Common Antidotes Used In Clinical Practice

Mohamed R. Ennara, M.D.

Toxicology Center, Cairo University

Antidote Drug Dose

Notes
Trade name Poison Method
Depends on
Antivenins Snake, spider severity of Hypersensitivity
S&S (vials)
0.5-2 mg
Organoph.,
I.V.,repeat Not in glaucoma,
carbamates, β-
in 5-10 myasthenia,
Atropine blockers, Ca
min.,dilute hypertension,
channel blockers,
in saline (1- tachyarrhythmias…
digoxin…etc.
2 ml)
1-2 vials
Botulinum antitoxin Botulism I.V.\4 h Hypersensitivity
(4-5 doses)
Ca channel
blockers, β- 10 ml slow
Ca chloride 10%  Not in digoxin
blockers, Mg, I.V.
Ca gluconate 10%  Shock if rapid I.V.
oxalates, fluorine, (repeat)
HF
 1-2 amp.
amyl
nitrite
Inhalation
 300 mg Na
nitrite 10
 Not in metHB
ml of 3%
> 40%
Cyanide antidote kit Cyanide sol. I.V.
Hypotension if rapid
over 5
I.V.
min.
 Na
thiosulfate
50 ml 25%
sol. I.V.
(5ml\min)
Deferoxamine 15 mg\kg\h
Iron Hypotension
(desferal) I.V.
 Dose
according  Hypersensitivity
FAB (digibind) Digoxin, digitoxin to Heart failure in patient
calculations taking digoxin
I.V.
3 mg\kg
deep I.M.\4
Arsenic, mercury, h for 2 Not in G6PD diff.,
BAL (dimercaprol)
gold, lead days, then \ hepatic, renal disease
12 h for 7-
10 days
10 mg\kg\8
h for 5
days, then
Lead, mercury,
DMSA (succimer) 10 Allergy, GI distress
arsenic
mg\kg\12 h
for 2 weeks
oral
750 mg\kg
Methanol, laoding,100
Ethanol Oral 50%, I.V. 5-10%
ethylene glycol mg\kg\h
oral or I.V.
30 mg\kg
in 2-3
doses deep
Lead, heavy
EDTA I.M. or Not in renal disease
metals
slow I.V. in
saline for 5
days
Flumazenil 0.2 mg Not in TCA or benzo
Benzodiazepines
(anexate) repeated addict
50 mg
Methanol,
Folic acid I.V.\4 h for ---
methotrexate
6 doses
5-10 mg
β-blockers, Ca
I.V. + 1-5 May cause
Glucagon channel blockers,
mg\h hyperglycemia
quinidine
infusion
1-2 mg\kg
I.V. slow,  Not in G6PD diff.
Methylene blue 1% Met HB
repeat in  Not in renal failure
30-60 min
4MP (fomepizole) Methanol, 15 mg\kg
 loading in
100 ml
saline over
ethylene glycol
30 min, 10
mg\kg\12 h
for 4 doses
150 mg\kg
I.V. in 200
Acetaminophen, Anaphylaxis if rapid
NAC (parvolex) ml 5%
CCl4, chloroform I.V.
D5W over
15 min

Antidote Drug Dose

Notes
Trade name Poison Method

0.4-2 mg
Naloxone (narcan) Opioids Not in addicts
I.V., repeat
100% mask
Oxygen CO, cyanide, HS Not in paraquat
4-5 L\min
20
mg\kg\day
Copper, lead,  Max. daily dose 2 g,
Penicillamine on empty
mercury  allergy
stomach in
3 doses
1-2 gm I.V.
Obidoxime
Organophosphates over 10 Not in myasthenia
(toxogonin)
min, repeat
Dose
depends on  Slow I.V.
Protamine Heparin
heparin  Hypersensitivity
dose
INH, ethylene 1 gm I.V.\1 Dilute in 50 ml D5W
Pyridoxine (vit. B6)
glycol g INH over 5 min.
Metabolic
acidosis, 1 mEq\kg
Measure potassium
NaHCO3 enhanced I.V. bolus,
level
elimination, TCA, repeat
tegretol…etc.
Starch Iodine
Thiamine (vit.B1) Alcoholism, 100 mg Hypersensitivity
ethylene glycol slow I.V. or
I.M.,
 repeat\6 h
5-10 mg
Warfarin, S.C., then
Konakion (vit. K1) Hypersensitivity
rodenticides oral 10-25
mg\day
Hydroxycobolamine 50 mg\kg
Cyanide
(vit.B12 ) I.V.
Always call the poison center first
 NEW ANTIDOTES

Advances in the use of Antidotes

For the Poisoned Patient

Ken Bizovi MD

Goals And Objectives: Review the indications, mechanisms, side

effects of the antidotes listed below. Concentrating on new antidotes.

New Antidotes:
Fomepizol – a newly approved antidote for Ethylene
Glycol
Insulin And Glucose – for treatment of Calcium channel
blocker overdose
Octreotide – for sulfonylurea overdose refractory to glucose
administration
Not So New Antidotes:
Flumazenil
Digoxin Specific Antibody Fragments
Brief Review of other Antidotes
Frequently used antidotes: N-acetylcysteine, Calcium Salts,
Glucagon, Sodium Bicarbonate, Naloxone

Rarely used Antidotes: Crotalid Antivenin, Cyanide Antidote

kit, Deferoxamine, Methylene Blue, Physostigmine, Atropine
and Pralidoxime, Pyridoxine.

Atropine (antidote for organophosphate and carbamate poisoning)

A. Mechanism
1. competitive inhibitor of acetylcholine at the muscarinic
receptor
a. reverses SLUG BAM
Salivation, Lacrimation, Urination, Gastrointestinal
distress
Bradycardia, Asthma (really bronchial secretions), Miosis

B. Indication
1. Organophosphate or carbamate toxicity with
a. respiratory secretions causing hypoxemia
b. fasciculations and weakness
c. lethargy
 d. bradycardia
1. tachycardia is not a contraindication

C. Contraindications
a. none in the setting of OP overdose
b. relative contraindications – angle closure glaucoma,
obstructive uropathy

D. Dosing
1. start with 0.5-1 mg in adults and 0.01 –0.02 mg/kg in
children and titrate up until bronchosecretions are dry
2. double the dose every 2 doses
3. Cases using hundreds of milligrams of atropine have been
reported

E. Side effects
1. Anticholinergic poisoning
a. hot as a hare, dry as a bone, blind as a bat, red as a beet,
mad as a hatter

F. Alternatives - none

G. Costs – 50 cents/mg

H. Cautions and Pitfalls

1. tachycardia is not a contraindication

Antivenin

A. Mechanism - horse antibodies to multiple snake venoms is

thought to bind to the venom and decrease local tissue damage
and coagulopathy.

B. Indication
1. progression of swelling beyond the area of the bite.
2. Systemic symptoms – fasciculations, weakness, hypotension,
coagulopathy, hemolysis

C. Contraindications - only relative contraindications exist

1. Known allergy to horse serum increases risk of anaphylaxis
a. Allergy to the current tetanus toxoid is not a
contraindication since this product has not been made
from horse serum since the 60’s
 2. Previous treatment with Polyvalent antivenin

D. Dosing
1. Moderate envenomation – progression of swelling beyond
the area of the bite. Anxiety, nausea, tingling, may be seen.
a. 5-10 vials mixed 1:10 volume: volume with normal
saline
b. have Benadryl, and epinephrine at the bedside
c. start drip at 25 ml/hour and increase rate every 10 –15
minutes with an infusion rate that equals 2-10 vials per
hour maximum.
d. Total dose for moderate envenomation 5-10 vials

E. Side effects
1. Anaphylactic and anaphylactoid reactions
2. Serum sickness –
a. Usually joint pain and swelling
b. Can develop more severe syndrome of immune complex
vasculitis, myocarditis, neuritis, and glomerulonephritis

F. Alternatives
1. supportive care and administration of antivenin better than
surgical excision

G. Costs - $ 180/vial

H. Cautions and Pitfalls

1. have epinephrine ready to administer Iv if necessary
2. Skin testing has multiple problems and is not recommended
by author
a. should not be given unless antivenin is going to be given
b. false positive 50 %
c. false negative 20 %
3. many “dry bites” and local reactions only occur and do not
merit treatment with antivenin.

Calcium Salts
Calcium Gluconate 10 ml of 10% = 4.5 meq of calcium
Calcium chloride 10 ml of 10% = 13.6 meq of calcium

A. Mechanism (depends on the toxin)

1. HFl – binds to the Fl ion
 1. CCB or Beta blocker – augment calcium influx during
phase 2 of cardiac contraction
2. Hyperkalemia – stabilizes myocardium
3. Black widow – may decrease severity of painful muscle
spasms
4. Hypermagnesemia – physiologic antagonist to magnesium

B. Indications
1. hypocalcemia
2. hydrofluoric acid exposure (calcium gluconate if
subcutaneous injection is needed)
3. Hypotension due to calcium channel blockers or beta
blockers
4. Hyperkalemia
5. Black widow Spider bite may be used
6. Hypermagnesemia
7. Ethylene glycol poisoning with hypocalcemia

C. Contraindications
1. digoxin

D. Dosing
1. CCB OD
1. ampule (10 ml of 10% CaCl) given IV over 10 minutes
2. may repeat up to 3 amps
2. HFl
a. topical – mix calcium gluconate with KY jelly 1:3 and
apply (2.5%)
b. intradermal injection of 5% calcium gluconate 0.5ml/cm2
do not inject CaCl intradermally

E. Side effects
1. Tissue necrosis if CaCl is given subcutaneously or
infiltrates

F. Alternatives
1. HFl – probably should be used with IV magnesium for
anything greater than small area of minor irritation from low
concentration
2. CCB or Beta blocker - multiple other agents used in these
overdoses with no clear agent of choice (glucagon,
catecholamines, amrinone..)
 3. Hyperkalemia – insulin and glucose, sodium bicarbonate,
dialysis
4. Black widow – opiate and benzodiazapine with or without
calcium salts are adequate for most cases

G. Costs - < $ 1 for 10 ml of 10% either CaCl or Ca-gluconate

H. Cautions and Pitfalls

1. Rapid administration of calcium salts may lead to
hypotension, bradycardia, dysrhythmia
2. Overdose could cause hypercalcemia
a. cognitive difficulties
b. hyporeflexia
c. coma

Cyanide Antidote kit

A. Mechanism
Amyl nitrite – can cause a small Methemoglobinemia which
provides a place for CN to bind other than cytochrome oxidase
A3

Sodium Nitrite - can cause a Methemoglobinemia which

provides a place for CN to bind other than cytochrome oxidase
A3

Sodium Thiosulfate – provide substrate for the enzyme

Rhodanese which combines CN and thiocyanate to form
thiocyanate. Thiocyanate is subsequently cleared by the
kidneys

B. Indication
1. Shock and acidosis in known cyanide exposure
2. Shock and acidosis in suspected cyanide exposure
3. In smoke inhalation victims who have shock and acidosis
that is not explained by hypoxemia, or CO consider
administration of sodium thiosulfate for CN

C. Contraindications – see side effects and cautions

 D. Dosing
See antidote kit

E. Side effects
1. Sodium Thiosulfate – vein irritation, minimal other
side effects
2. Nitrites – may cause hypotension similar to nitrates

F. Alternatives
1. Hyperbaric Oxygen

G. Costs - $ 160/kit

H. Cautions and Pitfalls

1. Careful when/if dosing a pediatric patient. The Sodium
nitrite needs to be carefully dosed. Overdose may cause life
threatening Methemoglobinemia.
2. Hypotension
3. Methemoglobinemia may be detrimental to a CO poisoned
fire victim

Deferoxamine

A. Mechanism
1. Chelates Iron
a. has high affinity for iron with little effect on other ions
b. 100 mg of deferoxamine binds 9.35 mg of elemental iron

B. Indication
1. Anion Gap acidosis attributable to iron overdose
2. CNS depression
3. Hypotension unresponsive to fluids and shock
4. Serum iron > 500 micrograms/dl

C. Contraindications – see side effects and cautions

D. Dosing
1. 15 mg/kg/hour
2. total dose
a. stop infusion when clinical symptoms and anion gap
acidosis resolves
b. stop infusion after 24 hours of therapy
 1. continuation may be considered if patient remains
profoundly ill
c. avoid giving over 6 grams if symptoms and anion gap
resolved

E. Side effects
1. anaphylaxis
2. flushing and hypotension
a. stop temporarily or slow down drip rate, give fluid bolus
3. ARDS – associated with prolonged infusion, large doses
4. Yersinia enterocolitica – may cause diarrhea syndrome after
treatment

F. Alternatives – supportive care

G. Costs
$ 11.60/500 mg

H. Cautions and Pitfalls

1. see side effects
2. Patients who resolve over the first several hours should not
have continuation of infusion.
3. Patients with persistent acidosis, coma, and/or shock may
merit continued treatment, or a break then continued
treatment.

Digibind
A. Mechanism - Fab antibody fragments bind to digoxin making it
inactive

B. Indications
1. Bradydysrhythmia
Severe sinus bradycardia
Second or third degree heart block unresponsive to
atropine
2. Ventricular dysrhythmias – V-tach, V-fib
3. Potassium > 5.0 associated with an acute ingestion (ref)
4. Acute ingestion
a. 4 mg in a child
b. 10 mg in an adult
5. Serum concentrations
a. 15 ng/ml in acute ingestion
 6. Consider for bradycardic overdose patient
with unknown ingestion

C. Dosing
1. Dosing is based on estimating the total body
load of digoxin and the binding capacity of
Digibind.
2. Each vial binds 0.5 mg of digoxin
3. Dosing based on ingested dose
a. # mg ingested X 0.8
(bioavailability of 80%) divided by
0.5 vial/mg
b. Example 25 X 0.25 mg Pills ingested

6.25 mg of digoxin X 0.8 = 5 mg total body

load
5 mg/ 0.5 mg/vial = 10 vials

4. Dosing based on steady state serum concentration

a. Total body load = Dig level
(ng/ml) X (Vol of dist) X (Wgt in
Kg) X 0.001 mg/ng
b. For a level of 4 ng/ml in a 100 kg patient
c. Total load = 4 ng/ml X 5 l/kg X 100 kg X 0.001 =
2 mg of dig
d. 2 mg/0.5 vials/mg = 4 vials
e. This should be used in a chronic overdose
5. Dosing empiric dosing
a. Acute ingestion
1. Adult 10-20 vials
2. Child 10-20 vials
b. Chronic ingestion
1. Adult 3-6 vials
2. Child ¼ - ½ vials
6. Administering Digoxin Specific Antibody
Fragments
a. IV over 30 minutes through a
22-micrometer filter
b. Acute overdose
4-6 vials as a load
 0.5 mg/minute for 8 hours
0.1 mg/min X6 hours

D. Side effects
1. Minimal side effects reported
a. Rash in 2 of 451 (< 1%) patient
in post marketing surveillance
b. Hypokalemia 6 of 150 (4%)
c. Worsening CHF 4 of 150 (3%)
d. At least 1 patient has received multiple doses at
different times without adverse reaction

E. Alternatives
Nothing really compares

E. Costs – 10mg/ml, $ 128/ml

F. Cautions and Pitfalls

1. Measuring digoxin levels after the administration of
Digoxin Fab is problematic
2. Levels will be astronomically elevated with many assays.
3. Possibility of rebound digoxin toxicity in patient with
renal failure
Flumazenil
A. Mechanism
1. competitive antagonist of the benzodiazepine site of the
GABA receptor
2. weak agonist properties of Benzodiazepine site

B. Indication
1. sedation from benzodiazepines in the absence of
contraindications
a. Pediatric ingestion of benzodiazepine or iatrogenic cause
are most likely to have a risk benefit ratio that favors the
administration of flumazenil.

C. Contraindications
1. Tricyclic Antidepressants
a. by history
b. ECG evidence of TCA – QRS or QT prolongation, R-
wave in aVR and S wave in AVL
2. Chronic benzodiazepine use
3. History of substance capable of causing seizures
 4. Abnormal vital signs
D. Dosing
1. 0.1 mg/min until sedation reverses up to 1 mg
2. 0.2 mg IV over 15 seconds, then 0.2 mg q 1 minute up to 1
mg total
3. Flumazenil drip using 0.25-1.0 mg/hour in D5W or normal
saline has been reported but is not FDA approved
4. Onset of action is 1-2 minutes
5. T ½ 53 minutes
6. Durations of action depends on dose and T ½ of
benzodiazepine and dose of flumazenil, as well as hepatic
function
a. Resedation may occur in 20–120 minutes

E. Side effects
1. Seizures
2. Cardiac Dysrhythmias

F. Alternatives
5. Supportive care with focus on airway management and
intubation as needed

G. Costs – 35.50/5ml which contains 0.5 mg

H. Cautions and Pitfalls – see contraindications

I. Fomepizol (Antizol {trade name}, 4-methyl pyrazole)

A. Mechanism - Works as a competitive inhibitor of ADH

B. Indications –
1. History consistent with
significant ingestion of Methanol
or Ethylene Glycol
a. Significant dose >.15 mg/kg
1.5 mg in a 10 kg child (approx. 1.5 ml)
15 mg in a 100 kg adult (approx. 15ml)
2. Ethylene Glycol level greater than 25 mg/dl
3. Anion gap acidosis - suspected EG or Methanol ingestion

C. Side effects
1. Headache 12%
2. Nausea 11%
3. Dizziness 7%
D. Dosing
1. 15mg/kg followed by 10 mg/kg q 12 hours X 4 doses
then
2. 15 mg/kg q 12 hours
3. During dialysis dose q 4 hours see package insert for
details

4. Note – Fomepizol induces its own

metabolism via the P450 mixed function
oxidase system. The eliminations rate increases
after 30-40 hours. Therefore dosing
recommendations include increases in dose
after 48 hours of therapy

E. Alternatives
1. Ethanol
Mechanism - Works as a competitive inhibitor of
ADH
Indications –
History consistent
with significant
ingestion
Methanol level greater than 10 mg/dl
Anion gap acidosis - suspected EG or Methanol
ingestion
Ethanol continued
Side effects
CNS depression
Hypoglycemia especially children
Negative metabolic effects (minor)
Dosing
Load
10cc/kg of 10%
ETOH IV over
30 minutes
OR 2.5 ml/kg of 40% po
Maintenance
0.8 – 1.9 ml/kg/hour of 10% ETOH
During Dialysis
2.7-3.8 ml/kg/hour of 10% ETOH

2. Comparison of Ethanol and Fomepizole

a. Side Effects
Ethanol is more likely to cause CNS depression
and exacerbate existing CNS depression.
Hypoglycemia (see pediatric considerations)
Minimal side effects with Fomepizole

b. Pediatric considerations
Neither Etoh or fomepizole is FDA approved
for pediatrics
More experience with ethanol
Hypoglycemia more likely in pediatric
population
CNS depression likely to be greater in children

c. Costs
Fomepizol – 1 vial containing 1.5 grams is
enough for 1 dose in a 100 kg adult costs $
1150.00

Cost analysis (not charges) for 36 hour course

with no dialysis
Ethanol drip $ 1360
Includes q 6 hour serum levels
Fomepizol - $ 4000

d. Scenarios where fomepizol might be “worth it”

Patient in a hospital who requires transfer for

dialysis with prolonged transport time. Lack of
CNS depression and ease of administration may
give fomepizol an advantage over ethanol.

Pediatric patient with a potentially significant

exposure that is in a setting where toxic alcohol
levels will take several hours.

A methanol or ethylene glycol level between 25

– 50 mg/dl may be managed without dialysis.
Either ethanol or fomepizol would work.

When/if fomepizol becomes close in cost to

ethanol.
Brent J, et al. Fomepizole for the treatment of Ethylene Glycol
Poisoning. NEJM 340:832-838, 1999
Barceloux DG, et al. AACT Practice guidelines on the treatment of
ethylene glycol poisoning. J Tox Clin Tox 37:537-560, 1999

Glucagon

A. Mechanism – Increase intracellular cyclic-AMP (cAMP), which

is a secondary messenger that increases influx of Ca 2+ from
the extracellular space and the sarcoplasmic reticulum.

B. Indication – bradycardia, heart block, and hypotension due to

calcium channel blockers or beta-blocker toxicity

C. Contraindications – see side effects and caution

D. Dosing
1. 50 microgram/kg (3.5 in a 70 kg adult) IV bolus infused over
1 minute{dilute with sterile water for injection)
2. Continuous infusion 2-5 mg/hour5 in D5W
3. Onset – within minutes
4. Peak – 5-7 minutes
5. Duration – 10-15 minutes

E. Side effects
1. nausea and vomiting (not maybe, for sure)
2. hyperglycemia
3. hypokalemia (intracellular shift)
4. allergic reactions

F. Alternatives – atropine, epinephrine, norepinephrine, dopamine,

dobutamine, isoproterenol
1. Glucagon is a relatively safe drug and should probably be
considered early in the management of beta-blocker or CCB OD

G. Costs – 1mg ampule $ 39

H. Cautions and Pitfalls

1. The package diluent includes phenol which should not be
used for IV injection
 2. Effectiveness appears to decline with 60-120 minutes in one
animal model of beta-blocker toxicity
Kerns W, Schroeder D, Williams C, Tomaszewski C,
Raymond R. Insulin improves survival in a canine model of
acute beta-blocker toxicity. Ann Emerg Med 29:748-57,
1997

II. Insulin and Glucose For Calcium Channel Blocker (CCB) OD

A. Mechanism – Increased myocardial carbohydrate metabolism
and increased contractility (Kline 1, Kline 2)

B. Indications – Calcium channel blocker overdose:

1. Hypotension
2. Hemodynamically significant bradycardia
3. Bradydysrhythmia
Treatment of CCB toxicity with insulin and
glucose is still experimental. It is unclear
whether insulin and glucose is more
efficacious than calcium salts, glucagon,
and catecholamines in humans.

C. Dosing
Bolus Regular insulin 10-20 IU IV
With a bolus of glucose (25 grams)
Drip: 0.2-1.0 IU/kg/h
Glucose infusion to
keep serum glu >
100mg/dl

D. Side effects
Hypoglycemia (surprise!!!)
Hypokalemia – replace gently for K+ levels less than 2.5
meq/L Decrease in serum K+ represents an intracellular
shift in K+, not a loss.

E. Alternatives - Calcium chloride, Glucagon,

Dopamine, Dobutamine, Epinephrine,
Amrinone, Pacing, Intra-aortic balloon pump

F. Costs
Regular insulin 1 vial (1000 units) $ 9.23
Ampule of D50 $ 16.18
1. Kline JA, Leonova E, Raymond RM. Beneficial myocardial
metobolic effects of insulin during verapamil toxicity in the
anesthetized canine. Crit Care Med 23:1251, 1995
2. Kline JA, Leonova E, Willians TC, Schroeder JD, Watts JA.
Myocardial metabolism during graded intraportal verapamil infusion
in awake dogs. J of Cardiovascular Pharm. 27:719-726, 1996
3. Yaun T, Kerns, Tomaszewski C, Ford M, Kline J. Insulin and glucose:
Novel Treatment for Calcium Agonist-Induced Shock. J Tox Clin Tox
1997;35:562 (abstract)
4. Kline J, Tomaszewski C, Schroeder JD, Raymond RM. Insulin is a
Superior Antidote for Cardiovascular Toxicity Induced by Verapamil
in the Anesthetized Canine . J Pharm and Exp Ther 267:744, 1993
5. Yuan TH. Kerns WP 2nd. Tomaszewski CA. Ford MD. Kline JA.
Insulin-glucose as adjunctive therapy for severecalcium channel
antagonist poisoning. Journal of Toxicology - Clinical Toxicology.
37(4):463-74, 1999.

Methylene Blue
A. Mechanism - Methylene is the substrate for the NADPH
methemoglobin reductase, which reduces Fe3+ to FE2+

B. Indication
1. Symptoms due to methemoglobinemia – dyspnea, syncope,
chest pain
2. Methemoglobinemia of 30% or greater

C. Contraindications
1. Known G6PD deficiency is a contraindication but pretesting
is not necessary

D. Dosing
1. 1-2 mg/kg (0.1 ml/kg of 1%{10 mg/ml} solution)

E. Side effects
1. may cause hemolysis in G6PD cases
2. overdose may worsen methemoglobinemia
3. turns all secretions blue (urine, tears …)
4. explain to parents that the blue IV fluid going into there blue
child is really the right thing to do
 F. Alternatives
1. ascorbic acid is used for congenital forms of
methemoglobinemia but not effective in treating drug induces
methemoglobinemia.

G. Costs – 7.80 ml = 10 mg

H. Cautions and Pitfalls

1. differential diagnosis of failure of methylene blue to work
a. G6PD deficiency – people with significant G6 PD
deficiency do not produce NADPH through the hexose
monophosphate pathway. The enzyme is NADPH
dependant.
b. Congenital Methemoglobinemia ir Hemoglobin M
c. Sulfhemoglobinemia – different entity which is rare and
causes cyanosis at concentrations of 0.5 gm/dl
N-acetylcysteine
A. Mechanism -
1. binds directly to N-acetyl-p-benzoquinonamine (NAPQI)
2. increases the production of glutathione which detoxifies
(NAPQI)
3. sulfation substrate: enhances non-toxic sulfation of
acetaminophen
4. hepatic injury acts as an antioxidant

B. Indications
a. Acute overdose - treat for patients whose acetaminophen
level falls above the possible toxicity line.
1. NOTE: Since the time of ingestion effects the
interpretation of the level use the earliest possible time
of ingestion.
2. give first dose prior to 8 hours post-ingestion, it
will not effect the interpretation of the nomogram
b. Chronic overdose
1. history of more than recommended dose and:
a. elevated LFT’s (AST, ALT)
b. persistent vomiting
c. elevated acetaminophen levels
c. Late presenters with history of acute or chronic overdose
with elevated LFTS

C. Dosing
Oral
 140 mg/kg po x 1
70 mg/kg q 4 hours x24 doses
Dilute to 5% solution
IV
48 hour protocol: 140 mg/kg load, 70 mg/kg q 4 hours
for 12 additional doses. give doses in dilute solution
over 1 hour
20 hour protocol: 1250 mg/kg over 15 minutes, the 50
mg/kg over 4 hours. then 100mg/kg over 16 hours

D. Side effects
1. Oral - nausea and vomiting
2. IV anaphylactoid reactions (rash, urticaria, bronchospasm,
hypotension, death)

G. Alternatives - other sulfhydryl chemicals have been studied but

non are as safe and effective.

H. Costs – $ 15.30/10 ml of 20% solution (200 mg/ml))

I. Cautions and Pitfalls

1. Treat within 8 hours post-ingestion, even if level not back
2. Multiple levels of APAP are unnecessary
3. Once patient qualifies for treatment the entire course of NAC
should be given. Regardless of subsequent APAP
4. Since the time of ingestion effects the interpretation of the
level use the earliest possible time of ingestion.

Naloxone (Narcan)
A. Mechanism – antagonist at
1. reverses the respiratory, CNS, and pain effects of opiates

B. Indications
1. primary indication is for respiratory depression in known or
suspected opiate overdose
2. Use for CNS depression in an suspected opiate overdose
may be diagnostic, allow history to be obtained and avoid
unnecessary diagnostic tests
a. Consider necessity of reversing CNS depression without
significant respiratory depression
C. Dosing
1. 0.4 or 2 mg IV push – for rapid reversal of respiratory and
CNS depression
2. may repeat 2 mg q 3-5 minutes up to 10 mg total
a. approved for IV dosing but is absorbed subcutaneously,
IM and endotracheally
b. poor bioavailability if given orally
3. Small doses 0.1 mg at a time to titrate an oversedated pain
patient
4. Drip rate for patients with resedation after initial use = 2/3 of
the dose required for reversal per hour
5. Kinetics
a. Onset 1-2 min if given IV
b. T1/2 of approx. 1 hour with duration of activity of 20-90
min
1. shorter than most opiates so resedation may occur
6. Pediatric consideration
a. 0.1 mg/kg dose, max of 2mg/dose
b. No adverse effect is expected when giving naloxone to a
patient who is not opiate dependent.

D. Side effects
1. Precipitation of opiate withdrawal (hypertension,
tachycardia, vomiting, gastrointestinal cramping, anxiety,
agitation)
a. titration of patients with suspected opiate tolerance may
make ED management much simpler
b. administration of naloxone in EMS setting should be
limited to those with respiratory depression.
2. Reports of hypertension, cardiac arrhythmias and non-
cardiogenic pulmonary edema are exceedingly rare and
probably represent unmasking of underlying condition.

E. Alternatives
1. Supportive care
2. naltrexone – duration of effect 24-72 hours, antagonist at
andcan be given orally
a. this may be useful in pediatric overdose
b. Down sides
1. too long a duration for pain patients
2. opiate abuser may be discharged and could use large
doses to override the antagonist effect and develop
respiratory depression when naltrexone wears off
 3. nalmefene – derivative of naltrexone, oral bioavailability
40%
a. Dosing – duration of activity is dependant on dose
1. 0.5 mg IV – 4 hours
2. 2 mg IV – 8 hours
3. 50 mg po – 50 hours
b. T ½ 8-9 hours
c. May be given IV or po
d. Downsides – see naltrexone

F. Costs - $ 3.40 /ml = 1 mg

G. Cautions and Pitfalls

1. see side effects
2. Resedation may occur
b. observe patient 2 hours after naloxone
c. consider what you will/should do if a patient with opiate
overdose and risk of resedation wakes up and wants to
leave AMA or refuses care
d. Opiate withdrawal may complicate patient care (consider
titrating dose if patient is not in immediate danger)

Octreotide
A. Mechanism
1. inhibits insulin release form Beta islet cells of the pancreas

B. Indication
1. hypoglycemia from sulfonylurea
2. OD unresponsive to po or IV administration of glucose.
a. I recommend using it for any patient who need more than
D 10 IV or who are having multiple episodes of
hypoglycemia
b. Additionally if a patient is in a setting where frequent
(hourly) capillary blood glucose (CBG) levels are
difficult or impossible to obtain consider octreotide
1. warning – use of octreotide does not guarantee
prevention of hypoglycemia, but evidence supports that it
decreases the chances of hypoglycemia
3. Has been used for hypoglycemia induced by quinine-
induced hypoglycemia

C. Contraindications - allergy
 D. Dosing
50 micrograms q 12 hours (I suggest this dosing to start)
30 ng/kg/min (use if pt. Gets hypoglycemic despite single dose
of octreotide) 1
1 microgram/kg maximum of 50 microgm
there is a case report of a 20 kg child tx’d with 25
micrograms octreotide

E. Side effects
1. Bradycardia (seems rare)
2. QT prolongation

F. Alternatives
1. diazoxide – octreotide appears to have considerably less side
effects than diazoxide

G. Costs – 10.70/ml (100mcg/ml)

1. Boyle PJ, Justice K, Krentz AJ, Nagy RJ, Schade DS. Octreotide
reverses hyperinsulinemia and prevents hypoglycemia induced by
sulfonylureas overdose J Clin Endorine Soc 76:752-756

2. McLaughlin SA, Crandall CS, McKinney PE. Octreotide: An antidote

for sulfonylurea-induced hypoglycemia Ann of Emerg Med 36:133-
137, 2000

3. Spiller HA. Management of sulfonylurea ingestions, Pediatric Emerg

Care 15:227-230, 1999

Physostigmine

A. Mechanism – inhibits the enzyme acetylcholinesterase. This

leads to increase acetylcholine at receptors to compete with
anticholinergic Rx
1. because it is a tertiary amine it is not charged and crosses the
blood brain barrier, unlike neostigmine (quaternary amine)

B. Indications
1. severe CNS agitation, or seizures due to anticholinergic
poisoning
2. severe tachydysrhythmias due to anticholinergic poisoning
3. diagnostic test to avoid other diagnostic and therapeutic
interventions
 C. Contraindications –
1. TCA poisoning
2. can prolong duration of action of succinylcholine

D. Dosing
1. adult – 1-2 mg IV over 5 min
2. pediatric – 0.02 mg/kg maximum of 0.5 mg IV over 5 min

E. Side effects
1. Cholinergic excess – have atropine at bedside
2. SLUG BAM (Salivation, Lacrimation, Urination, GI distress
Bradycardia, Asthma, Miosis)
3. May cause brady-asystole

F. Alternatives
1. Benzodiazepines will lower the seizure threshold, decrease
temp by decreasing agitation, and decrease sympathetic
overdrive.

G. Costs – $ 7.80/mg

H. Cautions and Pitfalls

1. Lack of effect (no response but no cholinergic signs may
indicate correct diagnosis but need for more physostigmine)
2. Administer dose over 5 minutes by the clock

Pralidoxime (2-PAM)
A. Mechanism – Binds to the organophosphate molecule and
removes it form the acetylcholinesterase enzyme
1. only effective prior to aging of the OP-acetylcholinesterase
bond
a. aging is the process where an unstable bond is replaced
by a permanent bond
2. acts at all sites of acetylcholine activity
a. nicotinic sites at parasympathetic and sympathetic
ganglion
b. nicotinic sites at neuromuscular junction
c. muscarinic sites of the parasympathetic system and sweat
glands
 3. pralidoxime administration may decrease the atropine
requirement

B. Indication
1. Organophosphate toxicity with
a. respiratory secretions causing hypoxemia
b. fasciculations and weakness
c. lethargy
d. bradycardia
1. tachycardia is not a contraindication
e. any case that requires atropine

C. Contraindications – none except known allergy

1. There is some controversy about a potential negative effect
in certain carbamate poisonings.
a. if the case is a known carbaryl (Sevin a carbamate)
poisoning do not administer pralidoxime
b. if the case is unknown then giving pralidoxime should be
administered

D. Dosing
1. Adult 500mg/hour over 4 hours give q 6 hours x 48 hours
2. Pediatric – 20-40 mg/kg dripped over 4 hour (maximum 1
gram)
3. Alternatively peds or adult 3.2 mg/kg/hour (max: 1 gram in
child, 2 gram in adult )
4. Package insert dosing is slightly different
a. Adult – 1-2 grams in 100 ml of NS over 15 –30 minutes,
maximum rate 200mg/min
b. Pediatric – 20-40 mg/kg over 15-30 min
c. Pralidoxime has a shorter duration of effect if given as
directed in the package insert
E. Side effects
1. may cause cholinergic symptoms if given too fast
a. reports of respiratory and cardiac arrest with rapid
administration
2. other side effects – dizziness, blurred vision, increase in
diastolic BP,
F. Alternatives – other oximes (obidoxime, H-series) not available
in US

G. Costs – 29.80 / gram

 H. Cautions and Pitfalls
1. Do not administer too fast
2. Give to any OP or suspected OP poisoning that requires
atropine even if symptoms resolve with atropine
3. Do not withhold pralidoxime to patients who present after 24
hour
a. previous in vitro data on certain organophosphates
suggested lack of efficacy after 24-48 hours
b. due to differences in in-vivo activity fat solubility and
prodrug conversion to active drug pralidoxime should be
given to patients who have indications, regardless of
timing of exposure.

Pyridoxine
A. Mechanism – pyridoxine is a cofactor that is necessary in the
synthesis of gamma amino butyric acid (GABA).
a. INH depletes pyridoxine and its active metabolite
pyridoxine-5’phosphate

B. Indication - known or suspected exposure ot isoniazid with

seizure
1. seizures from INH, Gyromitra, and monomethylhydrazine 1.
2. consider administration of 5 grams empirically in patients with
status epilepticus

C. Contraindications – known allergy

D. Dosing
1. dose - A gram of pyridoxine should be given IV for each
gram of INH ingested, up to 5 grams total.(INH 3)
2. If the dose ingested is unknown, then 5 grams should be
given.
3. Pediatric dose - 70 mg/kg up to a maximum of 5 grams
4. Administration - 1 gram IV should be given every 2-3
minutes until the seizure stops. The remainder may be
given more slowly.
5. If IV pyridoxine is not available in sufficient quantities
then NG administration can be considered.

E. Side effects
1. peripheral Neuropathy has occurred with chronic use (INH 6)
and high doses (INH 7)
2. the diluent chlorobutanol has caused fatality (INH 8)
 F. Alternatives – no substitute
1. If IV pyridoxine is not available in sufficient quantities then
NG administration can be considered.

G. Costs $ 37.00/100 mg $ 1850 for 5 grams !

H. Cautions and Pitfalls

1. Benzodiazepines will not work in INH overdose with out the
GABA(INH 4, 5). GABA synthesis is pyridoxine dependent

Sodium Bicarbonate

A. Mechanism for Tx of TCA overdose

1. pH dependent effect – increases the non-ionized fraction of
drug. The non-ionized drug can more easily diffuse out of
the channel
2. increase sodium gradient counteracts the sodium channel
blockade

B. Indication
1. QRS < 100 msec
2. Hypotension

C. Contraindications – none
1. CHF is a relative contraindication due to sodium load but
increase in contractility in setting of TCA toxicity outweighs
risk

D. Dosing – 1-2 meq/kg bolus over 1-2 minutes

E. Side effects

F. Alternatives
1. Hyperventilation is effective but not as efficacious as sodium
bicarbonate
2. Treatment with hypertonic sodium is described but is not as
well documented as sodium bicarbonate or hyperventilation
and has the theoretic risk of central pontine myelinolysis

G. Costs $ 7.40/50 ml (50 meq)

 H. Cautions and Pitfalls
1. patient must be monitored closely for recurrent QRS
widening even if bicarbonate drip is hanging

Last Update 10/10/00

 Antidotes for Bioterrorism
Ken Bizovi MD

Goals And Objectives: Review the indications, mechanisms, side

effects of the antidotes listed below.

Atropine (antidote for organophosphate and carbamate poisoning)

I. Mechanism
2. competitive inhibitor of acetylcholine at the muscarinic
receptor
b. reverses SLUG BAM
Salivation, Lacrimation, Urination, Gastrointestinal
distress
Bradycardia, Asthma (really bronchial secretions), Miosis

J. Indication
2. Organophosphate or carbamate toxicity with
e. respiratory secretions causing hypoxemia
f. fasciculations and weakness
g. lethargy
h. bradycardia
1. tachycardia is not a contraindication

K. Contraindications
c. none in the setting of OP overdose
d. relative contraindications – angle closure glaucoma,
obstructive uropathy

L. Dosing
4. Adults start with 0.5-1 mg IV
a. 1-2 mg IV q 5 minutes and titrate up until
bronchosecretions are dry and hemodynamically
significant bradycardia resolved
b. IM administration can be considered if IV acces is not
available
5. Pediatrics - 0.01 –0.04 mg/kg in children (never use less
than 0.1 mg)
a. 1-2 mg IV q 5 minutes and titrate up until
bronchosecretions are dry and hemodynamically
significant bradycardia resolved
b. IM administration can be considered if IV acces is not
available
 6. Cases using hundreds of milligrams of atropine have been
reported
a. 10-15 mg/hour rates may be required titrate to effect
(above)

M. Side effects
1. Anticholinergic poisoning
a. hot as a hare, dry as a bone, blind as a bat, red as a beet,
mad as a hatter

N. Alternatives - none

O. Costs –
1. 1mg/ml x 1ml vial - 50 cents/mg AWP
2. 0.1 mg/ml x 10 ml (AMP) $ 13 AWP

P. Cautions and Pitfalls

2. tachycardia is not a contraindication

Cyanide Antidote kit (Sodium Thiosulfate)

I. Mechanism
Sodium Thiosulfate – provide substrate for the enzyme
Rhodanese which combines CN and thiocyanate to form
thiocyanate. Thiocyanate is subsequently cleared by the
kidneys

J. Indication
1. Shock and acidosis in known cyanide exposure
2. Shock and acidosis in suspected cyanide exposure
3. In smoke inhalation victims who have shock and acidosis
that is not explained by hypoxemia, or CO consider
administration of sodium thiosulfate for CN. There is little
downside to administration of sodium thiosulfate in any
seriously ill smoke inhalation victim.

K. Contraindications – see side effects and cautions

L. Dosing
1. Adult – 12.5 grams = 50 ml of 25 % solution
2. Pediatric – 0.4125 grams/kg = 1.65 mL/kg of 25% solution
max dose 12.5 grams
M. Side effects
1. Sodium Thiosulfate – vein irritation, minimal other
side effects

N. Alternatives
1. Hyperbaric Oxygen

O. Costs - $ 275/ Cyanide antidote kit

1. 12.5 gram vial alone $22.50 AWP

P. Cautions and Pitfalls

4. Sodium Thiosulfate is a drug of low toxicity.
Pralidoxime (2-PAM)
I. Mechanism – Binds to the organophosphate molecule and
removes it form the acetylcholinesterase enzyme
3. only effective prior to aging of the OP-acetylcholinesterase
bond
4. acts at all sites of acetylcholine activity
d. nicotinic sites at parasympathetic & sympathetic ganglion
& neuromuscular junction
e. muscarinic sites of the parasympathetic system and sweat
glands
5. pralidoxime administration may decrease the atropine
requirement

J. Indication
2. Organophosphate toxicity with
e. respiratory secretions causing hypoxemia
f. fasciculations and weakness
g. lethargy
h. bradycardia - tachycardia is not a contraindication
i. consider for any case that requires atropine

K. Contraindications – none except known allergy

2. There is some controversy about a potential negative effect
in certain carbamate poisonings.
c. if the case is a known carbamate poisoning do not
administer pralidoxime
d. if the case is unknown then giving pralidoxime should be
administered

L. Dosing
1. Intermittent dosing
d. Adult – 1-2 grams in 100 ml of NS over 15 –30 minutes,
maximum rate 200mg/min
1. May repeat in 1 hour if weakness is not
resolved then q 6 hours.
e. Pediatric – 20-40 mg/kg over 15-30 min
1. May repeat in 1 hour if weakness is not resolved then
q 6 hours
2. Drip dosing
a. Adult - 1-2 grams in 100 ml of NS over 15 –30 minutes,
then 500mg/hour
b. Pediatric – 20-40 mg/kg over 15-30 min, then 5-10 mg/kg
drip(maximum 500 mg/hour gram)
 c. duration varies with the agent (organophosphate or nerve
agent) intermittent evaluation with drip off may be
required
3. Intermittent versus drip - Intermittent uses less pralidoxime
but may lead to periods of sub-therapeutic serum
concentration. If supplies are limited consider intermittent
dosing with increase frequency if indicated by fasciculations
or weakness

M. Side effects
2. may cause cholinergic symptoms if given too fast
b. reports of respiratory and cardiac arrest with rapid
administration
3. other side effects – dizziness, blurred vision, increase in
diastolic BP,

N. Alternatives – other oximes (obidoxime, H-series) not available

in US

O. Costs – $108 / gram AWP

P. Cautions and Pitfalls

4. Do not administer too fast
5. Do not withhold pralidoxime to patients who present after 24
hour
c. previous in vitro data on certain organophosphates
suggested lack of efficacy after 24-48 hours
d. due to differences in in-vivo activity fat solubility and
prodrug conversion to active drug pralidoxime should be
given to patients who have indications, regardless of
timing of exposure. BUT expect less efficacy as time
since exposure increases.

Cyanide Antidote kit (Nitrites)

A. Mechanism
Amyl nitrite – can cause a small Methemoglobinemia which
provides a place for CN to bind other than cytochrome oxidase
A3
Sodium Nitrite - can cause a Methemoglobinemia which
provides a place for CN to bind other than cytochrome oxidase
A3
 B. Indication
4. Shock and acidosis in known cyanide exposure
5. Shock and acidosis in suspected cyanide exposure
6. In smoke inhalation victims who have shock and acidosis
that is not explained by hypoxemia, or CO consider
administration of sodium thiosulfate for CN

C. Contraindications – see side effects and cautions

1. do not give either nitrite to a patient with elevated Carbon
monoxide level (CO)

D. Dosing Amyl nitrite – ampule to be broken and inhaled by the

patient for 30 seconds out of every minute. Use a new ampule
every 3 minutes.
a. Do not use amyl nitrite if you already have IV
access use sodium nitrite instead.
E. Dosing Sodium Nitrite –
1. Adult - 300 mg IV over AT LEAST 5 minutes
a. Alternatively – dilute 300 mg in 50-100 ml of NS and run
in slowly. Rate can be increased as long as no
hypotension develops.
2. Pediatric- average dose based on normal (12 grams ) of
hemoglobin. Lesser doses should be considered for children
with anemia.
a. 0.33 mL/kg of 3% sodium nitrite = 10 mg/kg
Hemoglobin Sodium Nitrite initial
dose
ML/kg of 3%
(mg/kg)
8 grams 0.22 mL/kg
6.6 mg/kg
10 grams 0.27 mL/kg
8.7 mg/kg
12 grams (average) 0.33mL/kg
10 mg/kg
14 grams 0.39 mL/kg
11.6 mg/kg

F. Side effects
1. Nitrites – may cause profound hypotension similar to nitrates

G. Alternatives
1. Hyperbaric Oxygen
 2. Hydroxocobalamin (when the FDA gets around to approving
it)

H. Costs - $ 275/kit AWP

I. Cautions and Pitfalls

5. Careful when/if dosing a pediatric patient. The Sodium
nitrite needs to be carefully dosed. Overdose may cause life
threatening Methemoglobinemia.
6. Hypotension
7. Methemoglobinemia may be detrimental to a CO poisoned
fire victim

Pyridoxine
B. Mechanism – pyridoxine is a cofactor that is necessary in the
synthesis of gamma amino butyric acid (GABA).
b. INH & hydrazines deplete pyridoxine and its active
metabolite pyridoxine-5’phosphate

B. Indication - known or suspected exposure ot isoniazid with

seizure
3. seizures from INH, Gyromitra, and hydrazine
4. consider administration of 5 grams empirically in patients with
status epilepticus

I. Contraindications – known allergy

J. Dosing
6. Hydrazine exposure – 25 mg /kg for adult and pediatric
patients
7. INH OD -
a. A gram of pyridoxine should be given IV for each gram
of INH ingested, up to 5 grams total.(INH 3)
b. If the dose ingested is unknown, then 5 grams should be
given.
c. Pediatric dose - 70 mg/kg up to a maximum of 5 grams
d. Administration - 1 gram IV should be given every 2-3
minutes until the seizure stops. The remainder may be
given more slowly.
e. If IV pyridoxine is not available in sufficient quantities
then NG administration can be considered.
 K. Side effects
3. peripheral Neuropathy has occurred with chronic use (INH 6)
and high doses (INH 7)
4. the diluent chlorobutanol has caused fatality (INH 8)

L. Alternatives – no substitute
2. If IV pyridoxine is not available in sufficient quantities then
NG administration can be considered.

M. Costs $ 2.00/100 mg $ 100 for 5 grams

N. Cautions and Pitfalls

1. Benzodiazepines will not work in INH overdose with out the
GABA(INH 4, 5). GABA synthesis is pyridoxine dependent

Update in Toxicology – New Antidotes

Intentional and unintentional poisonings remain a major cause of

morbidity and mortality worldwide and management in the majority of
case is limited to gastrointestinal decontamination and good supportive
care. In recent years, an increasing number of antidotes have become
available for the management of poisoning due to specific agents. In this
article, I will review recent developments with regards to antidotes for
poisonings due to sulfonylurea agents, calcium channel blockers and the
toxic alcohols (methanol and ethylene glycol).

Sulfonylurea Agents
and Octreotide

Sulfonylurea (SU) compounds are widely used for the management

of non-insulin dependent diabetes mellitus and in the United States more
then 21 million prescriptions are written annually.1 In 2000, the Toxic
Exposure Surveillance System (TESS) data complied by the American
Association of Poison Control Centers (AAPCC) reported 6,910
exposures to SU agents of which 1,188 were associated with moderate or
major effects requiring treatment.2
SU compounds act by enhancing insulin release from the beta-islet
cells of the pancreas. This is accomplished by binding a SU specific
receptor site on the beta-islet cell, which results in decreased potassium
efflux across an ATP sensitive potassium channel. The subsequent
increase in intracellular potassium leads to a reduced membrane potential
and cell depolarization, which triggers the opening of voltage dependent
calcium channels. Calcium entry into the cell then triggers insulin release
via exocytosis of preformed insulin vesicles.
The main clinical feature of SU poisoning is hypoglycemia and
conventional therapies include dextrose and diazoxide. Dextrose infusion
which is readily available in most hospitals is cheap and the first line
treatment for SU-induced hypoglycemia. Severe SU poisonings require
intensive monitoring (blood glucose checks every 30-60 minutes) and
central venous access since hypertonic dextrose concentrations > 10% are
highly irritating to peripheral veins. Unfortunately, dextrose itself is a
potent inhibitor of the ATP sensitive potassium channel and a potent
stimulus for the release of additional insulin. Dextrose therapy for SU
poisoning has been associated with significant rebound hypoglycemia,
which can be recurrent and prolonged.1,3. Diazoxide, an anti-hypertensive
drug, is the traditional second line agent for severe SU-induced
hypoglycemia. It competitively inhibits the effects of the SU by opening
the ATP dependent K channel, leading to decreased insulin release from
the beta-islet cell. Its efficacy is limited primarily by significant side
effects, which include hypotension, nausea, vomiting, reflex tachycardia
and fluid retention.
Octreotide is a synthetic long acting analogue of somatostatin that
inhibits the secretion of several hormones in the body including glucagon,
gastrin and growth hormone. Established indications for its use including
growth hormone secreting pituitary adenomas, metastatic islet cell and
carcinoid tumors as well as acute esophageal variceal bleeding.4
Octreotide acts by binding receptors on the voltage dependent calcium
channel to decrease calcium influx and calcium induced hormone release.
In a human randomized crossover volunteer clinical trial, Boyle et al.
compared the efficacy of dextrose, octreotide and diazoxide following a
large single dose of glypizide.1 Supplementary dextrose was used to
maintain euglycemia in the octreotide and diazoxide arms and plasma
insulin concentrations as well as dextrose requirements were measured. 1
Octreotide administration was associated with a return of insulin
concentrations to basal levels and a marked decrease in the need for
glucose infusion to maintain euglycemia when compared to the other two
arms. More recently, McLaughlin and colleagues published their
experience with octreotide therapy for patients presenting with SU-
induced hypoglycemia. 3 In this case series of 9 patients, single dose
octreotide therapy also dramatically reduced the number of episodes of
hypoglycemia.
In summary, octreotide along with dextrose and gastrointestinal
decontamination should be considered as first-line therapies for SU-
induced hypoglycemia. Repeated dosing may be necessary since the half-
life of octreotide is shorter then that of most SU agents. Details regarding
administration of octreotide are summarized in Figure 1.

Calcium Channel Blockers and High-Dose

Insulin Euglycemia

Calcium Channel Blocker (CCB) overdose is the leading cause of

death from cardiovascular drug poisoning in the United States. In 2000,
the TESS reported 8,975 exposures to CCB’s of which 1,743 were
intentional. Moderate or major toxicity developed in 1203 patients and
there were 44 deaths. 2
CCB’s’ act by antagonizing calcium entry though the L-type
calcium channel in cardiomyocytes and smooth muscle cells. Since
calcium is necessary for contractile function and electrical conduction,
CCB toxicity is characterized by hypodynamic circulatory shock with
hypotension, metabolic acidosis and conduction disturbances. 5
Treatment remains a challenge since conventional therapy with calcium,
glucagon, catecholamines, atropine and cardiac pacing fails to improve
myocardial function and hemodynamics in severe cases.
The positive inotropic properties of insulin have been recognized in
multiple species especially in the context of depressed hearts. 6 In the
unstressed aerobic state, the myocardium relies primarily on the oxidation
of free fatty acids for its energy needs. During stressed states, myocardial
substrate preference shifts from free fatty acid to carbohydrate utilization.
Unfortunately, CCB’s also interfere the with myocardial utilization of
carbohydrates through several mechanisms. These include impaired
insulin release from the pancreas, generalized body insulin resistance and
poor substrate delivery. In this setting, altered myocardial carbohydrate
utilization may lead to a vicious cycle of poor heart function and
hypodynamic shock ultimately resulting in death..
In a canine model of verapamil poisoning, high-
dose insulin euglycemia (HIE) therapy
improved survival, myocardial contractility and
systemic perfusion when compared to
conventional therapies such as calcium,
glucagon and epinephrine.7,8 In this model, the
primary mechanism of action for insulin-
dextrose appears to be improved myocardial
carbohydrate metabolism.9 Human experience
with insulin-euglycemia therapy is limited
largely to one case series and several case
 reports. Yuan et al. reported on 5 patients who
were treated with HIE after failing to respond to
conventional treatments. 6 In all 5 patients, the
hemodynamic status of the patients improved
after insulin-dextrose infusion and all patients
survived. More recently, Boyer and Shannon
reported on two additional patients that
responded dramatically to HIE therapy after
failing to respond to conventional therapy. 10
In summary, CCB toxicity is characterized by hypodynamic
circulatory failure and HIE therapy appears to be a promising therapeutic
option in cases that are refractory to conventional treatments. Pending
further studies, its use should be considered experimental and as a
therapeutic option when standard measures fail. 5 Details summarizing
HIE therapy (Kerns R, personal communication) are outlined in Figure 2.

Toxic Alcohols and Fomepizole

Ethylene glycol (EG) and methanol are small chain alcohols that
are widely used as industrial solvents and as components of automobile
products such as antifreeze and windshield wiper fluid. In 2000, TESS
reported 2,620 exposures to these two alcohols and 30 deaths.2
Although the EG and methanol are themselves non-toxic,
metabolism by hepatic alcohol dehydrogenase (ADH) initiates the
enzymatic conversion of these alcohols to their toxic metabolites which
are glycolic acid and formic acid respectively. Intoxication with both EG
and methanol is classically characterized by an anion gap metabolic
acidosis. Conventional therapy includes administration of ethanol to
competitively block hepatic ADH, correction of metabolic acidosis and
urgent hemodialysis to remove the parent alcohol and toxic metabolites.
Ethanol can be administered orally or intravenously and blood
concentrations of > 100 mg/dl are required for effective competitive
blockade of ADH. Unfortunately, ethanol use produces intoxication in the
patient and therapeutic levels can be difficult to maintain despite frequent
monitoring. Additional side effects include hepatotoxicity and
hypoglycemia especially in children. Of note, the use of ethanol as an
antidote has never been validated and it is not FDA approved for this
purpose.
Fomepizole (4-methylpyrazole) is a competitive inhibitor of ADH
that has been available as an antidote for EG poisoning in France since
1982 and now is also FDA approved for use in the United States. The
treatment regimen (Figure 3) is designed to maintain efficacious blood
levels throughout the course of therapy and no levels need to be
monitored. During the Methylpyrazole for Toxic Alcohols (META) trial,
fomepizole was shown to effectively stop EG and methanol metabolism
and reduce the accumulation of toxic metabolites.11,12 It also reduced the
need for hemodialysis with EG but not methanol.
In summary, fomepizole is the preferred
antidote for EG and methanol poisoning. Its
efficacy and safety have been demonstrated in
prospective human studies and the primary
factor limiting its widespread use at this time is
cost.

Figures

Octreotide

Indications: SU-induced hypoglycemia

Dose: 50 g SC q12 hours or IV infusion of 30 g/kg/min (Pediatric dose

is 1 g/kg to maximum of 50 g)

Side Effects: Bradycardia, QT prolongation

Cost: $10.70/ml

Figure 1: Overview of octreotide

High-dose Insulin Euglycemia

Indications: Calcium channel blocker overdose with hypodynamic

circulatory failure

Dose: Bolus Regular Human Insulin 1 unit/kg to

saturate receptors along with 0.5 gm/kg of dextrose.
Initiate insulin drip at 0.5 unit/kg/hr. If no
hemodynamic response is evident within 30 minutes,
increase drip rate to 1 unit/kg/hr. In conjunction with
insulin infusion, begin dextrose infusion at rate of 0.5
gm/kg/hr. Titrate to maintain euglycemia (100-200
mg/dl). Since concentrated solutions are irritating to
peripheral veins, central access is recommended.

Side effects: Hypoglycemia (monitor serum glucose

levels every 30 minutes), Hypokalemia (due to
intracellular shifting of potassium, replace gently for
K+ levels less than 2.5 meq/L)

Costs; Regular insulin 1 vial (1000 units) $ 9.23,

Ampoule of D50 $ 16.18

Figure 2: Suggested regimen for HIE therapy in CCB poisoning

Fomepizole

Indications: History consistent with significant ingestion of Methanol or

Ethylene Glycol, Ethylene Glycol level greater than 25 mg/dl, Anion gap
acidosis and suspected EG or Methanol ingestion

Dose: 15mg/kg followed by 10 mg/kg q 12

hours X 4 doses then 15 mg/kg q 12 hours
(Note – Fomepizole induces its own metabolism via the P450 mixed
function oxidase system and eliminations rate increases after 30-40 hours.
Current dosing recommendations include increases in dose after 48 hours
of therapy. Dosing adjustments are also necessary during pregnancy and
during dialysis)

Side effects: Headache, nausea, and dizziness

Fomepizole – 1 vial containing 1.5 grams costs $ 1150.00

Figure 3: Fomepizole dosing in ethylene glycol and methanol poisoning