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BENZODIAZEPINE
POISONING
DR.VIVEK BENJAMIN,MD
• Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of psychoactive drugs whose
core chemical structure is the fusion of a benzene ring and a diazepine ring.
• The first such drug, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955,
and made available in 1960 by Hoffmann–La Roche,.
• In 1977 benzodiazepines were globally the most prescribed medications. They are in the family of drugs
commonly known as minor tranquilizers.
HISTORY
TYPES
Benzodiazepines
• Hypnotic Antianxiety Anticonvulsant
• Diazepam Diazepam Diazepam
• Flurazepam Chlordiazepoxide Lorazepam
• Nitrazepam Oxazepam Clonazepam
• Alprazolam Lorazepam Clobazam
• Temazepam Alprazolam
• Triazolam
THE INTEREST IN
BENZODIAZEPINES INCREASED
OVER THE PAST DECADE
SELECTIVITY:
 For different GABA neurons
 For different receptorsubtypes
 For the tonic GABAfiring
 ANXIOLYTIC EFFECT: Benzodiazepines inhibit the
activationof amygdala, by binding at GABA- A receptors in
the amygdala.
 HYPNOTIC EFFECT: Benzodiazepines promote sleep by
binding at GABA-A receptors in the VLPO, causing
sleepiness.
 Traumatic memories stored in the hippocampus can
activate the amygdala, causing the amygdala in turn to
activate the hippocampus and generate a fear response,
REEXPERIENCING(PTSD).
HYPNOTIC EFFECT OF
BENZODIAZEPINES
Benzodiazepines are also hypnoticdrugs.
The hypothalamus contains
the sleep and wakefulness
promoters:
VLPO (sleep promoter)
TMN (wakefulness promoter).
TUBEROMAMMILARY NUCLEUS (TMN) OF HYPOTHALAMUS
IS THE WAKEFULNESS PROMOTER (THE COFFEE- HOUSE OF
THE BRAIN)
 TMN of hypothalamuscontains histamine producing neurons thatare
activated by glutamate and inhibited by GABA andBenzodiazepines.
 These neurons are thewakefulness promoter.
*Lateral hypothalamus
contains
orexin/hypocretin
neurons that promote
weight loss in addition
to wakefulness.
VENTRO-LATERAL PREOPTIC NUCLEUS OF
THE HYPOTHALAMUS(VLPO) - THE SLEEP
PROMOTER
 VLPO nucleus contains GABA neurons thatinhibit
TMN and thus promotesleep.
 Benzodiazepines augment the action of GABAin
VLPO nucleus.
THE BALANCE OF SLEEP AND
WAKEFULNESS
TMN SCN VLPO
INTERNAL CLOCK:
Suprachiasmatic nucleus
of the hypothalamus –
THE SWITCH (activated
by light, melatonin). It
can promote either sleep
orwakefulness.
WAKE PROMOTER:
Tuberomammillary
nucleus –TMN-of the
hypothalamus promotes
wakefulness( produces
histamine )
SLEEP
PROMOTER:
Ventrolateral
preoptic area –
VLPO-of the
hypothalamus
promotes sleep
(produces GABA )
BENZODIAZEPINES – FDA
INDICATIONS
 In addition to anxiety, benzodiazepines areindicated
for muscle tension, insomnia, status
epilepticus(diazepam), myoclonic
epilepsy(clonazepam), preoperative anesthesia, and
alcohol witdhrawal.
 Two benzodiazepines: alprazolam and lorazepam
have FDA indication for anxiety associated with
depression.
 Clonazepam and Alprazolam are indicated in the
treatment of panicdisorder.
BENZODIAZEPINES – ADVERSE
EFFECTS
 Sedation
 Lethargy
 Dependency/Withdrawal
 Respiratorydepression
 Possible cognitive impairment.
 Safe in overdose: up to 30 times the normaldaily dose. Usual symptoms of
overdose include sedation, drowsiness, ataxia,and slurred speech. May result in
respiratory depression in combination with otherCNS depressants.
Management includes gastric lavage, forced emesis, and assistedventilation.
 Drug interactions:
1. drugs that increase benzodiazepine levels include P4503A4 inhibitors,
ketoconazole, fluconazole, nefazodone.
2.drugs that decrease benzodiazepine levels includeP4503A4 inducers such as
carbamazepine.
BENZODIAZEPINES -
SUBCLASSES
2 keto (chlordiazepoxide, clonazepam, clorazepate, diazepam,
halazepam, prazepam, and flurazepam).
The 2-ketodrugsand theiractive metabolitesareoxidized in the liver,
and because this process is relatively slow, these compounds have
relatively long half-lives.
3 hydroxy(lorazepam, oxazepam, temazepam)
The 3-hydroxycompoundsare metabolized viadirectconjugationwith
a glucuronide radical, a process that is more rapid than oxidation
and does not involvethe formationof active metabolites.
Triazolo (alprazolam, adinazolam, estazolam, andtriazolam)
The triazolocompoundsarealsooxidized, howeverthey havea more
limited active metabolitesand thusshorter half-lives.
BENZODIAZEPINE
PROPERTIES
The effects of benzodiazepines depend ontheir
properties:
 1. half-life
 2. liposolubility
 3. receptoraffinity
Five benzodiazepines are FDA approved for insomnia are:
 flurazepam and quazepam, (ultra-long half-lives);
 triazolam (ultra-short half-life)
 estazolam and temazepam (moderate half-lives).
FDA APPROVED BENZODOAZEPINE
HYPNOTICS
LIPOSOLUBILITY
 Highly lipophilic benzodiazepines such as diazepam
enter the brain more quickly, “turning on” the effect
promptly, but “turning off” theeffect morequicklyas
well as theydisappear into body fat.
 Less lipophiliccompoundssuch as lorazepam produce
clinical effects more slowly, but may provide more
sustained relief in spite of shorter half life.
RELATIVE RECEPTOR
AFFINITY
 The higher theiraffinity for GABA-A receptors, the
more intensewithdrawal symptoms theycause.
 High potency benzodiazepines such as lorazepamand
alprazolam have high receptor affinity – intense
withdrawal symptoms.
 Oxazepam has low receptor affinity –fewer
withdrawal symptoms.
MEMORY IMPAIRMENT (FACT OR
MYTH)
 Lucki et al. (1986) conducted a study on long-term
benzodiazepine treatment. It failed to showsignificant
cognitive impairment on psychometrictests.
 The most recent controlled study in this area failed to find
significant long-term cognitive effects for alprazolam XR in
panicdisorder patients (Gladsjo et al. 2001).
 In spite of these studies some investigators believe that
cognitive impairment can occur, particularly in elderly
patients.
BENZODIAZEPINES MIGHT CAUSE
MEMORY IMPAIRMENT IN ELDERLY
HOW ADDICTIVE ARE
BENZODIAZEPINES?
 How long does one have to takea benzodiazepine before
withdrawal is seen withdiscontinuation?
 Studies in animals have indicated that benzodiazepinescan
reinforce use and can produce physical dependence and
tolerance.
 Available data seem to reveal that benzodiazepines are
rarely sought after or craved in the sense that heroin or
cocaine are. Rather, theyare used as part of a polysubstance
abuse pattern to modulate the effects of primary drug of
abuse(e.g. cocaine) or as a backup drug when more
euphoriant drugs are notavailable.
BENZODIAZEPINES POTENTIATE THE EFFECT OF
ALCOHOL
ADVERSE EFFECTS
■ Weakness, headache, amnesia, vertigo, diplopia, nausea,
diarrhoea, and rarely chest pain.
■ Paradoxical effects (disinhibition or dyscontrol reaction)
may sometimes occur characterised by restlessness, agitation,
and hallucinations.
■ Flurazepam has been associated with nightmares and
hallucinations.
■ Allergic, hepatotoxic, and haematological reactions are
rare.
CLINICAL (TOXIC) FEATURES
• Benzodiazepines are remarkably safe drugs and rarely produce
serious toxic effects even with substantial ingestion.
Death is uncommon unless other synergistic drugs have also been
ingested.
However, newer benzodiazepines such as alprazolam,triazolam, and temazepam are associated with
fatalities.
Acute Poisoning:
a. Mild—Drowsiness, ataxia, weakness.
b. Moderate to Severe—
– Vertigo, slurred speech, nystagmus, partial ptosis, lethargy, coma.
– Hypotension and respiratory depression.
– Analysis of acute benzodiazepine overdoses in relation to the incidence of coma indicate
that short acting benzodiazepines (midazolam and triazolam) and intermediate acting
(flunitrazepam) have a higher acute toxicity, as compared to diazepam, lorazepam and
nitrazepam.
–memory impairment/ amnesia in a significant number of patients (TRIAZOLAM).
Clinical (Toxic) Features
– Administration of benzodiazepines to a pregnant woman prior to delivery
may produce signs of poisoning in the neonate.A condition called “floppy
infant syndrome”, characterised by hypotonia that may last several days, may
occur following maternal diazepam use.
Chronic Poisoning:
Long-term use of benzodiazepines is associated with the development of tolerance.
Abrupt cessation provokes a mild withdrawal reaction characterised by anxiety,
insomnia,headache,tremor, and paraesthesia.
Restlessness, encephalopathy, and hallucinations may occur after abrupt withdrawal from high
daily doses. Convulsions may occur after a lapse of 3 to 10 days.
Diagnosis
Estimation of plasma levels of benzodiazepines is usually not
necessary. Qualitative testing for presence of benzodiazepine is
helpful to confirm presence, especially when overdose historyis
sketchy. Quantitative levels are not usually clinically useful.
Blisters of skin (bullae) can occur following overdose with
nitrazepam, oxazepam, and temazepam.
Treatment
1.Monitor CBC, serum electrolytes, glucose, blood urea nitrogen,creatinine, and urine
myoglobin in patients with significant intoxication.
2. Gastric lavage (preferably with a large-bore, double-lumen tube), can be done with
benefit upto 12 to 24 hours postingestion.
3. Multiple dose activated charcoal has been shown to be effective.
4. Establish clear airway. Oxygen and assisted ventilation are often necessary.
5. IV fluids (Ringer’s lactate at a rate of 150 ml/hr for adults).
6. Correction of hypotension: Begin by infusing 10 to 20 ml/kg of isotonic fluid, and place
patient in Trendelenburg position. If hypotension persists, administer dopamine or
noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy.
■ – Flumazenil is effective in reversing the coma induced by benzodiazepines as well as
zolpidem.
The mode of action is competitive antagonism.
– In practice, most patients achieve complete reversal of benzodiazepine effect with a total
slow IV dose of just 1 mg.
Some investigators suggest that flumazenil is better administered in a series of smaller doses in
an incremental manner beginning with 0.2 mg and progressively increasing by 0.1 to 0.2 mg
every minute until a cumulative total dose of 3.5 mg is reached.
However, resedation occurs within ½ hour to 2 hours (depending on the nature and dose of
benzodiazepine ingested), and therefore patients must be carefully monitored and subsequent
doses of flumazenil should be administered as needed.
The use of continuous flumazenil maintenance infusion over 5 to 24 hours seems of
therapeutic value in the event of resedation after initial response.
– Flumazenil has also been reported to reverse cardiovascular depression secondary to
benzodiazepine use.
– Flumazenil does not reverse respiratory depression very well and hence fundamental
procedures such as supplemental oxygen, endotracheal intubation, and ventilation must not
be neglected.
– Flumazenil is contraindicated in mixed ingestions involving tricyclic antidepressants and
drugs which induce seizures, e.g. theophylline, carbamazepine, chloroquine, etc. But there
are indications that it may be beneficial in hepatic encephalopathy and ethanol overdose.
– Flumazenil may cause the following adverse effects: fatigue, nausea, vomiting,
hypertension, tachycardia, anxiety, confusion, restlessness, aggression, and rarely
convulsions and cardiac arrhythmias..
Forensic Issues
■ Ever since the introduction of benzodiazepines in the 1960s, they have become
progressively more popular as
anxiolytic agents and sedatives, displacing the barbiturates from their previously held
top spot.
In spite of extensive use worldwide, there have been only a few cases reported involving
fatalities, demonstrating the wide margin of safety of benzodiazepines.
Deaths have been reported in some recent cases even from unexpectedly low doses of
certain benzodiazepines.
There are also indications that some of the newer benzodiazepines have a slightly
smaller margin of safety.
This is particularly true with reference to paediatric and geriatric patients who are more
susceptible to the toxicity of these drugs.
■ An area of concern with long-term benzodiazepine use is the possibility of
behavioural disinhibition which may induce a person to hostile acts, aggressive
behaviour, and verbal indecency.
■ Yet another important issue is with reference to the use of benzodiazepines to
deliberately induce amnesia in certain individuals in order to accomplish an
immoral act (e.g. date rape). Many of these drugs, particularly flunitrazepam, are
capable of causing retrograde amnesia.
Flunitrazepam (Rohypnol®; “Roofies”) has become popular as a drug of abuse,
often combined with alcohol, marijuana, or cocaine to produce an intense “high”. It
has been used as a “date rape” drug, both for its properties of lowering inhibitions
and because it can cause retrograde amnesia.
■ Severe dysmorphism, malformations, intrauterine and
extrauterine growth retardation, and central nervous system
dysfunction have been described in infants born of mothers who
used benzodiazepines during pregnancy.
Case Report: A 37 year old married female, with history of psychiatric problems,
Presentation-unconscious state.
Alleged history of ingestion of 60 tablets of alprozolam (Alprax- Rx) tablets 3 hour
back, with the intention of suicide.
The relatives of the patient showed us all the empty packs, containing the tablets,
found near her body. There were about 60, 1mg tablets of alprazolam that had
been ingested by her.
Further, her relatives gave history that patient had been suffering from panic
disorder, since last five years, for which she had been on medication off and on, as
advised by a psychiatrist. Her medications included alprazolam and fluoxetine.
Off late, she was also under stress, as she could not conceive in last four years of
her marriage, and was pursuing infertility treatments, without any success.
On general examination mild cyanosis and pallor was present. Patient’s vitals on
admission were as follows-- pulse -100/min feeble, blood pressure-80/mm hg
systolic, respiratory rate 30/min regular, temperature - 36.8 C. Neurological
examination showed deep coma, bilateral constricted pupils , which reacted
minimally to light, diminished tendon reflexes and retention of urine, and plantar
reflexes were not illicitable bilaterally. There was no response to painful stimuli. Her
Glasgow coma scale (GCS) was 3. Respiratory system examination was within
normal limits. On cardiovascular system (CVS) examination tachycardia was noted,
and ECG showed sinus tachycardia. Routine Biochemical and hematological tests
were normal.
As suggested by the evidences above, probability diagnosis of alprazolam over
dosage was made. Patient was admitted in ICU. A nasogastric tube was placed
and catheterization was done. Patient’s gastric lavage returned no pill fragments.
She was urgently intubated and kept on mechanical ventilation with continuous
oxygen administration and parenteral fluids. Rest of her treatment was
symptomatic. Flumazenil, which is the antidote of alprazolam poisoning was used.
Patient showed improvement after few hours and was extubated. Patient got
recovered and discharged.
Benzodiazepine poisoning

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Benzodiazepine poisoning

  • 2. • Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of psychoactive drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. • The first such drug, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and made available in 1960 by Hoffmann–La Roche,. • In 1977 benzodiazepines were globally the most prescribed medications. They are in the family of drugs commonly known as minor tranquilizers. HISTORY
  • 3. TYPES Benzodiazepines • Hypnotic Antianxiety Anticonvulsant • Diazepam Diazepam Diazepam • Flurazepam Chlordiazepoxide Lorazepam • Nitrazepam Oxazepam Clonazepam • Alprazolam Lorazepam Clobazam • Temazepam Alprazolam • Triazolam
  • 4. THE INTEREST IN BENZODIAZEPINES INCREASED OVER THE PAST DECADE SELECTIVITY:  For different GABA neurons  For different receptorsubtypes  For the tonic GABAfiring
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  • 12.  ANXIOLYTIC EFFECT: Benzodiazepines inhibit the activationof amygdala, by binding at GABA- A receptors in the amygdala.  HYPNOTIC EFFECT: Benzodiazepines promote sleep by binding at GABA-A receptors in the VLPO, causing sleepiness.  Traumatic memories stored in the hippocampus can activate the amygdala, causing the amygdala in turn to activate the hippocampus and generate a fear response, REEXPERIENCING(PTSD).
  • 13. HYPNOTIC EFFECT OF BENZODIAZEPINES Benzodiazepines are also hypnoticdrugs. The hypothalamus contains the sleep and wakefulness promoters: VLPO (sleep promoter) TMN (wakefulness promoter).
  • 14. TUBEROMAMMILARY NUCLEUS (TMN) OF HYPOTHALAMUS IS THE WAKEFULNESS PROMOTER (THE COFFEE- HOUSE OF THE BRAIN)  TMN of hypothalamuscontains histamine producing neurons thatare activated by glutamate and inhibited by GABA andBenzodiazepines.  These neurons are thewakefulness promoter. *Lateral hypothalamus contains orexin/hypocretin neurons that promote weight loss in addition to wakefulness.
  • 15. VENTRO-LATERAL PREOPTIC NUCLEUS OF THE HYPOTHALAMUS(VLPO) - THE SLEEP PROMOTER  VLPO nucleus contains GABA neurons thatinhibit TMN and thus promotesleep.  Benzodiazepines augment the action of GABAin VLPO nucleus.
  • 16. THE BALANCE OF SLEEP AND WAKEFULNESS TMN SCN VLPO INTERNAL CLOCK: Suprachiasmatic nucleus of the hypothalamus – THE SWITCH (activated by light, melatonin). It can promote either sleep orwakefulness. WAKE PROMOTER: Tuberomammillary nucleus –TMN-of the hypothalamus promotes wakefulness( produces histamine ) SLEEP PROMOTER: Ventrolateral preoptic area – VLPO-of the hypothalamus promotes sleep (produces GABA )
  • 17. BENZODIAZEPINES – FDA INDICATIONS  In addition to anxiety, benzodiazepines areindicated for muscle tension, insomnia, status epilepticus(diazepam), myoclonic epilepsy(clonazepam), preoperative anesthesia, and alcohol witdhrawal.  Two benzodiazepines: alprazolam and lorazepam have FDA indication for anxiety associated with depression.  Clonazepam and Alprazolam are indicated in the treatment of panicdisorder.
  • 18. BENZODIAZEPINES – ADVERSE EFFECTS  Sedation  Lethargy  Dependency/Withdrawal  Respiratorydepression  Possible cognitive impairment.  Safe in overdose: up to 30 times the normaldaily dose. Usual symptoms of overdose include sedation, drowsiness, ataxia,and slurred speech. May result in respiratory depression in combination with otherCNS depressants. Management includes gastric lavage, forced emesis, and assistedventilation.  Drug interactions: 1. drugs that increase benzodiazepine levels include P4503A4 inhibitors, ketoconazole, fluconazole, nefazodone. 2.drugs that decrease benzodiazepine levels includeP4503A4 inducers such as carbamazepine.
  • 19. BENZODIAZEPINES - SUBCLASSES 2 keto (chlordiazepoxide, clonazepam, clorazepate, diazepam, halazepam, prazepam, and flurazepam). The 2-ketodrugsand theiractive metabolitesareoxidized in the liver, and because this process is relatively slow, these compounds have relatively long half-lives. 3 hydroxy(lorazepam, oxazepam, temazepam) The 3-hydroxycompoundsare metabolized viadirectconjugationwith a glucuronide radical, a process that is more rapid than oxidation and does not involvethe formationof active metabolites. Triazolo (alprazolam, adinazolam, estazolam, andtriazolam) The triazolocompoundsarealsooxidized, howeverthey havea more limited active metabolitesand thusshorter half-lives.
  • 20. BENZODIAZEPINE PROPERTIES The effects of benzodiazepines depend ontheir properties:  1. half-life  2. liposolubility  3. receptoraffinity
  • 21. Five benzodiazepines are FDA approved for insomnia are:  flurazepam and quazepam, (ultra-long half-lives);  triazolam (ultra-short half-life)  estazolam and temazepam (moderate half-lives). FDA APPROVED BENZODOAZEPINE HYPNOTICS
  • 22. LIPOSOLUBILITY  Highly lipophilic benzodiazepines such as diazepam enter the brain more quickly, “turning on” the effect promptly, but “turning off” theeffect morequicklyas well as theydisappear into body fat.  Less lipophiliccompoundssuch as lorazepam produce clinical effects more slowly, but may provide more sustained relief in spite of shorter half life.
  • 23. RELATIVE RECEPTOR AFFINITY  The higher theiraffinity for GABA-A receptors, the more intensewithdrawal symptoms theycause.  High potency benzodiazepines such as lorazepamand alprazolam have high receptor affinity – intense withdrawal symptoms.  Oxazepam has low receptor affinity –fewer withdrawal symptoms.
  • 24. MEMORY IMPAIRMENT (FACT OR MYTH)  Lucki et al. (1986) conducted a study on long-term benzodiazepine treatment. It failed to showsignificant cognitive impairment on psychometrictests.  The most recent controlled study in this area failed to find significant long-term cognitive effects for alprazolam XR in panicdisorder patients (Gladsjo et al. 2001).  In spite of these studies some investigators believe that cognitive impairment can occur, particularly in elderly patients.
  • 25. BENZODIAZEPINES MIGHT CAUSE MEMORY IMPAIRMENT IN ELDERLY
  • 26. HOW ADDICTIVE ARE BENZODIAZEPINES?  How long does one have to takea benzodiazepine before withdrawal is seen withdiscontinuation?  Studies in animals have indicated that benzodiazepinescan reinforce use and can produce physical dependence and tolerance.  Available data seem to reveal that benzodiazepines are rarely sought after or craved in the sense that heroin or cocaine are. Rather, theyare used as part of a polysubstance abuse pattern to modulate the effects of primary drug of abuse(e.g. cocaine) or as a backup drug when more euphoriant drugs are notavailable.
  • 27. BENZODIAZEPINES POTENTIATE THE EFFECT OF ALCOHOL
  • 28. ADVERSE EFFECTS ■ Weakness, headache, amnesia, vertigo, diplopia, nausea, diarrhoea, and rarely chest pain. ■ Paradoxical effects (disinhibition or dyscontrol reaction) may sometimes occur characterised by restlessness, agitation, and hallucinations. ■ Flurazepam has been associated with nightmares and hallucinations. ■ Allergic, hepatotoxic, and haematological reactions are rare.
  • 29. CLINICAL (TOXIC) FEATURES • Benzodiazepines are remarkably safe drugs and rarely produce serious toxic effects even with substantial ingestion. Death is uncommon unless other synergistic drugs have also been ingested. However, newer benzodiazepines such as alprazolam,triazolam, and temazepam are associated with fatalities.
  • 30. Acute Poisoning: a. Mild—Drowsiness, ataxia, weakness. b. Moderate to Severe— – Vertigo, slurred speech, nystagmus, partial ptosis, lethargy, coma. – Hypotension and respiratory depression. – Analysis of acute benzodiazepine overdoses in relation to the incidence of coma indicate that short acting benzodiazepines (midazolam and triazolam) and intermediate acting (flunitrazepam) have a higher acute toxicity, as compared to diazepam, lorazepam and nitrazepam. –memory impairment/ amnesia in a significant number of patients (TRIAZOLAM). Clinical (Toxic) Features
  • 31. – Administration of benzodiazepines to a pregnant woman prior to delivery may produce signs of poisoning in the neonate.A condition called “floppy infant syndrome”, characterised by hypotonia that may last several days, may occur following maternal diazepam use.
  • 32. Chronic Poisoning: Long-term use of benzodiazepines is associated with the development of tolerance. Abrupt cessation provokes a mild withdrawal reaction characterised by anxiety, insomnia,headache,tremor, and paraesthesia. Restlessness, encephalopathy, and hallucinations may occur after abrupt withdrawal from high daily doses. Convulsions may occur after a lapse of 3 to 10 days.
  • 33. Diagnosis Estimation of plasma levels of benzodiazepines is usually not necessary. Qualitative testing for presence of benzodiazepine is helpful to confirm presence, especially when overdose historyis sketchy. Quantitative levels are not usually clinically useful. Blisters of skin (bullae) can occur following overdose with nitrazepam, oxazepam, and temazepam.
  • 34. Treatment 1.Monitor CBC, serum electrolytes, glucose, blood urea nitrogen,creatinine, and urine myoglobin in patients with significant intoxication. 2. Gastric lavage (preferably with a large-bore, double-lumen tube), can be done with benefit upto 12 to 24 hours postingestion. 3. Multiple dose activated charcoal has been shown to be effective. 4. Establish clear airway. Oxygen and assisted ventilation are often necessary. 5. IV fluids (Ringer’s lactate at a rate of 150 ml/hr for adults). 6. Correction of hypotension: Begin by infusing 10 to 20 ml/kg of isotonic fluid, and place patient in Trendelenburg position. If hypotension persists, administer dopamine or noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy.
  • 35. ■ – Flumazenil is effective in reversing the coma induced by benzodiazepines as well as zolpidem. The mode of action is competitive antagonism. – In practice, most patients achieve complete reversal of benzodiazepine effect with a total slow IV dose of just 1 mg. Some investigators suggest that flumazenil is better administered in a series of smaller doses in an incremental manner beginning with 0.2 mg and progressively increasing by 0.1 to 0.2 mg every minute until a cumulative total dose of 3.5 mg is reached. However, resedation occurs within ½ hour to 2 hours (depending on the nature and dose of benzodiazepine ingested), and therefore patients must be carefully monitored and subsequent doses of flumazenil should be administered as needed. The use of continuous flumazenil maintenance infusion over 5 to 24 hours seems of therapeutic value in the event of resedation after initial response.
  • 36. – Flumazenil has also been reported to reverse cardiovascular depression secondary to benzodiazepine use. – Flumazenil does not reverse respiratory depression very well and hence fundamental procedures such as supplemental oxygen, endotracheal intubation, and ventilation must not be neglected. – Flumazenil is contraindicated in mixed ingestions involving tricyclic antidepressants and drugs which induce seizures, e.g. theophylline, carbamazepine, chloroquine, etc. But there are indications that it may be beneficial in hepatic encephalopathy and ethanol overdose. – Flumazenil may cause the following adverse effects: fatigue, nausea, vomiting, hypertension, tachycardia, anxiety, confusion, restlessness, aggression, and rarely convulsions and cardiac arrhythmias..
  • 37. Forensic Issues ■ Ever since the introduction of benzodiazepines in the 1960s, they have become progressively more popular as anxiolytic agents and sedatives, displacing the barbiturates from their previously held top spot. In spite of extensive use worldwide, there have been only a few cases reported involving fatalities, demonstrating the wide margin of safety of benzodiazepines. Deaths have been reported in some recent cases even from unexpectedly low doses of certain benzodiazepines. There are also indications that some of the newer benzodiazepines have a slightly smaller margin of safety. This is particularly true with reference to paediatric and geriatric patients who are more susceptible to the toxicity of these drugs.
  • 38. ■ An area of concern with long-term benzodiazepine use is the possibility of behavioural disinhibition which may induce a person to hostile acts, aggressive behaviour, and verbal indecency. ■ Yet another important issue is with reference to the use of benzodiazepines to deliberately induce amnesia in certain individuals in order to accomplish an immoral act (e.g. date rape). Many of these drugs, particularly flunitrazepam, are capable of causing retrograde amnesia. Flunitrazepam (Rohypnol®; “Roofies”) has become popular as a drug of abuse, often combined with alcohol, marijuana, or cocaine to produce an intense “high”. It has been used as a “date rape” drug, both for its properties of lowering inhibitions and because it can cause retrograde amnesia.
  • 39. ■ Severe dysmorphism, malformations, intrauterine and extrauterine growth retardation, and central nervous system dysfunction have been described in infants born of mothers who used benzodiazepines during pregnancy.
  • 40. Case Report: A 37 year old married female, with history of psychiatric problems, Presentation-unconscious state. Alleged history of ingestion of 60 tablets of alprozolam (Alprax- Rx) tablets 3 hour back, with the intention of suicide. The relatives of the patient showed us all the empty packs, containing the tablets, found near her body. There were about 60, 1mg tablets of alprazolam that had been ingested by her. Further, her relatives gave history that patient had been suffering from panic disorder, since last five years, for which she had been on medication off and on, as advised by a psychiatrist. Her medications included alprazolam and fluoxetine.
  • 41. Off late, she was also under stress, as she could not conceive in last four years of her marriage, and was pursuing infertility treatments, without any success. On general examination mild cyanosis and pallor was present. Patient’s vitals on admission were as follows-- pulse -100/min feeble, blood pressure-80/mm hg systolic, respiratory rate 30/min regular, temperature - 36.8 C. Neurological examination showed deep coma, bilateral constricted pupils , which reacted minimally to light, diminished tendon reflexes and retention of urine, and plantar reflexes were not illicitable bilaterally. There was no response to painful stimuli. Her Glasgow coma scale (GCS) was 3. Respiratory system examination was within normal limits. On cardiovascular system (CVS) examination tachycardia was noted, and ECG showed sinus tachycardia. Routine Biochemical and hematological tests were normal.
  • 42. As suggested by the evidences above, probability diagnosis of alprazolam over dosage was made. Patient was admitted in ICU. A nasogastric tube was placed and catheterization was done. Patient’s gastric lavage returned no pill fragments. She was urgently intubated and kept on mechanical ventilation with continuous oxygen administration and parenteral fluids. Rest of her treatment was symptomatic. Flumazenil, which is the antidote of alprazolam poisoning was used. Patient showed improvement after few hours and was extubated. Patient got recovered and discharged.