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MEDICAL GRANDROUNDS Acetaminophen Toxicity “how much is too much?”

MEDICAL GRANDROUNDS Acetaminophen Toxicity “how much is too much?”. Ivy Rose C. Nisce, M.D. September 6, 2007. Paracelsus . “All things are poison, and nothing is without poison. The right dose differentiates a poison from a remedy” . Objectives. To present a case of acetaminophen toxicity

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MEDICAL GRANDROUNDS Acetaminophen Toxicity “how much is too much?”

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  1. MEDICAL GRANDROUNDSAcetaminophen Toxicity“how much is too much?” Ivy Rose C. Nisce, M.D. September 6, 2007

  2. Paracelsus “All things are poison, and nothing is without poison. The right dose differentiates a poison from a remedy”

  3. Objectives • To present a case of acetaminophen toxicity • To discuss the pathophysiology, clinical stages, diagnosis, treatment and complications of acetaminophen toxicity

  4. General Data • 25 year old • Female • Filipino • Married

  5. Chief Complaint nausea andvomiting

  6. History of Present Illness 18 hours PTA Ingested 20 tab of Tylenol® 500mg/tab 11 hours PTA (+) nausea, vomiting (+) abdominal discomfort 5 hours PTA (+) pallor (+) anorexia,weakness consult done at another hospital MMC-ER

  7. Review of Symptoms • No headache, dizziness • No fever, weight loss • No cough, colds, difficulty of breathing • No chest pain, palpitations, PND • No bowel or bladder changes

  8. Past Medical History • (+) dysmenorrhea – Tylenol 500mg/tab • No hypertension, diabetes, asthma • No previous operations

  9. Family History • unremarkable

  10. Personal and Social History • Husband and children reside in the U.S. • Unemployed • Nonsmoker • Not an alcoholic beverage drinker • No illicit drug use • No previous history of overdose

  11. Physical Examination • Conscious, coherent, ambulatory, not in cardiorespiratory distress • Vital Signs BP: 120/80mmHg HR: 72 bpm,reg RR: 18 cpm Temp: 37.2 C • Height: 5’2’’ Weight: 55 kgs BMI: 21

  12. Physical Examination • Warm moist skin, no jaundice, no active dermatosis • Pink palpebral conjunctiva, anicteric sclerae • Supple neck, no lymphadenopathy • Symmetrical chest expansion, no retractions, clear breath sounds • Adynamic precordium, regular rate and rhythm, apex beat at 5th LICS, no murmurs • Flat, soft, normoactive bowel sounds, no tenderness on palpation, no hepatomegaly • No edema or cyanosis, pulses full and equal

  13. Salient Features • 25 year old female • Ingested 20 tablets of Acetaminophen (Tylenol®) • Nausea, vomiting, abdominal discomfort • Pallor, anorexia, body weakness • Stable vital signs • Essentially normal physical examination

  14. Initial Impression Acetaminophen Toxicity

  15. Nausea, Vomiting, Abdominal Discomfort CHOLECYSTITIS • nausea & vomiting • triad sudden onset of RUQ tenderness, fever, leukocytosis VIRAL HEPATITIS • prodromal sx: anorexia, nausea, vomiting, malaise • jaundice, RUQ pain and discomfort • serum transaminases peak at 400 - 4000 IU/L

  16. Nausea, Vomiting, Abdominal Discomfort PEPTIC ULCER • nausea • epigastric pain: gnawing or burning discomfort DRUG-INDUCED • appropriate temporal sequence from administration of the drug to onset of event • an appropriate course of the reaction after cessation of the offending drug • absence of alternative causes

  17. At the emergency room • Referral to toxicology service • Referral to psychiatry service • Assessment: adjustment disorder

  18. Laboratory Results

  19. Laboratory Tests

  20. Single Acute Acetaminophen Overdose Normogram(Rumack-Matthew)

  21. Therapeutics • NPO • D5NSS IL + 30meqs KCL x100cc/hr • Plasil 10mg IV q8 • Esomeprazole 40mg IV OD • Vit K 1 amp IV OD

  22. N-acetylcysteine (NAC) Treatment Protocol Phase I 150 mg/kg IV NAC 20% in 200ml D5W x 1 hr 150mg/kg = 150mg x 55kg = 8250 mg Phase II 50 mg/kg IV NAC 20% in 500ml D5W x 4 hr 50mg/kg = 50mg x 55mg = 2790 mg Phase III 100 mg /kg IV NAC 20% in 1000ml D5W x 16hr 100mg/kg = 100mg x 55mg = 5500 mg

  23. 1st Hospital Day • Ultrasound of the upper abdomen • Gallbladder polyp • Cholecystolithiasis • Normal liver, BT, pancreas, spleen, kidneys • Endoscopy • Gastritis • GERD A • Duodenitis

  24. Therapeutics • General liquids • N-Acetylcysteine 600mg/tab BID • Lansoprazole 40mg/tab OD • Rebamipide 100mg/tab TID • Motilium 10mg/tab TID

  25. 2nd Hospital Day • Nausea • Vomiting • Ab Discomfort 271

  26.  Vitamin K 10mg to BID • Aminoleban 500cc x 12 hrs INR: 1.3 INR: 1.7

  27. 3rd Hospital Day • (-) jaundice • (-) RUQ pain • good UO

  28. INR: 1.3 INR: 1.7 INR: 1.9

  29. Serum APAP level <10 ug/ml (10-30) • T Bili 1.4 Direct 0.5 Indirect 0.9 • Referral to toxicology service • Acetaminophen Ingestion,non-accidental • NAC tablet discontinued Phase III 5500 mg IV NAC 20% in 1000ml D5W x 16hr

  30. 4th Hospital Day

  31.  Vitamin K 10mg to OD INR: 1.2 INR: 1.9

  32. 7th Hospital Day

  33. Protime 1.0 1.3 1.9

  34. Take Home Medications • Lansoprazole 30mg/tab OD • Rebamipide 100mg/tab TID • Domperidone 10mg/tab TID • Lactulose 20cc OD HS

  35. Final Diagnosis • Acetaminophen Toxicity, non-accidental, resolved • Gastritis, GERD A, Duodenitis s/p EGD • Adjustment disorder

  36. Discussion

  37. Acetaminophen • Most widely used analgesic and antipyretic in the world today • One of the most frequent causes of poisoning due to a pharmaceutical agent worldwide Clinical Management Poisoning and Drug Overdose 3rd edition

  38. Leading Causes of Toxicity • Pesticide • Sodium Hydrochloride • Acetaminophen • Ferrous Sulfate • Isoniazid • ***UP National Poison Management and Control Center

  39. Epidemiology • Majority of APAP-related injury have resulted from large single overdoses • Suicide attempts • Adolescents or young adults • 60% female

  40. Pharmacokinetics • Absorption is rapid and usually complete by 1 hour after a therapeutic dose • Half life: 2.5 to 4 hours • Protein binding: 10%

  41. Acetaminophen Toxicity NAPQI Glutathione Stores Dose Biotransformation

  42. Acetaminophen Metabolism sulfate moiety glucoronide moiety ACETAMINOPHEN NAPQI C-P450 N-acetyl-p-benzoquinonimine GLUTATHIONE LIVER kidneys cysteine and mercapturic moeity

  43. Hepatic necrosis occurs when doses deplete >70% of the hepatic GSH Glutathione Stores GSH levels are depleted Malnutrition Fasting Alcohol

  44. Histopathology • Zone 3 hemorrhagic hepatic necrosis • Centrilobular hepatic necrosis with periportal sparing

  45. Factors Affecting Toxicity of a Single Large Overdose  Formation of NAPQI DOSE Saturation of conjugation pathway

  46. Factors Affecting Toxicity of a Single Large Overdose Biotransformation of APAP Cytochrome P450 induction CYP2E1 CYP3A4 Alcohol Phenytoin Carbamazepine ISONIAZID +/rifampicin FASTING

  47. Recommended daily dose 4 grams per day (adults) Toxic dose 7.5 to 10 grams as single dose (adults) 140mg/kg (7700mg) How much is too much?

  48. Clinical Stages of Acetaminophen Toxicity Anorexia Nausea Vomiting Malaise Pallor Resolution Reappearance Renal dysfxn Resolution Sx RUQ pain Oliguria FULMINANT HEPATIC FAILURE OLIGURIC renal failure DEATH SGOT SGPT LAB 10X BILI 5x Protime 0h 24h 48h 72h 96h 2w I II III IV

  49. History of acute APAP overdose Time since overdose 0 - 4 hours 4 - 8 hours 8 - 24 hours Activated Charcoal Loading dose NAC APAP level Baseline LFT, PT, Bili, Crea No further NAC treatment Is APAP level above possible toxicity? NO YES Complete course NAC

  50. Single Acute Acetaminophen Overdose Normogram • To determine the risk of hepatotoxicity • Guide to recommend n-acetylcysteine therapy

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