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

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

7. 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

8. 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

9. 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.

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

11. mcg/ml 4 8 12 16 20 24 Hours After Acetaminophen Ingestion 150 5 10 50 500 Rumack and Matthew Nomogram 100 Late Not valid after 24 hours

12. <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

13. Treatment Your subtitle goes here  GI decontamination  Antidote ( acetylcysteine)  Supportive care adequate

14. 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

15. 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

16. 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

17. 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)

18. 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

19. Your Title Goes Here Your subtitle goes here Oral IV AdultIV Pediatric (<40 kg) PreparationAvailable as 10% and 20% solutions. Available as 20% solution. Dilute to 5% solution for oral administration. Dilute to 2% solution by mixing 50 mL in 450 mL 5% dextrose in water. Loading dose 140 milligrams/kg.150 milligrams/kg in 200 mL 5% dextrose in water infused over 15–60 min. 150 milligrams/kg (7.5 mL/kg ) infused over 15–60 min. Maintenance dose 70 milligrams/kg every 4 h for 17 doses. 50 milligrams/kg in 500 mL 5% dextrose in water infused over 4 h. 50 milligrams/kg (2.5 mL/kg) infused over 4 h. followed by 100 milligrams/kg (5 mL/kg) infused over 16 h. 100 milligrams/kg in 1000 mL 5% dextrose in water infused over 16 h. Duration of therapy 72 h.20 h. CommentsDilute with powdered drink mix, juice, or soda. Monitor for drug-related adverse effects and anaphylactoid reactions. Serve chilled.500 mL of the 2% solution prepared as described above is enough to treat a 33- kg child for the full 20-h course. Drink through a straw to reduce disagreeable smell.

20. Treatment Guidelines

21. Your subtitle goes here "decision-time window" coingestion

22. 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

23. 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.

24. 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

25. Thanks for your attention