ParacetamolParacetamol Poisoning PoisoningKent R. Olson, M.D.Clinical Professor of MedicineUniversity of California, San FranciscoMedical Director, San Francisco DivisionCalifornia Poison Control SystemCase Study:Case Study:uuA 17 year old young man took “pills” and some alcohol after failing his exams. He is drunk and depressed.uuBP 120/80 HR 105uuResp 14/min Temp 37 CuuHis airway is patent, he is breathing normallyCase, continued:Case, continued:uuHe is treated with intravenous fluids, watched until sober, given a psychiatric referral, and sent home with his family.uu3 days later he returns with jaundice.WHAT IS YOUR DIAGNOSIS?WHAT IS YOUR DIAGNOSIS?ParacetamolParacetamol poisoning poisoninguuDiagnosis easily missedoften overlooked in historyno characteristic early symptoms or signsParacetamolParacetamol Poisoning PoisoninguuCommon analgesicoften found in combination productseg, with antihistamines, codeineAcetaminophenMetabolism Glucuronidation(non toxic)Sulfation(non toxic)NAPQIP450 5%Glutathione + NAPQI= nontoxic productLiver cell damageN-acetylcysteine (NAC) 45% 50%ParacetamolParacetamol Toxicity: Toxicity:uuOverdose:sulfation and glucuronidation saturatedincreased production of p-450 metaboliteglutathione eventually depleted glutathione eventually depleted reactive intermediate NAPQI injures cellsreactive intermediate NAPQI injures cellsPCM toxicity, cont.PCM toxicity, cont.uuHigh-risk groups: enhanced p-450 activity chronic alcoholicschronic use of isoniazid (INH)PharmacokineticsPharmacokineticsuuTablets dissolve rapidlyuuPeak level 3-4 hours after ingestionMay be delayed in the presence of other drugs May be delayed in the presence of other drugs ( (egeg, antihistamines, anticholinergics, opiates), antihistamines, anticholinergics, opiates)Pharmacokinetics, cont.Pharmacokinetics, cont.uuVolume of Distribution approx. 1L/kgIngestion of 200 mg/kg 200 mg/L est. blood levelIngestion of 200 mg/kg 200 mg/L est. blood leveluuElimination half-life normally 1-3 hoursIncreased to 4-6 hours or more after overdoseIncreased to 4-6 hours or more after overdoseClinical Manifestations of Toxicity:Clinical Manifestations of Toxicity:uuEarly: non-specificanorexia, vomitinganorexia, vomitingClinical Clinical toxicicitytoxicicity, cont., cont.uu24-48 hrs:onset of liver injuryonset of liver injury AST, ALT may exceed 10,000 IUAST, ALT may exceed 10,000 IUrenal injury may also occurrenal injury may also occurParacetamolParacetamol Toxicity, continued: Toxicity, continued:uu2-5 days:liver & kidney injury resolve in most patientsliver & kidney injury resolve in most patientssome patients may develop some patients may develop fulminant liver failurefulminant liver failure progressive rise in PT/INR, bilirubinprogressive rise in PT/INR, bilirubin metabolic acidosis, hypoglycemiametabolic acidosis, hypoglycemia encephalopathy encephalopathy DEATHDEATHRarely - massive ingestions only:Rarely - massive ingestions only:uu 600 mg/kg: early onset metabolic acidosisNot due to liver failureNot due to liver failureProbably mitochondrial poisoningProbably mitochondrial poisoninguuOne case of massive ingestion 1500 mg/kgComaComaHypotensionHypotensionAcidosisAcidosisPrediction of Prediction of ParacetamolParacetamol Toxicity: Toxicity:uuHistory:acuteacute ingestion of 200 mg/kg or 10 gm ingestion of 200 mg/kg or 10 gm 20 tablets in average-sized person20 tablets in average-sized personchronicchronic use of 4-6 gm/day in a high-risk group use of 4-6 gm/day in a high-risk group Chronic alcohol abuse, isoniazid useChronic alcohol abuse, isoniazid usePrediction of PCM toxicity, cont.Prediction of PCM toxicity, cont.uuClinical evaluation:serum PCM level is best predictor, if availableserum PCM level is best predictor, if availablelevels associated with “probable toxicity”:levels associated with “probable toxicity”: 200 mg/L at 4 hrs after acute ingestion200 mg/L at 4 hrs after acute ingestion 100 at 8 hrs100 at 8 hrs 50 at 12 hrs50 at 12 hrsAPAP(mg/L)Poss. ToxicProb. ToxichrsSerum PCM levelNote: co-ingestion of Nyquil plus up to 44 g Tylenol ERRef: Bizovi K et al: J Toxicol Clin Toxicol 1995; 33:510 Tylenol “Extended Relief” Case:Tylenol “Extended Relief” Case:Potential Pitfalls with Nomogram:Potential Pitfalls with Nomogram:uuChronic intoxicationuuDelayed or erratic absorptionmassive ingestionmassive ingestionmixed ingestion with mixed ingestion with opioidsopioids, anticholinergics , anticholinergics uuVery early and transient increase in the PT/INR may predict later LFT riseNormal PT/INR at 24 hrs may have good negative Normal PT/INR at 24 hrs may have good negative predictive valuepredictive valueGut decontamination for PCMGut decontamination for PCMuuNO forced emesisuuActivated charcoal preferreduuGastric lavage?only for massive ingestions (only for massive ingestions (egeg, 600 mg/kg), 600 mg/kg)Treatment, continuedTreatment, continueduuAntidote: N-acetylcysteine (NAC)provides SH group - binds to NAPQIprovides SH group - binds to NAPQI most effective if started within 8-10 hrs after ingestionmost effective if started within 8-10 hrs after ingestioncan be given PO or IVcan be given PO or IVif vomiting, use IV route or give if vomiting, use IV route or give antiemeticantiemeticuuAlternate medication: oral methionineSummarySummaryuuIngestion 200 mg/kg probably not toxicuuIf no serum level available treat based on doseuuIV acetylcysteine or oral methionineuuStart antidote within 8 hoursuuLiver or kidney damage delayed 24-48 hrs