Paracetamol Toxicity

TOXICOLOGY LABORATORY - PRELIMS

C8H9NO

Acetaminophen

• 60 %

• Glucuronic acid conjugate

• excreted in urine

Glucuronide conjugation

• 30 %

• Sulfate conjugate

• excreted in urine

Sulfate conjugation

• 5 – 10 %

• NAPQI

• binds with GSH

• mercapturic & cysteine metabolite

• excreted in urine

Cytochrome P450 2E1

T or F: are all part of the acute overdose? if NOT which number is wrong?

1. Depletes glutathione stores in the kidney

2. NAPQI accumulates

3. Hepatocellular necrosis happens

4. Possible damage to other organs

• No

• number 1 (liver)

Dosing definitions:

• Defined as ≤4 g in adults and ≤75 mg/kg in children per 24 hr period

Therapeutic dose

Dosing definitions:

• Refers to multiple ingestions over a period > 8 hours totaling >4 g per 24 hour period

RSTI or Chronic overdose

Dosing definitions:

• Defined as toxic amount ( >4 g ) ingested in ≤ 8 hours

Acute overdose

RSTI means

REPEATED SUPRATHERAPEUTIC INGESTION

WHAT STAGE OF ACUTE OVERDOSE:

• anorexia, nausea, vomiting

• 0 to 24 hrs

Stage I

WHAT STAGE OF ACUTE OVERDOSE:

• 24 to 72 hrs (3 days)

• right upper quadrant abdominal pain and if poisoning is severe, bilirubin and PT (usually reported as the INR) sometimes elevated

Stage II

WHAT STAGE OF ACUTE OVERDOSE:

• >5 days

• resolution of hepatotoxicity or progression to multisystem organ failure (sometimes fatal)

Stage IV

WHAT STAGE OF ACUTE OVERDOSE:

• 72 to 96 hrs

• vomiting and symptoms of liver; peaking of AST, ALT, bilirubin and INR; sometimes renal failure and pancreatitis

Stage III

Pathophysiology: T or F

• NAPQI covalently binds to the cysteinyl sulfhydryl groups of hepatocellular proteins

• Excessive NAPQI formation

• Oxidative damage & mitochondrial dysfunction

• Reduction in glutathione stores (70%)

• Hepatocellular injury and death

TRUE

TRUE OR FALSE

Etiology: Conditions that reduce glutathione stores in the body

• Restricted diet

• Older age

• Compromised nutritional status

• Underlying hepatic or renal disease

TRUE

CYTOCHROME P450 (CYP2E1) INDUCERS

• Ethanol ingestion Tobacco smoking

• Isoniazid, Rifampicin

• Phenytoin, Phenobarbital, Barbiturates, Carbamazepine

• Co-trimoxazole

• Zidovudine

Site the Diagnosis of Acetaminophen toxicity

• Serum acetaminophen levels

• Rumack-Matthew nomogram

• liver tests

• Prothrombin time measurement

• AST

• ALT

• it is an antidote of Acetaminophen toxicity

• a sulfhydryl compound and protects against liver damage in early paracetamol poisoning by providing cysteine, for glutathione synthesis.

• It also acts by supplying additional thiol groups, which bind directly with NAPQI encouraging its reduction to acetaminophen without inhibiting its production.

Acetylcysteine

Site the Treatment & Management

• Gastric decontamination

• Oral N-Acetylcysteine

• Intravenous N-Acetylcysteine

Site the Prognosis

• Mortality rate

• Hepatic failure

• Chronic ethanol use

• Children younger than 6 yrs old

• Appropriate treatment

Poor prognostic indicators at 24 to 48 hours post ingestion include all of the following:

• pH < 7.3 after adequate resuscitation

• Coagulopathy ( International normalized ratio - INR >3 )

• Renal failure ( Serum creatinine >2.6 )

• Hypoglycemia

• Thrombocytopenia

Poor prognosis

• Hepatic encephalopathy grade III ( confusion and somnolence )

• Hepatic encephalopathy grade IV ( stupor and coma )

• Metabolic acidosis

• Elevated bilirubin