APAP and SalicylatePoisoning Corinne M. Hohl R5, EM Training Program McGill University September 2003
APAP – Question 1 • What is the therapeutic mechanism of action of APAP?
Q1: mechanism of action • Central prostaglandin synthetase inhibitor analgesic, antipyretic with weak anti-inflammatory properties.
APAP – Question 2 • Name 4 metabolic pathways of APAP and the proportion of APAP metabolized by each pathway in a normal adult host with a therapeutic ingestion.
Q2: met pathways of APAP • Hepatic glucuronide conjugation(40-65%) 90% • Hepatic sulfate conjugation(20-45%) inactive metabolites excreted in the urine. • Excretion of unchanged APAP in the urine (5%). • Oxidation by P450 cytochromes (CYP 2E1, 1A2, and 3A4) to NAPQI(5-15%) GSH combines with NAPQI nontoxic cysteine/mercaptate conjugates excreted in urine.
Q2: metabolic pathways of APAP • The safety of acetaminophen depends on the availability of electron donors such as reduced glutathione (GSH) and other thiol-containing substances required to detoxify NAPQI.
APAP – Question 3 • What happens to APAP metabolism in an OD situation?
Q3: APAP metabolism in OD • Saturation of glucuronidation and sulfation pathways • Amount of APAP metabolized by p450 cytochromes to NAPQIincreases. • Normally NAPQI is detoxified by reduced GSH (glutathione) and thiol-containing substances. • In OD: rate and quantity of NAPQI formation overwhelms GSH supply and regeneration: elimination of NAPQI prolonged free NAPQI binds critical cell proteins with sulfhydryl groups cellular dysfunction and cell death. • Animal models: hepatotoxicity when GSH stores fall <30% of baseline large margin of safety where therapeutic dose 10-15mg/kg to toxic dose of 150mg/kg for single acute ingestion.
APAP – Question 4 • Name 3 factors which adversely affect APAP metabolism.
Q4: APAP metabolism • Upregulation (i.e. induction) of CYP 2E1 enzyme activity: • smoking, barbituates, rifampin, carbamazepine, phenytoin, INH, + ethanol • use of APAP by alcoholics has not been associated with higher risk of liver injury in prospective trials • Decreased glutathione stores. • Frequent dosing interval of APAP. • Prolonged duration of excessive dosing. (Kuffner et al. 2001)
APAP – Question 5 • Name 3 factors which decrease GSH stores. • Name 2 ways in which GSH stores can be replaced.
Q5: GSH stores • Glutathione stores are determined by: • age • diet • liver disease • fasting prior ingestion • chronic malnutrition (anorexia) • gastroenteritis • chronic alcoholism • HIV • Glutathione replacement by sulfhydryl compounds: • eating • NAC • Whitcomb DC, Block GD: Association ofacetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994; 272:1845
Q5: toxicity in children • Most APAP ODs in children occur in the scenario of acute febrile illness. • It is unclear whether short-term fasting in acute febrile illness in children prediposes them to oxidant stress which depletes GSH leading to APAP toxicity, or whether this is simply the most common setting in which children most commonly receive multiple excessive dosing. • Given the large therapeutic index children are unlikely to become toxic from ingestion on one or two tablets. • Whitcomb DC, Block GD: Association ofacetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994; 272:1845
APAP – Question 6 • Why is APAP toxic to the kidney as well? (Name 2 mechanisms).
Q6: renal toxicity • Organ dysfunction results everywhere where local oxidative metabolism (via p450) creates NAPQI that cannot be detoxified direct toxicity: • cytochrome P-450 enzymes produce NAPQI in the renal tubules NAPQI binds cellular macromolecules acute tubular necrosis. (25% of hepatotoxic cases). • Hepatorenal Syndrome • Volume depletion
APAP – Question 7 • How could one distinguish with a simple lab test between hepatorenal syndrome and ATN?
Q7: HRS vs. direct toxicity • Fractional excretion of sodium (FeNa) : FeNa: >1 in primary renal injury FeNa: <1 hepatorenal syndrome
APAP – Question 8 • What other 2 organs are most commonly (although overall rarely) damaged in an APAP overdose?
Q8:other organs damaged • Heart myocarditis • Pancreas pancreatitis It is controversial whether these entities are part of multisystem organ failure (MSOF) from fulminant hepatic failure (FHF) or from the local accumulation of toxic metabolites.
APAP – Question 9 • What percent of pts whose APAP level falls above the upper line of the Rumack-Matthew normogram will develop hepatotoxicity? (defined as elevation of the plasma transaminases above 1,000 U/L)
APAP – Question 10 • By how many hrs after ingestion do you expect the transaminases to rise if an APAP ingestion was hepatotoxic? In which clinical stage would this be?
Q10: time of AST/ALT rise • I 0.5-24h n/v, anorexia, asymptomatic. • II 24-48 h resolution of stage I sxs • RUQ pain, elevation of PTT, INR, bili + enzymes (at the latest by36h) • III 48-96h coagulopathy, peaking of enzymes, acidosis, hypoglycemia, bleeding diathesis, jaundice, anuria, cerebral edema, coma. ARF in 25% of pts with hepatotoxicity • IV 4-14d resolution
APAP – Question 11 • Which lab test is the most sensitive for early detection of hepatotoxicity.?
Q11: lab test • AST
APAP – Question 12 • Your resident saw a patient 90min post APAP ingestion of unknown quantity: He tells you the APAP is <10 and AST 40. How would you dispo and manage this pt.
Q12: 1h level • This patient needs a 4-hr APAP level – there is no point in doing an APAP level in an acute single ingestion before 4h post ingestion unless it is a chronic ingestion or the history is unreliable. • There is no point in doing LFTs either unless the 4hr APAP is on or near the treatment line, the pt has symptoms suggestive of liver injury or pt looks unwell (i.e. prior liver disease).
APAP – Question 13 • Another resident tells you another patient has a 4 hr APAP of 70mg/mL with an AST of 50. As you pursue the story you find out that your patient is from Europe and may have ingested an extended release form of paracetamol. What is your management?
Q12: XR tablets • Check 6h and 8h APAP levels. • Tx with NAC if: • 4, 6 or 8h level above the R-M tx line full course NAC. • If all levels are below the tx line and the 8h APAP level is less than 50% of tx line D/C home (NYPC). • If the 8h APAP line is btw 50% of tx line and tx line NAC. for 24-36h and D/C once APAP <10 or transaminases normal (NYPC). • If the 6-hour level is greater than the 4-hour level, begin NAC therapy. * More prolonged monitoring of levels may be necessary if the patient has food in the stomach or co-ingestants that delay gastric emptying.
Q12: XR tablets • Several studies show that elimination of extended and immediate-release acetaminophen are nearly identical after 4 hours. • However, some case reports have documented APAP levels falling above the treatment normogram line as late as 11-14 hours post ingestion of the extended-release preparation.
Q12: XR tablets Healthy 17yo girl after ingestion of 13g of ER tylenol. Both a 3 and 5hr level were below the treatment line. NAC was started after the 11hr level was above the treatment line. She did not develop hepatotoxicity. Vasallo et al. Ann Intern Med. 1996; 125 (11) 940.
APAP – Question 13 • Name four indications (lab criteria) for treating a patient for repeated excessive APAP dosing.
Q13: chronic OD • If the APAP level is above the treatment line (plot earliest possible dose to have high sensitivity). • Symptomatic pt with AST >normal. • Any asymptomatic patient with a hx of chronic excessive APAP ingestion and an AST > 2x normal. • AST >normal with APAP >10. • If the APAP level is greater than expected for the appropriate dose.
APAP – Question 14 • A 3rd ingestion comes in:18 yr old pregnant girl ingested 20g of Tylenol in a suicidal gesture 36h ago because she found out it is too late for her to have an abortion. Her APAP is <10 and her AST is 90. • How will you manage her medically? • She asks you whether her baby will have any defects.
Q14: APAP in pregnancy • APAP crosses the placenta. • She needs a full course of NAC. • There is no point in giving her AC at this point, although AC would probably be safe in an acute OD. • Birth defects: poorly studied in OD, some evidence for birth defects.
Q14: Pregnancy and APAP • AC: Class C • Safety for use during pregnancy has not been established. • NAC: Class A • Safe in pregnancy
APAP – Question 15 • Name 4 mechanisms by which NAC works.
Q15: 4 mech of action of NAC • Early Prevents binding of NAPQI to hepatocytes. • GSH precursor increases GSH stores • Increases sulfation metabolism of APAP less NAPQI formed • Reduces NAPQI back to APAP (at least in animal models). • Sulfur group of NAC binds and detoxifies NAPQI to cysteine and mercaptate conjugate (= GSH substitute). • Late (12-24h) Modulates the inflammatory response. • Antioxidant, free radical scavenger. • Reservoir for thiol groups (i.e. GSH). • Impairs WBC migration and function antiinflammatory. • Positive inotropic and vasodilating effects (NO) improves microcirculatory blood flow and O2 delivery to tissues. • Decreases cerebral edema formation, prevents progression of hepatic encephalopathy and improves survival.
APAP – Question 16 • Name 4 indications for NAC therapy.
Q16: 4 indications for NAC • APAP level above the treatment line. • Hx of significant APAP ingestion presenting close to 8h (give while waiting for level). • All APAP ingestions who present late (>24h with either detectable APAP or elevated transaminases. • Chronic lg ingestions (>4g/day in adult, >120mg/d in child) with elevated transaminases. • Hx of exposure and FHF.
IV NAC • 3 situations in which IV NAC is undoubtedly preferable to oral: • Fulminant hepatic failure • Pregnancy • Inability to tolerate oral NAC.
APAP – Question 17 • Name 4 poor prognostic indicators:
Q17: poor prognostic indicators • pH <7.3 (2 days after OD, after fluids) • Hepatic encephalopathy • PT >1.8 times normal. • Serum creatinine >300mmol/L • Coagulation factor VIII/V ratio of >30 Note: Transaminase levels do NOT predict the clinical course. They can decline during hepatic recovery or with FHF.
Q17: other rules of thumb • If PT in seconds > number of hours since ingestion. • If INR is abnormal and still increasing on 4th day post ingestion.