Lahari Paladugu
PharmD 2009-2010
BARBITURATE & BENZODIAZEPINE
POISONING
TOXICOLOGY
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
GABA
BZD Potentiates GABA
Increased opening of Cl- Channels
Membrane Hyperpolarization
Mechanism Of Action
• 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
HISTORYPHYSICAL PRESENTATION
• 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.
• 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.
ADVERSE EFFECTS TOXIC EFFECTS
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
• Treatment of INSOMNIA• Phenobarbitone for EPILESPY
• Thiopentane for ANAESTHESIA
• Adjuvants in psychosomatic disorders
• Pre-operative sedation
• Treatment of seizure disorder
USES - BARBITURATES
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
THANK YOU
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