ABSTRACT
The benzodiazepines (BZDs) and Z-drugs are important classes of medications that are useful in the pharmacotherapy of a wide range of neural and psychiatric medical conditions. Each of these drug classes achieves their pharmacologic effects by binding to or near the BZD binding site on the pentameric GABAA receptor complex. There are three types of ligand–receptor complex binding interactions: positive allosteric modulators (PAMs), which are primarily agonists such as diazepam and other BZDs, which cause anxiolytic and sedative types of activity; null or silent allosteric modulators (NSAMs), which antagonize the agonist effects of the BZDs and are represented by the prototype antagonist flumazenil; and negative allosteric modulators (NAMs), which are represented by the β-carbolines. The NAMs act as inverse agonists and elicit the opposite pharmacologic effects that are caused by agonists (anxiogenic, arousal, and convulsant actions). The major therapeutic indications for the BZDs are panic disorder, alcohol withdrawal, skeletal muscle spasms, seizure disorders, and insomnia. Most of the BZDs have moderate to long half-lives, and several are metabolized to active metabolites, making them challenging to find the appropriate dose that achieves the desired therapeutic effect without causing excessive side effects and adverse events. Common side effects associated with the BZDs include drowsiness, lethargy, anterograde amnesia, fatigue, and impaired cognitive skills. When these side effects are severe, they can lead to falls and fractures, especially in the elderly; for these reasons, the BZDs are not recommended for use in persons over the age of 65. The BZDs should not be co-prescribed with opioids, in any age group, unless absolutely necessary, due to an increased risk of exaggerated psychomotor impairment plus the increased risk of overdose from respiratory depression. Flumazenil is an effective BZD antagonist and has received FDA approval for reversing overdose or oversedating effects associated with BZD use. Another class of drugs, known as the Z-drugs (zolpidem, zaleplon, and eszopiclone), have shorter half-lives than the BZDs and were developed specifically for the management of insomnia. These drugs have a similar adverse event profile as the BZDs and can also cause falls and fractures, and are therefore also not recommended for use in the elderly. The Z-drugs have their own unique adverse event of causing complex sleep-related behaviors such as sleep-eating, sleep-sex, sleep-driving, and other bizarre behaviors while in a semi-awake state of consciousness. Both the Z-drugs and the BZDs are useful in managing multiple types of medical conditions, but they should always be administered with caution using the lowest effective dosage for the shortest period of time necessary for optimal therapeutic outcomes.
