Toxicity of Acetaminophen PDF

Toxicity of acetaminophen  Introduction Acetaminophen (n-acetyl-para-aminophenol, APAP, paracetamol ) Analgesics were first among the substances most frequently involved in human adult exposures, accounting for 12.5% of all chemical substance poisoning, and th...

Toxicity of acetaminophen  Introduction Acetaminophen (n-acetyl-para-aminophenol, APAP, paracetamol ) Analgesics were first among the substances most frequently involved in human adult exposures, accounting for 12.5% of all chemical substance poisoning, and third among pediatric cases (7.2%). Acetaminophen “in combination” was fourth among the top 25 substance categories with the highest number of fatalities. Poisoning cases with APAP exceed those of all other agents in this category (five times greater incidence than with aspirin). It is the most common drug involved in overdose (O.D.), registering approximately 60% of all analgesic exposures, and the second most common cause of liver failure in the United States. The U.S. Food and Drug Administration (FDA) reports that over 56,000 emergency room visits per year are due to acetaminophen O.D. as a sole agent, resulting in about 100 deaths per year, one-fourth of which are intentional  Medicinal chemistry and pharmacology Acetaminophen is the major hydroxylation metabolite of two potent analgesic parent compounds, acetanilid and phenacetin. The antipyretic activity of the molecules resides in the aminobenzene structure. APAP reduces fever by a direct action on the heat- regulating centers in the hypo-thalamus, dissipating heat via vasodilation and increased sweating. Its analgesic and antipyretic properties are equivalent to those of aspirin. Its inhibition of central prostaglandin synthetase is more effective than its peripheral action, rendering it a weak anti- inflammatory agent compared with aspirin. The site and mechanism of its analgesic action are, to this day, unclear.  clinical use APAP is recommended as an analgesic/antipyretic in the presence of aspirin allergy, in patients who demonstrate blood coagulation disorders, in children, and in patients who receive oral anticoagulants or who demonstrate upper gastrointestinal disease. It is useful in a variety of arthritic and rheumatic conditions, including musculoskeletal disorders, headache, and other minor pain, and for the management of fever associated with bacterial and viral infections.  Metabolism Acetaminophen is rapidly absorbed from the gastrointestinal tract and uniformly distributed, with peak plasma levels achieved by 0.5 to 2.0 h. Hepatic glucuronide and sulfate conjugation (Reactions 1 and 2) produce the inactive corresponding conjugates, which account for 95% of metabolism and elimination in urine. In addition, at therapeutic acute doses, the remaining 4 to 5% of the product is detoxified and eliminated in the minor cytochrome P450 oxidase pathway (Reaction 3). The result is the production of the reactive intermediate, N- acetyl-p- benzoquinoneimine (NAPQI) metabolite. Further conjugation by cellular glutathione results in the production of mercapturic acid and cysteine conjugates (Reaction 4). With chronic use or with large doses, the glucuronide and sulfate conjugation metabolic routes (1 and 2) are saturated, and more importantly, glutathione stores are depleted. This leaves the cytochrome P450 oxidase pathway (Reaction 3) to accumulate the toxic NAPQI metabolite. Metabolism  Mechanism of toxicity The binding of NAPQI to hepatocyte mem-branes and sulfhydryl proteins accounts for the hepatotoxic sequelae. The NAPQI is then thought to covalently bind to critical cellular macromolecules in hepatocytes and cause cell death. Hepatic necrosis and inflammation develop as a consequence of hepatocellular death, which results in development of clinical and laboratory findings consistent with liver failure. A similar mechanism is postulated for the renal damage that occurs in some patients following acetaminophen toxicity. Signs and symptoms of acute toxicity  Clinical Management Activated charcoal or other gastrointestinal decontamination procedures can be utilized as deemed necessary. Induction of emesis is not recommended as prolonged emesis may interfere with N-acetyl cysteine (NAC) therapy. Blood acetaminophen concentrations of 200 mg/dl (or higher) at 4 h post ingestion indicate severe risk of hepatic failure and are treated with a standard NAC treatment regimen. NAC is a glutathione substitute and prevents hepatic damage by quenching the reactive NAPQI. Studies have also suggested that an increase in alpha fetoprotein, a surrogate for hepatic regeneration following injury, is strongly associated with a favorable outcome in patients with acetaminophen-induced liver injury and hence may be used as a supplement to existing prognostic criteria.  A special mention of the interaction of acetaminophen and alcohol consumption is warranted. Large numbers of reports in the scientific literature and public media suggest that a potentially high risk of liver toxicity due to acetaminophen exists when consumed following alcohol intake.  Assignment 1-…………. Is glutathione substitute 2- induction of emesis is recommended in acetaminophen toxicity a) True b) False 3-…………. Is toxic metabolite of APAP 4- The following pathway is responsible of acetaminophen Toxicity a) glucuronoid pathway b) Sulphate pathway c) CYP450 pathway