Acetaminophen

Acetaminophen, also called paracetamol, is an analgesic, or pain-relief drug, used primarily for body and menstrual aches, headaches, and other mild to moderate pain. One of the leading nonprescription drugs in the general treatment of minor pain for a wide range of ages, acetaminophen lowers the sensory indicators to pain and cools the body as it provides relief. It is also an antipyretic used to reduce fevers and alleviate joint pain, such as that caused by osteoarthritis, although it is not recommended to treat the underlying inflammation, as the drug does not have noticeable anti-inflammatory effects. Acetaminophen’s expansive therapeutic effects are under examination for the drug’s interaction with a wider array of diseases. Use of acetaminophen in combination with non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac can lead to more therapeutic and inhibitory actions toward cardiovascular and carcinogenic diseases.

Brief History

During the Middle Ages, typical antipyretic agents were derived from cinchona bark and white willow bark, more commonly known as the chemical family of salicins. By the 1880s, the scarcity of the cinchona tree fueled the need for an alternative source for antipyretic agents. Harmon Northrop Morse first produced and unknowingly discovered acetaminophen in 1878 through the reduction of p-nitrophenol with tin in the presence of glacial acetic acid. Acetaminophen was not properly used for medical purposes until fifteen years later, when researchers justified its effectiveness as an antipyretic. However, initial trials relayed acute toxicity in testing animals such as Hungarian frogs, guinea pigs, rabbits, and dogs. Given the troubling effects, acetaminophen did not receive any further interest until the 1940s.

In the late 1940s, researchers at Yale University determined that acetaminophen was the major metabolite of acetanilide, a known analgesic and antipyretic, and that in fact it was acetaminophen that was responsible for acetanilide's efficacy. Soon after, biochemists Bernard Brodie and Julius Axelrod demonstrated acetaminophen’s analgesic effects on human volunteers and determined that it was less toxic than acetanilide, which was known to cause methemoglobinemia (elevated methemoglobin in the blood), and most likely safer than phenacetin, another acetanilide derivative that also metabolized into acetaminophen. The rediscovery of acetaminophen sparked public interest in the United States, where it was subsequently sold, in combination with aspirin and caffeine, under the trade name Triagesic. Within a year, Triagesic was withdrawn from the market after three users were reported to have been diagnosed with the blood disease agranulocytosis. However, it soon became apparent that the disease had not been caused by the acetaminophen, and by 1955 it had been reintroduced to the US market as a single nonprescription analgesic.

By the 1960s, acetaminophen proved its safety and reliability among its predecessors, particularly acetanilide and phenacetin, whose side effects included gastrointestinal ulceration and hemorrhage, among others. However, the ensuing widespread availability of the drug increased reports of self-overdosing, and in 1966 the first cases of severe liver damage were reported in Scotland. Initially, the severity of the drug’s liver damage was misunderstood; liver abnormalities would only appear after three or four days of delay, and though many of the patients reported swift recoveries, a few developed acute liver failure within four to six days. In the 1970s, scientists discovered a breakthrough way of preventing acetaminophen’s conversion into a toxic metabolite, followed by the first successful treatment of critical acetaminophen poisoning with cysteamine and the presentation of N-acetylcysteine as the foremost and current antidote to acetaminophen poisoning.

Acetaminophen Today

Acetaminophen is the prevailing antipyretic and analgesic against mild to moderate pain and symptoms. Other chemical compounds, such as aspirin and other NSAIDs, are also available in similar doses, although these present grave problems with toxicity. Acetaminophen is increasingly used as treatment for osteoarthritis, although a 2015 review by Gustavo C. Machado and colleagues found that it provided only "minimal short term benefit" to osteoarthritis patients, and has managed to maintain low gastrointestinal toxicity effects even at over-the-counter (OTC) doses. Although rare, serious acetaminophen complications can include liver failure or death, though these are usually related to self-prescribing and misuse of the drug. Such actions often lead to acetaminophen overdosing and toxicity, especially in relation to the combination of acetaminophen with alcohol, fasting, other drugs, or diet.

The discovery of two cyclooxygenase (COX) inhibitors, namely COX-1 and COX-2, has transformed the use and advancement of analgesic anti-inflammatory drugs. Current and available drugs relate the majority of side effects to the hindrance of the enzyme COX-1, while effectiveness is related to the hindrance of COX-2, both of which are provoked by inflammatory means. The interaction of acetaminophen and COX-3, another COX inhibitor, could expand acetaminophen’s therapeutic effects. COX-3 is induced from the uptake of diclofenac, a type of NSAID, so the most therapeutic use of acetaminophen in the future may involve a combination of these drugs.

Further examination into the therapeutic effects of acetaminophen in other areas of medicine may lead to vastly improved uses of the drug. Low-density lipoproteins (LDL) have a significant effect on the treatment of atherosclerosis, cardiovascular disease, and stroke. Higher LDL levels signify agglomeration of the fat cells on the walls of the body’s blood vessels, increasing the potential for blockage and sudden blood clots that can ultimately lead to heart attack or stroke. Acetaminophen, along with other dietary or chemical antioxidants, can reduce the oxidation of LDLs by acting as a free-radical scavenger to prevent the development of any cardiovascular problems.

Other studies have also noted acetaminophen’s effects on the decrease of binding, cell association, and degradation of the cultured HepG2 cells. HepG2 cells are a long-lasting cell line derived from a hepatocellular carcinoma, the most common type of primary liver cancer.

Acetaminophen has long been one of the best-selling OTC analgesics, with no significant contradictory reports to hinder consumers from continuing its use. The continuous and increasing understanding of the drug and its interactions with the human biological system can expand its utility for a broader range of clinical use.

Bibliography

"Acetaminophen." MedlinePlus, US National Library of Medicine, 15 Apr. 2017, www.nlm.nih.gov/medlineplus/druginfo/meds/a681004.html. Accessed 16 Feb. 2018.

"Acetaminophen Information." US Food and Drug Administration, 14 Nov. 2017, www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm165107.htm. Accessed 16 Feb. 2018.

Dronsfield, Alan. "Pain Relief: From Coal Tar to Paracetamol." Education in Chemistry, Royal Society of Chemistry, 1 July 2005, eic.rsc.org/section/feature/feture-pain-relief-from-coal-tar-to-paracetamol/2020140.article. Accessed 19 Feb. 2018.

Javaherian, Atash, and Pasha Latifpour, editors. Acetaminophen: Properties, Clinical Uses, and Adverse Effects. Nova Science Publishers, 2012. eBook Academic Collection (EBSCOhost), search.ebscohost.com/login.aspx?direct=true&db=e000xww&AN=540919&site=eds-live. Accessed 16 Feb. 2018.

Liew, Zeyan, et al. "Acetaminophen Use during Pregnancy, Behavioral Problems, and Hyperkinetic Disorders." JAMA Pediatrics, vol. 168, no. 4, 2014, pp. 313–20. MEDLINE Complete, search.ebscohost.com/login.aspx?direct=true&db=mdc&AN=24566677&site=eds-live. Accessed 16 Feb. 2018.

Machado, Gustavo C., et al. "Efficacy and Safety of Paracetamol for Spinal Pain and Osteoarthritis: Systematic Review and Meta-Analysis of Randomised Placebo Controlled Trials." The BMJ, vol. 350, no. 8002, 2015, doi:10.1136/bmj.h1225. Accessed 19 Feb. 2018.

Prescott, Laurie F. "Paracetamol: Past, Present, and Future." American Journal of Therapeutics, vol. 7, no. 2, 2000, pp. 143–48.

Williams, C. David, et al. "Protection against Acetaminophen-Induced Liver Injury by Allopurinol Is Dependent on Aldehyde Oxidase–Mediated Liver Preconditioning." Toxicology and Applied Pharmacology, vol. 274, no. 3, 2014, pp. 417–24. Print.