline workflow, enhance operational efficiency and support improved patient care. Syva, EMIT, EMIT II, EMIT d.a.u., and all associated marks are trademarks of General Siemens Healthcare Diagnostics Inc. All Drugs other trademarks and brands are the Global Division property of their respective owners. of Abuse Siemens Healthcare Product availability may vary from Diagnostics Inc. country to country and is subject 1717 Deerfield Road to varying regulatory requirements. Deerfield, IL 60015-0778 Please contact your local USA representative for availability. www.siemens.com/diagnostics Siemens Global Headquarters Global Siemens Healthcare Headquarters Siemens AG Understanding Wittelsbacherplatz 2 Siemens AG 80333 Muenchen Healthcare Sector Germany Henkestrasse 127 Benzodiazephine Use, 91052 Erlangen Germany Abuse, and Detection Telephone: +49 9131 84 - 0 www.siemens.com/healthcare www.usa.siemens.com/diagnostics Answers for life. Order No. A91DX-0701526-UC1-4A00 | Printed in USA | © 2009 Siemens Healthcare Diagnostics Inc. Syva has been R1 R2 a leading developer N and manufacturer of AB R3 X N drugs-of-abuse tests R4 for more than 30 years. R2 C Now part of Siemens Healthcare ® Diagnostics, Syva boasts a long and Benzodiazepines have as their basic chemical structure successful track record in drugs-of-abuse a benzene ring fused to a seven-membered diazepine ring. testing, and leads the industry in the All important benzodiazepines contain a 5-aryl substituent ring (ring C) and a 1,4–diazepine ring. production of enzyme immunoassays. In addition to drugs-of-abuse assays, Syva Introduction has been a key player in the development When researchers synthesized the earliest and manufacture of therapeutic drug benzodiazepines in the 1960s, the medical monitoring assays. community was hoping for an effective Syva products are sold in more than anti-anxiety agent that would not produce tolerance, dependence, or withdrawal symptoms. 45 countries worldwide. Nor would the hoped-for medication possess recreational value. While the benzodiazepines were an improvement over the widely-used barbiturates, the medical community is still waiting for an anti- anxiety agent free of addictive qualities. Librium1 (chlordiazepoxide) was the first benzodiazepine, and the immensely successful Valium2 (diazepam) followed just a few years later. 1 Librium is a registered trademark of Hoffman-LaRoche, Inc. 2 Valium is a registered trademark of Hoffman-LaRoche, Inc. Today pharmaceutical companies market more patient to normal functioning. Because subjects than 35 brands of benzodiazepines worldwide. rapidly develop a tolerance towards the mood- Among these structurally-similar compounds exists altering effects of benzodiazepines, these drugs a wide variance in selectivity, dosage, metabolic work best as short-term treatment. Over the half-life, treatment indication, and potency. long- term, dependence can, and does develop. Dependence on prescription benzodiazepines Benzodiazepines Possess Unique is well documented. Antianxiolytic Properties Benzodiazepines are also used as sedatives, The immense success of benzodiazepines is largely hypnotics, anticonvulsants, muscle relaxants, attributable to their unique antianxiolytic properties. anesthesia, and pre-anesthesia. They are used to They provide relief from anxiety, and their degree of treat insomnia, seizure disorders, muscle spasms, sedation is much less than that of the barbiturates. and alcohol withdrawal. One benzodiazepine, Because of their pharmacological action, they alprazolam, appears to work as an anti-depressant. are safer than both barbiturates and dicarbamates. Studies have revealed significant residual Unlike barbiturates, benzodiazepines do not effects after the administration of hypnotic-doses cause general neuronal depression by themselves. of benzodiazepines. In one study evaluating They are, therefore, almost incapable of causing driving performance, residual effects following respiratory or circulatory collapse. Deaths involving two nightly 30-mg doses were at least as great benzodiazepine use are almost always the result as the acute effects of 100 mg/dL blood of interactions with one or more drugs. alcohol concentration—the legal intoxication Benzodiazepines are sedative—hypnotic central level in most states. nervous system (CNS) depressants. They work with the γ-aminobutyric acid (GABA) receptors of the CNS. Screening for Benzodiazepines GABA is a neurotransmitter stored in the nerve cells Syva Company has designed the EMIT® and released by the brain to calm the body. Benzodiazepine Assays to detect the presence of nearly 30 benzodiazepines and their metabolites. In state of anxiety, polypeptides stimulate the The EMIT® II and EMIT® d.a.u.™ Benzodiazepine nerve cells and suppress the release of GABA. Assays detect the compounds and metabolites Benzodiazepines interact with receptors to allow listed in Table 1. Also listed are the concentrations its release. Once GABA is released, the stimulation at which the compounds produce results by the polypeptides ceases, and the state of anxiety approximately equal to the cutoff calibrator ends. Benzodiazepines produce an additional (200 ng/mL oxazepam).3 calming effect with GABA. Syva Company has developed a more sensitive Effective, Relatively Safe, Often Abused antibody, and has changed the cut off for the Medical practitioners generally consider EMIT d.a.u. Benzodiazepine Assay from 300 benzodiazepines safe and effective in appropriate ng/mL to 200 ng/mL; equal to that of the EMIT II therapeutic circumstances. Because of their relative Benzodiazepine Assay. These new assays detect medical safety, they have effectively displaced the the widely-used alprazolam, temazepam, and barbiturates as antianxiolytics. triazolam at concentrations 3 to 5 times lower than formerly possible. Benzodiazepines are most often used to treat acute anxiety rather than chronic depression. Physicians prescribe benzodiazepine treatment to restore the Table 1: Benzodiazepines and Concentrations that Produce a Result Approximately Equivalent to EMIT® Calibrator A Level 1 (200 ng/mL Oxazepam) Benzodiazepine Trade EMIT II EMIT d.a.u. Benzodiazepine Trade EMIT II EMIT d.a.u. Compounds and Name Concentration Concentration Compounds and Name Concentration Concentration Metabolics (ng/mL) (ng/mL) Metabolics (ng/mL) (ng/mL) 200 300 200 300 200 300 200 300 Alprazolam Xanax 100 150 50 100 Ketazolam* Anseren, 210 250 50 100 α-Hydroxyalprazolam* 120 160 60 100 Ansieten, Anxon, Bromazepam Lectopam, 340 800 400 550 Contamex, Lexotanil Larpaz, Chlordiazepoxide Librium 800 1890 500 1400 Loftran, Clobazam** Frisium 180 290 100 270 Marcen, Clonazepam Clonopin, 250 1000 500 640 Parcil, Rivotril Sedotime, Solatran, Clorazepate Tranxene † † † † Unakalm Clotiazepam** Clozan, 400 580 100 250 Lorazepam Ativan 750 1400 1000 1300 Distensan, Rize, Rizen, Lormetazapam* Ergocalm, 230 350 200 280 Ticnor, Lembrol, Trecalmo, Loramet, Veratran Minias, Noctamid, Demoxepam** Demoxepam 500 1050 900 1000 Pronoctan N-Desalkyl-flurazepam* 230 320 100 180 Medazepam Nobrium 130 180 100 140 Diazepam Valium 110 150 40 80 Midazolam Hypnovel, 100 200 120 180 Flunitrazepam** Rohypnol 220 450 100 230 Versed Flurazepam Dalmane 110 230 100 130 Nitrazepam Mogodan 200 350 200 260 1-N-Hydroxyethyl- 130 160 60 100 Norchlor-diazepoxide** 670 1850 1800 1800 flurazepam* Nordiazepam** 100 150 60 100 Halazepam Paxipam 140 210 80 160 Oxazepam Serax 200 300 200 300 Prazepam Verstran 110 170 80 100 3 These concentrations apply only to the EMIT d.a.u. (Centrax) Benzodiazepine Assay. Temazepam Restoril 190 250 70 190 * Benzodiazepine metabolite. Tetrazepam* Musaril, 150 250 100 100 ** Not sold in U.S. Myolastan † Clorazepate degrades rapidly in stomach to nordiazepam Triazolam Halcion 120 250 70 110 which hydroxylates to oxazepam. α-Hydroxy-triazolam* 120 160 100 140 * Not sold in U.S. ** Benzodiazepine metabolite Short-Acting Compounds Are More Table 2: Benzodiazepines by Structure Difficult to Detect Group I Group II For testing purposes, we can divide the benzodiazepines into two general groups. The Three-Ring Structures: Four-Ring Structures: longer-acting, higher dosages shorter-acting, lower dosages first grouping consists of longer-acting compounds, 1,4-Benzodiazepines: 1,5-Benzodiazepines: characterized by a three-ring chemical structure. (diazolobenzodiazepines) clobazam These are the 1,4-benzodiazepines, or diazolos. bromazepam Imidazo-1,4-benzodiazepines: camazepam climazolam The diazolos metabolize slowly, breaking down chlordiazepoxide midazolam clonazepam to biologically active compounds (compounds clorazepate Triazolobenzodiazepines: that have CNS effects). The phase in which active diazepam adinazolam ethyl loflazepate alprazolam metabolites form is quite slow; the half time is flunitrazepam triazolam 40 to 50 hours. This long half time allows for the flurazepam Thienodiazepines: halazepam clotiazepam build-up of active metabolites that are responsible ketazolam for the long-acting effects. Finally, the metabolites lorazepam attach to glucuronides and are eliminated. lormetazepam medazepam nitrazepam The second grouping consists of