Acetaminophen

( Paracetamol ) Poisoning

By Wasim R. Issa
Internship Doctor

 1955, N-acetyle-p-aminphenol (APAP )

Potent anti-pyretic and analgesic ,
very weak anti-inflammatory action
Although its safe but
Most common cause of acute liver
failure

MO
A

Inhibition of Cyclooxygenase ( cox-2 )

CNS

PNS

dec PG E2

dec PG H2

lowers the hypothalamic setpoint to

reduce fever, and activation
of descending inhibitory
serotonergic pathways to
produce analgesia

pro-inflammatory compounds

Pharmacokinetics
Rapid and complete absorption from
GIT
Serum Peak within 0.5 1 hr
Half-life 2 4 hrs
Therapeutic serum concentrations
range from 10 to 20mcg/mL(65 to
130micromol/L).

 The therapeutic dose is

- 10 to 15mg/kg per dose in children
- 325 to 1000 mg per dose in adults,
- given every four to six hours,
- maximum recommended daily dose of
80mg/kgin children or 4 g in adults
Minimum toxic acetaminophen dosages
- Adult >> 7.5 10 g
- Children >> 150mg/kg
200mg/kg ( 1 6 yrs )

NAPQI :N-acetyl-p-benzoquinone imine

binds covalently to the cysteine groups on hepatic
,macromolecules
This process is irreversible and leads to oxidative injury and
hepatocellular centrilobular necrosis

CLINICAL FACTORS INFLUENCING

TOXICITY
Excessive intake ofacetaminophen
Excessive cytochrome P450 activity
Decreased capacity for glucuronidation or
sulfation
Depletion of glutathione stores

Risk factors to toxicity

Alcohol ingestion
Chronic liver dz
Medication
Nutrition
Genetic
Age
Tobacco

Clinical Manifestation

Lab Investigation
Acetaminophen level
LFTs
KFTs
PT, PTT, INR
ABG, Glucose

As baseline

APAP level
Obtain 4 hrs after time of ingestion
If in doubt about time >> obtain
immediately
Serum concentrations drawn before four
hours may not represent peak values .
Modified Rumack-Matthew nomogram
- Used for single acute ingestion
- Within 24 hrs of ingestion

Modified Rumack-Matthew
nomogram

Management
The management of the acetaminophenpoisoned patient may include
stabilization,
decontamination, and
administration of N-acetylcysteine, a specific
antidote.
The duration of N-acetylcysteine treatment is
determined by the type of ingestion and the
presence or absence of elevated serum alanine
aminotransferase (ALT) concentrations.

GASTROINTESTINAL
DECONTAMINATION
activated charcoal (AC),
1g/kg(maximum dose 50 g) by
mouth in all patients who present
within four hours .

Contraindication :
Unconscious
Shock
GIT bleeding , obstruction

N-ACETYLCYSTEINE
( NAC )
N-acetylcysteineprevents
acetaminophen-induced hepatic
injury by restoring hepatic
glutathione stores.

Indication of NAC therapy

1. Serum APAP >> above treatment line
2. Ingestion of greater than 150mg/kg(7.5 g
total dose regardless of weight)
3. Patient with an unknown time of ingestion and a
serum APAPconcentration
>10mcg/mL(66mol/L).
4. Patient with a history of APAP ingestion and
evidence of ANY liver injury.
5. Patients with delayed presentation (>24 hours
after ingestion) have evidence of liver injury or

20 hour IV protocol
Administer an initial loading dose of 150mg/kgIV
over 15 to 60 minutes ( in 200 cc D5W )
Next, administer a 4 hour infusion at
12.5mg/kgper hour IV (ie, total of 50mg/kgover 4
hours). >> in 500 cc D5W
Finally, administer a 16 hour infusion at
6.25mg/kgper hour IV (ie, total of 100mg/kgover
16 hours). >> in 1000 cc D5W

72 hour oral protocol

A loading dose of 140mg/kgPO,
followed by
A dose of 70mg/kgPO every four
hours for a total of 17 doses

Other protocols- 12-hour protocol

- administration of 100mg/kg of Nacetylcysteine over two hours as a
loading dose, and then administration
of 200mg/kgover 10 hours.
- Fewer side effect, the study was too
small to allow conclusions about
efficacy

IV versus oral
both routes are effective and differences are
minimal
IV administration is favored for patients with any
of the following:
- Vomiting
- Contraindications to oral administration (ie,
pancreatitis, bowel ileus or obstruction, bowel
injury)
- Hepatic failure
- Patients who refuse oral administration

Adverse reaction
Anaphylaxis or anaphylactoid reation
- 10 20 %
- Need close monitoring
- Continue effusion or not ?
If Flushing without pruritus or urticaria >> continue
effusion
If urticaria, angioedema or respiratory symptoms >>
stop >> treat anaphylaxis >> restart effusion after
resolution of symptoms
If hypotension stop >> treat anaphylaxis >> effusion
should not restarted ( alternative >>> oral )

 Vomiting
- 33 % of oral NAC
- Palatability improved by diluting it
with cola or juice .
- Persistence >> give IV NAC

Duration of treatment
three common clinical scenarios based upon the type
of ingestion and the clinical status of the patient:
1- Acute ingestion , ttt started when ALT not elevated or
within 8 hrs >>> minimum 20 hrs
Check After 18 hrs >> elevated ALT or APAP
detectable >> continue ttt
- IV 6.25 mg/kg / hr
- Oral 70 mg/kg / 4 hrs
- Measure ALT and APAP every 12 hrs
When to stop ?
- APAP undetectable
- ALT is clearly decreasing
(decrease of more than 50 percent from the peak
measurement or three consecutive decreasing values, all
below 1000 internationalunits/L )

2- repeated ingestion , ttt started when ALT not

elevated or within 8 hrs >>> minimum 12 hrs
Check After 11 hrs >> elevated ALT or APAP
detectable >> continue ttt
- IV 6.25 mg/kg / hr
- Oral 70 mg/kg / 4 hrs
- Measure ALT and APAP every 12 hrs
When to stop ?
- APAP undectable
- ALT is clearly decreasing
(decrease of more than 50 percent from the peak
measurement or three consecutive decreasing
values, all below 1000 internationalunits/L )

3- Evidence of hepatic injury following

either acute or repeated ingestion
Administer IV or oral NACuntil
- the ALT is clearly decreasing,
- the INR <2 , AND
- APAP undetectable.

Monitoring during
treatment
At end of treatment
- ALT
- APAP level
- INR
+HCO3
+Cr
Pt with ALT > 1000, INR > 1.5 ,
encephalopathy >> acute liver failure

 In case of Hepatic Failure

- IV NAC
- final infusion rate (6.25mg/kgper
hour) is continued until
Liver transplant
Encephalopathy resolves
INR < 2

Kings College Criteria

In acetaminophen induce ALF , there are two broad
criteria for referral for liver transplantation:
pH < 7.3 ( irrespective of grade of Encephalopathy
)
or
grade 3 4 encephalopathy +
PT > 100 sec +
Cr > 3.4 mg/dl

Pregnancy
APAP cross placenta >> fetal haptic
necrosis and death
The most important intervention to
prevent pregnancy loss is early
treatment with NAC
increasing time to N-acetylcysteine
administration was associated with
an increased risk of miscarriage and
fetal death

Other ttt
Cimietidin, methionine,cysteamine,
anddimercaprol : these treatments were
limited by adverse effects and play no role
in current management.
Hemodialysis :
- should never be considered an alternative to
N-acetylcysteine therapy
- Sever APAP poisoning and ARF >>
necessary

prognosis

Nearly always good

No death reported
Mortality rate < 2%
Hepatotoxicity >> fewer than 4% >>
hepatic failure