Management of
Acetaminophen
Toxicity
History
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Synthesized in 1877 in U.S.
Extensive use began around 1947
Initially prescription only in the U.S.
Otc status gained in 1960
toxic effects first noted in U.S. in 1971
It’s everywhere!
• APAP is found in over 200 products
Tylenol
Tylenol cold
Contac Severe Cold
Sinutab Sinus
Sinarest
Midol PMS
Vicks 44M
Pyrroxate
Dimetapp allergy
Actifed Sinus
Anacin 3
Goody’s
Junior Strength Tylenol
Theraflu
Robitussin Cold
Sudafed Sinus
Unisom
Midol teen
Drixoral Cold
Benadryl allergy
Tempra
Comtrex multi sx
Vicks Nyquil
Sine-off
Panadol
Vanquish
Singlet
Coricidin
Alka Seltzer Plus
Panex
Actions
Analgesia
 Relieves mild to moderate pain
 Efficacy equivalent to salicylates
 Inhibits brain prostaglandin synthetase
 Blocks pain impulses peripherally
• Antipyresis
• Efficacy similar to salicylates
• Inhibits prostaglandin synthetase in the
hypothalamus
In overdose situations, liver enzymes become
saturated, glutathione is depleted, NAPQI
(N-acetyl-p-benzoquinoneimine)
accumulates, and hepatic necrosis occurs
Pharmacokinetics
• Absorption
– Rapidly absorbed from the GI tract
– Peak concentration usually occurs between 60
and 120 minutes
– Peak plasma levels almost always occur within
4 hours
Distribution
• Vd 1.0 - 2.0 L/Kg
• Approximately 20% plasma protein bound
may increase to 50% in overdose
• Has been reported to cross the placenta
Metabolism
– Occurs via several pathways in the liver
• 52% by sulfation
• 42% by glucuronidation
• 2% excreted unchanged in the urine
• 4% biotransformed by C-P450 MFO system
Excretion
• APAP’s metabolic products are excreted by
the kidneys
• Minimal excretion into breast milk
Half life
• Average 2 hours
– range 0.9 to 3.25 hours
• No age related differences
• No change in patients with renal disease
• With liver dysfunction, may increase to 17
hours
Extracorporeal elimination
• Hemodialysis
– Not proven effective in reducing or
preventing liver damage in overdose
• Peritoneal dialysis
– Not effective
Toxicity
• Factors involved in predicting hepatotoxicity
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total quantity ingested
time from ingestion to treatment
age of the patient
alcoholism
enzyme inducing medications
serum concentration in relation to Rumack
nomogram
• Toxic dose
– In adults, threshold for liver damage is 150 to
250 mg/kg
– Children under 10 appear to be more resistant
• Potential liver damage
– Adults: > 150 mg/kg in acute dose
– Adults: > 7.5 Grams in 24 hours (chronic)
– Children (<10 yrs): > 200 mg/kg
4 Stages of Acetaminophen
Poisoning
• Phase I (30 minutes to 4 hours)
– Within a few hours after ingestion, patients
experience anorexia, nausea, pallor, vomiting,
and diaphoresis. Malaise may be present.
Patient may appear normal
• Phase II (24 to 48 hours)
– Symptoms of Phase I are less severe. May seem
like a period of recovery. Right upper quadrant
pain may be present due to hepatic damage.
Blood chemistry becomes abnormal with
elevations of liver enzymes. Prothrombin times
may be prolonged. Renal function may begin
to deteriorate.
• Phase III (3 to 5 days)
– Characterized by symptoms of hepatic necrosis.
Coagulation defects, jaundice, and renal failure
have all been noted. Hepatic encephalopathy
has been noted. Hepatic biopsy at this time
would indicate centrilobular necrosis. Nausea
and vomiting may reappear. Death is due to
hepatic failure
• Phase IV (4 days to 2 weeks)
– Complete resolution or death
Treatment
• GI decontamination
– Syrup of Ipecac
• return usually 30-40% at best
• best if used early (first 1-2 hours)
– Gastric lavage
• effectiveness diminishes with time
• Activated charcoal
– Should not be witheld
– dose 50-100 Grams
• Cathartic
– utilized to speed transit time
• Hemodialysis
– Limited benefit
– Damage occurs quickly
• Hemoperfusion
– No benefit
• Peritoneal dialysis
– No benefit
Blood Sample
• 4 hour post ingestion APAP level
– levels drawn earlier may be
erroneous
– levels may be accurate out to 18
hours
• Plot level on Rumack-Matthews
nomogram
–150 mg/dl at 4 hours is possibly toxic
– Do not use therapeutic “normal” values to
determine potential toxicity!
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Baseline CBC
creatinine, BUN, blood sugar, electrolytes
prothrombin times
AST, ALT
– repeat q 24 hours
– elevations typically seen 24-36 hours post
ingestion
Rumack and Matthew Nomogram
500
Late
150
100
50
Not valid after
24 hours
10
5
mcg/ml
4
8
12
16
20
Hours After Acetaminophen Ingestion
24
• If APAP level plots above the possible risk
line administer N-acetylcysteine (NAC).
• If NAC is indicated, full regimen should be
followed. Do not stop NAC early if
nomogram indicates toxic possibility
N-acetylcysteine (NAC)
• Mechanism of action
– glutathione substitute
– may supply inorganic sulfur, altering
metabolism
• Route of administration
– Orally or IV
• IV not approved in the U.S.
• NAC dosing
– Oral 72 hour protocol
• Loading dose is 140 mg/kg
• Maintenance doses: 70 mg/kg
– Given every 4 hours x 17 doses starting 4 hours after
loading dose
• NAC supplied as 10 or 20% oral solution
– dilute to 5% final concentration with juice or
soft drink
– May be administered via NG tube
– If emesis occurs within 1 hour of
administration, repeat the dose
• If emesis persists, antiemetics may be used
– Reglan® (metoclopramide)
• 0.1 to 1.0 mg/kg iv is often effective
– If emesis is refractory, may consider
Zofran® (ondansetron) or Kytril® (granisetron)
• Expensive, but very effective
Pediatric overdoses
• More resistant to toxicity vs. adults
– if a child plots in the possible risk category on
the Rumack nomogram, do not resist using
NAC because of this greater tolerance to APAP
– Administer full course of NAC if nomogram
indicates that it is needed
Special considerations with NAC
• NAC administered on basis of nomogram
plot
• if initial level indicates need for NAC do
not discontinue
• subsequent APAP levels of interest only
• If NAC begun before APAP level obtained,
may DC NAC if level plots subtoxic on
nomogram
NAC side effects
• Relatively free of side effects when given
orally
• Emesis may occur
– extremely offensive sulfur odor
ED Admission
Estimate time of ingestion
Less than 4 hours since overdose
Less than 2 hours
since overdose
More than 2 hours
since overdose
Gastric emptying
Activated charcoal
4 or more hours since overdose
Activated charcoal
Draw blood plasma 4 hours after overdose for
plasma acetaminophen assay
Acetaminophen concentration available
within 8 hours of overdose
Wait for acetaminophen assay result
Draw blood ASAP for plasma
acetaminophen assay
Acetaminophen concentration not
available within 8 hours of overdose
Start NAC pending assay result
Loading does: 140 mg/kg
APAP level below risk line on nomogram
APAP level on or above risk line
DC NAC if started
Treat with full course of NAC
No further medical management needed
Daily LFT’s, prothrombin times
Treat other med or psychiatric problems
Provide supportive care
Summary
In overdose, APAP may overwhelm the liver
stores of glutathione. A rise in liver enzymes may
occur, which reflects the hepatic toxicity which
may ensue. Timely administration of NAC may
protect the patient from hepatic damage. Therapy
should be initiated as soon as possible, but NAC is
beneficial at any time. If APAP levels can not be
obtained, assume a toxic dose has been ingested,
initiate NAC, and continue until regimen
complete.
Case Studies
Case 1
A 32 year old female presents to the ED 30
minutes after taking 31 Tylenol Extra
Strength caplets in an apparent suicide
attempt. She weighs 134 pounds,
ambulated into the ED, is in no obvious
distress, has had no symptoms prior to
arrival.
Signs/symptoms
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Patient is awake and alert
HEENT: normal
No GI distress
PERRLA
Temp 98.7°F
HR 84, BP 128/76, R 19
Lab results
• APAP pending
• Salicylate pending
• Tox screen Negative
Calculations
• Patient weighs 60.9 kilograms
• 15,500 mg of APAP ingested
• mg/kg = 254
– a potentially toxic “acute” dose
Treatment
• Lavage
• Activated charcoal
• Cathartic
– Hold NAC until APAP level results obtained
• can get APAP level back within 2 hours
Outcome
• APAP level 56 mg/dl drawn 4 hours post
ingestion
• ASA level 0
• patient discharged asx to mental health unit
7 hours after arrival
Case 2
A 25 year old male is brought to the ED by
his girlfriend. She states that he has taken
24 “Tylenol” tablets. She brought the bottle
with her and in fact the product is “Tylenol
ER”. He ingested the caplets approximately
5 hours ago.
Tylenol ER is a relatively new product
which throws a curve into the traditional
management of APAP overdoses. This
product releases 325 mg of APAP
immediately and 325 mg over the next 8
hours.
Tylenol “ER” is referred to by poison center
staff as
Tylenol Emergency Room
• Unsure if nomogram is useful with this
product
• 1 case demonstrated to have biphasic peaks
Signs/symptoms
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Patient has vomited x 6 prior to arrival
Complaining of GI discomfort
HEENT: normal
PEERLA
Temp 98.9°F
HR 80, BP 130/78, R 20
Labs
• APAP level 110 mcg/ml at 5.0 hours post
ingestion
• ASA level 0
• Tox screen negative for other substances
Calculations
• Patient weighs 85 kilograms
• 11,050 mg APAP was ingested
• 183 mg/kg APAP ingested
– Potentially toxic amount in acute od
Treatment
• Activated charcoal with sorbitol given
• Repeat APAP level 4 hours past the 1st level
• Strongly consider NAC with this level
– Initial 4 hour level > 100 start NAC
Outcome
• Patient was treated with full course NAC
• Liver enzymes were AST 220 U/L, and ALT
388 U/L at 27 hours post ingestion.
• Liver enzymes returned to normal ranges
within 72 hours.
• Patient recovered uneventfully
Points to remember
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APAP is present in many poly drug overdoses
No symptoms may be present…screen
150 mcg/ml at 4 hours is a “treat” level
NAC loading dose is 140 mg/kg
NAC maintenance doses are 70 mg/kg
Once NAC is started, DO NOT DC
Metoclopramide 0.1-1.0 mg/kg is very effective in
controlling nausea/vomiting associated with APAP
toxicity
The End