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

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