a detailed presentation on paracetamol toxicity

1. Presentation on Paracetamol toxicity
-Balaji M N
Pharm-D
Sarada vilas college of pharmacy, Mysuru

2. Paracetamol:
Definition:
its is a nonsteroidal anti-inflammatory drug with
potent antipyretic and analgesic action but with
weak anti-inflammatory action.
Synonyms:
Acetaminophen; N-acetyl-p-aminophenol; 4-
hydroxyacetanilide.
Physical Appearance:
Paracetamol exists as white, odourless, bitter tasting
crystals.

3. History:
 It was first synthesized in 1877 in US.
 It was more used during 1947.
 It got included in OTC drugs in 1960.
 It is a metabolite of phenacetin, and was widely
accepted in 1970.
 Its first toxic effects were noted in 1971.

4. Brand names:
It is available in lot many names-
Crocin
 Dolo
 calpol
Tylenol
 Acetox
 Aeknil
Alcocin
 Amidol
 Apyric, Etc.

5. Therapeutic uses with action:
Analgesia-
 Relieves mild-moderate pain.
 Efficacy is equal to salicylates.
 Inhibits brain PGs synthetase.
 Blocks pain impulse peripherally.
Antipyretic-
 Reduces body temperature by inhibiting PGs synthetase
in hypothalamus.

6. Toxicokinetics:
Paracetamol gets rapidly absorbed in GIT completely.
Plasma half-life is about 2hrs,where the peak plasma
level is between ½-1hrs
Overdose-peak plasma aren't achieve in 4hrs,and
absorption may delay due to other drugs and high
carbohydrate food.
Protein binding for paracetamol is 5 to 20%.
Volume of distribution is 0.8 to 1 L/kg (adult).
The half-life of paracetamol may exceed 12 hours in
acute overdose.

7. Mechanism:
90% of paracetamol gets hepatic conjugation with
glucuronide and sulfuric acid to form inactive
metabolites.
10% of the drug is oxidized to N-acetyl-p-
benzoquinoneimine (NAPQI), which is a highly
reactive intermediate. Normaly glutathione rapidly
detoxifies this intermediate to cysteine and
mercapturate conjugates.
In overdose condition- glutathione become depleted
and the toxic NAPQI binds covalently with
hepatocytes of the liver causing centrilobular hepatic
necrosis. Which finally leads to hepatotoxicity.

8. Clinical features:
Acute poisoning-
 Phase 1 – 0-24 hours
 Nausea, vomiting.
 Phase 2 – 24-72 hours
 RUQ( Right Upper Quadrant) pain, elevated liver enzymes,
prolonged PT
 Phase 3 – 72-96 hours
 Hepatic necrosis, encephalopathy, coagulopathy(bleeding
disorder), ATN(acute tubular necrosis)
 Phase 4 – 4 days- 2 weeks
 If damage is not irreversible, complete resolution of hepatic
dysfunction will occur

9. Chronic poisoning:
 it occurs in rare cases where the patient has taken
large doses of paracetamol for certain duration to get
rid off chronic pain due to toxic hepatitis.
 It is majorly seen in children rather than adults,
because of dose miscalculation.
 There is no specific reason that neither paracetamol
nor N-acetylcysterine is teratogenic. Severe maternal
toxicity might be one of the reason.

10. Toxic dose:
Acute overdose is usually considered to be a single
ingestion
Generally, 7.5 gm in an adult or 150 mg/kg in a child
are the lowest threshold capable of toxicity

11. Diagnosis:
 Based on hypoglycemia, metabolic acidosis.
 Based on hepatocellular injury.
a. Elevated aspartate aminotransferase (AST), alanine
aminotransferase (ALT) , blirubin and prothrombin
time. AST and ALT rise with in 24hrs after ingestion,
peak-48-72hrs.
b. Hypophosphatemia.
c. Decreased serum interlukin-6 or C-reactive protein
d. Bilirubin level greater than 4mg/100ml.
 Based on renal damage.
 Based on myocardial damage.
 Based on serum paaracetamol level.

13. Treatment:
1. stomach wash- given during early presentation of
overdose which is <1 hr.
2. Activated charcoal- absorbs drug(paracetamol)
should be given within 4hrs of ingestion, because it
absorbs antidote.
3. Anti-emetic- in case of vomiting.
4. Supportive measures:
i. 10-20% dextrose - hypoglycemia.
ii. Vit-k1 – prothrombin time is elevated.
iii. Fresh frozen plasma in case of excess bleeding.
iv. Mannitol 0.5gm/kg over 10 mins to treat cerebral oedema.
v. H2 antagonists to prevent upper GI haemorrhage.
vi. Sedatives, benzodiazepines, or NSAIDs should not be
given.

14. 5. Antidotal therapy:
a. methionine- oral antidote.
glutathione precursor.
protects against paracetamol-induced hepatic and renal
damage should be given within 8-10hrs of ingestion.
dose-2.5gms 4times Q4H.
(not available in India)
b. N-acetylcysteine(NAC)- L-cysteine derivative.
It is widely used as the antidote for paracetamol poisoning.
protects against hepatotoxicity should be given within
10hrs of ingestion.

15. Dose-
Oral: within 10hrs.
Adults- 140mg/kg followed by 17 more doses at 70mg/kg
Q4H finally make upto 1330mg/kg over 72hrs.
Children- 140mg/kg single dose, followed by 70mg/kg Q4H
for 68hrs.
within 24hrs.
140mg/kg, followed by 70mg/kg, Q4H until serum
paracetamol level is completely reduced.

16. Intravenous:
Prescott protocol (20hour regimen)
150mg/kg +200ml of 5% dextrose , IV over 15mins. Followed
by 50mg/kg in 500ml of 5% dextrose over 4hrs and
100mg/kg in 1ltr of 5% dextrose over 16hrs
Total 300mg/kg given over 20hrs.
Children- 150mg/kg infused over 15mins (infuse 3.75ml/kg
over 15mins ) followed by 50mg/kg infused over 4hrs
(infuse 0.31 ml/kg/hr) and 100mg/kg over 16hrs (infuse
0.16 ml/kg/hr).

17. 48 hour regimen-
140mg IV over 1hr, followed by 4hrs later by 12 maintenance
doses of 70mg/kg, each adminstered over 1hr
Total dose should be 980mg/kg over 48hrs.

18. Liver transplantation:
it’s the only treatment left after massive
paracetamol overdose, for liver failure.
There are few indications for transplantation like PH should
be <7.3, and prothrombin time should be >100secs, serum
creatinine >3.4mg/100ml.
Schiodt et al (1999) developed a model, to predect hepatic
encephalopathy (HE) in paracetamol overdose.
O’grady criteria- it’s a multivariate prognostic scoring
system for predicting the need liver transplantation .
Bernal et al have proposed the criteria for liver
transplantation in paracetamol-induced acute liver
failure.

19. 7. Forced diuresis, hemodialysis, and charcoal
haemoperfusion used in preventing paracetamol induced
hepatotoxicity.
8. Albumin dialysis- a molecular adsorbent recirculating
system(MARS) a modified dialysis method used in
massive paracetamol overdose with hepatic
encephalopathy, severe acidosis.
9. Continuous hemofiltration: preferable to intermittent
hemodialysis in patient with paracetamol-induced and
renal failure.

20. Autopsy features:
 Enlargement and yellowish color of liver.
 Microscopy reveals centrilobular necrosis.
 Histological evidence of renal damage.
 Cerebral oedema.
Forensic issues:
There are alarming indications of rising incidence of
attempted suicide with paracetamol in India.
Accidental poisoning results from therapeutic overdose
either as acute or chronic. It might case hypersensitivity
reactions and may even cause serious manifestations from
dermal to respiratory reactions
On November 1997, FDA approves the alcohol warning on
all OTC pain relievers.

21. Thank you…