Introduction

• A benzodiazepine (sometimes colloquially "benzo"; often abbreviated "BZD") is

a psychoactive drug. The first such drug, chlordiazepoxide (Librium), was discovered

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accidentally by Leo Sternbach in 1955, and made available in 1960 by Hoffmann–La

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Roche, which has also marketed the benzodiazepine diazepam (Valium) since 1963

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 Introduction (contd)
• Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric
acid (GABA) at the GABAA receptor, resulting in sedative, hypnotic (sleep

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inducing), anxiolytic (anti-anxiety), euphoric, anticonvulsant, and muscle

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relaxant properties

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• Wider therapeutic window and lower drug tolerance for abuse with the

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benzodiazepines

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 Mechanism of action of bezodiazepines

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 Classification based on duration of action

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 Uses
• Due to the ability to calm the mind and body, benzodiazepines are often used to
treat anxiety, panic attacks, insomnia, agitation, muscle spasms, alcohol withdrawal

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and on occasion, premedication for medical or dental procedures

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 Risk assessment
• Isolated benzodiazepine overdose usually causes only mild sedation, irrespective of
the dose ingested, and can be easily managed with simple supportive care

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• Alprazolam overdose is associated with greater degree of CNS depression and is

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more likely to require intubation and ventilation

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• Zolpidem and zopiclone (non-benzodiazepine sedative-hypnotics) rarely cause

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severe CNS or respiratory depression when taken alone

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 Risk assessment (contd)
• Co-ingestion of other CNS depressants (e.g. alcohol, opioids) increases the risk of
complications, prolonged length of stay and death

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• The elderly and patients with cardiorespiratory co-morbidities may suffer greater

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complications

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• Children: Ingestion of one or two benzodiazepines usually manifests as mild

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sedation and ataxia within 2 hours

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 Benzodiazepine Side effects
• Relaxation

• Euphoria

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• Sense of wellbeing

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• Sedation

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• Dizziness

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• Impaired vision

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• Decreased motor skills/ unsteadiness
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• Dizziness

• The side effects of benzodiazepines are increased when paired with other drugs such as
barbiturates, alcohol, narcotics or tranquilizers
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 Toxic Mechanism
• Benzodiazepines act by enhancing gamma-amino butyric acid (GABA) mediated
neurotransmission. They bind to the GABAA receptor complex and increase the

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frequency of chloride channel opening

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• Zolpidem and zopiclone are non-benzodiazepine sedative-hypnotics that also act at

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the GABAA receptor complex

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 Toxicokinetics
• Benzodiazepines are rapidly absorbed orally. Most are highly protein bound and have
volumes of distribution that vary from 0.5 to 4 L/kg

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• Benzodiazepines undergo hepatic metabolism

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• Many have active metabolites. For example, diazepam is metabolised to N-

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desmethyldiazepam, oxazepam and temazepam, and alprazolam is metabolized to 1-

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and 4-hydroxyalprazolam

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 Toxicokinetics (contd)

• Duration of effect following overdose depends on CNS tolerance and redistribution,

rather than rate of elimination

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• Clinical features of intoxication are poorly correlated to serum benzodiazepine levels

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 Clinical features

Acute poisoning

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• Mild—Drowsiness, ataxia, weakness

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• Moderate to Severe— Vertigo, slurred speech, nystagmus, partial ptosis, lethargy,

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coma

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 Clinical features

• Onset of symptoms occurs within 1–2 hours. Ataxia, lethargy, slurred speech and

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drowsiness are followed by decreased responsiveness

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• Apnoea is a complication of airway obstruction

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• In very large ingestions hypothermia, bradycardia and hypotension may occur.

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Resolution of CNS depression usually occurs within 12 hours

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• More prolonged coma is common in the elderly
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 Clinical features

• Short acting benzodiazepines (midazolam and triazolam) and intermediate acting

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(flunitrazepam) have a higher acute toxicity, as compared to diazepam, lorazepam

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and nitrazepam

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• Administration of benzodiazepines to a pregnant woman prior to delivery may

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produce signs of poisoning in the neonate. A condition called “floppy infant

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syndrome”, characterised by hypotonia that may last several days, may occur
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following maternal diazepam use

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 Clinical features

Chronic Poisoning

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• Long-term use of benzodiazepines is associated with the development of tolerance

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• Abrupt cessation provokes a mild withdrawal reaction characterised by anxiety,

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insomnia, head- ache, tremor, and paraesthesia, restlessness

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 Management

Acute Poisoning

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• Decontamination—Ipecac-induced emesis is not recommended because of the

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potential for CNS depression

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• Stomach wash may be helpful if the patient is seen within 6 to 12 hours after the

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ingestion

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• Endotracheal intubation is a prerequisite in comatose patients
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• Activated charcoal adsorbs benzodiazepines and can be administered in the usual

manner
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 Management

• Establish clear airway

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• Oxygen and assisted ventilation are often necessary

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• IV fluids (Ringer’s lactate at a rate of 150 ml/hr for adults)

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• If hypotension persists, administer dopamine or noradrenaline

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• Forced diuresis and haemodialysis are ineffective
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 Antidotes
• Flumazenil is a competitive benzodiazepine antagonist with a limited role in
benzodiazepine overdose. Its indications include:

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– Management of airway and breathing when resources are not available to safely

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intubate and ventilate the patient

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– Diagnostic tool to avoid further investigation

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– Reversal of conscious sedation

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 Antidotes (contd)
• Flumazenil is a recently discovered pharmacologic antagonist of the CNS effects of
benzodiazepines

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• It acts by binding CNS benzodiazepine receptors and competitively blocking

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benzodiazepine activation of inhibitory GABA ergic synapses

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• Most patients achieve complete reversal of benzodiazepine effect with a total slow IV

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dose of just 1 mg

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 Antidotes (contd)

• Flumazenil also has the tendency to induce a withdrawal reaction in benzodiazepine-

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dependant patients

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• Flumazenil is contraindicated in mixed ingestions involving tricyclic antidepressants

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and drugs which induce seizures, e.g. theophylline, chloroquine, etc

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 Management

Chronic poisoning

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• Phenobarbitone-substitution technique is recommended for benzodiazepine

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withdrawal which employs propranolol for acute somatic symptoms, while

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phenobarbitone is used for detoxification

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• However the most frequently used method is the replacement of a short half-life

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benzodiazepine (such as alprazolam) with a long half-life benzodiazepine (such as
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clonazepam), before initiating a taper and final discontinuation

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