Benzodiazepines toxicity

toxicology

1. Benzodiazepines toxicity

2. Background Benzodiazepines (BZDs) are sedative-hypnotic agents that were first introduced in 1960. BZDs commonly are used for a variety of situations that include seizure control anxiety alcohol withdrawal insomnia control of drug-associated agitation muscle relaxants preanesthetic agents. They also are combined frequently with other medications for procedural sedation .

3. Because of their widespread use, these drugs have propensity for abuse. In addition, benzodiazepines frequently are used in overdose, either alone or in association with other substances.

4. Pathophysiology Benzodiazepines (BZD) exert their action by potentiating the activity of GABA. They bind to a specific receptor on the GABA A receptor complex, which facilitates the binding of GABA to its specific receptor site. BZD binding causes increased frequency of opening of the chloride channel complexed with the GABA A receptor. Chloride channel opening results in membrane hyperpolarization , which inhibits cellular excitation.

5. Enhanced GABA neurotransmission results in sedation, striated muscle relaxation, anxiolysis , and anticonvulsant effects. Stimulation of peripheral nervous system GABA receptors may cause decreased cardiac contractility and vasodilation . These changes could have the potential to alter tissue perfusion.

6. Long-acting benzodiazepines 1-3 days Intermediate –acting benzodiazepines 16 hours hours Short-acting benzodiazepine 3-8 hours Clorazepate Chlordiazepoxide Diazepam Flurazepam Quzepam Alprazolam Estazolam Lorazepam Temazepam Oxazepam Triazolam Toxicity of Benzodiazepines Classification of benzodiazepines

7. BZDs are metabolized predominantly in the liver by oxidation and/or conjugation. Most BZDs are broken down into pharmacologically active metabolites, which may have longer half-lives than the parent compounds.

8. The rate of BZD onset of action is determined by its ability to cross the blood-brain barrier. The relatively lipophilic BZDs usually produce a faster onset of effect than the relatively water-soluble BZDs. BZD effects can be potentiated when ethanol is present as coingestant . Peak blood concentrations of most agents occur within 1-3 hours. After a single dose, the lipophilic agents can have a shorter duration of action (shorter CNS effect) than water-soluble agents because rapid redistribution from the CNS to peripheral sites ( eg , adipose tissue); thus, lorazepam (water soluble) has a longer CNS duration of action than diazepam ( lipophilic ). However, diazepam metabolizes to active intermediates with prolonged half-life extending its therapeutic effects.

9. toxicity Benzodiazepines generally are thought to be safe and death is rare. Mortality and morbidity from a pure oral BZD overdose is rare; it usually occurs in conjunction with concomitant alcohol ingestion or use of other sedative-hypnotics. Intravenous administration or overdose of ultrashort -acting BZDs ( eg , triazolam ) is more likely to result in apnea and death. Elderly individuals and very young persons are more susceptible to the CNS depressant effects of BZDs than people in other age groups. Intravenous administration is associated with greater degrees of hypotension than other routes of administration and occasional cardiac and respiratory arrest.

10. Benzodiazepines toxicity (cont’d): - Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given over a prolonged period. Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms , including anxiety, agitation, restlessness, rebound insomnia, tension, tremors and rarely, seizures. Because of the long half-lives of some benzodiazepines (e.g. Diazepam ), withdrawal symptoms may occur slowly and last a number of days after discontinuation of therapy. Benzodiazepines with a short elimination half-life, such as triazolam , induce more abrupt and severe withdrawal reactions than those seen with drugs that are slowly eliminated, such as flurazepam Toxicity of Benzodiazepines

11. History should include the time, dose, and intent of the overdose. Determine if co- ingestants are present and the duration of benzodiazepine use. Signs and symptoms Dizziness, Confusion,Drowsiness , Unresponsiveness, Anxiety, and Agitation Blurred vision and Nystagmus Slurred speech, ataxia, Weakness hypotension Respiratory depression Coma

12. Work up - as barbiturates. Management As barbiturates Flumazenil is a competitive BZD receptor antagonist and should be used cautiously because it has potential to precipitate BZD withdrawal in chronic users, resulting in seizures. Flumazenil administration is contraindicated in mixed overdoses ( eg , TCAs) because BZD reversal can precipitate seizures and cardiac arrhythmias.