Mechanism & management ofParaceamol toxicityUses of paracetamolUses of paracetamol• AnalgesicAnalgesic• AntipyreticAntipyretic• ArthritisArthritis• HeadacheHeadache• DysmenorrheaDysmenorrhea
Absorption: Paracetamol is well absorbed from the GItractHalf life: 2-3 hoursExcreion: 5% excreted unchanged in the urine,remainder metabolized in the liver by thecytochrome p-450 system.Toxicokinetics of ParacetamolToxicokinetics of Paracetamol
Paracetamol can produce fatal hepatotoxicity in untreatedpatients through the generation of a toxic metaboliteAdverse Effects (overdose >10 gram)• Phase I (12-24 hours post ingestion): nausea, vomiting,anorexia and diaphoresis (sweating).• Phase II (1-4 days post ingestion): asymptomatic.• Phase III (2-3 days in untreated patients): nausea, abdominalpain, progressive evidence of hepatic failure, coma and death.Adeverse Effect of Paraceamol
• Acetaminophen is rapidly absorbed from the stomach and smallintestine and metabolized by conjugation in the liver to nontoxicagents, which then are eliminated in the urine.• In acute overdose or when maximum daily dose is exceeded over aprolonged period, the normal pathways of metabolism becomesaturated.• Excess acetaminophen is then metabolized in the liver via theoxidase P450 system to a toxic metabolite.• Under conditions of excessive metabolite formation or reducedglutathione stores, the reactive metabolite is free to covalently bindto vital proteins and the lipid bilayer of hepatocytes; this results inhepatocellular death and subsequent liver necrosis.Mechanism of paracetamol toxicityMechanism of paracetamol toxicity
Management/treatment of Paracetamol toxicityManagement/treatment of Paracetamol toxicityAdult patients who have ingested >7 gram or children who have ingested>100 mg/kg require treatment.• The recommended treatment is gastrointestinal decontamination withsyrup of ipecac (induce vomiting) or gastric lavage (wash out) for patientspresenting within 2 hours of ingestion.• Antidote therapy with N-acetyl cysteine (NAC) is indicated for patientswith toxic blood levels of paracetamol.Dose: 140 mg/kg as a loading dose followed by 70 mg/kg every 4 hours fora total of 17 doses.Patients with severe nausea secondary to NAC may be prevented with IVmetoclopramide (antiemetic and increase the rate of absorption of NAC)10 mg 6 hours.• Supportive care with IV electrolyte and Vitamin-K if bleeding isoccurred.• In severe case hemoperfusion is necessary for quick elemination of thetoxic intermediate.
• Initially, hyperventilation develops (loss of CO2) secondary todirect stimulation of the respiratory centers. This may be the onlyconsequence of mild salicylism. Disturbance in acid-base occurs.• A severe metabolic (ketolactic) acidosis may develop with severesalicylate intoxication.• Excretion of hydrogen ions produces acidic urine.• Overdose produces: Tinnitus, tachycardia, CNS depression,seizures, nausea & vomiting, GI hemorrhage, prolonged bleedingtime, dehydration. Death may occur from acidosis.Adverse Effect (>15-20g)Prolong administration of large doses (3.6 gram daily) producesadverse effects. At a dose >150, >250 & >500 mg/kg produce mild,moderate & severe poisoning respectively.
• Salicylates cause oxidative phosphorylation.• Thus catabolism occurs with the following results:- increase oxygen consumption,- increase carbon dioxide production,- accelerate activity of the glycolytic and lipolyticpathways,- depletion of hepatic glycogen, hyperpyrexia.Mechanism of Action
• Gastric lavage may be beneficial, up to 60 minutes aftersalicylate ingestion.• Fluid losses from vomiting and sweating are replaced by IVfluid.• Hemodialysis is effective method for enhanced elimination ofsalicylate and correcting acid-base and fluid balanceabnormalities.• Sodium bicarbonate is given to alkalinize the urine & increasesalicylate excretion.• Use of multiple doses of activated charcoal is currentlyrecommended.• Monitored glucose levels closely.Management/Treatment