Paracetamol PoisoningParacetamol PoisoningParacetamol PoisoningParacetamol Poisoning

Kent R. Olson, M.D.Kent R. Olson, M.D.Clinical Professor of MedicineClinical Professor of Medicine

University of California, San FranciscoUniversity of California, San FranciscoMedical Director, San Francisco DivisionMedical Director, San Francisco Division

California Poison Control SystemCalifornia Poison Control System

Case Study:Case Study:Case Study:Case Study:

A 17 year old young man took “pills” and some A 17 year old young man took “pills” and some alcohol after failing his exams. He is drunk and alcohol after failing his exams. He is drunk and depressed.depressed.

BP 120/80BP 120/80 HR 105 HR 105

Resp 14/minResp 14/min Temp 37 C Temp 37 C

His airway is patent, he is breathing normallyHis airway is patent, he is breathing normally

Case, continued:Case, continued:Case, continued:Case, continued:

He is treated with intravenous fluids, watched He is treated with intravenous fluids, watched until sober, given a psychiatric referral, and until sober, given a psychiatric referral, and sent home with his family.sent home with his family.

3 days later he returns with jaundice.3 days later he returns with jaundice.

WHAT IS YOUR DIAGNOSIS?WHAT IS YOUR DIAGNOSIS?

Paracetamol poisoningParacetamol poisoningParacetamol poisoningParacetamol poisoning

Diagnosis easily missedDiagnosis easily missed– often overlooked in historyoften overlooked in history

– no characteristic early symptoms or signsno characteristic early symptoms or signs

Paracetamol PoisoningParacetamol PoisoningParacetamol PoisoningParacetamol Poisoning

Common analgesicCommon analgesic– often found in combination productsoften found in combination products

– eg, with antihistamines, codeineeg, with antihistamines, codeine

AcetaminophenAcetaminophenMetabolism Metabolism

Glucuronidation(non toxic)

Sulfation(non toxic)

NAPQI

P450

~ 5%

Glutathione + NAPQI= nontoxic product

Liver cell damage

N-acetylcysteine (NAC)

~ 45% ~ 50%

Paracetamol Toxicity:Paracetamol Toxicity:Paracetamol Toxicity:Paracetamol Toxicity:

Overdose:Overdose:– sulfation and glucuronidation saturatedsulfation and glucuronidation saturated

– increased production of p-450 metaboliteincreased production of p-450 metabolite• glutathione eventually depleted glutathione eventually depleted • reactive intermediate NAPQI injures cellsreactive intermediate NAPQI injures cells

PCM toxicity, cont.PCM toxicity, cont.PCM toxicity, cont.PCM toxicity, cont.

High-risk groups: High-risk groups: enhanced p-450 activityenhanced p-450 activity

– chronic alcoholicschronic alcoholics

– chronic use of isoniazid (INH)chronic use of isoniazid (INH)

PharmacokineticsPharmacokineticsPharmacokineticsPharmacokinetics

Tablets dissolve rapidlyTablets dissolve rapidly Peak level 3-4 hours after ingestionPeak level 3-4 hours after ingestion

– May be delayed in the presence of other drugs May be delayed in the presence of other drugs (eg, antihistamines, anticholinergics, opiates)(eg, antihistamines, anticholinergics, opiates)

Pharmacokinetics, cont.Pharmacokinetics, cont.Pharmacokinetics, cont.Pharmacokinetics, cont.

Volume of Distribution approx. 1L/kgVolume of Distribution approx. 1L/kg– Ingestion of 200 mg/kg ~ 200 mg/L est. blood levelIngestion of 200 mg/kg ~ 200 mg/L est. blood level

Elimination half-life normally 1-3 hoursElimination half-life normally 1-3 hours– Increased to 4-6 hours or more after overdoseIncreased to 4-6 hours or more after overdose

Clinical Manifestations of Toxicity:Clinical Manifestations of Toxicity:Clinical Manifestations of Toxicity:Clinical Manifestations of Toxicity:

Early: Early: non-specificnon-specific– anorexia, vomitinganorexia, vomiting

Clinical toxicicity, cont.Clinical toxicicity, cont.Clinical toxicicity, cont.Clinical toxicicity, cont.

24-48 hrs:24-48 hrs:– onset of liver injuryonset of liver injury

• AST, ALT may exceed 10,000 IUAST, ALT may exceed 10,000 IU

– renal injury may also occurrenal injury may also occur

Paracetamol Toxicity, continued:Paracetamol Toxicity, continued:Paracetamol Toxicity, continued:Paracetamol Toxicity, continued:

2-5 days:2-5 days:

– liver & kidney injury resolve in most patientsliver & kidney injury resolve in most patients

– some 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 • DEATHDEATH

Rarely - massive ingestions only:Rarely - massive ingestions only:Rarely - massive ingestions only:Rarely - massive ingestions only:

> 600 mg/kg: early onset metabolic acidosis> 600 mg/kg: early onset metabolic acidosis– Not due to liver failureNot due to liver failure– Probably mitochondrial poisoningProbably mitochondrial poisoning

One case of massive ingestion >1500 mg/kgOne case of massive ingestion >1500 mg/kg– ComaComa– HypotensionHypotension– AcidosisAcidosis

Prediction of Paracetamol Toxicity:Prediction of Paracetamol Toxicity:Prediction of Paracetamol Toxicity:Prediction of Paracetamol Toxicity:

History:History:– 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 person

– chronicchronic 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 use

Prediction of PCM toxicity, cont.Prediction of PCM toxicity, cont.Prediction of PCM toxicity, cont.Prediction of PCM toxicity, cont.

Clinical evaluation:Clinical evaluation:– serum PCM level is best predictor, if availableserum PCM level is best predictor, if available– levels 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 hrs

1

10

100

1000

0 5 10 15 20 25

APAP(mg/L)

Poss. Toxic

Prob. Toxic

hrs

Serum PCM level

Note: 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:Tylenol “Extended Relief” Case:Tylenol “Extended Relief” Case:

Potential Pitfalls with Nomogram:Potential Pitfalls with Nomogram:Potential Pitfalls with Nomogram:Potential Pitfalls with Nomogram:

Chronic intoxicationChronic intoxication

Delayed or erratic absorptionDelayed or erratic absorption– massive ingestionmassive ingestion– mixed ingestion with opioids, anticholinergics mixed ingestion with opioids, anticholinergics

Very early and transient increase in the PT/INR Very early and transient increase in the PT/INR may predict later LFT risemay predict later LFT rise– Normal PT/INR at 24 hrs may have good negative Normal PT/INR at 24 hrs may have good negative

predictive valuepredictive value

Gut decontamination for PCMGut decontamination for PCMGut decontamination for PCMGut decontamination for PCM

NO forced emesisNO forced emesis Activated charcoal preferredActivated charcoal preferred Gastric lavage?Gastric lavage?

– only for massive ingestions (eg, > 600 mg/kg)only for massive ingestions (eg, > 600 mg/kg)

Treatment, continuedTreatment, continuedTreatment, continuedTreatment, continued

Antidote: Antidote: N-acetylcysteine (NAC)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 ingestion

– can be given PO or IVcan be given PO or IV– if vomiting, use IV route or give antiemeticif vomiting, use IV route or give antiemetic

Alternate medication: oral Alternate medication: oral methioninemethionine

SummarySummarySummarySummary

Ingestion < 200 mg/kg probably not toxicIngestion < 200 mg/kg probably not toxic If no serum level available treat based on doseIf no serum level available treat based on dose IV acetylcysteine or oral methionineIV acetylcysteine or oral methionine Start antidote within 8 hoursStart antidote within 8 hours Liver or kidney damage delayed 24-48 hrsLiver or kidney damage delayed 24-48 hrs