TOXICOLOGY BARBITURATE BENZODIAZEPINE POISONING Lahari Paladugu Pharm D

TOXICOLOGY BARBITURATE & BENZODIAZEPINE POISONING Lahari Paladugu Pharm. D 2009 -2010

WHAT ARE THEY? • CNS Drugs --- Sedative-Hypnotics • SEDATIVES: A drug that subdues excitement and calms the subject without inducing sleep, though drowsiness may be produced. • HYPNOTICS: A drug that induces and/or maintains sleep, similar to normal arousable sleep.

BARBITURATES - Long acting: Phenobarbitone - Short acting: Butobarbitone, Pentobarbitone - Ultra-short acting: Thiopentane, Methohexitone BENZODIAZEPINES - Hypnotic: Diazepam, Flurazepam, Nitrazepam, Alprazolam, Temazolam, Triazolam - Antianxiety: Diazepam, Chlordiazepoxide, Oxasepam, Lorazepam, Alprazolam - Anticonvulsant: Diazepam, Lorazepam, Clonazepam, Clobazam

BENZODIAZEPINE TOXICITY

BENZODIAZEPINES USES • Sedative-Hypnotics • seizure control, anxiety, alcohol withdrawal, insomnia, control of drug-associated agitation, as muscle relaxants, and as preanesthetic agents; combined frequently with other medications for procedural sedation

Mechanism Of Action GABA BZD Potentiates GABA Increased opening of Cl- Channels Membrane Hyperpolarization

HISTORY PHYSICAL PRESENTATION • • Dizziness • • • Confusion • • Drowsiness • • Blurred vision • • Unresponsiveness • • Anxiety • • Agitation • • Nystagmus Hallucinations Slurred speech Ataxia Coma Hypotonia Weakness Altered mental status, impairment of cognition Amnesia Paradoxical agitation Respiratory depression Hypotension

ADVERSE EFFECTS TOXIC EFFECTS • Weakness, headache, amnesia, vertigo, diplopia, nausea, diarrhea, and rarely chest pain • Chronic poisoning – • Development of tolerance • Abrupt cessation provokes a mild withdrawal reaction – anxiety, insomnia, headache, tremor, paresthesia • Acute poisoning – • Mild: drowsiness, ataxia, weakness • Moderate to severe – vertigo, slurred speech, nystagmus, lethargy, coma. Hypotension and respiratory depression supervene in potentially • Paradoxical effects – disinhibition of dyscontrol reaction may sometimes occur characterized by restlessness, agitation, and hallucinations.

DIAGNOSIS • Gas chromatography- mass spectrometry – used to analyze urine levels of benzodiazepines • A less effective alternative is TLC, which can be done on urine, gastric aspirate, or scene residue. • Estimation of plasma levels of benzodiazepines is usually not necessary.

TREATMENT – ACUTE POISONING • Decontamination – Stomach wash may be helpful within 6 -12 hours of ingestion. Activated charcoal can also be given in usual manner. • Establish a clear airway – Oxygen and assisted ventilation if necessary. • IV fluids • Correction of hypotension with dopamine or levarterenol.

TREATMENT – ANTIDOTE • FLUMAZENIL – Antidote which acts by competitive antagonism. • Complete reversal can be obtained with total slow IV dose of 1 mg • Can also be admin. In a series of smaller doses in increment manner, starting with 0. 2 mg and progressively increasing by 0. 1 – 0. 2 mg every minute until a cumulative total dose of 3. 5 mg is reached. • Resedation can occur within 30 minutes to 2 hours… therefore, patients must be carefully monitored and subsequent doses of flumazenil must be given as needed.

TREATMENT – CHRONIC POISONING • Phenobarbitone-substitution technique • Recommended for benzodiazepine withdrawal • Propranolol for somatic symptoms • Phenobarbitone for detoxification • Replacement of short half-life benzodiazepine with a longer half-life benzodiazepine, before initiating a taper and final discontinuation.

BARBITURATE TOXICITY

USES - BARBITURATES • Treatment of INSOMNIA • Phenobarbitone for EPILESPY • Thiopentane for ANAESTHESIA • Adjuvants in psychosomatic disorders • Pre-operative sedation • Treatment of seizure disorder

Enhance GABA mediated Cl currents Mechanism Of Action Increases duration of ionophone opening Prolongs inhibitory actions of GABA

BARBITURATES ~ TOXICOKINETICS • Usually administered orally. Parenteral route is usually reserved for management of status epilepticus or induction/maintenance of general anesthesia. • Following absorption, barbiturates are distributed widely. • Metabolism – oxidation in liver resulting in the formation of alcohols, ketones, phenols, or carboxylic acids • Excretion – in urine as such or in the form of glucuronic acid conjugates.

BARBITURATES ~ ADVERSE EFFECTS • Residual depression after the main effect of drug has passed • Paradoxical excitement • Hypersensitivity reaction – localized swelling of eyelid, cheek, or lip, erythematous or exfoliative dermatitis • Synergistic action with ethanol and antihistamines

BARBITURATES ~ TOXIC EFFECTS • Slurred speech, ataxia, lethargy, confusion, headache, nystagmus • CNS depression, coma, shock • Pupils first constrict and then dilate because of hypoxia • hypothermia • Cutaneous bullae • Death due to respiratory arrest of cardiovascular collapse • Chronic abuse tolerance. • Withdrawal reaction: anorexia, tremor, insomnia, cramps, seizures, delirium, orthostatic hypotension

BARBITURATES ~ USUAL FATAL DOSE • Phenobarbitone – 6 -10 g • Amobarbitone, pentobarbitone, secobarbitone – 2 -3 g • Lethal blood level for short/intermediate acting barbiturate varies from 3 -4 mg/100 m. L • LBL for phenobarbitone varies from 815 mg/100 m. L

BARBITURATES ~ DIAGNOSIS • TLC – urine, stomach contents, scene residue • GC or HPLC • EEG – alpha coma indicates poor prognosis

BARBITURATES ~ TREATMENT • Gastric lavage can be done with benefit upto 6 -12 hours post ingestion • Activated charcoal can be given at usual dose • Forced alkaline diuresis is said to be particularly helpful in the case of phenobarbitone poisoning • Hemodialysis or haemoperfusion • Supportive measures – supplemental oxygen, intubation, assisted ventilation, IV fluids

REFERENCES • Textbook of Forensic Medicine and Toxicology by VV Pillay • Wikipedia • Medscape

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