Mechanism of action
Acetaminophen is absorbed from the upper gastrointestinal tract with peak plasma levels occurring between 30 and 60 minutes after therapeutic doses and usually within 4 hours following an overdose. It is extensively metabolized in the liver to form principally the sulfate and glucoronide conjugates which are excreted in the urine. A small fraction of an ingested dose is metabolized in the liver by isozyme CYP2E1 of the cytochrome P-450 mixed function oxidase enzyme system to form a reactive, potentially toxic, intermediate metabolite. The toxic metabolite preferentially conjugates with hepatic glutathione to form nontoxic cysteine and mercapturic acid derivatives, which are then excreted by the kidney. Recommended therapeutic doses of acetaminophen are not believed to saturate the glucuronide and sulfate conjugation pathways and therefore are not expected to result in the formation of sufficient reactive metabolite to deplete glutathione stores. However, following ingestion of a large overdose, the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the cytochrome P-450 pathway and therefore, the amount of acetaminophen metabolized to the reactive intermediate increases. The increased formation of the reactive metabolite may deplete the hepatic stores of glutathione with subsequent binding of the metabolite to protein molecules within the hepatocyte resulting in cellular necrosis.
Acetylcysteine I.V. Treatment:
Acetylcysteine has been shown to reduce the extent of liver injury following acetaminophen overdose. It is most effective when given early, with benefit seen principally in patients treated within 8-10 hours of the overdose. Acetylcysteine likely protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite.
The steady-state volume of distribution (Vdss) and the protein binding for acetylcysteine were reported to be 0.47 liter/kg and 83%, respectively.
Acetylcysteine may form cysteine, disulfides and conjugates in vivo (N, N'-diacetylcysteine, N-acetylcysteine-cysteine, N-acetylcysteine-glutathione, N-acetylcysteine-protein, etc). Based on published data, it was reported that after an oral dose of 35S-acetylcysteine, about 22% of total radioactivity was excreted in urine after 24 hours. No metabolites were identified.
After a single intravenous dose of acetylcysteine, the plasma concentration of total acetylcysteine declined in a poly-exponential decay manner with a mean terminal half-life (T1/2) of 5.6 hours. The mean clearance (CL) for acetylcysteine was reported to be 0.11 liter/hr/kg and renal CL constituted about 30% of total CL.
Gender: Adequate information is not available to assess if there are differences in pharmacokinetics (PK) between males and females.
Pediatric: The mean elimination T1/2 of acetylcysteine is longer in newborns (11 hours) than in adults (5.6 hours). Pharmacokinetic information is not available in other age groups.
Pregnant Women: In four pregnant women with acetaminophen toxicity, oral or I.V. acetylcysteine was administered at the time of delivery. Acetylcysteine was detected in the cord blood of 3 viable infants and in cardiac blood of a fourth infant sampled at autopsy [ see Pregnancy ].
Hepatic Impairment: In subjects with severe liver damage, i.e., cirrhosis due to alcohol (with Child-Pugh score of 7-13), or primary and/or secondary biliary cirrhosis (with Child-Pugh score of 5-7), mean T1/2 increased by 80% while mean CL decreased by 30% compared to the control group.
Renal Impairment: Pharmacokinetic information is not available in patients with renal impairment.
Geriatric Patients: Adequate information on acetylcysteine PK in geriatric patients is not available.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of acetylcysteine.
Acetylcysteine was not genotoxic in the Ames test or the in vivo mouse micronucleus test. It was, however, positive in the in vitro mouse lymphoma cell (L5178Y/TK+/-) forward mutation test.
Treatment of male rats with acetylcysteine at an oral dose of 250 mg/kg/day for 15 weeks (0.8 times the recommended human dose of 300 mg/kg) did not affect the fertility or general reproductive performance.
Reproductive and Developmental Toxicology
Reproduction studies were performed in rats at oral doses up to 2000 mg/kg/day (6.7 times the recommended human dose of 300 mg/kg) and in rabbits at oral doses up to 1000 mg/kg/day (3.3 times the recommended human dose of 300 mg/kg) and revealed no evidence of impaired fertility or harm to the fetus due to acetylcysteine [ see Pregnancy ].