Acetaminophen toxicity


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A brief description of the management of Acetaminophen toxicity

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  • APAP (N-acetyl-p-aminophenol_
    Paracetamol in the UK, Mexico, many other countries
    Now surpasses ASA as a major cause of poisoning in US
    Use incr. Dramatically as Reyes syndrome was linked to salicylate use.
    Now considered “safed” than aspirin
    One of the most commonly used analgesic/antipyretic agents in the US
    Has none of ASA’sunderirable side effects when used in therapeutic dose
    Due to this increased availability and use, toxic exposures have also increased.
    Toxic effects seen in great Britain in late 1960’s.
    In each of the last few years, over 60,ooo queries related to APAP thru TESS each year
  • In over 50 “Trade” name products
    Some are APAP alone, many others in combo with other agents.
    Most pain meds today contain APAP
    Codeine/APAP, Hcodone/APAP,
    Suppositories, elixirs, tablets, caplets, geltabs, capsules, powdered (Tylenol Cold?Flu)
    some up to 1000 mg/dose
  • Peripheral action is blockade of Pain Impulse generation
    Less effect on peripheral enzyme
    Studies have shown that both apap and asa have equal effects on pain when given in equiv. Doses when the pain in non inflammatory in origin
    For inflammatory pain, salicylates are superior.
    They also inhibit prostaglandin synthetase peripherally, resulting in anti inflammatory activity.
  • Inhib. Prost. Snythetase in the hypothalamus, altering response of the heat regulating center.
    Studies comparing APAP and ASA have shown no significant difference in temperature response, time of onset, time of peak activity, or duration of antipyretic activity
  • Peak concentration occur even more quickly with liquid formulations
    Bezoar formation has not been seen with APAP like it has with ASA
  • The 4% metab by the P450 system is an active intermediate (NAPQI)
    Normally, this minor metabolite of hydroxylation is detoxified by conjugation with hepatic glutathione, with the conjugated products mercapturic acid and cysteine excreted in the urine
    When large doses of APAP are ingested, both the glucoronidation and sulfation pathways become saturated, shunting more APAP toward the P-450 system and increasing NAPQI formation.
    When glutathione depletes to 30% of normal, NAPQI accumulates. The NAPQI arylates to protein in the cytosol and endoplasmic reticulum in the centrilobular zone of the liver, producing cell necrosis and death.
    NAPQI is neutralized by glutathione
    NAPQI contains a sulfhydryl group. If all glutathione is used up, other sulfhydryl groups in the liver are attacked and cells are damaged or destroyed
  • Haemodialysis readily removes APAP, but the toxic metabolite is formed rapidly
    Peritoneal dialysis- Protein binding may increase up to 50% in overdose
    Forced diuresis- Not effective because of small amount excreted unchanged in the urine.
  • Acetaminophen toxicity

    1. 1. Management of Acetaminophen Toxicity
    2. 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. 3. It’s everywhere! • APAP is found in over 200 products Tylenol Tylenol cold Contac Severe Cold Sinutab Sinus Sinarest Midol PMS Vicks 44M Pyrroxate Dimetapp allergy Actifed Sinus Anacin 3 Goody’s Junior Strength Tylenol Theraflu Robitussin Cold Sudafed Sinus Unisom Midol teen Drixoral Cold Benadryl allergy Tempra Comtrex multi sx Vicks Nyquil Sine-off Panadol Vanquish Singlet Coricidin Alka Seltzer Plus Panex
    4. 4. Actions Analgesia  Relieves mild to moderate pain  Efficacy equivalent to salicylates  Inhibits brain prostaglandin synthetase  Blocks pain impulses peripherally
    5. 5. • Antipyresis • Efficacy similar to salicylates • Inhibits prostaglandin synthetase in the hypothalamus
    6. 6. In overdose situations, liver enzymes become saturated, glutathione is depleted, NAPQI (N-acetyl-p-benzoquinoneimine) accumulates, and hepatic necrosis occurs
    7. 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. 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. 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. 10. Excretion • APAP’s metabolic products are excreted by the kidneys • Minimal excretion into breast milk
    11. 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. 12. Extracorporeal elimination • Hemodialysis – Not proven effective in reducing or preventing liver damage in overdose • Peritoneal dialysis – Not effective
    13. 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. 14. • Toxic dose – In adults, threshold for liver damage is 150 to 250 mg/kg – Children under 10 appear to be more resistant
    15. 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. 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. 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. 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. 19. • Phase IV (4 days to 2 weeks) – Complete resolution or death
    20. 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. 21. • Activated charcoal – Should not be witheld – dose 50-100 Grams • Cathartic – utilized to speed transit time
    22. 22. • Hemodialysis – Limited benefit – Damage occurs quickly • Hemoperfusion – No benefit • Peritoneal dialysis – No benefit
    23. 23. Blood Sample • 4 hour post ingestion APAP level – levels drawn earlier may be erroneous – levels may be accurate out to 18 hours
    24. 24. • Plot level on Rumack-Matthews nomogram – 150 mg/dl at 4 hours is possibly toxic – Do not use therapeutic “normal” values to determine potential toxicity!
    25. 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. 26. Rumack and Matthew Nomogram 500 Late 150 100 50 Not valid after 24 hours 10 5 mcg/ml 4 8 12 16 20 Hours After Acetaminophen Ingestion 24
    27. 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. 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. 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. 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. 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. 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. 33. Special considerations with NAC • NAC administered on basis of nomogram plot • if initial level indicates need for NAC do not discontinue • subsequent APAP levels of interest only • If NAC begun before APAP level obtained, may DC NAC if level plots subtoxic on nomogram
    34. 34. NAC side effects • Relatively free of side effects when given orally • Emesis may occur – extremely offensive sulfur odor
    35. 35. ED Admission Estimate time of ingestion Less than 4 hours since overdose Less than 2 hours since overdose More than 2 hours since overdose Gastric emptying 4 or more hours since overdose Activated charcoal Activated charcoal Draw blood plasma 4 hours after overdose for plasma acetaminophen assay Acetaminophen concentration available within 8 hours of overdose Wait for acetaminophen assay result Draw blood ASAP for plasma acetaminophen assay Acetaminophen concentration not available within 8 hours of overdose 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. 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. 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. 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. 39. Lab results • APAP pending • Salicylate pending • Tox screen Negative
    40. 40. Calculations • Patient weighs 60.9 kilograms • 15,500 mg of APAP ingested • mg/kg = 254 – a potentially toxic “acute” dose
    41. 41. Treatment • Lavage • Activated charcoal • Cathartic – Hold NAC until APAP level results obtained • can get APAP level back within 2 hours
    42. 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. 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. 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. 45. Tylenol “ER” is referred to by poison center staff as Tylenol Emergency Room
    46. 46. • Unsure if nomogram is useful with this product • 1 case demonstrated to have biphasic peaks
    47. 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. 48. Labs • APAP level 110 mcg/ml at 5.0 hours post ingestion • ASA level 0 • Tox screen negative for other substances
    49. 49. Calculations • Patient weighs 85 kilograms • 11,050 mg APAP was ingested • 183 mg/kg APAP ingested – Potentially toxic amount in acute od
    50. 50. Treatment • Activated charcoal with sorbitol given • Repeat APAP level 4 hours past the 1st level • Strongly consider NAC with this level – Initial 4 hour level > 100 start NAC
    51. 51. Outcome • Patient was treated with full course NAC • Liver enzymes were AST 220 U/L, and ALT 388 U/L at 27 hours post ingestion. • Liver enzymes returned to normal ranges within 72 hours. • Patient recovered uneventfully
    52. 52. Points to remember • • • • • • • APAP is present in many poly drug overdoses No symptoms may be present…screen 150 mcg/ml at 4 hours is a “treat” level NAC loading dose is 140 mg/kg NAC maintenance doses are 70 mg/kg Once NAC is started, DO NOT DC Metoclopramide 0.1-1.0 mg/kg is very effective in controlling nausea/vomiting associated with APAP toxicity
    53. 53. The End