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Benzodiazepines

Definition

  • A class of drugs with a three-ringed chemical structure consisting of a benzene ring, a seven-member diazepine ring, and a phenyl ring attached to the 5-position of the diazepine ring. The CNS depressant activity of these drugs is mediated through the neurotransmitter, GABA.
  • Specific agents: alprazolam (Xanax), chlordiazepoxide (Librium), diazepam (Valium), temazepam (Restoril), oxazepam (Serax), flunitrazepam (Rohypnol), lorazepam (Ativan), midazolam (Versed), clonazepam (Klonopin), and triazolam (Halcion).
  • Normal range: see Table 16.11.

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TABLE 16 " “11Reference Ranges of BenzodiazepinesView LargeTABLE 16 " “11Reference Ranges of Benzodiazepines Normal Range (serum/plasma; ng/mL) Alprazolam 10 " “100 Chlordiazepoxide 500 " “2,500 Clonazepam 5 " “75 Diazepam 100 " “1,500 (may be higher to control alcohol withdrawal and in schizophrenic patients) Flunitrazepam 10 " “20 Lorazepam 5 " “240 Midazolam 8 " “150 (higher for surgical anesthesia; may be >1,000) Oxazepam 300 " “1,500 Temazepam 200 " “1,200 Triazolam 2 " “10

Use

  • Assistance in the treatment of panic attacks, panic disorders, and agoraphobia (alprazolam, clonazepam)
  • Treatment of anxiety (diazepam, lorazepam)
  • Treatment of seizures (diazepam, clonazepam)
  • Treatment of insomnia (temazepam, triazolam)
  • Preoperative sedation and to assist in induction of surgical anesthesia (midazolam, diazepam, lorazepam)
  • Muscle relaxant (diazepam)
  • Treatment of alcohol dependence (chlordiazepoxide, diazepam)

Interpretation

  • When evaluating concentrations in plasma/serum, effect of multiple active moieties must be considered. When evaluating concentrations in urine, metabolite rather than parent may be detected. Active metabolites are Alprazolam: alpha-hydroxy alprazolam Flunitrazepam: 7-aminoflunitrazepam Midazolam: alphahydroxy and 4-hydroxy midazolam Triazolam: alphahydroxy and 4-hydroxy triazolam Diazepam: nordiazepam, temazepam, oxazepam Chlordiazepoxide: demoxepam, norchlordiazepoxide, nordiazepam, oxazepam Temazepam: oxazepam

Limitations

  • Testing: screening by immunoassay for urine and serum ELISA (serum) Target analyte: temazepam Cutoff concentration: 10 ng/mL No cross-reactivity with clonazepam, flunitrazepam, lorazepam and metabolites, and oxazepam EMIT (serum/urine) Target analyte: nitrazepam (urine), diazepam (serum) Cutoff concentration: 200 or 300 ng/mL urine, 50 ng/mL serum Due to low cross-reactivity, will not detect flunitrazepam, clonazepam, lorazepam (urine); low cross-reactivity with chlordiazepoxide and demoxepam (serum) Cross-reactivity with alprazolam manufacturer (vendor) dependent
  • Confirmation for urine and serum Sample pretreatment necessary Derivatization may be necessary for metabolite detection. Hydrolysis of urine samples increases detectability. Gas chromatography (GC). HPLC. Low-dose benzodiazepines may not be measurable by GC and HPLC (triazolam, flunitrazepam). GC/MS [MS]. LC/MS/[MS]. Target drug: parent drug and metabolites. Limit of quantitation: typically 5 " “20 ng/mL.