Neurochemical and pharmacokinetic correlates of the clinical action of benzodiazepine hypnotic drugs.

Benzodiazepine derivatives are presumed to exert their pharmacologic activity via interaction with specific molecular recognition sites, termed benzodiazepine receptors, within the brain. The various benzodiazepines used in clinical practice differ considerably in their intrinsic receptor affinity, but the qualitative character of the drug-receptor interaction is similar or identical among this class of drugs. All benzodiazepines are lipophilic (lipid-soluble) substances that relatively rapidly cross the blood-brain barrier and equilibrate with brain tissue. After equilibrium is attained, a constant brain:plasma ratio is maintained, such that plasma concentrations proportionately reflect concentrations of drug in brain. Brain concentrations are proportional to the extent of receptor occupancy, which in turn determines the acute behavioral effect. Clinical differences among benzodiazepines largely reflect differences in pharmacokinetic properties. The onset of action after single oral doses reflects the rate of absorption from the gastrointestinal tract, whereas the duration of action is determined by the rate and extent of drug distribution to peripheral tissues, as well as by the rate of elimination and clearance. During multiple dosage, long half-life drugs accumulate, with the concurrent possibility of daytime sedation. However, a benefit of long half-life drugs is that rebound insomnia on abrupt termination is unlikely. Short half-life drugs accumulate minimally and have a lower likelihood of producing daytime sedation. However, they may be more likely to produce rebound insomnia on abrupt discontinuation.