benzodiazepines toxicity

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  • 1. Benzodiazepines (BZDs) are sedative-hypnotic agentsthat were first introduced in 1960. BZDs commonly are used for a variety of situationsthat include1. seizure control2. anxiety3. alcohol withdrawal4. insomnia5. control of drug-associated agitation6. muscle relaxants7. preanesthetic agents.8. They also are combined frequently with othermedications for procedural sedation.

2. Because of their widespread use, thesedrugs have propensity for abuse. In addition, benzodiazepines frequentlyare used in overdose, either alone or inassociation with other substances. 3. Benzodiazepines (BZD) exert their action bypotentiating the activity of GABA. They bindto a specific receptor on the GABA A receptorcomplex, which facilitates the binding ofGABA to its specific receptor site. BZD binding causes increased frequency ofopening of the chloride channel complexedwith the GABA A receptor. Chloride channel opening results inmembrane hyperpolarization, which inhibitscellular excitation. 4. Enhanced GABA neurotransmission results insedation, striated muscle relaxation,anxiolysis, and anticonvulsant effects. Stimulation of peripheral nervous systemGABA receptors may cause decreased cardiaccontractility and vasodilation. These changescould have the potential to alter tissueperfusion. 5. Long-actingbenzodiazepines1-3 daysIntermediate actingbenzodiazepines16 hours hoursToxicity of BenzodiazepinesShort-actingbenzodiazepine3-8 hoursClorazepateChlordiazepoxideDiazepamFlurazepamQuzepamAlprazolamEstazolamLorazepamTemazepamOxazepamTriazolamClassification ofbenzodiazepines 6. BZDs are metabolized predominantly in theliver by oxidation and/or conjugation. Most BZDs are broken down intopharmacologically active metabolites, whichmay have longer half-lives than the parentcompounds. 7. The rate of BZD onset of action is determined byits ability to cross the blood-brain barrier. The relatively lipophilic BZDs usually produce afaster onset of effect than the relatively water-solubleBZDs. BZD effects can be potentiated when ethanol ispresent as coingestant. Peak blood concentrations of most agents occurwithin 1-3 hours. After a single dose, the lipophilic agents canhave a shorter duration of action (shorter CNSeffect) than water-soluble agents because rapidredistribution from the CNS to peripheral sites(eg, adipose tissue); thus, lorazepam (watersoluble) has a longer CNS duration of action thandiazepam (lipophilic). However, diazepam metabolizes to activeintermediates with prolonged half-life extendingits therapeutic effects. 8. Benzodiazepines generally are thought to be safeand death is rare. Mortality and morbidity from a pure oral BZDoverdose is rare; it usually occurs in conjunctionwith concomitant alcohol ingestion or use ofother sedative-hypnotics. Intravenous administration or overdose ofultrashort-acting BZDs (eg, triazolam) is morelikely to result in apnea and death. Elderly individuals and very young persons aremore susceptible to the CNS depressant effectsof BZDs than people in other age groups. Intravenous administration is associated withgreater degrees of hypotension than other routesof administration and occasional cardiac andrespiratory arrest. 9. Toxicity of Benzodiazepines Benzodiazepines toxicity (contd):- Psychological and physical dependence onbenzodiazepines can develop if high doses ofthe drugs are given over a prolonged period.- Abrupt discontinuation of the benzodiazepinesresults in withdrawal symptoms, includinganxiety, agitation, restlessness, reboundinsomnia, tension, tremors and rarely,seizures.- Because of the long half-lives of somebenzodiazepines (e.g. Diazepam), withdrawalsymptoms may occur slowly and last a numberof days after discontinuation of therapy.Benzodiazepines with a short elimination half-life,such as triazolam, induce more abruptand severe withdrawal reactions than thoseseen with drugs that are slowly eliminated,such as flurazepam 10. History should include the time, dose, andintent of the overdose. Determine if co-ingestants are present andthe duration of benzodiazepine use. Signs and symptoms1. Dizziness, Confusion,Drowsiness,Unresponsiveness, Anxiety, and Agitation2. Blurred vision and Nystagmus3. Slurred speech, ataxia, Weakness4. hypotension5. Respiratory depression6. Coma 11. Work up- as barbiturates.Management As barbiturates Flumazenil is a competitive BZD receptorantagonist and should be used cautiouslybecause it has potential to precipitate BZDwithdrawal in chronic users, resulting inseizures. Flumazenil administration is contraindicatedin mixed overdoses (eg, TCAs) because BZDreversal can precipitate seizures and cardiacarrhythmias.