Acetaminophen
N-acetyl-P-aminophenol
(APAP)
Paracetamol Overdose
-Most common drug taken in overdose
-As little as 12g can be fatal (therapeutic dose = 2.6 gm/24 hour)
-It is a hepatic and renal toxin (Centrolobular necrosis)
-More toxic if liver enzymes are induced or with reduced
ability to conjugate toxin (alcoholics, phenytoin, phenobarbitone)
-The safety of acetaminophen depends on the availability
of electron donors such as reduced glutathione (GSH)
and other thiol-containing substances required to
detoxify NAPQI.
Met pathways of APAP
1-
Hepaticglucuronide
glucuronide
conjugation(40-65%)
Hepatic
conjugation(40-65%)
Hepatic sulfat conjugation(20 - 45%)
Hepatic sulfat conjugation(20 - 45%)
90% inactive metabolites excreted in the urine.
2-
Excretion of unchanged APAP in the urine (5%).
3-
Oxidation by P450 cytochromes to NAPQI (5-15%)
 GSH combines with NAPQI
 nontoxic cysteine/mercaptate conjugates
 excreted in urine.
Mechanism of Toxicity:
The ingested APAP undergo oxidative metabolism
by CYP- 450 to reactive intermediate metabolite
(N-acetyl –P-benzoquinone imine=NAPQI) which is
rapidly bounded to glutathion ,detoxified through
conjugation pathway ,and excreted. In the presence of
adequate GSH stores , there is no fear from any toxicity.
However, overdose of APAP saturate the conjugation
pathways and NAPQI overwhelms the GSH detoxification mechanism , finally leading to liver necrosis and
may be death.
Paracetamol Metabolism
What happens to APAP metabolism in an OD
situation?
1-Saturation of glucuronidation and sulfation pathways
2-Amount of APAP metabolized by p450 cytochromes to NAPQI
increases.
3-Normally NAPQI is detoxified by reduced GSH (glutathione) and
thiol containing substances.
4-In OD: rate and quantity of NAPQI formation overwhelms GSH
supply and regeneration:
 elimination of NAPQI prolonged
 free NAPQI binds critical intracellular proteins with sulfhydryl
groups
 cellular dysfunction and cell death.
Factors which adversely affect APAP
metabolism
1-Upregulation (i.e. induction) of CYP 2E1
enzyme activity:
smoking, barbituates, rifampin, carbamazepine, phenytoin,
ethanol
2-Decreased glutathione stores (malnutrition)
3-Frequent dosing interval of APAP.
4-Prolonged duration of excessive dosing.
GSH stores
Glutathione stores are
determined by:
Glutathione replacement by
sulfhydryl compounds:
-Age
-Diet
-Liver disease
-Fasting prior ingestion
-Chronic malnutrition
-Anorexia
-Gastroenteritis
-Chronic alcoholism
-HIV
-Eating
-NAC
Renal toxicity
Organ dysfunction results everywhere where
local oxidative metabolism (via p450)
creates NAPQI that cannot be detoxified 
direct toxicity:
cytochrome P-450 enzymes produce NAPQI in
the renal tubules  NAPQI binds cellular
macromolecules  acute tubular necrosis.
(25% of hepatotoxic cases)
Hepatorenal
Syndrome &Volume depletion
Other organs damaged
Heart  myocarditis
Pancreas  pancreatitis
It is controversial whether these entities
are part of multisystem organ failure
(MSOF) from fulminant hepatic failure
(FHF) or from the local accumulation of
toxic metabolites.
Clinical presentation
Phase 1 (few hrs after ingestion up to 24 hr) : Malaise , nausea , vomiting
and diaphoresis.
Phase 2 (24-72 hrs after ingestion) : Increase in liver enzymes, serum
bilirubin , prothrombin time , and pain in the right upper abdominal quadrant.
Phase 3 (72-96 hrs after ingestion) : Peak in the liver function,
altered
consciousness, hypoglycemia, jaundice , and coagulation abnormalities.
Hepatic failure can develops in 4th or in the 5th day if hepatic damage is sever.
Myocardial necrosis, pancreatitis , heamolytic anemia and skin rashes may
develop but are rare.
Phase 4 (7-10 days after ingestion) : Liver enzymes abnormalities reaching
resolution. If hepatic damage is massively sever sepsis and death may
occure at 7-10 days
Laboratory analysis
1-Determination of plasma APAP level.
2-Monitoring liver profile including serum ALT, AST ,
bilirubin , glucose , prothrombin time, platelet count…etc
3- Determination of kideny functions by measuring plasma
creatinine and BUN.
4-ECG for assessment of myocardial injury.
5- Urine analysis.
Management Steps:
General measures
(if the patient is presented to ER within 4 hrs of ingestion
-Gastric lavage
-Activated charcoal ,cathartics (saline sulfate are prefered to enhance
sulfate metabolic pathway).
glucose, bicarbonate, Vit K for elevated prothrombin time
<8 hours
-Take level of APAP after four hours (Peak concentration at 4 hrs then
hepatic metabolism)
-Start N-aceylcysteine (antidote) if APAP concentration is high
=APAP is on or above nomogram tx line.
-Patients should be advised to return to hospital if vomiting or abdominal
pain develop or reoccur.
Nomogram
Management 2
>8 hours
Urgent action required because the efficacy of
NAC declines progressively from 8 hours after
the overdose
Therefore, if > 150mg/kg or > 12g (whichever is
the smaller) has been ingested, start NAC
immediately, without waiting for the result of
the plasma paracetamol concentration
>24 hours
Still benefit from starting NAC
N-acetylcysteine (Antidote)
Supplies glutathione precursor (cysteine)
Dosage for NAC infusion
(1) 150mg/kg IV infusion in 200ml 5% dextrose over 15
minutes, then
(2) 50mg/kg IV infusion in 500ml 5% dextrose over 4
hours, then
(3) 100mg/kg IV infusion in 1000ml 5% dextrose over 16
hours
Side-effects
Flushing, hypotension, wheezing, anaphylactoid
reaction
-Alternative is methionine PO , it increase GSH synthesis.
-Hemodialysis and hemoperfusion can be considered in
extremly elevated APAP level.