1. Acetaminophen Intoxication Ali Labaf M.D. Assistant professor Department of Emergency Medicine Tehran University of Medical Science

2. n Acetaminophen has been approved for OTC use since 1960 n Although the drug is remarkably safe, toxicity can occur even with therapeutic doses. n Alcoholics are particularly susceptible to hepatotoxicity n Therapeutic dose of acetaminophen is 10-15 mg/kg/dose in children and 325-1000 mg/dose every 4-6 hours in adults, with a maximum of 4g/day.

3. Biochemical Basis of Acetaminophen Toxicity n At therapeutic doses, 90% of APAP is metabolized in the liver to sulfate and glucuronide conjugates that are then excreted in the urine n The remaining 10% is metabolized via the cytochrome CYP2E1 (P450 2E1) to a toxic, reactive, N-acetylimidoquinone (NAPQI) n NAPQI binds covalently with hepatocyte macromolecules, producing hepatic cell lysis

5. Factors influencing toxicity Chronic alcoholics are at increased risk of developing severe hepatic disease even at therapeutic doses n In contrast, acute alcohol ingestion is not a risk factor for hepatotoxicity and may even be protective by competing for CYP2E1

6. CLINICAL MANIFESTATIONS the latent period n stage I (0 to 24 hours), the latent period the onset of hepatotoxicity n stage II (24 to 48 hours), the onset of hepatotoxicity maximal hepatic injury n stage III (72 to 96 hours), maximal hepatic injury recovery n stage IV (4 days to 2 weeks), recovery

7. n 2 to 12 hours after ingestion, nausea, vomiting, diaphoresis, pallor, lethargy and malaise are seen n This is followed by temporary symptomatic improvement at 24 to 48 hours n Signs of liver involvement begin at this time, including right upper quadrant pain and hepatomegaly, elevations in the plasma levels of hepatic enzymes, and prolongation of the prothrombin time n Signs of severe hepatic damage become apparent 72 to 96 hours after ingestion CLINICAL MANIFESTATIONS

8. n Systemic symptoms of the first stage reappear in conjunction with confusion, marked elevation in hepatic enzymes, hyperammonemia, and a bleeding diathesis n Signs of severe hepatotoxicity include plasma AST levels that often 10,000 IU/L, prolongation of the PT, hypoglycemia, lactic acidosis, and a plasma bilirubin concentration above 4.0 mg/dL n Acute renal failure may also be seen at this time, due primarily to ATN CLINICAL MANIFESTATIONS

9. n Clinical recovery typically begins within 4 to 14 days, leading to resolution of symptoms and normalization of laboratory values over several weeks n Histologic changes vary from cytolysis to centrilobular necrosis n Centrilobular region is preferentially involved because it is the area of greatest concentration of CYP2E1 and therefore the site of maximal production of NAPQI n Histologic recovery lags behind clinical recovery and may take up to three months CLINICAL MANIFESTATIONS

10. DIAGNOSIS n In the patient with a history of APAP overdose, a serum APAP level should be measured between 4 and 24 hours after ingestion n The value obtained should be evaluated according to the Rumack-Matthew nomogram for determining the risk of hepatotoxicity and the need for NAC therapy

12. DIAGNOSIS n Characteristic laboratory findings of APAP hepatotoxicity include –marked elevation in plasma hepatic enzyme levels (>5000 IU/L) –rising prothrombin time n These abnormalities distinguish this syndrome from alcoholic liver disease where transaminase values almost never exceed 500 IU/L n AST level typically exceeds that of ALT in both conditions

13. TREATMENT n The mainstays of the therapy of APAP intoxication include gastric decontamination with activated charcoal and the administration of N-acetylcysteine (NAC) n Activated charcoal avidly adsorbs APAP, reducing its absorption by 50 to 90% n However, activated charcoal also adsorbs NAC and, by causing nausea and vomiting, may interfere with the administration of NAC

14. TREATMENT n NAC should optimally be given within 8 to 10 hours after ingestion n More delayed therapy is associated with a progressive increase in hepatic toxicity although some benefit may still be seen 24 hours or later after ingestion

15. TREATMENT n NAC is indicated in –All patients with a serum APAP concentration above the possible hepatic toxicity line on the Rumack-Matthew nomogram –Patients with an estimated ingestion of greater than 140 mg/kg –Patients with an unknown time of ingestion –Patients with a presentation more than 24 hours after ingestion with elevated transaminases

16. TREATMENT n 72-hour course of oral NAC given as a 140 mg/kg loading dose, followed by 17 doses of 70 mg/kg every 4 hours. n 20-hour course of intravenous NAC given as an initial bolus of 150 mg/kg, followed by continuous infusion of 50 mg /kg over the next 4 hours and 100 mg/kg over the remaining 16 hours

17. Oral therapy n Antiemetics (e.g., metoclopramide, 0.1 to 1.0 mg per kg IV ) may be required. n If antiemetics fail, NAC can be given by gastric tube. n use a straw and covering the container. n If vomiting occurs within 1 hour of any dose, that dose should be repeated.

18. IV therapy n Transient skin rash occurred in approximately 15% of patients during the loading dose but did not necessitate discontinuing treatment. n Even with more serious reactions, NAC therapy can often be continued after treatment with diphenhydramine.

19. TREATMENT n Dialysis and hemoperfusion –In the management of patients who present late in the course (more than 24 hours) when NAC would be of limited value, hemoperfusion may be associated with lesser elevation in plasma transaminases when compared to supportive therapy alone or to the administration of NAC.

20. TREATMENT n Liver transplantation

21. Criteria for liver transplantation n presence of a progressive coagulopathy(PTin seconds exceeds the time in hours after overdose) –an INR >5 at any time –evidence of metabolic acidosis –hypoglycemia –renal failure

22. Do not forget: Time is Liver !!!