ASA_APAP - APAPand Salicylate Poisoning Corinne M Hohl R5...

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    APAP and  Salicylate Poisoning     Corinne M. Hohl R5, EM Training Program McGill University September 2003
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Acetaminophen
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What is the therapeutic mechanism of action of APAP? APAP – Question 1
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Q1: mechanism of action Central prostaglandin synthetase inhibitor analgesic, antipyretic with weak anti- inflammatory properties.
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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.
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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.
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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.
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APAP – Question 3 What happens to APAP metabolism in an OD situation?
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Q3:  APAP metabolism in OD Saturation of glucuronidation and sulfation pathways Amount of APAP metabolized by p450 cytochromes to NAPQI increases. 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.
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APAP – Question 4 Name 3 factors which adversely affect APAP metabolism.
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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)
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APAP – Question 5 Name 3 factors which decrease GSH stores. Name 2 ways in which GSH stores can be replaced.
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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 of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994; 272:1845
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Q5:  toxicity in children Most APAP ODs in children occur in the scenario of acute febrile illness.
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