This is a brief content about CNS depressants poisoning

1. CNS DEPRESSANTS
1. BARBITURATES POISONING
2. BENZODIAZEPINES POISONING
BARBITURATES POISONING
The barbiturates are derivatives of barbituric acid (2,4,6-trioxohexahydro-
pyrimidine) and were extensively used as sedative and hypnotics till the 1960s
when the benzodiazepines arrived and quickly displace them.
Barbiturate poisoning occurs due to ingestion of toxic dose of barbiturates. The
intoxication may be due to suicidal intention or rarely accidental
Examples:
1. Long acting (duration of action 6–12 hrs)
a. Mephobarbitone
b. Phenobarbitone.
2. Intermediate acting (duration of action 3–6 hrs)
a. Amobarbitone
b. Aprobarbitone
c. Butobarbitone.
3. Short acting (duration of action < 3 hrs)
a. Hexobarbitone
b. Pentobarbitone
c. Secobarbitone.
4. Ultra-short acting (duration of action <15–20 min)
a. Thiopentone
b. Methohexitone.
Uses:
1. Sedative-hypnotic.
2. Pre-operative sedation.
3. Treatment of seizure disorders.
Usual Fatal Dose:
Phenobarbitone: 6 to 10 grams.
Amobarbitone, pentobarbitone, secobarbitone: 2 to 3 grams.
Sedatives/
Hypnotics

2. Lethal blood level for short- and intermediate-acting barbiturates varies from 3
to 4 mg/100 ml, while for phenobarbitone it ranges from 8 to 15 mg/100 ml.
Toxicokinetics:
Administration: Mostly Oral, IV (Status epilepticus, Maintenance of general
anesthesia)
Distribution: Widely distributed
Metabolism: Oxidation in liver resulting in the formation of alcohols, ketones,
phenols, or carboxylic acids
Excretion: Urine
Note: Metabolism of barbiturates is more rapid in children and is slower in the
elderly
General MOA:
Barbiturates act primarily on the beta subunit of GABAA receptor and increases
the duration of opening of the GABA-gated chloride channels. This lead to influx
of more Cl- ions and thus hyperpolarisation of the postsynaptic cell. Thus in turn
inhibition of neurotransmission.
They also act on the AMPA receptor and inhibit the excitatory effects of
glutamate
They have been also found to inhibit voltage dependent NA+ and K+
channels
All these actions leads to CNS depressant affect.
Clinical (Toxic) features:
1. Slurred speech, ataxia, lethargy, confusion, headache, nystagmus.
2. CNS depression, coma, shock.
3. Pupils are at first constricted, but later dilate because of hypoxia.
4. Hypothermia.
5. Cutaneous bullae
6. Death may occur from respiratory arrest or cardiovascular collapse. Delayed
death may be due to acute renal failure, pneumonia, pulmonary oedema, or
cerebral oedema.

3. Note: Chronic barbiturate (ab)use is associated with the development of
tolerance which is responsible for decreasing the therapeutic to toxic index. An
addict may obtain therapeutic benefit only with 5 to 6 times the normal dose.
Abrupt withdrawal results in anorexia, tremor, insomnia, cramps, seizures,
delirium, and orthostatic hypotension.
Diagnosis:
1. Serial plasma levels may be useful in the management of phenobarbitone
overdose. Plasma levels exceeding 8 mg/dL (80 mcg/mL) (344 mcmol/L) are
generally associated with some degree of coma. In the absence of tolerance,
plasma levels exceeding 2 to 3 mg/dL may be associated with CNS
depression.
2. EEG: alpha coma (Normally, alpha activity in the EEG is associated with
wakefulness. When it occurs in coma, it is referred to as alpha coma.)
indicates poor prognosis.
Treatment:
There is no specific antidote for barbiturate poisoning
Re-establishment of vital function functions such as respiration and blood
circulation by the use of ABCD intervention
Gastric lavage can be done with benefit Upto 12 to 24 hours postingestion
Multiple dose activated charcoal has been shown to greatly increase
phenobarbitone elimination
Forced alkaline diuresis is said to be particularly useful in phenobarbitone
poisoning. However, it should be considered only in severe barbiturate toxicity
with life-threatening signs and symptoms. (Forced diuresis is of no value in the
treatment of short acting barbiturate intoxication)
Haemodialysis or haemoperfusion: Barbiturate elimination can be increased by
haemodialysis or charcoal haemoperfusion. However, these techniques are rarely
needed when managing even severe barbiturate intoxication, and should be
reserved for patients with haemodynamic compromise refractory to aggressive
supportive care. Even though haemoperfusion can clear barbiturates two to four
times more rapidly than dialysis, haemoperfusion will not correct electrolyte
imbalances, and has been associated with platelet consumption, hypothermia,
hypotension, and decreased serum calcium.

4. Exchange transfusion may be beneficial in severe cases.
For hypotension: First administer 10 to 20 ml/kg of isotonic intravenous fluids
and place in Trendelenburg position. Repeat boluses of isotonic intravenous fluids
should be administered prior to initiating vasopressor therapy. If the
patient is unresponsive to isotonic fluid therapy administer a vasopressor.
Dopamine or noradrenaline should be titrated to desired response.
Supportive measures: supplemental oxygen, intubation, assisted ventilation, IV
fluids
In order to get the patient out of coma, a combination of analeptics namely 5%
bemigride (10ml) and 1.5% leptazol (1 ml) are added to IV drip.
Withdrawal may be treated by reinstitution of phenobarbitone, and a
programme of gradual reduction over three weeks. A tapering schedule of 10
percent every 3 days has been used successfully
BENZODIAZEPINE POISONING
Examples:
Alprazolam, brotizolam, chlordiazepoxide, chlorazepate, clobazam, clonazepam,
diazepam, estazolam, flunitrazepam, flurazepam, halazepam, lorazepam,
lormetazepam, medazepam, midazolam, nitrazepam, oxazepam, pinazepam,
prazepam, quazepam, temazepam, triazolam and zolazepam
Uses:
1. Anxiety disorders
2. Seizure disorders
3. Insomnia
4. Movement disorders (adjunctive therapy)
5. Mania (adjunctive therapy)
6. Some of these drugs are also used for inducing skeletal muscle relaxation, as
pre-anaesthetic medication, and for the treatment of alcohol withdrawal.
Usual fatal dose:
Uncertain for most benzodiazepines. Even ingestion of up to 2000 mg diazepam
has not resulted in death, or for that matter, even serious morbidity.
However, several cases of fatality due to triazolam and flunitrazepam overdose
have been described.

5. Mode of action:
Benzodiazepines act by stimulating the GABAb (gamma aminobutyric acid b)
receptors, thereby opening up the chloride ion channel in the receptor complex,
resulting in the increased conductance of chloride ion across the nerve cell
membrane. This lowers the potential difference between the interior and exterior
of the cell, blocking the ability of the cell to conduct nerve impulses.
Toxicokinetics:
Administration: Mostly Oral or IV
Distribution: Widely distributed (Protein bound upto 70-99%)
Metabolism: By the liver (Metabolites are invariably as active as the parent
compound)
Excretion: Urine
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 (Ethanol). However, newer
benzodiazepines such as alprazolam, triazolam, and temazepam are associated
with fatalities.
Acute Poisoning:
Mild: - Drowsiness, ataxia, weakness.
Moderate to severe: -
 Vertigo, slurred speech, nystagmus, partial ptosis, lethargy, coma.
 Hypotension and respiratory depression supervene in potentially lethal
ingestions.
 Both miosis and mydriasis have been reported. Nystagmus may also occur.
 Triazolam, as well as other benzodiazepines, have been implicated in next-
day memory impairment/amnesia in a significant number of patients.
 Administration of benzodiazepines to a pregnant woman prior to delivery
may produce signs of poisoning in the neonate. A condition called “floppy

6. 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 history is sketchy. Quantitative levels are not usually
clinically useful.
Blisters of skin (bullae) can occur following overdose with nitrazepam, oxazepam,
and temazepam.
Treatment:
Acute Poisoning:
a. Decontamination-Ipecac-induced emesis is not recommended because of the
potential for CNS depression.
Stomach wash may be helpful if the patient is seen within 6 to 12 hours after
the ingestion. Cuffed endotracheal intubation is a prerequisite in comatose
patients.
Activated charcoal adsorbs benzodiazepines and can be administered in the
usual manner.
b. Establish clear airway. Oxygen and assisted ventilation are often necessary.
c. IV fluids (Ringer’s lactate at a rate of 150 ml/hr for adults).
d. 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.

7. e. Forced diuresis and haemodialysis are ineffective.
f. Antidote-
– 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, re-sedation 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 re-sedation 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.
Chronic Poisoning:
Phenobarbitone-substitution technique is recommended for benzodiazepine
withdrawal which employs propranolol for acute somatic symptoms, while
phenobarbitone is used for detoxification.
However, the most frequently used method among clinicians is the replacement
of a short half-life benzodiazepine (such as alprazolam) with a long half-life
benzodiazepine (such as clonazepam), before initiating a taper and final
discontinuation.