Paracetamol Overdose

Introduction of Paracetamol
• Paracetamol was first introduced into clinical
medicine towards the end of the 1900s but it attracted
little attention and was soon forgotten  
• There was a resurgence of interest in paracetamol
when it was found to be the major metabolite of
acetanilide and phenacetin and it was commonly
assumed to be responsible for the therapeutic effects of
both of these drugs.  
• Paracetamol has since been used increasingly as a
substitute for other analgesics such as aspirin and
phenacetin, and its sales have exceeded those of
aspirin”.
• Acetaminophen has been approved for OTC use since
1960.
• A safe and widely used analgesic for low level pain.
• Therapeutic dose of acetaminophen is 10-15
mg/kg/dose in children and 325-1000 mg/dose every
4-6 hours in adults, with a maximum of 4g/day.
• 9-12 g is sufficient to cause irreversible liver damage
in humans.
• Although the drug is remarkably safe, toxicity can
occur even with therapeutic doses.
• Alcoholics are particularly susceptible to
hepatotoxicity.
 The recommended doses of paracetamol
Adults 500-1000 mg each dose (1-2 tablets)

Age 12-16 years 500-1000 mg each dose (1-2 tablets)

Age 10-12 years 500 mg each dose

Age 8-10 years 375 mg each dose

Age 6-8 years 250 mg each dose

Age 4-6 years 240 mg each dose

Age 2-4 years 180 mg each dose

Age 6-24 months 120 mg each dose

Age 3-6 months 60 mg each dose

Age 2-3 months 60 mg once. A second dose of 60 mg may be

given after four hours
 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
 Analgesia
Actions
• 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
• AbsorptionPharmacokinetics
– 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
 Paracetamol-Normal Metabolism
• Paracetamol converted to:
• N-Acetyl-p-benzoquinonamine (TOXIC)
• This is conjugated with Glutathione
• Glutathione stored in the body
• Produces a NON TOXIC metabolite
 Paracetamol Metabolism in Overdose

• Glutathione stores are used up by the excess

Paracetamol
• Toxic Metabolite build up
• Binds IRREVERSIBLY to Hepatic Cell
membranes
• Resulting in LIVER NECROSIS
 Conjugation
Paracetamol Glucuronidation & 85%
Sulphation

P450

•N-acetylcysteine
•Methonine

Toxic
Metabolite

Glutathione
(SH)

Non toxic
metabolites
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
Paracetamol Toxicity
90% Conjugation

P4
50

Glutathione
NAPQI
NAPQI
 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
• Liver transplant
 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 Not valid after
50 24 hours

10

mcg/ml 4 8 12 16 20 24
Hours After Acetaminophen Ingestion
• 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
 Time to N-acetylcysteine (hours) and
hepatotoxicity (%)
30

25

20

15

10

0
0 to 4 4 to 8 8 to 12 12 to 16 16 to 20 20 - 24

Smilkstein MJ et al. Efficacy of oral N-acetylcysteine in the treatment of

acetaminophen overdose: Analysis of the national multicenter study (1976 to
1985). N Engl J Med 1988; 319:1557-1562
 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 4 or more hours since overdose

Less than 2 hours More than 2 hours
since overdose since overdose

Gastric emptying Activated charcoal

Activated charcoal

Draw blood plasma 4 hours after overdose for Draw blood ASAP for plasma
plasma acetaminophen assay acetaminophen assay

Acetaminophen concentration available Acetaminophen concentration not

within 8 hours of overdose available within 8 hours of overdose

Wait for acetaminophen assay result
APAP level below risk line on nomogram
DC NAC if started
No further medical management needed
Treat other med or psychiatric problems
Start NAC pending assay result
Loading does: 140 mg/kg
APAP level on or above risk line
Treat with full course of NAC
Daily LFT’s, prothrombin times
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.