The prototypical anxiolytics in common use for CS in the ED are the benzodiazepines, which potentiate the inhibitory activity of g-aminobutyric acid (GABA) in the CNS by binding to benzodiazepine-specific receptors on the GABAA-benzodiazepine receptor complex, which induces a conformational change that potentiates GABA-mediated chloride influx. This activity results in sedation, amnesia, anxiolysis, and anticonvulsant effects, as well as respiratory depression. The benzodiazepine most commonly used for CS in the ED is midazolam, which produces earlier sedation, more frequent amnesia, less pain on injection, and improved 90-min alertness and readiness for discharge when compared with diazepam.18
Midazolam has a number of characteristics favorable for use in ED CS. Its diazepine ring opens at pH values of less than 4, in which form it is quite water soluble. At physiologic pH, the ring closes, rendering midazolam highly lipid soluble, with associated rapid CNS uptake producing peak effects within a few minutes of IV administration. Midazolam's relatively high volume of distribution compared with other benzodiazepines derives from its lipophilicity. This characteristic is greatly amplified in obese patients, resulting in an increase in plasma half-life from 2.7 to 8.4 h. Midazolam is cleared by hepatic hydroxylation to 1-hydroxymidazolam (which is pharmacologically active) and to 4-hydroxymidazolam and 1,4-dihydroxymidazolam, which are conjugated and excreted in the urine.
The combination of midazolam with alcohol or opioids greatly increases sedative and respiratory-depressant effects, and increases the risk of cardiovascular depression. Midazolam should be used cautiously in such cases, with careful monitoring of respiratory and hemodynamic status.
The dose of midazolam should be individualized. Midazolam should be given in small incremental doses until the desired effect is achieved. Aliquots of 0.25 to 0.5 mg given every 3 to 5 min in healthy adults, or 0.1 to 0.25 mg every 5 to 10 min in the intoxicated or elderly patient, is a reasonable starting point. Chronic alcohol users who do not have cirrhosis may require relatively high doses of midazolam to achieve the clinical effects desired.
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