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Acetaminophen

Acetaminophen. Bidi nader. Tintinalli 7th edition Chapter 184. Pharmacology. Your subtitle goes here. Acetaminophen ( N -acetyl- p -aminophenol or APAP or paracetamol) 650 to 1000 mg (adults) /10 - 15 mg/kg in children, every 4 to 6 hours

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Acetaminophen

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  1. Acetaminophen Bidi nader Tintinalli 7th edition Chapter 184

  2. Pharmacology • Your subtitle goes here • Acetaminophen (N-acetyl-p-aminophenol or APAP or paracetamol) • 650 to 1000 mg (adults) /10 - 15 mg/kg in children, every 4 to 6 hours • maximum total daily dose is 4 gr in adults and 75 mg/kg in children • In an overdose: • peak serum levels : within 2 hr • delayed absorption : propoxyphene or diphenhydramine • extended-release preparations

  3. Pharmacology • Your subtitle goes here therapeutic doses: rapidly absorbed from the GI tract peak serum levels : within 30 minutes to 2 hr 100% bioavailability 20% bound to serum proteins volume of distribution = 0.85 L/kg elimination half-life = 2.5 hours antipyretic effect = 10 - 20 μgr/mL analgesic level = ?

  4. Pharmacology • Your subtitle goes here • metabolized by the liver • therapeutic amounts • sulfation = 20% to 46% • glucuronidation = 40% to 67% • < 5% undergoing direct renal elimination • cytochrome P-450 • (N-acetyl-p-benzoquinoneimine (NAPQI) →Glut→ nontoxic acetaminophen-mercapturate compound → renally eliminated) • ingestion of large amounts : • glucuronidation / sulfation are saturated • glutathione stores <30 % → ↑ NAPQI → centrilobular necrosis

  5. Recurrence of anorexia, nausea, and vomiting • Encephalopathy • Anuria • Jaundice • Hepatic failure • Metabolic acidosis • Coagulopathy • Renal failure • Pancreatitis Stage 3 days 3-4 Stage 1 first 24 h Anorexia Nausea Vomiting Malaise Hypokalemia Clinical Stages • Improvement in anorexia, nausea, and vomiting • Abdominal pain • Hepatic tenderness • ↑ transaminases • ↑bilirubin ↑ PT • Clinical improvement and recovery (7–8 d) • Deterioration to multi-organ failure and death • Improvement and resolution • Continued deterioration Stage 4 after day 5 Stage 2 days 2-3

  6. Clinical Features • Your subtitle goes here • at greater risk: • insufficient glutathione stores : • alcoholics • AIDS • induced cytochrome P-450 enzymatic activity : • alcoholics • anticonvulsant • antituberculous • at decreased risk: • children • greater ability to metabolize acetaminophen through hepatic sulfation

  7. Clinical Features • Your subtitle goes here • Extra hepatic toxic effects • cytochrome P-450 • similar enzymes (prostaglandin H synthase) • Ingestion of massive doses ( 4 hr → level >800 μgr/mL) • altered sensorium • lactic acidosis ( in the absence of liver failure or hypotension) • Renal insufficiency : • 1% - 2% • In rare cases • isolated renal insufficiency • cardiac toxicity • pancreatitis

  8. Diagnosis • Your subtitle goes here • toxic exposure : • adult ingests >10 gr or 200 mg/kg as a single ingestion • >10 gr or 200 mg/kg / 24 hr • >6 gr or 150 mg/kg /24 hr for at least 2 consecutive days • confirmation often depends • serum acetaminophen level • estimating the time since ingestion • the initial clinical findings • nonspecific • delayed in onset • An acetaminophen level is recommended for all patients presenting to the ED with a presumed intentional overdose of any type.

  9. Rumack-Matthew nomogram 200μgr/cc Nomogram 150μgr/cc

  10. 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

  11. <150μgr/cc >200μgr/cc >300μgr/cc 60% hepatotoxicity (ALT >1000 IU/mL) 1% risk of renal failure 5% risk of mortality 90% hepatotoxicity ALT >1000 IU/mL→1% 0 % mortality

  12. Treatment • Your subtitle goes here • GI decontamination • Antidote ( acetylcysteine) • Supportive care adequate

  13. Treatment • Your subtitle goes here • GI decontamination • activated charcoal (orally / through a NG tube) • ipecac syrup is undesirable →delays the administration of the antidote • more aggressive ( gastric lavage / whole-bowel irrigation) • unnecessary → rapid GI absorption of acetaminophen • the great success of treating with acetylcysteine • aggressive GI decontamination • polydrug overdose

  14. Treatment • Your subtitle goes here Antidote • The mainstay is the administration of acetylcysteine • mechanisms of action → ? • early (<8 hours after ingestion) • preventing the binding of NAPQI to hepatic macromolecules • acting as a glutathione precursor or substitute, a sulfate precursor • directly reduce NAPQI back to acetaminophen • >24 hours • ↓hepatic necrosis : antioxidant • ↓neutrophil infiltration • improving microcirculatory blood flow • ↑ tissue oxygen delivery

  15. Treatment • Your subtitle goes here within 8 hours nearly 100% effective (no hepatotoxicity) by 24 hours acetylcysteine treatment is associated with a lower risk of hepatotoxicity

  16. Treatment • Your subtitle goes here • IV acetylcysteine: • The major limitation→ anaphylactoid reactions 4% - 17% • occurring during the first 2 hours • in mild cases → diphenhydramine • in severe cases → temporarily slowing/stopping greater risk → asthmatics lower risk → overdose with high acetaminophen concentrations • 13% nausea and vomiting • Death → incorrect dosing • fulminant hepatic failure → choice ( oral acetylcysteine has not been adequately studied in this setting)

  17. Treatment • Your subtitle goes here IV acetylcysteine : greater ease of administration, greater patient acceptance, equivalent efficacy shorter duration of treatment safe and efficacious during pregnancy Separating the first dose of acetylcysteine and activated charcoal by 1 to 2 hours when possible is a reasonable method

  18. Your Title Goes Here • Your subtitle goes here

  19. Treatment Guidelines

  20. Treatment Guidelines • Your subtitle goes here coingestion "decision-time window"

  21. Disposition and Follow-Up • Your subtitle goes here • acetylcysteine therapy → admitted to the hospital • 24-hour direct observation: • hemodynamically unstable • suicide • observed in the ED for 4-6 hour • acetaminophen level below the nomogram • unmeasurable acetaminophen level + • normal hepatic transaminase levels • Psychiatric evaluation

  22. Fulminant Hepatic Failure • Your subtitle goes here • number one cause of acute liver failure (39% - 46%) • The mortality rate (without acetylcysteine therapy) • 5% - 80% • Most fatalities occur on days 3 to 5 after overdose • cerebral edema • hemorrhage • shock • acute lung injury • sepsis • multi-organ failure • recovery → days 5 to 7 • Survivors will eventually develop complete hepatic regeneration without any persistence of hepatic impairment.

  23. Fulminant Hepatic Failure • Your subtitle goes here Prognostic indicators for mortality: arterial pH <7.30 despite fluid and hemodynamic resuscitation PT >100 seconds) Cr >3.3 mg/dL) grade III or IV hepatic encephalopathy acute Physiology and Chronic Health Evaluation II score >15 serum lactate >3.0 mmol/L after fluid resuscitation serum phosphate >1.2 mmol/dL (3.75 mg/dL) on the second day after ingestion

  24. Thanks for your attention

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