BARBITURATE & BENZODIAZEPINE POISONING TOXICOLOGY BARBITURATE & BENZODIAZEPINE POISONING Lahari Paladugu PharmD 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 pre- anesthetic agents; combined frequently with other medications for procedural sedation

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

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

TOXIC EFFECTS ADVERSE EFFECTS Weakness, headache, amnesia, vertigo, diplopia, nausea, diarrhea, and rarely chest pain Paradoxical effects – disinhibition of dyscontrol reaction may sometimes occur characterized by restlessness, agitation, and hallucinations. 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 lethal ingestions.

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

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

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/100mL LBL for phenobarbitone varies from 8-15 mg/100mL

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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