Benzodiazepine Side Effects: Role of Pharmacokinetics and Pharmacodynamics

Abstract

Benzodiazepines have a wide variety of indications. However, CNS and psychiatric adverse reactions, tolerance, and withdrawal effects of benzodiazepines are becoming increasingly recognized and must be better understood for proper drug use. Certain benzodiazepines are associated with memory impairment and other cognitive defects and hyperexcitability phenomena during treatment (early-morning insomnia, daytime anxiety) and following withdrawal (rebound insomnia and anxiety, seizures). Elimination half-life, receptor-binding affinity, effects on the locus coeruleus-norepinephrine (LC-NE) and hypothalamic-pituitary-adrenal (HPA) axes, and the interaction of these factors appear to be major determinants of frequency and severity of these untoward effects. Rapid drug elimination and high receptor-binding affinity were initially suggested as primary underlying factors which determine frequency, severity, and type of the side effects of benzodiazepines during administration and withdrawal. Newer data and information on triazolobenzodiazepines indicate that these psychiatric adverse reactions also relate to whether 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 neurophysiologic and behavioral sensitization (kindling) of the limbic system and consequently contributes to central nervous system and psychiatric adverse reactions. The tendency of certain of these side effects to worsen over time supports empirically this neurophysiologic and biochemical model.

The basic pharmacoepidemiology of benzodiazepine use in Norway 2004-9

“…This long term use may be viewed as unfavorable because where there is use on a regular basis over longer periods of time and tolerance to the therapeutic effects may develop. The patients may experience only adverse effects (24), including sleeping and anxiety problems. The number of long term regular users may indicate that quite a few Norwegians will be in a situation where their sleeping and anxiety problems are in fact caused by the drugs meant to cure them.…”

Effects of Some H1-Antagonists on the Sleep-Wake Cycle in Sleep-Disturbed Rats

“…Insomnia is the most prevalent and it is characterized by difficulty in falling asleep, intermittent waking after falling asleep and early morning awakening. Benzodiazepine hypnotics are widely used to treat insomnia due to both their safety and effectiveness; however, benzodiazepines have troublesome side effects such as rebound insomnia, amnesia, muscle relaxation, and drug dependence (4,5); therefore, particular attention should be paid when benzodiazepines are used clinically. In addition, these drugs can induce unusual sleep patterns, increasing stage 2 sleep, characterized by sleep spindles, and reducing slow wave sleep (stage 3 and 4 sleep, characterized by delta waves), and changing delta activity, used as an indicator of sleep quality (6 -8).…”

Interdose Elevation in Plasma Cortisol During Chronic Treatment with Alprazolam but not Lorazepam in the Elderly

“…Thus, given the relatively short elimination half-life of alprazolam and a prolonged interdose interval, it is possible that a marked drop in plasma drug concentration could trigger increased HPA axis activity in the period prior to morning dose. Indeed, clinical data from individuals on chronic treatment with alprazolam and similar BZPs suggest that rebound anxiety and other symptoms of withdrawal reactions can develop between doses (Ashton, 1994;Cole and Kando, 1993;Hallstrom and Lader, 1981;Herman et al, 1987;Kales et al, 1983Kales et al, , 1987Noyes et al, 1985Noyes et al, , 1988Pecknold, 1993;Risse et al, 1990;Schweizer and Rickels, 1998;Slak, 1986;Vgontzas et al, 1995;Woods et al, 1992;Wolf and Griffiths, 1991). However, it appears that none of these studies have examined interdose plasma cortisol levels.…”