Management of

Acetaminophen
Toxicity

History

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

Its everywhere!
APAP is found in over 200 products
Tylenol Anacin 3 Tempra
Tylenol cold
Goodys Comtrex multi sx
Contac Severe Cold
Junior Strength Tylenol
Sinutab Sinus
Theraflu Sine-off
Sinarest Robitussin Cold
Panadol
Midol PMS
Sudafed Sinus
Vanquish
Vicks 44M
Unisom Singlet
PyrroxateMidol teen
Coricidin
Dimetapp allergy Drixoral Cold
Alka Seltzer Plus
Actifed Sinus
Benadryl allergy Panex

Vicks Nyquil

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
APAPs 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

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!

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

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 LFTs, 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

Patient is awake and alert

HEENT: normal
No GI distress
PERRLA
Temp 98.7F
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

Patient has vomited x 6 prior to arrival

Complaining of GI discomfort
HEENT: normal
PEERLA
Temp 98.9F
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

APAP is present in many poly drug overdoses

No symptoms may be presentscreen
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