BENZODIAZEPINE POISONING

SIGNS, SYMPTOMS & TREATMENT

Introduction of BZDs
Examples of some commonly used BZDs:

Alprazolam, Chlordiazepoxide, Clonazepam, Diazepam, Estazolam, Lorazepam, Triazolam, Flurazepam, Midazolam, Oxazepam, etc.
BZDs are commonly known as Sleeping Pills or

Minor Tranquilisers.

Therapeutic Uses of BZDs

BZDs are Sedative-Hypnotic agents primarily used as: Anxiolytic Muscle relaxant Anticonvulsant To treat alcohol withdrawal Treatment of insomnia They are administered preoperatively for their anterograde amnesia effects Drugs of abuse

Mechanism of Action
BZDs potentiate the activity of GABA. GABA is the major inhibitory neurotransmitter in the CNS. GABA receptor is a ligand gated ion channel (chloride

channel). BZDs bind to a specific binding site on GABA receptor which facilitates the binding of GABA to its specific binding site. BZD binding causes increased frequency of opening of the chloride channel. Chloride channel opening results in membrane hyperpolarisation, thereby inhibiting cellular excitation.

Aetiology of BZD poisoning

Intentional overdose in suicidal patients Accidental in combination with other CNS

depressants such as alcohol and opioids By medication errors Drug interaction (potentiation) with erythromycin, isoniazid, centrally acting antihistamines, tricyclic antidepressants, antifungal imidazoles.

Symptoms of Acute Toxicity

Lethargy Nystagmus Diplopia Amnesia Slurred speech Confusion Hypotonia

Hypotension Hypothermia Coma Respiratory Depression

Symptoms of Chronic Toxicity

Tolerance and physical dependence may develop Abrupt discontinuation of BZDs may result in

withdrawal symptoms consisting of anxiety, agitation, insomnia, tremors, headache and myalgias In more severe cases nausea, vomiting, diaphoresis, hyperpyrexia, psychosis, seizures may occur.

Toxicokinetics
Lipid soluble drugs, absorbed fairly rapidly. Highly protein bound and volume of distribution

(Vd=1 L/ Kg). Distribute well into CNS.

Most BZDs are hepatically metabolised with a renal

clearance accounting for less than 5%.

Because BZD overdose is rarely lethal, once the diagnosis is confirmed, most patients require only observation until metabolism of BZD leads to natural recovery.

Supportive Measures
It is the Mainstay of the treatment Observation of vital signs IV access with fluid administration to correct hypotension; catecholamines and dopamine may be required to increase blood pressure Maintenance of airway with intubation and artificial ventilation may be required if respiratory depression occurs

Flumazenil
Flumazenil is a benzodiazepine antagonist but its use

following BZD poisoning is controversial Diagnostic use: 0.1-0.2 mg IV may be given to unconscious patients. A rapid improvement in levels of consciousness (within 1 or 2 min) is expected in pure BZD poisoning.

Treatment with Flumazenil

0.2 mg IV given over 30 seconds; may give a further 0.3

mg after 30 seconds if necessary; further doses of 0.5 mg may be given at 1 min intervals as necessary; max. 2 mg total dose. Flumazenil can be used in patients who are first time or infrequent BZD users and there are no known contraindications. Flumazenil reverses CNS depression but does not reliably reverse respiratory depression. Has several contraindiactions and hence risk of flumazenil often outweigh the benefits.

Contraindications of Flumazenil
Flumazenil is contraindicated in: Patients who are on long term benzodiazepines Patients who have ingested a substance that lowers seizure threshold, eg, tricyclic anti-depressants Patients who have tachycardia, widened QRS complex on ECG.

Other treatment approaches

Not so useful in case of pure BZD poisoning. Although BZDs are absorbed by activated charcoal,

gastric decontamination with activated charcoal is not beneficial in pure BZD overdose. Gastric lavage should not be employed routinely because of the severe risks including hypoxia, lyrangospasm etc. Enhancing elimination of the drug with hemodialysis or forced diuresis is unlikely to be beneficial due to large volume of distribution and high lipid solubility of BZDs.

Refrences
Encyclopedia of Toxicology Meylers side effects of drugs Internet ( Wikitox, Wikipedia, Bestpractice,

e-medicine)