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APAP TOXICITY

Learn about the toxicity of Acetaminophen (APAP), its metabolism, stages, treatment options, and risk stratification in cases of overdose. Understand the importance of N-Acetylcysteine in managing APAP toxicity.

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APAP TOXICITY

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  1. APAP TOXICITY Anthony Ciorciari Associate Professor Emergency Medicine Albert Einstein College of Medicine

  2. N-ACETYL-PARA-AMINOPHENOL

  3. SALICYLIC ACID

  4. ACETYLSALICYLIC ACID

  5. APAP • First used in the US in 1950 • Over 100K cases reported to US poison Control centers each year • More admissions that any other common pharmaceutical agent • In the US, most common cause of acute hepatic failure

  6. APAP • Analgesic • Antipyretic • Weak peripheral anti-inflammatory

  7. APAP PHARMACOKINETICS • Immediate release-peaks in 45 minutes (liquid about 30 minutes) • Extended release: peaks in 1-2 hours with most absorbed in 4-5 hours • Total protein binding is about 10-30% • Does not change in overdose

  8. APAP METABOLISM • First pass about 25% of dose • Once absorbed • Hepatic conjugation (90%) • Oxidized by CYP2E1 • This results in NAPQI • Glutathione (GSH) quickly combines with NAPQI • Results in non-toxic cysteine or mercaptate conjugates (eliminated in urine)

  9. APAP TOXICITY • Glucuronidation and sulfaction are exceeded (saturated) • There is an increase in NAPQI • GSH supply diminished • NAPQI binds to hepatocytes (acrylates cell proteins) • Cell death (GSH < 30%) • Secondary inflammation

  10. N-ACETYLCYSTEINE (NAC)

  11. NAC • Regenerates GSH • May enhance sulfate conjugation • Anti-inflammatory properties • Anti-oxidant • Increases NO • Vasodilatory effect

  12. FACTORS FOR HEPATOTOXICITY • Increased dosing • Duration of excessive dosing • Increase in CYP2E1 • Decrease in GSH • Decrease glucuronidation and sulfaction

  13. OTHER ORGAN INJURY • Renal: occurs in about 25% with significant hepatic enzyme elevation • Other areas rarely reported • If there are alterations in mitochondrial function: • Anion-gap acidosis • Elevation of lactate

  14. STAGES

  15. STAGE I • No hepatic injury yet • May be a subclinical rise in AST • Nausea, vomiting, malaise, pallor diaphoresis

  16. STAGE II • Onset of liver injury • 24-72 hours (may be earlier in the severely poisoned) • RUQ pain • Looks like infectious hepatitis • Continued rise in AST • Could be a deterioration in renal function • BUN may be normal

  17. STAGE III • Time of maximal hepatotoxicity • 72-96 hours • Fulminant hepatic failure • Encephalopathy • Coma • Hemorrhage • AST and ALT > 10,000

  18. STAGE IV • Survivors of Stage III • Recovery phase • Hepatic regeneration is complete • No chronic hepatic dysfunction • Recovery will occur 5-7 after the overdose, but it may take weeks

  19. THE ACUTE INGESTION • > 7.5 g in adults • > 150 mg/kg in a child • Unknown amount • You are very confident about the time the medication was taken • Look at the nomogram

  20. RUMACK-MATTHEW NOMOGRAM

  21. TREATMENT/ACUTE • Activated Charcoal • Will decrease number of patients above treatment line • Most effective 1-2 hours after ingestion • Reasonable to give it within 4 hours • No evidence that AC and NAC interaction is clinically significant • If repeated AC dosing is needed, better to use IV NAC

  22. IV VS. PO NAC • Mostly they are equivalent • Oral has fewer side effects • Oral costs less • IV has shorter course • Old days: Oral was given IV • Had an excellent safety profile • No published bad outcomes • Not generally recommended • But if pushed to the wall. . .

  23. NAC PROTOCOLS • 72 hour oral protocol • 20 hour IV protocol

  24. SPECIFIC INDICATIONS FOR IV NAC • Hepatic failure • Cerebral edema • Cant tolerate PO • Pregnancy

  25. WHAT ABOUT: • Acute OD and ETOH? • OD and INH, phenobarbital, rifampin? • APAP < 4 hours? • Extended release? • Don’t have a time window, or > 24 hours? • Get APAP and LFTs • If LFTs elevated: treat • If APAP elevated: prudent to treat • If LFTs and APAP normal: no treatment

  26. REPEATED/CHRONIC EXCESSIVE APAP DOSING • Presence or signs of hepatotoxicity • Usually symptomatic for > 24 hours prior to diagnosis • If not symptomatic and ingested more than 4 g in a day • Do lab studies

  27. LAB STUDIES • AST • If the AST is normal the patient may still be at risk if APAP is elevated • The peak APAP should be • < 10 4-6 hours after ingestion • < 30 30-90 minutes after ingestion • Remember the high risk patients • Chronic ETOH • Malnutrition • Anorexia nervosa

  28. RISK STRATIFICATION • High risk (NAC) • AST > 2X normal • AST elevated, APAP > 10 • APAP is higher than expected • Moderate risk (follow-up) • Asymptomatic, less than expected APAP, normal AST • Asymptomatic, APAP < 10, AST < 2X normal

  29. RISK STRATIFICATION • Minimal risk (instruction) • APAP < 10 • Normal AST

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