2. Diazepam overdose describes the ingestion of diazepam in
quantities greater than are recommended or generally
practiced.
Death as a result of taking an excessive dose of diazepam alone
is uncommon (vs Combined drug intoxicaton).
Combinations of high doses of benzodiazepines with
alcohol, barbiturates, opioids or tricyclic antidepressants are
particularly dangerous, and may lead to severe complications
such as coma or death.
3. SIGNS AND SYMPTOMS
rapid with most developing symptoms within 4 hours.
Patients initially present with mild to moderate impairment of CNS function.
Initial signs and symptoms include somnolence, diplopia, impaired balance,
impaired motor function, anterograde amnesia, ataxia, and
slurred speech.
Paradoxical reactions such as anxiety, delirium, hallucinations, and
aggression .
4. GI symptoms such as nausea and vomiting have also been occasionally
reported.
Severe overdose can lead to prolonged deep coma , apnea, respiratory
depression, hypothermia, hypotension, bradycardia, cardiac arrest,
and pulmonary aspiration.
Symptoms such as sleepiness, agitation and ataxia occur much more
frequently and severely in children. Hypotonia may also occur.
5. TOXICITY
Benzodiazepines have a wide therapeutic index and taken alone
in overdose rarely cause severe complications or fatalities. Taken in overdose
in combination with alcohol, barbiturates, opioids, tricyclic antidepressants,
etc are particularly dangerous.
In the case of alcohol and barbiturates, not only do they have an additive
effect but they also increase the binding affinity of benzodiazepines to the
benzodiazepine binding site, which results in a very significant potentiation of
the CNS and respiratory depressant effects.
Elderly and those with chronic illnesses are much more vulnerable to lethal
overdose with benzodiazepines.
6. PATHOPHYSIOLOGY
Benzodiazepines bind to a specific benzodiazepine receptor,
thereby enhancing the effect of the neurotransmitter gamma-aminobutyric
acid (GABA) and causing CNS depression.
In overdose situations this pharmacological effect is extended leading to a
more severe CNS depression and potentially coma or cardiac arrest.
7. Benzodiazepine overdose related coma may be characterised by an alpha
pattern with the central somatosensory conduction time (CCT).
Brain-stem auditory evoked potentials demonstrate delayed interpeak latencies
(IPLs) I-III, III-V and I-V.
Toxic overdoses therefore of benzodiazepines cause prolonged CCT and IPLs.
8. DIAGNOSIS
Diagnosis is based on the clinical presentation of the patient along with a
history of overdose.
Obtaining a laboratory test for Diazepam blood concentrations can be useful
in patients presenting with CNS depression or coma of unknown origin.
Techniques available to measure blood concentrations include:
thin layer chromatography
gas liquid chromatography
radioimmunoassay.
9. TREATMENT
Medical observation and supportive care are the mainstay of treatment of
Diazepam overdose.
Although benzodiazepines are absorbed by activated charcoal, It is
recommended only if the drug has been taken in combination with other
drugs that may benefit from decontamination.
Gastric lavage or whole bowel irrigation are also not recommended.
Enhancing elimination of the drug with hemodialysis, hemoperfusion,
or forced diuresis is unlikely to be beneficial due to their large Vd and lipid
solubility .
10. SUPPORTIVE MEASURES
Supportive measures include observation of vital signs, especially Glasgow
Coma Scale and airway patency.
Supportive measures should be put in place prior to administration of any
benzodiazepine antagonist in order to protect the patient from both the
withdrawal effects and possible complications arising from the
benzodiazepine.
11. IV fluid administration and maintenance of the airway with intubation and
artificial ventilation may be required if respiratory depression or pulmonary
aspiration occurs.
Hypotension is corrected with fluid replacement,
although catecholamines such as norepinephrine or dopamine may be
required to increase BP.
Bradycardia is treated with atropine or an infusion of norepinephrine to
increase coronary blood flow and heart rate.
12. FLUMAZENIL
Flumazenil is a competitive BZD receptor antagonist that
can be used as an antidote for benzodiazepine overdose.
Abolishes the hypnogenic, psychomotor,cognitive and EEG effects
of BZDs.
Oral bioavailability ≈ 16%; not used orally
On I/V injection ,action starts within seconds and lasts for 1-2hrs.
Elimination half life is 1 hr due to rapid hepatic clearance.
13. A/E – Agitation, confusion ,anxiety, tremor, withdrawal seizures etc..
Dose- 0.2 mg/min injected I/V till the patient regains consciousness.
Contraindications :
-patients who are on long-term benzodiazepines.
-those who have ingested a substance that lowers the seizure threshold.
-in patients who have tachycardia.
-widened QRS complex on ECG.
-anticholinergic signs.
-history of seizures.
14. Due to these contraindications and the possibility of it causing severe adverse
effects , in the majority of cases there is no indication for the use of
flumazenil in the management of benzodiazepine overdose as the risks in
general outweigh any potential benefit of administration.
It also has no role in the management of unknown overdoses.
In addition, if full airway protection has been achieved, a good outcome is
expected, and therefore flumazenil administration is unlikely to be required.
15. Flumazenil is very effective at reversing the CNS depression associated with
benzodiazepines but is less effective at reversing respiratory depression.
Studies found that only 10% of the patient population presenting with a
benzodiazepine overdose are suitable candidates for flumazenil.
Due to its short half life, the duration of action of flumazenil is usually less
than 1 hour, and multiple doses may be needed.
When flumazenil is indicated the risks can be reduced or avoided by slow
dose titration of flumazenil.
