Tugas Mas Nu.docx

The mechanism of action of acetaminophen is considered as a weak inhibitors of cyclooxygenase activity, especially COX -2, and prostaglandin synthesis. Involvement of the serotonergic pathway and modulation of the cannabinoid system have also been suggested. In agreement with its negligible protein binding and its lipid solubility (logP 0.46). According to a study conducted by Bannwarth (1992) acetaminophen readily penetrates the intact blood brain barrier (BBB) into the central nervous system(CNS). The incidence of adverse drug reaction (ADR) is related to acetaminophen in longterm use, namely hepatotoxicity. Acetaminophen is mainly metabolized by glucuronidation and sulfation. A minor fraction (<10%) is oxidized, mostly by cytochrome P450 (CYP) 2E1 and CYP3A4, to the highly reactive intermediate N-acetyl -p - benzoquinone imine (NAPQI), which has to be detoxified by intracellular glutathione to avoid oxidative stress and hepatocytes necrosis (Kozer,2006). Some studies say that, the risk of hepatotoxicity significantly increases when detoxification mechanisms are saturated (massive ingestion of acetaminophen, presence of CYP2E1 and or CYP3A4 inducers) or when glutathione reserves are depleted (malnutrition, prolonged fasting, chronic liver disease). For acetaminophen side effects that must be considered, namely the risk of hypersensitivity and serious skin reactions although extremely rare. In 2013, the FDA published a warning about potential severe skin reactions, such as Stevens -Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, associated with acetaminophen. The data used by the FDA to support the causality came from a small number of published cases in which patients were rechallenged with acetaminophen and had a recurrence of a serious skin reaction (in both adults and children). These reactions are described after the first dose or at any time during acetaminophen intake (Food and Drug Administration, 2013). The use of acetaminophen with several drugs needs to be considered, because drug interactions can occur which cause an increased risk of hepatotoxic, so the use of acetaminophen with carbamazepine, phenytoin, isoniazid needs to be considered.