Management of
Acetaminophen Toxicity
Paul Marino RPh

History Of Acetaminophen
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 Anacin 3 Tempra
Tylenol cold Goody’s Comtrex multi sx
Contac Severe Cold Junior Strength Tylenol Vicks Nyquil
Sinutab Sinus Theraflu Sine-off
Sinarest Robitussin Cold Panadol
Midol PMS Sudafed Sinus Vanquish
Vicks 44M Unisom Singlet
Pyrroxate Midol teen Coricidin
Dimetapp allergy Drixoral Cold Alka Seltzer Plus
Actifed Sinus Benadryl allergy Panex

APAP 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

APAP 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

Excretion
- APAP’s metabolic products are excreted by
the kidneys
- Minimal excretion into breast milk
APAP Pharmacokinetics
Half life
- Average 2 hours
– range 0.9 to 3.25 hours
- No change in patients with renal disease
- With liver dysfunction, may increase to 17 hours

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
In overdose situations, liver enzymes become saturated,
glutathione is depleted, NAPQI (N-acetyl-p-benzoquinoneimine)
accumulates, and hepatic necrosis occurs

4 Stages of Acetaminophen
Poisoning
Stage 1: Pre-injury period– 0-24h
– Asymptomatic or minor N+V
Stage 2: Acute liver injury– 24-48h
– RUQ pain, ↑AST/ALT, PTT, INR, bili +/- ↑Cr
Stage 3: Maximal liver injury – 48-96h
– marked hepatic dysfnfulminant hepatic failure,
encephalopathy, coagulopathy, hypoglycemia,
acidosis, renal failure
Stage 4: Recovery period - 4-14 days
– Resolution of hepatic dysfunction and recovery

“Older” Treatments
GI decontamination
– Gastric lavage, (no more Ipecac)
effectiveness diminishes with time, limited to recent ingestion
Activated charcoal
– dose 50-100 Grams, limited to recent ingestion
Cathartic
– utilized to speed transit time
Oral NAC (Mucomyst®) Q4H x 17doses
Hemodialysis
– Limited benefit. Damage occurs quickly
Hemoperfusion
– No benefit
Peritoneal dialysis
– No benefit

Plasma Sample, Acute OD
Obtain serum level at 4hrs post ingestion and use
Rumack-Matthew nomogram, does not apply for
repeated supratherapeutic (chronic) ingestion.
If 8 -24 hrs, or unknown time of ingestion draw level and
start IV NAC (Acetadote®) immediately. Stop NAC if
APAP level is below 25% line of nomogram.
NAC protects the liver by maintaining/restoring
glutathione or by acting as alternate substrate of toxic
metabolite.
Efficacy of IV NAC (Acetadote®) decreases with time if
administered > 8 hrs post ingestion, give anyway, even
in cases > 24hrs post ingestion.
– No documented fatalities if given within 8 hrs

mcg/ml 4 8 12 16 20 24
Hours After Acetaminophen Ingestion
150
5
10
50
500
Rumack and Matthew Nomogram
100
Late
Not valid after
24 hours

Baseline CBC
creatinine, BUN, blood sugar, electrolytes
prothrombin times
AST, ALT
– repeat q 24 hours
– elevations typically seen 24-36 hours post
ingestion
Other recommended Labs
Once IV NAC started, APAP levels no
longer accurate

IV Acetylcysteine “NAC”(Acetadote®) Protocol
“3 bag protocol”, 300mg/kg administered over 21hs
Bag #1 Loading dose, 150mg/kg in 200ml over 60min
Bag #2 50mg/kg in 500ml over 4hrs
Bag #3 100mg/kg in 1000ml over 16hrs
Adverse reactions: Hypersensitivity reactions 18%
Nausea/Vomiting 16%
Tachycardia 5%
Flushing 4%
Pregnacy Category B
No Drug Interactions
Half life 5.6hrs
Dosage adjustments <40kg, <20kg

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
Chronic APAP Ingestion, Suspected OD

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 IV
NAC may protect the patient from hepatic
damage. Therapy should be initiated as soon
as possible, but IV NAC is beneficial at any
time. If APAP levels can not be obtained,
assume a toxic dose has been ingested,
initiate IV NAC, and continue until regimen
complete.