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Management of Acetaminophen Toxicity

Management of Acetaminophen Toxicity. History. Synthesized in 1877 in U.S. Extensive use began around 1947 Initially prescription only in the U.S. Otc status gained in 1960 toxic effects first noted in U.S. in 1971. It’s everywhere !. APAP is found in over 200 products

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Management of Acetaminophen Toxicity

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  1. Management of Acetaminophen Toxicity

  2. History • Synthesized in 1877 in U.S. • Extensive use began around 1947 • Initially prescription only in the U.S. • Otc status gained in 1960 • toxic effects first noted in U.S. in 1971

  3. It’s everywhere! • APAP is found in over 200 products Tylenol Anacin 3 Tempra Tylenol cold Goody’s Comtrex multi sx Contac Severe Cold Junior Strength Tylenol Vicks Nyquil Sinutab Sinus Theraflu Sine-off Sinarest Robitussin Cold Panadol Midol PMS Sudafed Sinus Vanquish Vicks 44M Unisom Singlet Pyrroxate Midol teen Coricidin Dimetapp allergy Drixoral Cold Alka Seltzer Plus Actifed Sinus Benadryl allergy Panex

  4. Actions • Analgesia • Relieves mild to moderate pain • Efficacy equivalent to salicylates • Inhibits brain prostaglandin synthetase • Blocks pain impulses peripherally

  5. Antipyresis • Efficacy similar to salicylates • Inhibits prostaglandin synthetase in the hypothalamus

  6. In overdose situations, liver enzymes become saturated, glutathione is depleted, NAPQI (N-acetyl-p-benzoquinoneimine)accumulates, and hepatic necrosis occurs

  7. Pharmacokinetics • Absorption • Rapidly absorbed from the GI tract • Peak concentration usually occurs between 60 and 120 minutes • Peak plasma levels almost always occur within 4 hours

  8. Distribution • Vd 1.0 - 2.0 L/Kg • Approximately 20% plasma protein bound may increase to 50% in overdose • Has been reported to cross the placenta

  9. Metabolism • Occurs via several pathways in the liver • 52% by sulfation • 42% by glucuronidation • 2% excreted unchanged in the urine • 4% biotransformed by C-P450 MFO system

  10. Excretion • APAP’s metabolic products are excreted by the kidneys • Minimal excretion into breast milk

  11. Half life • Average 2 hours • range 0.9 to 3.25 hours • No age related differences • No change in patients with renal disease • With liver dysfunction, may increase to 17 hours

  12. Extracorporeal elimination • Hemodialysis • Not proven effective in reducing or preventing liver damage in overdose • Peritoneal dialysis • Not effective

  13. Toxicity • Factors involved in predicting hepatotoxicity • total quantity ingested • time from ingestion to treatment • age of the patient • alcoholism • enzyme inducing medications • serum concentration in relation to Rumack nomogram

  14. Toxic dose • In adults, threshold for liver damage is 150 to 250 mg/kg • Children under 10 appear to be more resistant

  15. Potential liver damage • Adults: > 150 mg/kg in acute dose • Adults: > 7.5 Grams in 24 hours (chronic) • Children (<10 yrs): > 200 mg/kg

  16. 4 Stages of Acetaminophen Poisoning • Phase I (30 minutes to 4 hours) • Within a few hours after ingestion, patients experience anorexia, nausea, pallor, vomiting, and diaphoresis. Malaise may be present. Patient may appear normal

  17. Phase II (24 to 48 hours) • Symptoms of Phase I are less severe. May seem like a period of recovery. Right upper quadrant pain may be present due to hepatic damage. Blood chemistry becomes abnormal with elevations of liver enzymes. Prothrombin times may be prolonged. Renal function may begin to deteriorate.

  18. Phase III (3 to 5 days) • Characterized by symptoms of hepatic necrosis. Coagulation defects, jaundice, and renal failure have all been noted. Hepatic encephalopathy has been noted. Hepatic biopsy at this time would indicate centrilobular necrosis. Nausea and vomiting may reappear. Death is due to hepatic failure

  19. Phase IV (4 days to 2 weeks) • Complete resolution or death

  20. Treatment • GI decontamination • Syrup of Ipecac • return usually 30-40% at best • best if used early (first 1-2 hours) • Gastric lavage • effectiveness diminishes with time

  21. Activated charcoal • Should not be witheld • dose 50-100 Grams • Cathartic • utilized to speed transit time

  22. Hemodialysis • Limited benefit • Damage occurs quickly • Hemoperfusion • No benefit • Peritoneal dialysis • No benefit

  23. Blood Sample • 4hour post ingestion APAP level • levels drawn earlier may be erroneous • levels may be accurate out to 18 hours

  24. Plot level on Rumack-Matthews nomogram • 150mg/dl at 4hours is possibly toxic • Do not use therapeutic “normal” values to determine potential toxicity!

  25. Baseline CBC • creatinine, BUN, blood sugar, electrolytes • prothrombin times • AST, ALT • repeat q 24 hours • elevations typically seen 24-36 hours post ingestion

  26. Rumack and Matthew Nomogram 150 500 Late 100 Not valid after 24 hours 50 10 5 mcg/ml4 8 12 16 20 24 Hours After Acetaminophen Ingestion

  27. If APAP level plots above the possible risk line administer N-acetylcysteine (NAC). • If NAC is indicated, full regimen should be followed. Do not stop NAC early if nomogram indicates toxic possibility

  28. N-acetylcysteine (NAC) • Mechanism of action • glutathione substitute • may supply inorganic sulfur, altering metabolism • Route of administration • Orally or IV • IV not approved in the U.S.

  29. NAC dosing • Oral 72 hour protocol • Loading dose is 140 mg/kg • Maintenance doses: 70 mg/kg • Given every 4 hours x 17 doses starting 4 hours after loading dose

  30. NAC supplied as 10 or 20% oral solution • dilute to 5% final concentration with juice or soft drink • May be administered via NG tube • If emesis occurs within 1 hour of administration, repeat the dose

  31. If emesis persists, antiemetics may be used • Reglan® (metoclopramide) • 0.1 to 1.0 mg/kg iv is often effective • If emesis is refractory, may consider Zofran® (ondansetron) or Kytril® (granisetron) • Expensive, but very effective

  32. Pediatric overdoses • More resistant to toxicity vs. adults • if a child plots in the possible risk category on the Rumack nomogram, do not resist using NAC because of this greater tolerance to APAP • Administer full course of NAC if nomogram indicates that it is needed

  33. Special considerations with NAC • NAC administered on basis of nomogram plot • if initial level indicates need for NAC donot discontinue • subsequent APAP levels of interest only • If NAC begun before APAP level obtained, may DC NAC if level plots subtoxic on nomogram

  34. NAC side effects • Relatively free of side effects when given orally • Emesis may occur • extremely offensive sulfur odor

  35. ED Admission Estimate time of ingestion Less than 4 hours since overdose 4 or more hours since overdose Less than 2 hours More than 2 hours since overdose since overdose Gastric emptying Activated charcoal Activated charcoal Draw blood plasma 4 hours after overdose for plasma acetaminophen assay Draw blood ASAP for plasma acetaminophen assay Acetaminophen concentration available Acetaminophen concentration not within 8 hours of overdose available within 8 hours of overdose Wait for acetaminophen assay result Start NAC pending assay result Loading does: 140 mg/kg APAP level below risk line on nomogram APAP level on or above risk line DC NAC if started Treat with full course of NAC No further medical management needed Daily LFT’s, prothrombin times Treat other med or psychiatric problems Provide supportive care

  36. Summary In overdose, APAP may overwhelm the liver stores of glutathione. A rise in liver enzymes may occur, which reflects the hepatic toxicity which may ensue. Timely administration of NAC may protect the patient from hepatic damage. Therapy should be initiated as soon as possible, but NAC is beneficial at any time. If APAP levels can not be obtained, assume a toxic dose has been ingested, initiate NAC, and continue until regimen complete.

  37. Case Studies Case 1 A 32 year old female presents to the ED 30 minutes after taking 31 Tylenol Extra Strength caplets in an apparent suicide attempt. She weighs 134 pounds, ambulated into the ED, is in no obvious distress, has had no symptoms prior to arrival.

  38. Signs/symptoms • Patient is awake and alert • HEENT: normal • No GI distress • PERRLA • Temp 98.7°F • HR 84, BP 128/76, R 19

  39. Lab results • APAP pending • Salicylate pending • Tox screen Negative

  40. Calculations • Patient weighs 60.9 kilograms • 15,500 mg of APAP ingested • mg/kg = 254 • a potentially toxic “acute” dose

  41. Treatment • Lavage • Activated charcoal • Cathartic • Hold NAC until APAP level results obtained • can get APAP level back within 2 hours

  42. Outcome • APAP level 56 mg/dl drawn 4 hours post ingestion • ASA level 0 • patient discharged asx to mental health unit 7 hours after arrival

  43. Case 2 A 25 year old male is brought to the ED by his girlfriend. She states that he has taken 24 “Tylenol” tablets. She brought the bottle with her and in fact the product is “Tylenol ER”. He ingested the caplets approximately 5 hours ago.

  44. Tylenol ER is a relatively new product which throws a curve into the traditional management of APAP overdoses. This product releases 325 mg of APAP immediately and 325 mg over the next 8 hours.

  45. Tylenol “ER” is referred to by poison center staff as TylenolEmergency Room

  46. Unsure if nomogram is useful with this product • 1 case demonstrated to have biphasic peaks

  47. Signs/symptoms • Patient has vomited x 6 prior to arrival • Complaining of GI discomfort • HEENT: normal • PEERLA • Temp 98.9°F • HR 80, BP 130/78, R 20

  48. Labs • APAP level 110 mcg/ml at 5.0 hours post ingestion • ASA level 0 • Tox screen negative for other substances

  49. Calculations • Patient weighs 85 kilograms • 11,050 mg APAP was ingested • 183 mg/kg APAP ingested • Potentially toxic amount in acute od

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