BENZODIAZEPINE SIDE-EFFECTS - ROLE OF PHARMACOKINETICS AND PHARMACODYNAMICS

Benzodiazepines have a wide variety of indications. However, CNS and p sychiatric adverse reactions, tolerance, and withdrawal effects of ben zodiazepines are becoming increasingly recognized and must be better u nderstood for proper drug use. Certain benzodiazepines are associated with memory impairment and other cognitive defects and hyperexcitabili ty phenomena during treatment (early-morning insomnia, daytime anxiety ) and following withdrawal (rebound insomnia and anxiety, seizures). E limination half-life, receptor-binding affinity, effects on the locus coeruleus-norepinephrine (LC-NE) and hypothalamic-pituitary-adrenal (H PA) axes, and the interaction of these factors appear to be major dete rminants of frequency and severity of these untoward effects. Rapid dr ug elimination and high receptor-binding affinity were initially sugge sted as primary underlying factors which determine frequency, severity , and type of the side effects of benzodiazepines during administratio n and withdrawal. Newer data and information on triazolobenzodiazepine s indicate that these psychiatric adverse reactions also relate to whe ther the benzodiazepine has strong direct effects on the LC-NE and HPA systems. Initial suppression of the LC-NE and HPA systems is followed , on an interdose basis, by a significant rebound and activation. This repetitive pattern of suppression followed by rebound results in a ne urophysiologic and behavioral sensitization (kindling) of the limbic s ystem and consequently contributes to central nervous system and psych iatric adverse reactions. The tendency of certain of these side effect s to worsen over time supports empirically this neurophysiologic and b iochemical model.