Clinical pharmacokinetics and pharmacodynamics of anxiolytics and sedative/hypnotics

Abstract

Medications to promote sedation and reduce anxiety and its associated symptoms have been sought since recorded history. The development of the benzodiazepines represented a major therapeutic endeavor due to their safety profile especially when taken in overdose situations compared to the barbiturates and early non-barbiturates such as meprobamate. Benzodiazepines continue to be one of the most commonly prescribed agents available in a variety of dosage formulations used for all age groups. Their pharmacokinetic (PK) and pharmacodynamic (PD) profiles have been extensively studied in adult healthy volunteers, the elderly, and patients with hepatic and renal impairment. Most benzodiazepines are metabolized by the phase I oxidative CYP enzyme system and the remaining agents by the phase II glucuronidation. Many long-acting benzodiazepines are metabolized to an active metabolite desmethyldiazepam. Alprazolam and buspirone were FDA approved for panic and generalized anxiety disorders, respectively. Various sedative-hypnotic non-benzodiazepine agents have been developed that are agonists of the alpha-1 GABA-A subreceptor site and the melatonin receptors type 1 and 2. All of these agents produce common PD effects such as sedation and psychomotor impairment. Benzodiazepines also produce antiepileptic actions, muscle relaxation, and anterograde amnesia. PK-PD modeling has been conducted for benzodiazepines and non- benzodiazepines that mainly focus on sedation and psychomotor impairment. The elderly have more pronounced sedative and psychomotor impairment from these agents compared to the adult population. Gender can be another significant factor as females were found to have significantly higher zolpidem plasma concentrations than males and when given comparative doses also displayed more pronounced psychomotor impairment which led to the FDA recommendation of lower doses prescribed.