The main active metabolite of diazepam is desmethyldiazepam. Long-acting BZDs, such as diazepam and chlordiazepoxide, generally have pharmacologically active metabolites, accumulate in tissues after multiple doses, and demonstrate impaired clearance in older patients and those with liver disease. (See "Procedural sedation in adults: General considerations, preparation, monitoring, and mitigating complications".) However, successive doses of midazolam lead to bioaccumulation of its hydroxy-metabolites and may prolong the drug's sedative effects. Midazolam has a short half-life, very rapid onset of clinical effect, and a shorter duration of action than other BZDs, which explains its preferential use in procedural sedation. Short-acting BZDs, such as triazolam, alprazolam, and midazolam, generally have few active metabolites, do not accumulate with repeated doses, and demonstrate clearance that is largely unaffected by age and liver disease. īZDs are commonly divided into three groups based upon elimination half-life duration: short-acting (half-life of less than 12 hours), intermediate-acting (half-life between 12 and 24 hours), and long-acting (half-life greater than 24 hours) BZDs ( table 1). Chlordiazepoxide, diazepam, and flurazepam are metabolized to active metabolites, which are then conjugated and excreted. Oxazepam, temazepam, and lorazepam are directly conjugated to an inactive, water-soluble glucuronide metabolite that is excreted by the kidney. Diazepam is metabolized by both CYP3A4 and CYP2C19. Alprazolam and midazolam are metabolized by CYP3A4. Metabolism/elimination - BZDs are primarily hepatically metabolized, most by the CYP2C19 and CYP3A4 enzymes.Absorption/distribution - BZDs are rapidly absorbed in the gastrointestinal tract, and most are highly lipophilic and highly protein bound.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. This binding increases the frequency of the flow of chloride ions through the GABA ion channel, causing postsynaptic hyperpolarization and a decreased ability to initiate an action potential. BZDs do not alter the synthesis, release, or metabolism of GABA but rather potentiate its inhibitory actions by augmenting receptor binding.
BZDs 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 (which binds between alpha and beta subunits). The composition of subunits determines the affinity of the various xenobiotics that bind to the receptor. The GABA-A receptor is a ligand-gated ion channel composed of five subunits arranged in various combinations of alpha, beta, and gamma. Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the central nervous system. PHARMACOLOGY - BZDs exert their effect via modulation of the gamma-aminobutyric acid A (GABA-A) receptor.
(See "Initial management of the critically ill adult with an unknown overdose".).(See "General approach to drug poisoning in adults".).A general approach to the poisoned patient and the management of poisonings involving other agents with sedative properties are discussed elsewhere: The diagnosis and management of acute BZD poisoning and withdrawal will be reviewed here. Alprazolam, clonazepam, and lorazepam are the most commonly misused BZDs by both adolescents and adults. The pediatric rate of misuse, severity of outcomes, and presence of co-ingestants have steadily increased since 2000, especially in adolescents.
BZDs are also commonly misused and diverted. The high incidence of BZD overdose mirrors their widespread use and availability. Due to their many uses and wide therapeutic index, BZDs are widely prescribed, and nearly 50 different agents are available worldwide. They are also frequently combined with other medications for procedural sedation. BZDs are safer than older sedative-hypnotic agents, such as barbiturates, and thus are commonly used for sedation and to treat anxiety, seizures, withdrawal states, insomnia, and agitation. INTRODUCTION - Benzodiazepines (BZDs) are sedative-hypnotic agents that have been in clinical use since the 1960s.
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