 At the end of this session, students
will be able to identify usual signs
and symptoms of sedative-hypnotic
overdoses and be able to provide
appropriate treatment
recommendations for those
patients.
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Describe the usual signs and symptoms of
sedative-hypnotic overdoses;
List the usual treatments for managing
patients with overdoses of benzos/CNS
depressants;
Be able to develop an appropriate treatment
plan for simulated benzodiazepine, chloral
hydrate, and other sedative hypnotic overdose
patients;
Shakespeare: Not poppy, nor
mandragora,
Nor all the drowsy syrups of the world,
Shall ever medicine thee to that sweet
sleep
Which thou owedst yesterday.
Othello, act 3, sc 3, I. 330-3.
What a drag it is getting old
"Kids are different today,“
I hear ev'ry mother say
Mother needs something today
to calm her down
And though she's not really ill
There's a little yellow pill
She goes running for the shelter
of a mother's little helper
And it helps her on her way, gets
her through her busy day
Rolling Stones; Aftermath, 1966
Commonly used and misused in the middle
to late part of the 20th Century
 Several substances no longer commercially
produced (methaqualone, ethchlorvynol,
glutethamide, etc.)
 Most current sedative hypnotic use is
primarily focused on benzodiazepines

Substance
Total
Long acting
barbiturates
Benzodiazepines
2,041
47
0
79,989
306
17
68
2
0
Chloral hydrate
Major Death
Mowry JB et al: 2012 Annual report of the American Association of Poison Control
Centers National Poison Data System (NPDS): 30th Annual report. Clin Tox
2013;51:949-1229.
 Benzodiazepines
 Barbiturates
 Others (e.g., Chloral hydrate,
zolpidem, meprobamate, propofol)
 No longer marketed: Ethchlorvynol,
Glutethamide, Methaqualone)
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Nearly all sedative hypnotics work at or around
the GABA receptor
GABAA receptors have different distributions of
subunit families: alpha, beta, gamma, etc.
Nearly all sedative hypnotics bind to GABAA
receptors containing the alpha subunit.
Binding at benzodiazepine receptor enhances
binding of other GABA agonists to GABAA
receptor
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There is variability in binding, depending on
the specific agent (e.g., at low doses,
benzodiazepines bind primarily at the gamma
2 subunit)
Most sedative hypnotics ALSO bind to other
receptors (e.g., propofol also inhibits
glutamate mediated NDMA receptors which
results in decreased excitatory nerve
transmission)
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In general, onset of action is determined by the
drugs ability to cross the blood-brain barrier;
more lipophilic drugs cross the BBB more
readily than less lipophilic drugs
Most agents have very large volumes of
distribution; many are protein bound
After initial distribution, many drugs
demonstrate complex secondary distribution
to other tissues
Many agents are metabolized to active
metabolites
 Most agents are eliminated by the liver
(chloral hydrate and meprobamate are
renally cleared)

 Sedation
 Slurred speech
 Poor attention
 Coma
Patients commonly experience CNS
depression yet GENERALLY maintain
adequate vital signs
 May see respiratory depression in very
large oral overdoses or large intravenous
overdoses
 Exposure to multiple CNS depressants can
enhance depressive effects (e.g., ethanol +
alprazolam)
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Large exposures to intravenous formulations
may lead to toxic effects from diluents (e.g.,
propylene glycol in lorazepam).
One study showed that 2/3 of critical care
patients receiving > 0.16 mg/kg/hour lorazepam
for more than 48 hours developed hyperosmolar
metabolic acidosis secondary to propylene
glycol in lorazepam
Taylor J, Jabbour G, Saggi SJ. Severe hyperosmolar metabolic acidosis due to large
doses of intravenous lorazepam. N Engl J Med 2002;346:1253-1254.
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Supportive care (A, B, Cs) will be adequate to
treat the vast majority of sedative hypnotic
overdoses.
Some agents can produce cardiotoxicity that
requires additional treatment
 Chloral hydrate may produce ventricular
dysrhythmias; sort acting beta blockers (esmolol)
may be used in these cases

Don’t pull the plug too soon!
Oral activated charcoal should
be considered for all
substantial, recent oral
sedative hypnotic overdoses.
 For severe phenobarbital
overdoses, may consider use of
multiple dose activated charcoal
to enhance drug clearance
 Only consider MDAC for those
with bowel sounds
 Flumazenil (Romazicon®) is a
benzodiazepine antagonist
 Potential for life threatening
benzodiazepine withdrawal;
however, few cases of severe
withdrawal documented
Short acting vs. long
acting
 Can produce
profound CNS and
respiratory
depression
 Overdoses can lead
to “barb bullae”, even
in minor overdose
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First introduced in 1832
Well absorbed, but irritating to GI tract
Still occasionally used in pediatrics
Therapeutic half life of 4 – 12 hours
Can produce cardiac dysrhythmias due to
increased sensitivity of the myocardium to
catecholamines
Use beta blockers to treat ventricular
tachycardia, ventricular fibrilation
 Commonly used as muscle relaxants
 Similar actions to barbiturates at the
GABA receptor
 Case reports of bezoar formation in
large meprobamate overdose leading
to prolonged and delayed symptoms
 May see profound hypotention
 The most commonly prescribed
sleep medications
 Less likelihood to produce
dependence than other sedativehypnotics
 Symptoms more than drowsiness
are extremely rare
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Rapidly acting
intravenous agent
Postsynaptic GABA
agonist
Also stimulates
presynaptic release of
GABA
NMDA receptor
antagonist
 Produces dose dependent effects:
 Profound CNS depression and resp
depression
 Large doses associated with metabolic
acidosis, cardiac dysrhythmias, and
skeletal muscle injury (Propofol
Infusion Syndrome: PIS)
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Signs of PIS include new onset right bundle
branch block and ST segment elevation
More often seen in pediatric patients, those with
traumatic brain injuries, respiratory challenges,
exogenous catecholamine use, inadequate
carbohydrate intake
May be due to disruption of free fatty acid
utilization and metabolism
Treatment is to d/c propofol and provide
supportive care