Review, Nov/20: Benzodiazepine Toxicity

"Benzodiazepine Toxicity"

https://pubmed.ncbi.nlm.nih.gov/29489152/ 

Excerpt

Since the 1960s, with the development of chlordiazepoxide and shortly thereafter diazepam, benzodiazepines quickly became popular medications secondary to their vastly superior safety profiles when compared to previous sedative-hypnotics such as barbiturates and other non-barbiturates used for the treatment of anxiety and insomnia. Since their initial development, multiple benzodiazepine drugs have been developed over the course of several decades. Benzodiazepines are currently used to treat anxiety, seizures, withdrawal states, insomnia, agitation and are commonly used for procedural sedation. Due to their many uses and addictive properties, benzodiazepines have been widely prescribed and abused since their development several decades ago. Today, there are over 50 different agents available on the worldwide market, and the high incidence of benzodiazepine overdose mirrors their widespread use and availability.

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Pathophysiology

Benzodiazepines are organic bases with a benzene ring and a 7-member diazepine moiety, with variable side chains that determine the potency, duration of action, metabolite activity, and rate of elimination. Benzodiazepines exert their effect via modulation of the gamma-aminobutyric acid A (GABA-A) receptor, the primary inhibitory neurotransmitter in the central nervous system. The GABA-A receptor, depending on various arrangements of its subunits, determines its affinity for various agents that bind to the receptor. Benzodiazepines bind at the interface of the GABA-A receptor and subsequently locks the receptor into a configuration that increases its affinity for GABA. Benzodiazepines do not alter the production, release, or metabolism of GABA but instead potentiates its inhibitory actions by augmenting or enhancing receptor binding. This binding ultimately increases the flow of chloride ions through the GABA ion channel, causing postsynaptic hyperpolarization, which decreases the ability to generate an action potential. The low incidence of respiratory depression with benzodiazepines, which differentiates it from barbiturates, is related to the low density of binding sites in the brainstem, which houses the respiratory center.[5]

Toxicokinetics

Benzodiazepines taken in toxic doses without other coingestants rarely cause a significant toxidrome. The classic presentation in patients with isolated benzodiazepine overdose will include central nervous system (CNS) depression with normal or near-normal vital signs. Many patients will still be arousable and even provide a reliable history. Classic symptoms include slurred speech, ataxia, and altered mental status. Respiratory compromise is uncommon in isolated benzodiazepine ingestions, but if taken with coingestants such as ethanol or other drugs/medications, respiratory depression can be noted. It is important to note that most intentional ingestions of benzodiazepines do involve coingestants, the most common being ethanol, leading to substantial respiratory depression and airway compromise. The dose required to produce respiratory compromise is difficult to quantify and depends on multiple factors, including dosage, tolerance, weight, age, coingestants, and even genetics. Patients with severe toxicity will present in a stuporous or comatose state, and immediate airway management and mechanical ventilation may be required.

A unique toxidrome related to parenteral formulations of diazepam and lorazepam is propylene glycol poisoning. Propylene glycol is the diluent used in the parenteral formulations for these two benzodiazepines, and prolonged use can cause propylene glycol toxicity, which includes skin and soft tissue necrosis, hemolysis, cardiac dysrhythmias, hypotension, significant lactic acidosis, seizure, and multisystem organ failure. While propylene glycol toxicity is rare, it must be considered when patients are receiving large or continuous infusions of parenteral benzodiazepines, for example, when treating severe sedative or ethanol withdrawal syndromes such as delirium tremens.

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Treatment / Management

The mainstay treatment for acute benzodiazepine toxicity is supportive care, which may include endotracheal intubation to provide definitive airway management. Single-dose or multi-dose activated charcoal, hemodialysis, or whole bowel irrigation play no role in managing benzodiazepine toxicity.

While the mainstay treatment of acute benzodiazepine toxicity or overdose is supportive care, there is, however, an “antidote” that may be used in limited situations. Flumazenil is a nonspecific competitive antagonist at the benzodiazepine receptor that can reverse benzodiazepine induced sedation. However, in most cases, the risks of flumazenil usually outweigh the benefits in acute toxicity, and thus flumazenil is not recommended for routine reversal of this sedative agent. Seizures and cardiac dysrhythmias, particularly PSVT, can occur after flumazenil administration, and many fatalities have been reported. Flumazenil can precipitate acute withdrawal syndromes in those with chronic benzodiazepine dependence, which can be life-threatening. If a patient with a chronic dependence on benzodiazepines is given flumazenil, it can lower their seizure threshold and potentially cause life-threatening seizures. The treatment of seizures, which typically involves benzodiazepines, would be rendered useless, as the flumazenil has blocked the benzodiazepine receptors.

Flumazenil can be safely administered to the non-habituated user of benzodiazepines. This situation classically occurs in the pediatric population with accidental ingestion or after procedural sedation. It is recommended that the decision to use flumazenil be based on the balance of risk versus benefit in the assessment and treatment of a patient that is a non-habituated user of benzodiazepines, as most people with a benzodiazepine overdose will do well with supportive care and time alone.[7][8][9]

Full Review:

https://www.ncbi.nlm.nih.gov/books/NBK482238/#article-30312.s1