Benzodiazepine poisoning and withdrawal
- Howard Greller, MD
Howard Greller, MD
- Associate Professor of Emergency Medicine
- Hofstra North Shore/LIJ School of Medicine
- Amit Gupta, MD
Amit Gupta, MD
- Clinical Assistant Professor of Emergency Medicine
- New York Downstate Medical Center/Staten Island University Hospital
Benzodiazepines (BZD) are sedative-hypnotic agents that have been in clinical use since the 1960s. The first benzodiazepine, chlordiazepoxide, was discovered serendipitously in 1954 by the Austrian scientist Leo Sternbach. Three years later, it was marketed as a therapeutic medication under the brand name Librium. Following chlordiazepoxide in 1963, diazepam was released followed by multiple other compounds over subsequent years.
BZDs are used for sedation and to treat anxiety, seizures, withdrawal states, insomnia, and drug-associated agitation. They are frequently combined with other medications for procedural sedation. Due to their many uses, BZDs are widely prescribed and nearly 50 different agents are available worldwide. The high incidence of BZD overdose mirrors their widespread use and availability [1,2].
The diagnosis and management of acute benzodiazepine poisoning will be reviewed here. A general approach to the poisoned patient and the management of poisonings involving other agents with sedative properties are discussed elsewhere. (See "General approach to drug poisoning in adults" and "Ethanol intoxication in adults" and "Acute opioid intoxication in adults" and "Gamma hydroxybutyrate (GHB) intoxication".)
PHARMACOLOGY AND CELLULAR TOXICITY
Benzodiazepines (BZD) are organic bases with a benzene ring and a seven member diazepine moiety; various side chains determine the potency, duration of action, metabolite activity, and rate of elimination for specific agents . BZDs exert their effect via modulation of the gamma-aminobutyric acid A (GABA-A) receptor. Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the central nervous system.
The GABA-A receptor is composed of five subunits (alpha, beta, and gamma) arranged in various combinations [4-9]. The composition of subunits determines the affinity of the various xenobiotics that bind to the receptor. Benzodiazepines bind at the interface of the alpha and gamma subunits and, once bound, lock the GABA-A receptor into a conformation that increases its affinity for GABA. BZDs do not alter the synthesis, release, or metabolism of GABA but rather potentiate its inhibitory actions by augmenting receptor binding. This binding increases the flow of chloride ions through the GABA ion channel, causing postsynaptic hyperpolarization and a decreased ability to initiate an action potential. The low incidence of respiratory depression with orally ingested BZDs appears to be related to the low density of binding sites in the brainstem respiratory center .
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- PHARMACOLOGY AND CELLULAR TOXICITY
- CLINICAL FEATURES OF OVERDOSE
- Benzodiazepine poisoning
- Propylene glycol poisoning
- DIFFERENTIAL DIAGNOSIS
- LABORATORY EVALUATION
- Testing for benzodiazepine toxicity
- General diagnostic testing
- Initial treatment
- Antidote (flumazenil)
- Mechanism, signs, and prevention
- ADDITIONAL RESOURCES
- SUMMARY AND RECOMMENDATIONS