Pharmacokinetic determinants of the clinical effects of benzodiazepine agonist hypnotics

Abstract

Beginning with nitrazepam in the early 1960s, the class of drugs acting as benzodiazepine (BZ) receptor agonists has become the principal therapeutic option for the pharmacologic treatment of insomnia. With the development of analytic techniques to measure plasma drug concentrations, along with the more general application of pharmacokinetic methodologies, understanding of the pharmacokinetic determinants of hypnotic drug action has progressed along with the development and clinic use of a series of BZ agonist hypnotics. Absorption rate is a key determinant of the onset of drug action and the effectiveness of a hypnotic in shortening sleep latency. Rapid absorption implies high maximum plasma concentrations and short times to reach the maximum, thereby increasing the probability of rapid-onset effects. Elimination half-life is a determinant of the duration of action and a hypnotic drug's efficacy in prolonging sleep duration and reducing early morning awakening. However, half-life may not directly predict duration of action, since some rapidly absorbed drugs may have action terminated by distribution rather than elimination. In any case, attaining a duration of action that is long enough to sustain sleep but not so long as to produce residual daytime sedation is a difficult objective. Dosage is a major determinant of pharmacodynamics that is often overlooked. Higher doses produce effects of more rapid onset, greater intensity, and longer duration. During multiple dosage with hypnotics, drug accumulation will occur if the drug's elimination half-life exceeds the dosage interval (24h). This may lead to cumulative daytime sedative effects. In contemporary practice, short half-life BZ agonist hypnotics are most commonly prescribed. These have a low risk of daytime sedation and accumulation, but they must be tapered at the end of treatment to avoid rebound and other discontinuation effects. Ongoing pharmaceutical research has the objective of developing drug delivery innovations that can optimize hypnotic drug action by regulation of release and systemic exposure to short half-life BZ agonists.