Selected Antidotes
Jon B Cole, MD
Department of Emergency Medicine
Objectives
• Discuss the treatment of carbon monoxide
poisoning, including hyperbaric oxygen
• Discuss the treatment of organophosphate
poisoning, including the value of oxime
treatment
• Review old and new treatments of cyanide
toxicity
• Review the indications and uses of some
classic antidotes
Background
• Antidote: any substance which can
counteract a form of poisoning.
• Derived from the Greek “anti didonai,” which
literally translates as “given against.”
• Different mechanisms:
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Animal antibodies
Enzyme inhibitors
Cofactor
Competitive inhibition
“Universal” antidotes
Oxygen (O2)
Oxygen (O2)
• The treatment of choice for carbon
monoxide (CO) poisoning
• Normobaric (NBO) vs. Hyperbaric (HBO)
• HBO also used to treat:
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Cyanide (CN)
Hydrogen sulfide (H2S)
Carbon tetrachloride (CCl4)
Methylene chloride (Ch2Cl2)
Methemoglobinemia
Decompression sickness
Air embolism
Necrotizing fasciitis
Carbon Monoxide (CO)
• Binds hemoglobin with 230-270 times
the affinity of oxygen
• Also binds myoglobin, cytochrome
P450, and cytochrome aa3
– Note: CYP450 is named after the peak absorption of light at
450nm when the enzyme is 50% saturated with CO
• Transforms the hemoglobin binding
curve from a sigmoid to an asymptotic
shape
Carboxyhemogloin (COHb)
Hyperbaric Oxygen (HBO)
• Physiologic goal is elevation of partial
pressure of O2
• Outcome goal is restoration/preservation
of normal CNS function as well as
reduction in mortality
• Much controversy exists regarding the
benefit of HBO
– 6 prospective studies have been done to
date, all with mixed results
• 2 of these studies are fairly recent
60
min
HBO 2.5atm
3-4
hours
100% NBO
Room Air
Carboxyhemoblobin – half-life
20
min
HBO – Scheinkestel et al (AUS)
• 191 CO-poisoned patients of different
severity
• High flow O2 (for 3 or 6 days) vs. HBO
(3.0 ATA for 60 minutes daily)
• Outcome measured was
neuropsychiatric testing 1 month after
treatment
• No benefit shown, but…
HBO – Scheinkestel et al (AUS)
• Controversies:
– 69% of cases were suicide attempts
– 50% of patients co-ingested EtOH or other drugs
– Both the NBO and HBO regimens deviated from
standard regimens and were potentially toxic
– Many patients had active depression or CNSaffecting drugs on board at 1 month during their
neuro-psych testing
– Only 46% of the patients completed the follow-up
test
HBO – Weaver, et al (USA)
• 152 patients, stratified by age (<40 or >40),
time to end of CO exposure, start time of
treatment (< 6 hrs or > 6hrs), hx of LOC.
• Patients treated 3 times at 6-12 hr intervals
in a monoplace chamber
• Outcomes measured by CO poisoning
questionnaires, functional outcome
evaluations, neuropsychological test battery
given at 2 weeks, 6 weeks, 6 months, and 12
months
HBO – Weaver, et al (USA)
• NBO group did have a higher incidence of cerebellar
dysfunction, but this was accounted for
• HBO group had a lower incidence of cognitive
sequelae
• Risk factors for which HBO therapy was
recommended were:
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LOC
COHb ≥ 25%
Age 50 ≥ years
Base excess ≤ 2mEq/L
• Patients without any of these characteristics did not
have improved outcomes
HBO - Indications
• Definite:
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AMS/Abnormal Neuro Exam
LOC or near-syncope
Coma
Hypotension at any time
MI
“Prolonged” exposure
Pregnancy and COHb ≥ 15%
• Relative:
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Persistent Neurologic Sxs (including HA or dizzy) after 4hrs NBO
Persistent acidosis
Concurrent thermal or chemical burns
Pregnancy regardless of COHb level
HBO - Contraindications
• Paraquat poisoning
• General HBO contraindications (relative)
– Middle ear surgery
– Thoracic surgery
– Untreated pneumothorax
– Seizure disorder
– Severe sinusitis
HCMC Hyperbaric Chamber
HCMC HBO Indications (non-pregnant)
• LOC
• COHb ≥ 40%
• “Serious” toxicity including:
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Lethargy, confusion or disorientation on arrival to med facility
Hx of seizures
Focal neuro deficit
Ischemic chest pain
New dysrhythmias or ECG changes
Hypotension
• COHb ≥ 25% plus:
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Hx of CAD
Age ≥ 60 yrs or ≤ 2 years
HGB ≤ 10
Exposure duration ≥ 2 hours
HCMC HBO Indications (pregnant)
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Patients meeting any of the previous indications
COHb ≥ 20%
Exposure duration ≥ 5 hrs
Any signs of fetal distress
HCMC HBO protocol
• Non-pregnant
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100% O2 by non-rebreather mask until HBO
100% O2 at 2.4 ATA for 90 min
100% O2 by non-rebreather until pt without sxs and COHb ≤ 3
Dispo as appropriate, f/u w/ Neurology in 1 month
• Pregnant (as above, plus)
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Check for fetal distress prior to HBO
L&D fetal monitoring if gestation ≥ 28 weeks
Dispo as appropriate, same Neurology follow-up
F/u w/ OB/GYN in 1 week
N-Acetylcysteine (NAC)
• The mainstay of treatment for
acetaminophen (APAP) overdose
• Other uses include treatment of:
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Chloroform
CCl4
1,2-dicloropropane
Acrylonitrile
Doxorubicin
Cyclophosphamide
Radiographic contrast exposure
APAP metabolism
Glutathione (GSH) metabolism
NAC
• Provides a substrate for
sulfation
• Regenerates glutathione
(reduced form - GSH)
• GSH reduces NAPQI,
allowing it to be cleared
via the kidneys
APAP and NAC metabolism
• NAC allows safe
metabolism of the directly
hepatotoxic metabolite
NAPQI.
• NAC is itself an
antioxidant, which may be
more useful in latepresenting overdoses
Rumack-Matthew Nomogram
• Published 1975
• Based on a
retrospective analysis
of previous APAP
overdoses and their
clinical outcomes
• Original line at
200mcg/mL, but moved
to 150 at urging of FDA
• 200 still the treatment
threshold in Europe
NAC – additional indications
• Consider NAC if patients are on any
CYP 2E1 inducers
– Isoniazid
– Chronic alcohol use/abuse
• Signs of liver toxicity past 24 hours and
still-measurable APAP level
• Note: pregnancy is NOT a
contraindication
NAC – oral vs. IV
NAC - oral
• Advantages:
– reduced anaphylactoid reaction risk
– Safer in asthmatics
• Disadvantages:
– Horrible smell
– Vomiting common (may need antiemetics)
– Dosing is over 72 hours
• 140mg/kg load
• 70mg/kg dose q 4 hrs thereafter for 17 does
IV NAC - Acetadote®
IV NAC - Acetadote®
• Advantages:
– Shorter treatment course – 21 hours
• 150mg/kg loading dose over 1 hr (instead of 15 min)
• 50mg/kg in 500mL D5W over 4 hrs
• 100mg/kg in 1000mL D5W over 16 hrs
– New dosing guidelines for < 40kg patients now available
– Decreased GI effects
– Actually studied in hepatic failure
• Disadvantages:
– Increased anaphylactoid reactions
– More costly (debatable)
– Difficult Peds dosing
• Initial reports of hyponatremia from increased water infusion
Allergic reactions – What to do
• Stop the IV infusion immediately
• Treat accordingly
– Diphenhydramine, steroids, epi if indicated
• Once the reaction resolves, infusion
can be re-started
• If the reaction persists or worsens, stop
the IV infusion and either switch to oral
or re-evaluate the need for NAC
– Oral has been proven very safe in patients who have had
severe reactions to the IV perparation
Physostigmine (Antilirium®)
• The antidote for anti-cholinergic toxicity
• A carbamate that reversibly inhibitis
cholinesterases in both the CNS and
PNS
• Derived from the plant Physostigma
venenosum Balfour, from Nigeria
Physostigmine
• Originally used as a miotic agent to
treat glaucoma, and in the treatment of
myasthenia gravis
• Also used as an antidote to atropine
toxicity, and as an insecticide
• Structure is tertiary amine (other
“stigmines” are quaternary), which
allows better CNS penetration.
Tertiary vs. Quaternary Amines
Physostigmine
Neostigmine
• Uncharged
• Charged
Physostigmine
• Available only as an IV preparation
• Dose: 1-2mg infused over at least 5
min (0.02mg/kg in peds).
• Onset of action is within minutes
• Dose can be repeated q 10-15 min
• T1/2 is 16 minutes, but duration of
action is usually much longer
Physostigmine and TCA OD
• Physostigmine was used often in the
1970s to treat undifferentiated delerium
• Case report by Pentel in 1980 re: 2
patients who suffered asystole after
receiving physostigmine for TCA
overdoses
• Since then the antidote has greatly
fallen out of favor
Physostigmine - Indications
• Peripheral or Central anti-cholinergic
manifestations without evidence of
QRS or QTc prolongation, such as:
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Agitation
Hypertheria
Hallucinations
Delerium
Seizures
coma
• The patient to use this in is a known
non-TCA anti-cholinergic overdose
Physostigmine - contraindications
• Definite contraindications:
– Suspicion of TCA ingestion
– Widened QRS on ECG
• Relative contraindications:
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History of asthma
Concomitant use of succinylcholine
Parkinsonism
AV block
• Beware “evidence based medicine”
such as uptodate.com
Opioid Antagonists
• Primarily μ-antagonists, some
secondary antagonism of κ and δ
receptors.
• 3 options available:
– naloxone (Narcan®)
– nalmefene (Revex®)
– naltrexone (Revia®)
• The primary difference between the
three drugs is their duration of action
Opioid Antagonists
• Naloxone
– Duration of action 1-2 hours
– Can be started as a drip
– Re-assess for respiratory distress
• Nalmefene
– Duration of action up to 4 hours
– More expensive
• Naltrexone
– Duration of action up to 24 hours
– Oral preparation only
Opioid Antagonists
• Used primarily in the treatment of
opioid overdose, though naloxone is
used to treat other overdoses such as:
– Clonidine
– Ethanol
– Benzodiazepines
– Valproic acid
– captopril
• No major contraindications
Opioid Antagonists - Structure
Agonist
Antagonist
Naloxone Dosing
• “Waking up” vs. withdrawal – different
approaches
• Usual dosing is to start low and titrate up
– 0.4mg, then 2mg, then 10mg
– If no response, consider another cause of coma
• Remember, naloxone can be given via the
endotraheal tube, but dosing should be 23x.
Flumazenil (Romazicon®)
• A competetive benzodiazepine receptor
antagonist.
• Unlike naloxone, flumazenil is NOT
indicated as part of the “coma cocktail,”
as it has potentially serious side-effects
and minimal benefit
Flumazenil
• Flumazenil precipitates seizures in
benzodiazepine dependent patients,
and in patients with underlying seizure
disorders
– The “zero setpoint” of intrinsic CNS activity
may be influenced by GABA activity and
chronic benzo use
• Flumazenil can also unmask
dysrhythmias in patients who co-ingest
pro-arryhthmic drugs
Flumazenil - Indications
• Known benzo ingestion in benzo-naïve
patients, e.g.
– Iatrogenic exposure
– Toddler ingestion
– Paradoxic benzo response
• Postoperative or postprocedure
sedation reversal
• CNS depression from hepatic
encephalopathy
Flumazenil - dosing
• Start with 0.2mg IV over 30 seconds
(0.01mg/kg in children)
• If no response, then 0.3mg over 30
seconds
• If still no response give 0.5mg every 30
seconds up to 3 mg
Atropine
• A competetive anti-muscarinic drug that
acts both centrally and peripherally
• Derived from the plant Atropa
belladonna
• Similar to physostigmine it has a
teritiary amine structure, whereas other
anti-muscarinic drugs such as
glycopyrrolate are quaternary amines
Tertiary vs. Quaternary Amines
Atropine
Glycopyrrolate
Atropine - Indications
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Organophosphate poisoning
“Nerve Gases”
Carbamate poisoning
Bradycardia from:
– Beta blockers
– Calcium antagonists
– Digitalis
– Other AV node-blockers
Atropine - Contraindications
• All are relative
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Angle-closure glaucoma
Myasthenia gravis
Obstructive uropathy
Obstructive GI diseases (severe ulcerative colitis)
Hypertension
Thyrotoxicosis
Tachyarrhythmias
CAD
Valvular disease
Atropine Dosing in Organophosphates
• Based on work by Eddelstein, et al, J Clin
Tox, 2004
• Starting dose is 0.5-2mg, then doubling
every 5 minutes until “endpoint” is achieved
– Pediatric starting dose is 0.02mg/kg
• Goal is “atropinization”
– Clear chest on auscultation
– Increased heart rate > 80
• Each poisoned patient may need as much as
75mg of atropine, so be prepared to mobilize
stores
Pralidoxime (2-PAM® or Protopam®)
• Used in the treatment of
organophosphate (OP) poisoning
• OPs exert their effects by
phosphrylating cholinesterases,
inactivating them
• Cholinestereases break down
acetylcholine (ACh), so ACh builds up
in synapses and causes a cholinergic
or muscarinic crisis
Pralidoxime
Quaternary oxime
Pralidoxime - mechanism
• Bound (inactive) undergo one of three
processes:
– Endogenous hydrolysis and recovery (as with carbamates,
such as physostigmine)
– Reactivation by a strong nucleophile (e.g. 2-PAM)
– “Aging,” which involves biochemical changes to the enzyme
that result in permenant dysfunction
• Oximes work to prevent aging by
exerting a nucleophilic attack on the
phosphate moiety, releasing it from the
enzyme and preventing aging
Pralidoxime
• Believed to work synergistically with
atropine
• Can be used in severe carbamate
poisonings
• Some evidence the drug should be
used within 48 hrs – by this time aging
may be inevitable
• A mainstay of OP poisoning treatment,
but…
Pralidoxime – benefit?
• There is now evidence that oximes may not
only not improve mortality, they may be
harmful.
– Buckley, et al (2005) Cochrane Database
• Two published RCTs, one abstract RCT
• Insufficient evidence for harm or benefit of oximes
– Peter, et al (2006) Crit Care Med
• Two published RCTs, 5 controlled trials
• Oximes either ineffective or harmful
– Rahimi, et al (2006) Human Exp Toxicol
• Six clinical trials
• Oximes are not effective and can be dangerous
Pralidoxime
• For now, it is the standard of care
• Always use with atropine
• Field Dosing
– 600mg IM from the autoinjector, up to 3 doses
• Hospital Dosing is
– 1-2g IV over 15-30min as initial dose
• 25-50mg/kg in children
– Continuous infusion of 200-500mg/hr thereafter
• 5-10mg/kg in children
The Mark I Nerve Agent Antidote Kit
• 600mg IM of
pralidoxime
• 2mg IM of atropine
Treatment of cyanide (CN)
• CN is toxic because it binds the ferric
(Fe3+) ion in cytochrome oxidase,
uncoupling oxidative phosphorylation
and causing chemical asphyxia.
• Treatment involves
– creating other sources of Fe3+,
– inducing the enzyme that clears CN, and
– providing another oxidized ion (Co+) for the CN to bind with
Nitrites
• Nitrites (-NO2) oxidize the iron in
hemoglobin from Fe2+ to Fe3+ to create
methemoglobin
• Since CN reversibly binds the Fe3+ in
cytochrome oxidase, it now has a new
competetive pool of Fe3+ to bind
Amyl Nitrite
• A volatile (and flammable) gas
• Comes in 0.3mL ampules
• Administered by breaking open the
ampule and holding it in front of the
patient’s mouth for 15 seconds on, then
15 seconds off, etc.
• Should be discontinued as soon as an
IV can be established
• This is a stop-gap solution
Sodium Nitrite
• Comes in a 10mL vial, 300mg
• Administered IV at 2.5-5mg/min
• Should be followed immediately with IV
sodium thisulfate
Nitrites
• Indications
– Symptomatic cyanide poisoning
– Hydrogen sulfide (H2S) poisoning < 30 min ago
• Contraindications
– Significant (>40%) pre-existing
methemoglobinemia
– Severe hypotension
– Concomitant CO poisoning/smoke inhalation
Sodium Thiosulfate (Na2S2O3)
• This relatively non-toxic CN antidote
works to regenerate the mitochondrial
enzyme rhodanese.
• Rhodanese metabolizes CN to
thiocyante (SCN-) by using a unique
sulfur bond on the enzyme known as a
sulfane group
• This is the only type of sulfur that reacts
with CN
Sodium Thiosulfate (Na2S2O3)
• Comes in 50mL
bottles containing
12.5
• Given IV as a bolus
or over 10-30 min
depending on
severity of illness
• No significant
contraindications
Nitrites and Thiosulfate - Summary
Taylor Pharmaceuticals
Cyanide Antidote Kit
• 12 ampules of amyl
nitrite
• 2 ampules of
sodium nitrite
• 2 vials of sodium
thiosulfate
• Cost: $317.18 each
hydroxycobalamin (Cyanokit®)
• Hydroxycobalamin is a direct precursor
to cyanocobalamin (a member of the
vitamin B12 family)
• FDA approved in 2007
• Very safe
Hydroxycobalamin - metabolism
Hydroxycobalamin
Cyanocobalamin
Hydroxycobalamin
• Dosing:
– 5g IV given over 15 minutes
• Side effects:
– Turns body fluids bright red within minutes
• Interactions:
– Do not administer in the same line as
sodium thiosulfate, as they will bind each
other rendering them both ineffective
References
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Pentel, P, et al, “Asystole Complicating Physostigmine Treatment of Tricyclic
Antidepressant Overdose,” Ann Emerg Med, Nov 1980, pp 588-590
Cocuzza, et al, “Inappropriate Use of Physostigmine in TCA Toxicity: An Online Medical
Reference May Be Partially Responsible,” Clinical Toxicology, Vol 46, No 7, Aug 2008
Goldfrank, L, et al, “Goldfrank’s Toxicologic Emergencies,” McGraw-Hill, Mar 2006, pp 122, 544-549, 614-619, 794-797, 1112-1117, 1513-1518, 1519-1522, 1705-1711, 17251727, 1728-1730, 1731-1733
Dart, RC, “Medical Toxicology,” Ch. 5, “Antidote Stocking,” Lippincott, Wilkens, & William,
December, 2003, pp 159-163
Weaver, LK, et al, “Hyperbaric Oxygen for Acute Carbon Monoxide Poisoning,” NEJM, Oct.
3, 2002, pp 1057-1067
Scheinkestel, CD, et al, “Hyperbaric or normobaric oxygen for acute carbon monoxide
poisoning: a randomised controlled clinical trial,” Medical Journal of Australia, 1999, 170:
203-210
HCMC Guidelines for Treatment of Carbon Monoxide Poisoning, current as of August 2008
Olson, KR, et al, “Poisoning & Drug Overdose,” Lange Medical Books/McGraw-Hill, 2004,
pp406-519
Cyanokit manufacturer’s package insert, current as of August 2008
Acetadote manufacturer’s package insert, current as of August 2008