Case study on paracetamol poisoning(Acetaminophen toxicity)

1. CASE STUDY ON PARACETAMOL POISONING Prepared by Neeraj Ojha Om Acharya Yuvraj Kalathoki

2. INTRODUCTION • Acetaminophen is one of the most commonly used oral analgesics and antipyretics; • It has an excellent safety profile when administered in proper therapeutic doses, but hepatotoxicity can occur after overdose or when misused in at-risk populations; • An acute acetaminophen overdose in adults, in terms of FDA-labeled therapeutic dosing, is minimally defined as a cumulative dose of acetaminophen >4 g ingested over 8 hours or less (some authors use a period of 4 hours);

3. cont. • Acetaminophen or Paracetamol metabolism occurs primarily in the liver and is illustrated in the figure in the next slide;

4. Metabolism of Paracetamol

5. MECHANISM OF ACTION OF PARACETAMOL • To date mechanism of action is not completely understood. It inhibits the cyclooxygenase and recent findings suggests that it is highly selective for COX-2;

6. MOA OF TOXICITY A small proportion of acetaminophen is metabolised by a phase 1 reaction to a hepatotoxic metabolite formed from the parent compound by the cytochrome P450 CYPE21; This metabolite NAPQI is detoxified by binding to glutathione to become harmless water soluble mercapturic acid , which undergoes renal excretion; When excess amounts of NAPQI are formed ,or when glutathione levels are low ,permitting covalent binding to

7. Contd. nucleophilic hepatocyte macromolecules forming acetaminophen protein adducts; This binding is believed to lead to centrilobular hepatic necrosis.Even in absence of hepatotoxicity, renal failure can occur because of renal papillary necrosis;

8. SIGN AND SYMPTOMS Most patients who are overdosed on acetaminophen will initially be asymptomatic, as clinical symptoms of end-organ toxicity do not manifest until 24-48 hours after an acute ingestion.< Minimum toxic doses of acetaminophen for a single ingestion, posing significant risk of severe hepatotoxicity, are as follows: • Adults: 7.5-10 g • Children: 150 mg/kg; 200 mg/kg in healthy children aged 1-6 years

9. CONT. The clinical course of acetaminophen toxicity generally is divided into four phases. Physical findings may vary, depending on the degree of hepatotoxicity; • Phase 1(0.5-24 h) Anorexia ,nausea vomiting; • Phase 2 (18-72h); • Hepatic phase (72-96h); • Recovery phase( 4d to 3 week );

10. ROUTE OF INGESTION Oral route is the most common .

11. DIAGNOSIS The serum acetaminophen concentration is the basis for diagnosis and treatment. A diagnostic serum concentration is helpful, even in the absence of clinical symptoms, because clinical symptoms are delayed.

12. Contd. Recommended serum studies are as follows: • Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST]), bilirubin [total and fractionated], alkaline phosphatase); • Prothrombin time (PT) with international normalized ratio (INR); • Glucose; • Renal function studies (electrolytes, BUN, creatinine );

13. GENERAL MANAGEMENT These preliminary steps must be taken as soon as the paracetamol poisoning is suspected: • Monitor -GCS ,BP,ECG; • Supportive -correct hypoxia, hypotension,acidosis; • Antidotes-NAC and Methionine;

14. Contd. • Perform primary treatment ABCD at the spot; • Gastrointestinal decontamination agents can be used in the emergency setting during the immediate post-ingestion time frame. Administer activated charcoal (AC) if the patient is alert (ideally, within 1 hour post ingestion);

15. Specific management: The FDA-approved regimen for oral administration of NAC (Mucomyst) is as follows: • Loading dose of 140 mg/kg; • 17 doses of 70 mg/kg given every 4 hours; • Total treatment duration of 72 hours;

16. ANTIDOTE N-acetylcysteine is the accepted antidote for acetaminophen poisoning and is given to all patients at significant risk for hepatotoxicity.Serious hepatotoxicity is uncommon and death extremely rare if NAC is administered within 8 hours following acetaminophen overdose;

17. CASE STUDY A 16-year-old female patient arrives in the ED by ambulance after being found by a parent in what appeared to be an intoxicated state with empty pill bottles scattered about her room. The parent reports the patient was despondent recently after breaking up with her boyfriend. The patient is tearful and reports abdominal pain and admits to drinking alcohol and taking over-the-counter (OTC) pills in an apparent suicide attempt. The estimated time of ingestion is six hours prior to arrival in the ED. The patient does not use prescription, OTC medications, or dietary supplements and is not known to have a history of regular consumption of alcoholic beverages or use illicit drugs;

18. SUBJECTIVE DETAIL • Sex: Female; • Age: 16 yrs; • Estimated time of ingestion: 6 hrs prior to bringing her to ED;

19. OBJECTIVE DETAIL • Blood pressure: 118/80 mm Hg (Normal 120/80); • Pulse :88/min (Normal 72); • Regular, respiratory rate 18/min, and temperature 37.0°C; • Normal bowel sounds with mild epigastric tenderness; • Slurred speech; • Rectal examination, Chest and abdominal radiography: Normal;

20. ASSESSMENT: • Patient was awake ,responded to questions with slightly slurred speech. • The patient was given 1.5 g/kg oral activated charcoal as a slurry in a sorbitol cathartic and placed in the intensive monitoring section of the ED while the laboratory tests were being performed. Forty minutes later, the laboratory results returned and showed a mildly increased white blood cell count, liver transaminase values were elevated at approximately three times the upper limit of normal, and an acetaminophen concentration was 308 ug/mL. She denied taking any other medications with the acetaminophen and alcohol;

21. Contd. • The patient received the first dose of IV NAC in the ED and was admitted to the medical ward to complete the treatment course of IV NAC. Transient increases of hepatic transaminases were measured over the ensuing two days of the hospitalization. The patient was seen by the Psychiatry Consultation service, which determined she was not actively suicidal; she was discharged from the hospital two days after admission with scheduled psychiatric and medical follow-up appointments;

22. PLANNING: • Glucose: hypoglycaemia is common in hepatic necrosis and capillary blood glucose should be checked hourly; • Clotting screen: prothrombin time is the best indicator of severity of liver failure and the INR should be checked 12-hourly; • Arterial blood gas; acidosis can occur at a very early stage, even when the patient is asymptomatic; so, it must be monitored;

23. Contd. • She was discharged from the hospital two days after admission with scheduled psychiatric and medical follow-up appointments; • She was warned of emesis as emesis is frequently associated with APAP toxicity and is a common adverse effect of both AC and oral NAC administration; so, an anti-emetic therapy was recommended as well.

24. Personal perspective/Conclusion: • Paracetamol is a very common drug used for the alleviation of fever and pain in different parts of the world. Due to the lack of awareness of its proper use and toxicity, many people in the least developed parts of the world are experiencing different harmful consequences. We think our presentation is the perfect solution to reach out and let the common mass know more about the real nature of this drug.