Clinical symptoms and management of Paracetamol poisoning.

1. PARACETAMOL
POISONING
Ameena Kadar K.A
B Pharm
Grace College Of Pharmacy, Palakkad, Kerala.

2. PARACETAMOL
 Paracetamol is one of the important & most commonly used
Antipyretic, Analgesic and NSAID.
 It is one of the para amino phenol derivative; Phenacetin also
belong to this group.
 Removal ethyl from phenacetin forms Paracetamol.
 It is also known as Acetaminophen.

3. Paracetamol
PHARMACOKINETICS
• It can be taken by Orally and rectally, Well absorbed orally.
• About 1/4th of the drug bind with plasma protein and uniformly
distributed through out the body.
• Metabolism occurs via Sulphate and Glucoronic acid conjugation. Conjugates
are rapidly excreted through Urine.
• Plasma t1/2 is 2-3 hrs.
• Effect after an oral dose last for 3-5 hours.
Oral Bioavailability : 70-90%

4. Rectal Bioavailability : 30-70%
METABOLISM

5. Mechanism of Toxicity
When the dose of Paracetamol is high.
The Glucoronide $ Sulfate conjugation pathways become saturated and
increasing amounts undergo CYP-mediated N-hydroxylation to form
N-Acetyl –Para- Benzo Quinone Imine (NAPQI).
Eliminated rapidly by conjugation with Glutathione(GSH) and
then further metabolized to a mercapturic acid and excreted into
the urine.
In overdose, Hepatocellular levels of GSH become depleted.

6. The highly reactive NAPQI metabolite binds covalently to cell
macromolecules, leading to dysfunction of enzymatic systems &
structural and metabolic disarray.
Depletion of intracellular GSH renders the hepatocytes highly
susceptible to oxidative stress & apoptosis.
Binding covalently to cellular proteins, causes cell death.

7. Usual Fatal Dose
 20-25g
 However doses as low as 10g can cause serious Hepatotoxicity. Children
under the age of 10yrs appear to be more resistant to the toxic effects of
paracetamol.
Clinical Features
 Acute Poisoning:
 It occurs especially in small children who have low hepatic glucoronide
conjugating ability.
 If a large dose (>150 mg/kg or >10g in an adult) is taken, serious toxicity
can occur.
 Fatality is common with >250 mg/kg.
 Stage 1 (1/2 hr to 24 hr) : Anorexia, vomitting, sweating, malaise.
 Stage 2 (24 hr to 72 hr) : Relatively symptom free. There may be right
upper quadrant pain. Liver function tests may be abnormal.

8.  Stage 3 (72 hr to 96 hr): Hepatic necrosis sets in with coagulation
defects, jaundice and encephalopathy. Nausea & Vomiting reappear.
Renal failure and myocardial damage are frequently present. Death is
usually due to hepatic failure is preceded by coma.
 Stage 4 (4 days to 2 weeks): If the patient survives the 3rd stage,
complete resolution of hepatic damage is the rule rather than the
exception. There are no reported cases of chronic hepatic dysfunction
from paracetamol.
 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 resulted in toxic hepatitis.
• It is more common among children than adults mainly because of dose
miscalculation by Parents. Features include anorexia, vomiting, lethargy,
low body temperature, hepatomegaly and oliguria.

9. Diagnosis
 Evidence of Hypoglyceamia, metabolic acidosis.
 Hepatocellular injury: Elevated Aspartate aminotransferase(AST),
Alanine aminotransferase(ALT), bilirubin and prothrombin time.
 Renal damage: Proteinuria, phosphaturia.
 Myocardial damage: ECG changes indicative & arrhythmias.
 Serum Paracetamol level (PL)
Interpretation of serum paracetamol level is usually done on the
basis of the Rumack Mathew Nomogram. The purpose of the
nomogram is to predict the risk of hepatic injury at the outset &
begin antidotal therapy well in time.

10. Treatment
 Stomach wash useful only in cases of very early presentation
(<1 hr), or in concomitant ingestion of other drugs which delay GI
absorption.
 Activated charcoal can absorb paracetamol , but it can also
absorb the Antidote (N- Acetyl Cysteine) & hence must be adminitrated
earlier to 4hrs post-ingestion,
 Anti emetic, if the patient is vomiting repeatedly.
 Supportive Measures:
• 10 to 20% Dextrose for hypoglyceamia.
• Vit K, if PT is elevated.
• Fresh frozen plasma if there is over bleeding
• Mannitol for cerebral oedema
• Broad spectrum antibodies IV if necessary
• H2 Antagonists to prevent upper GI haemorrhage.
• Do not give sedatives, Benzodiazepines or NSAIDS.

11. Antidotal Therapy:
 Methionine : This is an oral antidote that is popular in the UK and
some other countries, but is presently not available in India.
 N-Acetyl Cysteine (NAC):
 It is a derivative of L-Cysteine, a naturally occuring aminoacid.
 It gives maximum protection against hepatotoxicity when administered
within 10hrs of paracetamol overdose, but can be given with (lesser)
benefit up to 36 hrs.
 Oral -5% solution given as loading dose of 140mg/kg. This is followed by
17 more doses at 70mg/kg ,4th hourly, total making up to1330mg/kg over
72 hrs.
 The calculated dose can be administrated mixed with Water or flavoured
or carbonated drink.
 Intravenous - 150 mg/kg made up in 200ml of 55 Dextrose is given IV
over 15mins, followed by 50mg/kg in 500ml of 5% Dextrose over 4hrs,
and 100mg/kg in 1 Litre of 5% dextrose over 16 hrs.

12. The total dose works out to 300mg/kg given over 20 hrs.
 ADR:
o Oral- Drinking NAC through a straw minimises its unpleasant odour.
The main problem with oral NAC is induction of vomiting,
Metoclopramide or Ondansetron may have to be administrated.
o Intravenous – Anaphylactoid reaction. If it occurs, it should be
managed, in the usual way with Antihistamines, Epinephrine etc.
 Liver Transplantation
When fulminent liver failure develops after a massive paracetamol
overdose , virtually the only treatment mode available is Liver
transplantation.

13. References:
 Textbook of Forensic medicine & toxicology by V.V Pillay,
15th edition , Page No. 592- 594.
 Essentials of Medical Pharmacology by K.D Tripathi,
8th edition , Page No. 223-224.

14. THANK YOU.