Paracetamol, also known as acetaminophen, is a widely used over-the-counter analgesic and antipyretic drug. While generally safe in therapeutic doses, paracetamol overdose can cause acute liver failure. Paracetamol is metabolized in the liver, but a small percentage is converted to a toxic metabolite that depletes glutathione stores and causes liver damage. N-acetylcysteine is the antidote of choice and works by replenishing glutathione levels; it is most effective if given within 10 hours of ingestion. Without treatment, paracetamol overdose can progress to liver failure and death.

1. PARACETAMOL POISONING
BY
KEERTHI ATHOTA

2. SYNONYMS:
 Acetaminophen
 N-acetyl-p-aminophenol
 4-hydroxyacetanilide
PHYSICALAPPEARANCE:
 White odourless
 Bitter tasting crystals or crystalline
powder

3. MARKETED FORMULATIONS:

4. HISTORY:
 Cahn and Hepp accidentally discovered the fever-
reducing property of Acetanilide and introduced
it into pharmacotherapeutics as “Anti-febrin” in
1886.
 Due to its unacceptable toxicity led to a search
for less toxic compounds, and a related
compound namey, Phenacetin was synthesized
and introduced in 1887.
 It was used extensively till recently when its role
in analgesic nephropathy was clear and led to
withdrawl.
 In 1893, Von Mering introduced which was stiil
in use.

5. USES OF PARACETAMOL:

7. Toxicokinetics and Mode of Action:
 Abosrption- Rapidly and completely absorbed from the GI tract.
 Absorption may be delayed by other drugs and high carbonate foods
which delay gastric emptying time.
 Peak plasma levels are reached in ½ to 1 hour.
 Plasma half-life is about 2 hours.
 Protein binding- 5 to 20%
 Volume of distribution- 0.8 to 1L(Adult)
 Metabolism- 90% of drug undergoes hepatic congugation with
glucuronide and sulfuric acid to form inactive and harmless metabolites
10% is oxidised (through P450 mediation) to
N-acetyl-p-benzoquinoneimine(NAPQI) which is a highly reactive
intermediate.

8.  NAPQI is capable of covalent binding and arylating critical cell
proteins inducing a series of events that result in cell death.
 In normal course, glutathione rapidly detoxifies this intermediate to
cysteine and mercapturate conjugates.
 In the overdose situation, glutathione stores become depleted and
the toxic NAPQI binds covalently with hepatocytes of the liver
causing centrilobular hepatic necrosis.
 Concomitant intake of drugs which induce P450 enzyme
(eg:phenobarbitone) can enhance the chances of hepatotoxicity.
 Alcoholism and chronic therapy with drugs such as Isoniazide and
anticonvulsants also predispose to hepatic failure.

9. Toxic Doses of Paracetamol:
 Single ingestion > 7 to 10 g (150 mg/kg body weight in children)
 Fatal cases usually involve doses of atleast 15 to 25 g
 In heavy drinkers, daily doses of 2 to 6 g have been associated
with fatal hepatotoxicity.

10. TOXIC FEATURES

11. 1. Acute poisoning:
a. stage-I(1/2 to 24 hrs):
 Patients may be asymptomatic or report
anorexia, nausea or vomiting and
malaise.
 Physical examination may reveal
pallor, diaphoresis, malaise and fatigue.

12. b. Stage-II:
 24 to 72 hrs after ingestion.
 Relatively symptom free.
 Patients generally develop right upper
quadrant abdominal pain, anorexia,
nausea.
 Right upper quadrant tenderness may be
present.
 Liver function tests may be abnormal.
 Some patients report decreased urine output.

13. c. Stage-III: Hepatic phase
 72 to 96 hrs after ingestion.
 Patients may have continued nausea and vomiting, abdominal pain, and a
tender hepatic edge.
 Hepatic necrosis and dysfunction are associated with jaundice,
coagulopathy, hypoglycemia, and hepatic encephalopathy.
 ALT - often between 2000 and 10,000 U/L
 Acute renal failure develops in some critically ill patients.
 Death from multiorgan failure may occur.

14. d. Stage-IV: Recovery phase
 4 days to 2 wks after ingestion.
 Patients who survive critical illness in stage 3 have complete
resolution of symptoms and complete resolution of organ failure.
Chronic poisoning:
 This is uncommon, but cases have been reported where in an individual
has consumed large doses of paracetamol over a period of time for relief of
chronic pain which results in toxic hepatitis.
 This is more common in alcoholics, AIDS patients( in whom there is
depletion of glutathione), and patients receiving other medications which
are cytochrome P450 inducers, eg: Isoniazide, Rifampicin, Phenytoin,
Carbamazepine, and Barbiturates.
 Chronic overdose is more common among children than in adults because
of dose miscalculation by parents.

15. Daignosis:
Blood investigations:
1. Blood glucose
2. Blood & Urine toxicology screening
3. Serum PCM level
4. ALT and AST levels.

16. Treatment:

17. Treatment:
Childrren who have an unobtainable history or in whom a layer amount of
paracetamol is suspected to have been ingested (>200mg/kg) should be referred
to a health care facility for a 4 hour paracetamol serum level determination, and
consideration for administration of activated charcoal.
1. Stomach wash: useful only in cases of very early presentation (<1 hour), or
in concomitant ingestion of other drugs which delay GI absorption.
2. Actiavted charcoal: can absorb paracetamol, but it can also absorb the
antidote (N-acetylcysteine) and hence must be administered earlier to post
ingestion of a liquid formulation or a tablet formulation.
3. Anti-emetic, if the patient is vomiting repeatedly.

18. 4. Supportive therapy:
a. 10 to 20% dextrose for hypoglycemia.
b. Vitamin K1, if PT is elevated.
c. Fresh-frozen plasma if there is over bleeding.
d. Mannitol (0.5 gm/kg given over 10 minutes) for central oedema.
e. Broad spectrum antibiotics IV (Ceftazidime or Fluoxacillin) if necessary.
f. H2 antagonists to prevent upper GI haemorrhage.
g. Do not give sedatives, benzodiazepines or NSAIDs.

19. Two treatment methods:
Activated Charcoal
 Works by absorbing unabsorbed drug in the stomach
N-acetylcysteine (NAC)
 Works by increasing hepatic glutathione stores.

20. N-acetylcysteine: Antidote of choice
Oral
 Loading dose 140 mg/kg
 Maintenance dose 70 mg/kg every 4 hours for 17 doses
By IV:
Loading dose : 150mg/kg in 5% Dextrose over 15 mins
Followed by : 50mg/kg in 500 ml of D5 over 4 H then 100mg/kg/16H in 1L of
D5
Adverse effects:
1. The main problem with oral NAC is induction of vomiting.
Metaclopramide or Ondansetron may have to be administered.
2. Intravenous- anaphylactoid reaction. If it occurs, it should be managed in
the usual way with antihihstamines, epinephrine etc.,.
3. Isolated effects include pruritis, angioedema, nausea, bronchospasm,
tachycardia.
4. Facial and chest flushing is common, beginning 15 to 75 minutes after
initiation of infusion.

21. Methionine:
 This is a oral antidote that is popuklar in UK and some other countries, but
mot available in India.
 In patients known to be sensitized to NAC.
 Should be administered within 8 to 10 hours of ingestion.
 Dose: 2.5 grams, 4 doses at 4 hour interval.
Liver transplantation:
When fulminant liver failure develops after a massive paracetamol overdose,
virtually the only treatment modality available is liver transplantation.