Paracetamol poisoning

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 o f 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 1/4 th 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 3 rd 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 P aracetamol 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 H 2 Antagonists to prevent upper GI haemorrhage . Do not give sedatives, Benzodiazepines or NSAID S.

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 ,4 th 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: 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 . 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 , 15 th edition , Page No. 592- 594. Essentials of Medical Pharmacology by K.D Tripathi , 8 th edition , Page No. 223-224.

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