Paracetamol poisoning by Dr. Aryan

PCM poisoning: doses, clinical features, investigations and management

1. Paracetamol poisoning Prepared by:Anish Dhakal Medical Student a [email protected]

2. Paracetamol (acetaminophen) Non-steroidal anti-inflammatory drug(NSAID) Has analgesic and antipyretic effects but weak anti-inflammatory properties Exerts its effects through the inhibition of cyclo-oxygenase (COX) COX catalyses the formation of prostaglandins (PGs) and other mediators that are important in the processing and signaling of pain and control of the thermoregulatory center of the brain.

3. Pharmacokinetics Oral acetaminophen has excellent bioavailability Peak plasma concentration occur within 30 to 60 minutes The half-life in plasma is about 2 hours after therapeutic doses

4. Metabolism Metabolized in the liver by conjugation with sulfate or glucuronate (90%), and by CYP2E1 enzymes(5%), and the remainder is secreted unchanged in the urine(5%) The CYP2E1 enzyme pathway is the basis for acetaminophen toxicity

5. Dose of paracetamol Therapeutic dose is 10-15 mg/kg Toxic dose: More than 7.5 gm (around 15 tablets) – minimal toxicity, severe liver toxicity if > 15gms (30 tablets) In adults toxic dose is 150mg/kg In children under 12 years toxic dose is 200mg/kg In the presence of chronic liver disease or malnutrition, even 2g of PCM can be a toxic dose

6. Mechanism of toxicity When the dose of paracetamol is high The glucuronide and sulfate conjugation pathways become saturated, and increasing amounts undergo CYP-mediated N -hydroxylation to form N-acetyl- para - benzoquinoneminine (NAPQI) Eliminated rapidly by conjugation with glutathione (GSH) and then further metabolized to a mercapturic acid and excreted into the urine In acetaminophen overdose, hepatocellular levels of GSH become depleted.

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

8. Hepatotoxicity : In adults, hepatotoxicity may occur after ingestion of a single dose of 10 to 15 g (150 to 250 mg/kg) of acetaminophen Doses of 20 to 25 g or more are potentially fatal High risk people: Conditions of CYP induction ( e.g. heavy alcohol consumption, those on anticonvulsant drugs) Condition of GSH depletion ( e.g. fasting or malnutrition) With pre-existing liver disease Those suffering from anorexia nervosa and other eating disorders & HIV infection

9. Phases of intoxication 1) Stage 1 (time of ingestion to 24 hours) : Patient typically has anorexia, nausea, vomiting, and diaphoresis Results of laboratory tests are usually normal 2) Stage 2 (24-72 hours): Results of laboratory tests begin to be abnormal Abnormalities include increases in serum transaminases , bilirubin and PT Nephrotoxicity may be evident

10. Contd … 3) Stage 3 (72 to 96 hours): Also known as hepatic stage Severe signs of hepatotoxicity appear This includes: Plasma ALT and AST levels often >10,000 IU/L, increased in PT or INR Hypoglycemia Lactic acidosis and A total bilirubin concentration above 70umole/l (primarily indirect) Death most commonly occurs in this stage, usually from multiorgan system failure.

11. Contd … 4) Stage 4 (4 days-2 weeks) : Is the recovery stage Patients who survive stage III enter a recovery phase that usually begins by day 4 and is complete by 7 days after overdose However, transient renal failure may develop 5-7 days after ingestion (Back pain, proteinuria , hematuria ) Complete hepatic recovery may take 3-6 months.

12. Approach to the patient ABCDE History Examination Investigations Initial baseline investigations LFT, PT/INR, blood glucose, platelet count, electrolyte, urine routine Plasma paracetamol level Determined after 4 hours of ingestion

13. Management 1) Activated charcoal may be used in patients presenting within 1 hour. 2) Antidotes for paracetamol poisoning N- acetylcysteine (NAC) Methioinine Act by replenishing hepatic glutathione N-acetyl cysteine may also repair oxidation damage caused by NAPQI

14. Nomogram for paracetamol

15. N- Acetylcysteine (NAC) IV is highly efficacious if administered within 8 hours of the overdose Should not be delayed in patients presenting after 8 hours to await a paracetamol blood concentration result. Dose: 150mg/kg in 200 ml 5% dextrose over 15 minutes Followed by 50mg/kg in 500 ml 5% dextrose over 4 hours Followed by 100mg/kg in 1000 ml 5% dextrose over 16 hours

16. Contd … Can be stopped if the paracetamol concentration comes below the appropriate treatment line. Important adverse effect is related to dose-related histamine release The ‘ anaphylactoid ’ reaction - itching and urticaria , and in severe cases, bronchospasm and hypotension, angio -edema Managed by temporary discontinuation of acetylcysteine and administration of a antihistamine Chlorpheniramine 10-20 mg i.v . in an adult may be given

17. Methionine An alternative antidote in paracetamol poisoning 2.5 g orally 4-hourly to a total of four doses Less effective, especially after delayed presentation

18. contd …. If patient presents after 15 hours of ingestion LFTs,PT , RFT measure and antidote started Severe liver function abnormality  Arterial blood gas sample taken Liver transplantation should be considered in patient if liver failure due to paracetamol poisoning

19. Summary of management

20. The management of a paracetamol overdose

21. Antidote regimens for paracetamol poisoning N - acetylcysteine (intravenously) 150 mg/kg over 15 min, then 50 mg/kg in 500 mL of 5% dextrose in the next 4 hours and 100 mg/kg in 1000 mL of 5% dextrose over the ensuing 16 hours. Injection Vitamin K 10 mg iv Total dose: 300 mg/kg over 20-25 hours. Methionine (orally) 2.5 g initially, then 2.5 g 4-hourly for a further three doses. Total dose: 10 g methionine over 12 hours. N - acetylcysteine (orally) 140 mg/kg initially, then 60 mg/kg every 4 hours for 17 additional doses. Total dose: 1330 mg/kg over 72 hours

22. References: Tintinallis Emergency Medicine, A Comprehensive Study Guide 7 th edition Kumar and Clark's clinical medicine, 8 th edition Goodman & Gilman‘s pharmacological basis of therapeutics - 11th edition

23. THANK YOU