ACETAMINOPHEN

POISONING
ACETAMINOPHEN
Is a nonsteroidal anti-inflammatory drug with
potent antipyretic and analgesic actions but with
very weak anti-inflammatory activity

 Analgesia at serum APAP concentration of 10mcg/mL

 Central inhibition of COX-2 and prostaglandin
synthase
 Antipyresis at 4-18mcg/mL
 CNS inhibition of PGE2
ACETAMINOPHEN

can be:
- Unintentionally ingested by young children
- Taken in an intentional overdose by
adolescents and adults
- Inappropriately dosed in all ages
ACETAMINOPHEN
METABOLISM

42% - 67%

26% - 36% 5% - 8%
NAPQI
In therapeutic use:
Only a small percentage of a dose (approximately
5%) is metabolized by the hepatic cytochrome P450
enzyme CYP2E1 to NAPQI, which is then
immediately conjugated with glutathione to form a
nontoxic mercapturic acid conjugate.
DOSING
Therapeutic:

Pediatric: 15 mg/kg every 4 hours; no more than 5 doses/day

Adult: 1 gram every 4 hours, not to exceed 4 grams/day

Toxic:
Acute: >150mg/kg (pediatric) or >7.5g

Chronic: less clear

>150mg/kg/day or 7.5g/day
Febrile children: >75mg/kg/day
ACETAMINOPHEN
TOXICITY

Results from the formation of a highly

reactive intermediate metabolite, N-acetyl-
p-benzoquinone imine (NAPQI)
NAPQI

In overdose:
Glutathione stores are overwhelmed, and
NAPQI is free to combine with
able
macromolecule hepatic to produce
hepatocellular
s damage
 Normal conjugation metabolism routes are saturated
 More NAPQI is produced
 Glutathione reserves fall below 30%
 Unable to detoxify all NAPQI formed
 Cellular injury results
 ACETAMINOPHEN OVERDOSE
O
Acetaminophen O
ll O ll
HN-C-CH3 ll HN-C-CH3
HN-C-CH3

Glucuronidation Sulfation

Glucuronide Sulfate
OH

P450

NAPQI

Glutathione
Oxidant tissue Oxidant tissue
damage damage
Non-toxic
metabolites
HEPATIC PATHOLOGY

Centrolobular necrosis
STAGES OF ACETAMINOPHEN
TOXICITY:
4 STAGES
Stage 1
• Within first 0.5 -24 hr
• Clinically:
Anorexia ,Nausea ,Vomiting ,Malaise,
Pallor ,Diaphoresis
• Lab findings :
Normal except acetaminophen level
STAGES OF ACETAMINOPHEN
TOXICITY (CONT.)
Stage 2
• Within 24-48 hr
• Clinically:
-Resolution of earlier symptoms
-Right upper quadrant abdominal pain
and tenderness
• Lab findings :
-↑Bilirubin , Prothrombin time ,Hepatic
enzymes
- Oliguria
STAGES OF ACETAMINOPHEN
TOXICITY (CONT.)
Stage 3
• Within 72-96 hr
• Clinically& Lab findings:
- Peak liver function
abnormalities
- Fulminant hepatic failure
- Multisystem organ failure
- Potential death
STAGES OF ACETAMINOPHEN
TOXICITY (CONT.)
Stage 4

• Within 4 days – 2 weeks

• Clinically& Lab findings:
- Resolution of liver abnormalities
- Clinical recovery precedes histologic
recovery
OTHER OVERDOSE SEQUELAE

 Renal toxicity
 Occasionally renal failure can occur from massive overdoses
 Possibly 2° to P450 activity in the kidney
 Pancreatitis
 Pneumonitis
LABORATORY
INVESTIGATIONS

If a toxic ingestion is suspected, a serum

acetaminophen level should be measured 4 hr
after the reported time of ingestion.
For patients who present to medical care
>4 hr after ingestion, a stat acetaminophen
level should be obtained.
LABORATORY
INVESTIGATIONS (CONT.)
Acetaminophen levels obtained <4 hr after
ingestion are difficult to interpret and cannot be
used to estimate the potential for toxicity.

Other important baseline labs

include :
- Hepatic transaminases
- Renal function tests
- Coagulation parameters
Rumack-Matthew
Normogram for
Acute
Acetaminophen
Toxicity
The Normogram
 Is a guideline for determining who should
be treated for a single acute ingestion
 Is not a representation of the elimination
kinetics
 Serial levels not useful

 In US, line positioned 25% lower

 ↑ sensitivity – no missed cases
 ↓ specificity

 Important to use a 4-hour level whenever

possible
RUMACK-MATTHEW NOMOGRAM
FOR ACETAMINOPHEN POISONING

This nomogram is only

intended for use in
patients who
within 24 present
hr of a single
acute acetaminophen
ingestion with a known
time of ingestion
 Treatment indicated if:

INGESTION OF SINGLE DOSE

 Level above 150mg/dL at 4 hours

 Ingestion of 150 mg/kg in children

 Ingestion of 7.5 g in adults

 Patient is unreliable or unconscious

RUMACK-MATTHEW NOMOGRAM FOR
ACETAMINOPHEN POISONING(CONT.)

Any patient with a

serum acetaminophen
level in the possible or
probable hepatotoxicity
range per the Rumack-
Matthew nomogram
should be treated with
N-acetylcysteine (NAC)
RUMACK-MATTHEW NOMOGRAM FOR
ACETAMINOPHEN POISONING(CONT.)

Patients who have an

initially nontoxic level and
have ingested
combination products or
co-ingestants that can
slow GI diphenhydramine,
(e.g., motility
opioids) should have a
second acetaminophen
level drawn 6-8 hr
after ingestion
UNKNOWN TIME OF INGESTION OR A HISTORY
OF CHRONIC SUPRATHERAPEUTIC INGESTION?

For assessment of such patient,

check :
- Acetaminophen level
- Hepatic transaminases
- Coagulation parameters.
If the acetaminophen level is
>10 μg /mL, even with normal
liver function tests, this patient
is a candidate to be treated
with NAC
 WHY
?

To catch patients in the

asymptomatic phase of
toxicity,before hepatotoxicity
develops, because a level of
10 g/ mL is potentially toxic
at 20 hr after ingestion
REMEMB
ER
Patients who have any signs of hepatotoxicity (elevated transaminases
and international normalized ratio [INR]), even with a low or
nondetectable acetaminophen level, are also candidates for antidotal
therapy

Patients who have Acetaminphen level <10microgm/ml and

normal transaminases are unlikely to develop significant toxicity
TREATM
ENT
Initial treatment : •

• Basic life support (ABCs)

• Decontamination with
charcoal
activated (within 1-2 hr of
ingestion)
• The antidote for acetaminophen
poisoning is N- acetylcysteine
(NAC) ( which works primarily
via hepatic
glutathione
replenishingstores )
N-
ACETYLCYSTEINE
(NAC)
• Most effective when initiated
within 8 hr of ingestion
• There is no demonstrated benefit
to giving NAC before the 4 hr
post-ingestion mark.
• Both oral and I.V rotes available
 ACETAMINOPHEN OVERDOSE:
NAC ROLE
O
Acetaminophen O
ll O ll
HN-C-CH3 ll HN-C-CH3
HN-C-CH3

Glucuronidation Sulfation

Glucuronide Sulfate
OH

P450

NAPQI NAC

Glutathione
Oxidant tissue Oxidant tissue
damage damage
Non-toxic
metabolites
MECHANISM OF
N-ACETYLCYSTEINE
 Restores glutathione:
 Allows NAPQI detoxification
 Augments sulfation reaction
 Direct anti-oxidant:
 Directly detoxifies NAPQI
 Improves organ function and limits hepatocyte injury
N- ACETYLCYSTEINE (NAC)
DOSING ORAL

N- Acetylcysteine (Mucomyst)
Dosage: 150 mg /kg loading ,followed by 70 mg / Kg
every 4 hrs. for 17 doses
Route of administration : Oral
Side effects: Nausea ,vomiting
N.B. Most effective if given within 8 hr of ingestion
N- ACETYLCYSTEINE
(NAC) I.V DOSING

N- Acetylcysteine (Acetadote)
Dosage: 150 mg /kg over 1 hr ,followed by 50 mg /
Kg over 4 hrs. followed by 100 mg /Kg over 16
hrs.
Route of administration : IV
Side effects: Anaphylactoid reactions
(most commonly with loading dose)
WHAT IS NEXT
A patient who is being on NAC ,the
following lab tests :
Measure ALT and INR every 12hours
IfALT>1000;alsomeasure
bicarbonate,glucose,creatinine every 12 hours

Patients who develop hepatic failure in spite of

NAC therapy may be candidates for liver
transplantation
KING’S COLLEGE
CRITERIA
• Are used to determine which patients should be
referred for consideration of liver transplant.
• These criteria include :
1. Acidosis (pH 7.3) after adequate fluid
resuscitation,
2. Coagulopathy (prothrombin time [PT] 100
sec),
3. Renal dysfunction (creatinine 3.4 mg/dL),
4. Hepatic encephalopathy grade III or IV
OTHER TREATMENTS

CIMETIDINE inhibitor of acetaminophen

metabolism

FOMEPIZOLE

EXTRACORPOREAL REMOVAL