1. BARBITURATE & BENZODIAZEPINE POISONING
TOXICOLOGY
BARBITURATE & BENZODIAZEPINE POISONING
Lahari Paladugu
PharmD

2. 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.

3. 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

4. BENZODIAZEPINE TOXICITY

5. 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

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

7. 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

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. BARBITURATE TOXICITY

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

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

16. 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.

17. 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

18. 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

19. 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 mg/100mL

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

21. 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

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

23. Thank YOU