The Clinical and Forensic Toxicology of Z-drugs

Abstract

The Z-drugs zolpidem, zopiclone, and zaleplon were hailed as the innovative hypnotics of the new millennium, an improvement to traditional benzodiazepines in the management of insomnia. Increasing reports of adverse events including bizarre behavior and falls in the elderly have prompted calls for caution and regulation. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. Z-drugs exert their effects through increased γ-aminobutyric acid (GABA) transmission at the same GABA-type A receptor as benzodiazepines. Their pharmacokinetics approach those of the ideal hypnotic with rapid onset within 30 min and short half-life (1-7 h). Zopiclone with the longest duration of action has the greatest residual effect, similar to short-acting benzodiazepines. Neuropsychiatric adverse events have been reported with zolpidem including hallucinations, amnesia, and parasomnia. Poisoning with Z-drugs involves predominantly sedation and coma with supportive management being adequate in the majority. Flumazenil has been reported to reverse sedation from all three Z-drugs. Deaths from Z-drugs are rare and more likely to occur with polydrug overdose. Zdrugs can be detected in blood, urine, oral fluid, and postmortem specimens, predominantly with liquid chromatography-mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Zaleplon with its ultra-short half-life has been detected in few clinical or forensic cases possibly due to assay unavailability, low frequency of use, and short window of detection. Though Z-drugs have improved pharmacokinetic profiles, their adverse effects, neuropsychiatric sequelae, and incidence of poisoning and death may prove to be similar to older hypnotics.

Sedative Hypnotic Medication Use and the Risk of Motor Vehicle Crash

“…1---3 Residual sedation is common with sedatives, especially the class of short-acting GABAagonists commonly referred to as "z-hypnotics" (zolpidem, zopiclone, and zaleplon), 4,5 and sedation in itself is a causal factor for many motor vehicle crashes in the United States and abroad. 6---8 Little is known about the impact of sedative medications on crash rates in the United States, with most research focused on elderly drivers or in simulation studies.…”

“…14 A longer half-life may promote continued sedation during the morning following a sleep induced by the drug. 4 These delayed effects may produce slow reaction time and lack of appropriate judgment by someone operating a motor vehicle. Sedatives may increase the likelihood of crash by modifying 2 processes: (1) judgment governing when to operate a motor vehicle, and (2) increasing drowsiness or delaying reaction times.…”

Zopiclone degradation in biological samples : Characteristics and consequences in forensic toxicology

“…At α1 subunit, ZOP shows agonist activity whereas S(+)-ZOP differs from its racemic mixture and has greater efficacy at α2 and α3 subunits. The R(−)-ZOP interacts allosteric to effect the activity of S(+)-ZOP [82,83,87]. Moreover, some studies suggest that the ZOP metabolite S(+)-desmethylzopiclone enantiomer elicits an anxiolytic effect without central nervous depression [88].…”

“…However, large individual differences exist in plasma protein concentrations and competition between different drugs for binding sites occur in vitro, stability studies in blood on authentic samples might be important. Blood and urine are the commonest matrices for analysis of ZOP in forensic toxicology [87]. Stability tests of ZOP in stored urine samples was not investigated or reported in recently validated methods for forensic applications [137][138][139][140][141][142].…”

Pharmacists' perceptions and communication of risk for alertness impairing medications

“…10,11 Many AIMs are also often implicated in cases of accidental poisoning. 12 Much research in the area of risk management (e.g. drugs and driving)focuses either on medication misuse rather than use or on de-prescribing interventions.…”