Toxicity and treatment of 0aracetamol poiaoning

1. PARACETAMOL
POISONING
DR. JOE ANN RODRIGO

2. INTRODUCTION
• Acetaminophen toxicity is the second most
common cause of liver transplantation
worldwide and the most common cause of
liver transplantation in the US.
• These slides reviews the etiology,
evaluation, and treatment of
Acetaminophen overdose and highlights
the importance of both managing and
preventing this problem.

3. INTRODUCTION
• Acetaminophen is an antipyretic analgesic
with a mechanism of action different from
NSAIDs.
• It inhibit cyclooxygenase (COX) in the brain
selectively. This results in its ability to treat
fever and pain.
• It may also inhibit prostaglandin synthesis in
the central nervous system (CNS).
Acetaminophen directly acts on the
hypothalamus producing an antipyretic effect.

4. RUMACK MATTHEW
NORMOGRAM

5. RUMACK –MATTHEW
NORMOGRAM
• Rumack-Matthew nomogram for single acute
acetaminophen ingestions.
• Semilogarithmic plot of plasma acetaminophen levels vs
time. Cautions for use of this nomogram:
• The time coordinates refer to time after ingestion.
• Serum levels drawn before 4 hours may not represent peak
levels.
• The graph should be used only in relation to a single acute
ingestion.
• The lower solid line 25% below the standard nomogram is
included to allow for possible errors in acetaminophen plasma
assays and estimated time from ingestion of an overdose.

6. DOSAGE :
• The recommended dose of Acetaminophen
for adults is 650 mg to 1000 mg every 4 to 6
hours, not to exceed 4 grams/day.
• In children, the dose is 15 mg/kg every 6
hours, up to 60 mg/kg/day.
• Toxicity develops at 7.5 g/day to 10 g/day or
140 mg/kg.
• Acetaminophen is rapidly absorbed from the
gastrointestinal (GI) tract and reaches
therapeutic levels in 30 minutes to 2 hours.

7. PATHO-PHYSIOLOGY :
• The principal toxic metabolite
of acetaminophen, N-acetyl-p-benzoquinone
imine (NAPQI), is produced by the hepatic
cytochrome P-450 enzyme system.
• Glutathione stores in the liver detoxify this
metabolite. An acute overdose depletes
glutathione stores in the liver.
• As a result, NAPQI accumulates, causing
hepatocellular necrosis and possibly damage to
other organs (eg, kidneys, pancreas).

8. HALF –LIFE :
• Acetaminophen has an elimination half-
life of 2 hours but can be as long as 17
hours in patients with hepatic
dysfunction.
• It is metabolized by the liver, where it is
conjugated to nontoxic, water-soluble
metabolites that are excreted in the
urine.

9. HISTOPATHOLOGY
• The histological features of acetaminophen
toxicity will reveal cytolysis and the presence
of centrilobular necrosis.
• The injury to the latter is chiefly due to the
elevated levels of N-acetyl-p-benzoquinone
imine (NAPQI) in this zone.

10. STAGES :
• The clinical course of acetaminophen toxicity is
divided into four stages.
• During the FIRST stage (30 min to 24 hours),
• the patient may be asymptomatic or may have emesis.
• In the SECOND stage (18 hours to 72 hours),
• There may be emesis plus right upper quadrant pain and
hypotension.
• In the THIRD stage (72 hours to 96 hours),
• Liver dysfunction is significant with renal failure, coagulopathies,
metabolic acidosis, and encephalopathy. Gastrointestinal (GI)
symptoms reappear, and death is most common at this stage.
• The FOURTH stage (4 days to 3 weeks) is marked by recovery.

11. EVALUATION
• The diagnosis of Acetaminophen toxicity is based
on serum levels of the drug, even if there are no
symptoms.
• Other laboratory studies needed include ,
• Liver function tests
- Coagulation profile (PT/INR).
If the ingestion is severe, LFTs can rise within 8 to
12 hours of ingestion.
• Normally LFTs remain elevated in the second
stage at 18 to 72 hours.

12. TREATMENT
• The treatment of acetaminophen poisoning
depends on when the drug was ingested. If
the patient presents within 1 hour of ingestion,
GI decontamination may be attempted.
• In alert patients, activated charcoal can be
used.

13. GI DECONTAMINATION
The three general methods of GI
decontamination involves
- Removing toxins from gut
- Binding toxins in the stomache
- Enhancing transit through intestines

14. ACTIVATED CHARCOAL
• Decontamination can be achieved by
Activated Charcoal.
• It works by adsorbing substances in
the gut lumen.
• Benefit of activated charcoal is
greater when administered soon after
drug ingestion.

15. DOSE OF ACTIVATED
CHARCOAL
• Activated charcoal – PEDIATRIC DOSE
1gm/kg PO
• Adult dose - 50-100 grams

16. TREATMENT :
• All patients with high levels of acetaminophen
need admission and treatment with N-acetyl-
cysteine (NAC) and activated charcoal.
• This agent is fully protective against liver
toxicity if given within 8 hours after ingestion.
• It prevents the binding of NAPQI to hepatic
macromolecules, acts as a substitute for
glutathione, is a precursor for sulfate, and
reduces NAPQI back to Acetaminophen.

17. DOSAGE OF NAC :
• 150 mg/kg in 200ml 0f 5% Dextrose over 15
mins then,
• 50 mg/kg in 500ml of 5% Dextrose over 4
hours then,
• 100mg/kg in 1 Litre Dextrose over 16 hours
• INJ.VITAMIN K – 10mg – IV stat.

18. ORAL ADMINISTRATION
• Loading dose - 140 mg/kg PO followed
by
• 70mg/kg every 4 hours for 17 total
doses
•

19. ADMINISTRATION :
• NAC can be administered both intravenously (IV) and
orally.
• The IV form has been shown to decrease the length
of the hospital stay and may be better tolerated by the
patient as the oral form has a foul rotten egg odor and
taste.
• The oral form also requires 17 doses given 4 hours
apart, with the total treatment time being 72 hours. In
comparison, the IV form requires only 20 hours of
treatment.
• The IV form also is preferred in pregnant patients
and when there is a fulminant hepatic failure.

20. CONTD……
• Patients who continue to have detoriation
such as renal failure, metabolic acidosis,
encephalopathy, and coagulopathy should
have a referral to a transplant surgeon.
• In patients who present 24 hours after the
ingestion of acetaminophen, NAC
administration should still be attempted and
may improve survival.

21. MOA :
• NAC act as an antioxidant that diminishes
Hepatic necrosis,
• Decreases neutrophil infiltration,
• Improves microcirculatory blood flow, and
increases tissue oxygen delivery.
• Hemodialysis can also be an effective
treatment, especially with concurrent renal
failure.

22. DIFFERENTIAL DIAGNOSIS
• Hepatorenal syndrome
• Viral hepatitis
• Wilson disease
• Pancreatitis
• Emergent management of pancreatitis
• Acute tubular necrosis
• Amatoxin toxicity
• Cytomegalovirus infection
• Gastroenteritis
• Peptic ulcer disease
• Viral hepatitis
• Wilson disease

23. PROGNOSIS :
• If the patient is diagnosed and treated promptly,
the mortality for acetaminophen toxicity is less
than 2%.
• However, if patients present late and have
developed severe liver failure, the mortality is
high.
• About 1% to 3% of patients with severe liver
failure need to undergo a liver transplant as a life-
saving measure.

24. KINGS COLLEGE CRITERIA
FOR LIVER
TRANSPLANTATION:
• CATEGORY 1
• PH < 7.25 for more than 24 hrs after overdose, inspite of
fluid resuscitation.
• CATEGORY 2
• PT > 100 or INR >6.5 and Serum.Creat >300 or anuria
and Grade 3-4 Encephalopathy
• CATEGORY 3
• Serum Lactate >3.5 on admission or > 3 after fluid
resusitation
• CATEGORY 4
• 2 of 3 criteria from CATEGORY 2 with clinical deterioration
{ increased ICP , inotropes requirement }

25. INDICATIONS FOR
HEMODIALYSIS
• Despite instigating N-acetylcysteine
treatment, due to evidence of
mitochondrial dysfunction together with
an exceedingly high paracetamol level.
• Fluctuating Consciousness
• Persistent Lactic Acidosis despite fluid
resuscitation

26. COMPLICATIONS :
• Acetaminophen can cause dangerous skin
reactions.
• These include Stevens-Johnson syndrome
(SJS),
• Toxic Epidermal Necrolysis (TEN),
• Acute generalized exanthematous pustulosis
(AGEP).
• These conditions are extremely painful and
can lead to blindness and death.
Acetaminophen can lead to acute liver failure,
which may only be treated with an emergency