Toxicological Property of Acetaminophen: The Dark Side of a Safe Antipyretic/Analgesic Drug?

Abstract

Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is the most popular analgesic/antipyretic agent in the world. APAP has been regarded as a safer drug compared with non-steroidal anti-inflammatory drugs (NSAIDs) particularly in terms of lower risks of renal dysfunction, gastrointestinal injury, and asthma/ bronchospasm induction, even in high-risk patients such as the elderly, children, and pregnant women. On the other hand, the recent increasing use of APAP has raised concerns about its toxicity. In this article, we review recent pharmacological and toxicological findings about APAP from basic, clinical, and epidemiological studies, including spontaneous drug adverse events reporting system, especially focusing on drug-induced asthma and pre-and post-natal closure of ductus arteriosus. Hepatotoxicity is the greatest fault of APAP and the most frequent cause of drug-induced acute liver failure in Western countries. However, its precise mechanism remains unclear and no effective cure beyond N-acetylcysteine has been developed. Recent animal and cellular studies have demonstrated that some cellular events, such as c-jun N-terminal kinase (JNK) pathway activation, endoplasmic reticulum (ER) stress, and mitochondrial oxidative stress may play important roles in the development of hepatitis. Herein, the molecular mechanisms of APAP hepatotoxicity are summarized. We also discuss the not-so-familiar "dark side" of APAP as an otherwise safe analgesic/antipyretic drug.

COVID-19: Is There Evidence for the Use of Herbal Medicines as Adjuvant Symptomatic Therapy?

“…Safety. Paracetamol (acetaminophen) is hepatotoxic (Athersuch et al, 2018), and several side effects have been reported (Ishitsuka et al, 2020), such as nausea (up to 34%), vomiting (up to 15%); abdominal pain, diarrhea, constipation, dyspepsia and enlarged abdomen (1% to 10%); anemia, postoperative hemorrhage (1% to 10%); rash, pruritus (1% to 10%); dyspnea, abnormal breath sounds, pulmonary edema, hypoxia, pleural effusion, stridor, wheezing, coughing (1% to 10%); cardiovascular effects (1% to 10%): peripheral edema, hypertension, hypotension, tachycardia, chest pain; metabolic alterations (1% to 10%): hypokalemia, hyperglycemia; headache, dizziness (1% to 10%). Other side effects: dystonia; muscle spasms, trismus (1% to 10%); insomnia, anxiety (1% to 10%); oliguria (1% to 10%); pyrexia, fatigue (1% to 10%) (Drugs.com, 2020b).…”

Cytochrome P450 2E1 should not be neglected for acetaminophen-induced liver injury in metabolic diseases with altered insulin levels or glucose homeostasis

“…This recommendation was actually driven by a concern regarding the incidence of acute liver failure (ALF) due to APAP overdose. Indeed, APAP intoxication after intentional or accidental overdoses can lead to massive hepatocellular necrosis and acute liver failure, which can be fatal if liver transplantation is not performed [2,3]. Different predisposing factors are known, or suspected, to enhance the risk and severity of APAP-induced hepatotoxicity such as fasting, chronic alcohol intoxication, hepatitis C virus infection, nonalcoholic fatty liver disease (NAFLD) and diabetes, as discussed below [2,4].…”

Hepatoprotective Effects of Crude Stem Bark Extracts and Solvent Fractions of Cordia africana against Acetaminophen-Induced Liver Injury in Rats

“…First, the model has its own prescreening lethality test, which serves as a prestudy test. Second, APAP induces hepatotoxicity, which resembles the liver injury in humans [ 35 ]. Administration of both extracts of C. africana stem bark showed no mortality and signs of toxicity, which might justify the edibility of the pulp of mature fruit of the plant to human beings in Ethiopia [ 36 ].…”