LAB 3.1. Managing Paracetamol Overdose

PARACETAMOL

• Acetaminophen

• N-acetyl-p-aminophenol (APAP)

• Standard antipyretic and analgesic for mild to moderate pain

• For use to a wide variety of patients

• OTC and prescription medications

• Seldom causes serious side effects

• Broad tolerability

• May still have a much broader clinical benefits in years to come

1893

• First clinical of paracetamol use by von Mering

1947

• Extensive paracetamol medical use as prescription drug

1950

• Paracetamol commercial availability in US

1960

• Paracetamol became OTC

1966

• Discovery of hepatotoxicity as Paracetamol ADR

1980

• Paracetamol as mainstay analgesic and antipyretic

SMALL INTESTINES & STOMACH

• Paracetamol absorption site

8% - 43%

• Paracetamol toxic concentrations

SULFATION & GLUCORONIDATOPM

• Paracetamol hepatic metabolism

7H

• Paracetamol ½ life elimination of NEONATES

~4H

• Paracetamol ½ life elimination of INFANTS

3H

• Paracetamol ½ life elimination of CHILDREN

~3H

• Paracetamol ½ life elimination of ADOLESCENTS

~2H

• Paracetamol ½ life elimination of ADULTS

SEVERE RENAL INSUFFICIENCY

• May affect paracetamol ½ life elimination

RENAL

• Excretion path of paracetamol

<5%

• Paracetamol % excreted UNCHANGED

60 - 80%

• Paracetamol % GLUCURONIDE metabolites

20% - 30%

• Paracetamol % SULFATE metabolites

~8%

• Paracetamol % CYSTEINE and MERCAPTURIC A. metabolites

LESS THAN AN H

• Paracetamol ORAL onset of action

5 - 10M

• Paracetamol IV ANALGESIA onset of action

W/IN 30M

• Paracetamol IV ANTIPYRESIS onset of action

4 - 6H

• Paracetamol IV ANALGESIA duration of action

> 6H

• Paracetamol IV ANTIPYRESIS duration of action

PARACETAMOL TOXICITY

• excellent safety profile in proper therapeutic doses

HEPATOTOXICITY

• Paracetamol misuse and overdose

• Caused one to three days after ingestion

END-ORGAN TOXICITY

• Often delayed 24 to 48 H after acute ingestion

GASTROENTERITIS

• Can caused within hours after ingesti

2E1

1A2

2A6

3A4

• CYP Enzymes involved in metabolism

N-ACETYL-P-BENZOQUINONEIMINIE (NAPQI)

• Extremely short half-life

• Rapidly conjugated with glutathione

• In excess formation or with glutathione reduction

  • Covalently binds to the cysteinyl sulfhydryl groups of hepatocellular proteins

NAPQI-PROTEIN ADDUCTS

• Ensuing cascade of oxidative damage and mitochondrial dysfunction

• Subsequent inflammatory response propagates hepatocellular injury and death

CENTRILOBULAR (ZONE III) REGION

• Necrosis primarily occurs in _, owing to the greater production of NAPQI by these cells

HEPATIC ENZYME PRECONDITIONING

• May increase formation of NAPQI

UNDERNUTRITION

• common among alcoholics

• reduces hepatic glutathione stores

75 mg/kg BW

• Paracetamol CHILDREN daily dose

10-15 mg/kg / 4-6 hrs

• Paracetamol CHILDREN daily dose

• If younger than 12 y.o. and/or less than 50 kg

4 g

• Paracetamol Adult daily dose

150 mg/kg BW

• CHILDREN Minimum Hepatotoxic Dose As a Single Acute Ingestion

7.5 - 10g

• ADULT Minimum Hepatotoxic Dose As a Single Acute Ingestion

PRECLINICAL TOXIC EFFECTS

• Phase I

HEPATIC INJURY

• Phase II

HEPATIC FAILURE

• Phase III

RECOVERY PHASE

• Phase IV

PHASE I

• 30 min to 24 hrs after ingestion

• May be asymptomatic

• Report anorexia, N/V, and malaise

• Liver function tests may remain within normal limits

• Metabolic acidosis → comatose state

PHASE II

• 24 to 48 hrs after ingestion

• Elevation of transaminases levels

• Elevated PT, INR and bilirubin

• RUQ tenderness may be present

• Some patients may report oliguria

• Tachycardia and hypotension indicate ongoing volume losses

PHASE III

• 72 to 96 hrs after ingestion

• Moderate elevations in hepatic transaminases

• Hepatic necrosis and dysfunction associated with jaundice, coagulopathy, hypoglycemia, and hepatic encephalopathy

• May have continued N/V, abdominal pain, and a tender hepatic edge

• Acute renal failure in some critically ill patients

• Death from multiple organ failure

PHASE IV

• 4 days to 3 wks after ingestion

• 2 possible outcomes:

  • Complete recovery and resolution of symptoms

  • Death = liver failure

RUMACK - MATTHEW NOMOGRAM

• Interpret plasma paracetamol values to assess hepatotoxicity risk after a single, acute ingestion

• Tracking begins 4 hours after ingestion

• Ends 24 hours after ingestion

• 60% of patients with values above the "probable" line develop hepatotoxicity

LIPASE & AMYLASE

• Recommended serum studies for patients with abdominal pain

SERUM HUMAN CHORIONIC GONADOTROPIN

• Recommended serum studies in females of childbearing age

SALICYLATE LEVEL

• Recommended serum studies in patients with concern of co-ingestants

ABG & AMMONIA

• Recommended serum studies in clinically compromised patients

URINALYSIS

• Recommended serum studies to check for hematuria and proteinuria

ECG

• Recommended serum studies to detect additional clues for coingestants

CT SCANE

• Recommended serum studies in patients with altered mental status

SUBCLINICAL RISE TRANSAMINASE

• Approximately 12 hours after an acute ingestion

DECONTAMINATION

• If within 1 to 2 hours post ingestion

NAC

• nearly 100% hepatoprotective

• Given within 8 hours after an acute paracetamol ingestion

• Also beneficial in patients who present more than 24 hours after ingestion

• both oral and IV

140 mg/kg BW

• NAC Loading dose

72h

• Total NAC tx duration

1330 mg/kg BW

• Total NAC delivered

IV NAC

• commonly used for the treatment of paracetamol ingestion

• For:

  • Altered mental status

  • GI bleeding and/or obstruction

  • history of caustic ingestion

  • Potential fetal paracetamol toxicity in a pregnant woman

  • Inability to tolerate oral NAC because of emesis refractory to proper use of antiemetics

D5W + NAC

• IV NAC formulation

INTERMITTENT IV INFUSION

• for late-presenting or chronic ingestion

15,000 mg INFUSED IV / 1H

• Loading dose in patients who weigh more than 100 kg

140 mg/kg BW

• Loading dose for intermittent IV infusion

FLUSHING

PRURITUS

RASH

BRONCHOSPASM

HYPOTENSION

• NAC adverse S/E

50g

• Activated charcoal adult dose

1 g/kg BW - 50g

• Activated charcoal children dose

METABOLIC ACIDOSIS

RENAL FAILURE

COAGULOPATHY

ENCEPHALOPATHY

• Criteria for liver transplantation

CHRONIC PARACETAMOL POISONING

• Supratherapeutic doses

• (+) Persistent serum APAP concentration laboratory indicators of hepatotoxicity

• Rumack-Matthew nomogram cannot be used

• Begin NAC therapy

• Consult a regional poison control center for guidance on a treatment regimen