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Acetaminophen
Acetaminophen K Shankar, University of Arkansas for Medical Sciences, Little Rock, AR, USA HM Mehendale, University of Louisiana at Monroe, Monroe, LA, USA Ó 2014 Elsevier Inc. All rights reserved. l l l
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Name: Acetaminophen Chemical Abstracts Service Registry Number: 103-90-2 Synonyms: APAP, 40 -Hydroxyacetanilide, P-hydroxyacetanilide, Acetamide N-(4-hydroxyphenyl), N-acetyl-paminophenol, N-acetyl-p-aminophenol, P-acetamidophenol; 4-Acetamidophenol, 4-Acetaminophenol, Paracetamol, Tylenol Pharmaceutical Class: Acetaminophen is a synthetic nonopioid congener of acetanilide in the paraaminophenol class Molecular Formula: C8H9NO2 Chemical Structure: O CH3 HO
NH
prescription drugs, alone or in combination with other drugs. The pharmacology and toxicology of this drug have been extensively studied and reviewed. The first clinical use of acetaminophen dates back to 1893 by von Mering (and subsequently by Hinsberg and Treupel, 1894) as an effective antipyretic with comparable pharmacological effects to antipyrine and phenacetin. However, after a hiatus of almost half a century, acetaminophen was rediscovered as the major metabolite of phenacetin and acetanilide in man and was marketed in the United States as a combination with aspirin and caffeine in 1950. In the 1960s and 1970s, concerns about gastrointestinal adverse effects of aspirin and methemoglobinemia of acetanilide only led to increased popularity of acetaminophen as a generally safe antipyretic analgesic. Hepatotoxicity of acetaminophen began to be reported in the late 1960s and has been a topic of intense scientific evaluation to this day. The impact of acetaminophen-induced liver toxicity, accidental or otherwise, will be taken up in later sections.
Routes of Exposure Uses Acetaminophen is a nonnarcotic analgesic and antipyretic drug. It is used to relieve pain of moderate intensity, such as usually occurs in headache and in many muscle, joint, and peripheral nerve disorders. Headaches are one of the most common indications for the use of acetaminophen. Acetaminophen is used to treat acute tension headaches and mild to moderate migraine, especially in combination with caffeine and aspirin. Acetaminophen is indicated in chronic pain associated with rheumatoid arthritis, back or hip pain, osteoarthritis, dental pain, or acute pain due to soft-tissue injury. Acetaminophen is a suitable substitute for aspirin for its analgesic or antipyretic uses in cases where aspirin is contraindicated (gastric bleeding) or when the prolongation of bleeding time caused by aspirin would be a disadvantage. Acetaminophen has been used in studies of pain relief following obstetric and gynecological procedures, including Caesarean section, hysterectomy, tubal ligation, primary dysmenorrhea, and termination of pregnancy. Acetaminophen is also used to manage chronic pain of cancer, postpartum pain, and postoperative pain after minor surgery. In a double-blind crossover study, the analgesic oral butorphanol, and acetaminophen in combination, showed additive analgesic effects against moderate to severe pain due to metastatic carcinoma over that of the individual drug. Acetaminophen is also widely used as an antipyretic drug to reduce fever.
Background Information Acetaminophen can be found as the active ingredient in more than 100 over-the-counter products and a number of
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Acetaminophen is available in several dosage forms, including tablets, capsules, syrups, elixirs, and suppositories. Oral ingestion is the most common route for both accidental and intentional exposure to acetaminophen.
Toxicokinetics Absorption of acetaminophen occurs in the gastrointestinal tract primarily by passive nonionic diffusion and is highly dependent on several factors, including dose, presence of food and other chemicals, mucosal blood flow, age, body weight, time of day, and coexisting disease condition. At pharmacological doses, acetaminophen is absorbed rapidly, with about 75–95% of the therapeutic oral dose being recovered in the urine by 12–24 h as unchanged acetaminophen or metabolite. A large number of studies have evaluated the pharmacokinetic parameters of acetaminophen in man after oral or intravenous dosing. Most studies consistently report volume of distribution to be between 0.8 and 1 l kg1. Total clearance and plasma half-life with therapeutic doses in healthy subjects were usually 3–5 ml min kg1 and 1–3 h, respectively. After suprapharmacological or toxic doses, absorption may be delayed after producing peak blood concentrations at approximately 4 h postingestion. In humans, the majority of acetaminophen is metabolized in the liver to glucuronide and sulfate conjugates that are eliminated in the urine. Estimates in humans from urinary metabolites report 50–60% as glucuronide conjugate, 25–35% as sulfate conjugate, and between 2 and 5% of cysteine and mercapturate conjugates each. In young children, the sulfate conjugate predominates. The water-soluble glucuronide and sulfate conjugates are eliminated via the
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00215-3
Acetaminophen
kidneys. Approximately 2–5% is eliminated in the urine as unchanged acetaminophen. The half-life of therapeutic dose is 1–3 h. In overdose patients, this may be increased to more than 4 h and may even exceed 12 h in patients with severe acetaminophen-induced liver toxicity.
Mechanism of Toxicity Although a major part of the ingested dose of acetaminophen is detoxified, a very small proportion is metabolized via the cytochrome P450-mixed function oxidase pathway to a highly reactive n-acetyl-p-benzoquinoneimine (NAPQI). The toxic intermediate NAPQI is normally detoxified by endogenous glutathione to cysteine and mercapturic acid conjugates and excreted in the urine. Recent studies have shown that hepatic P450s, CYP2E1, and to a lesser extent CYP1A2 are responsible for conversion of acetaminophen to NAPQI. In acetaminophen overdose, the amount of NAPQI increases and depletes endogenous glutathione stores. Time course studies have shown that covalent binding of reactive NAPQI and subsequent toxicity occur only after cellular glutathione stores are reduced by 70% or more of normal. Mitochondrial dysfunction and damage can be seen as early as 15 min after a toxic dose in mice, suggesting that this may be a critical to cellular necrosis. The NAPQI is then thought to covalently bind to critical cellular macromolecules in hepatocytes and cause cell death. Recent proteomic studies have identified at least 20 known proteins that are covalently modified by the reactive acetaminophen metabolite. The resulting acetaminophen-cysteine (APAP-CYS) protein adducts can be quantified via a highpressure liquid chromatography coupled with electrochemical detection (HPLC-EC). 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. In the past two decades, several studies have indicated that acetaminophen is a powerful inducer of programmed cell death or apoptosis in addition to necrosis. Acetaminopheninduced apoptosis involves a complex interplay of cell signaling pathways involving the organelles mitochondria, nucleus, and cytoplasm. Key players that propel toxic events leading to various forms of cell deaths are oxidative stress (mediated by BRIs and ROS), intracellular perturbation of Ca2þ, and a complex interplay of proteolytic caspases.
Acute Toxicity Animal A large body of evidence is available examining the acute toxicity of acetaminophen in animal models. Mice and rats have been widely used to study the toxic effects of acetaminophen. Since the rat is relatively resistant, the mouse has been the most widely used species to study the mechanisms of acetaminophen toxicity and to examine chemicals that potentiate or protect from the toxicity. Hepatotoxicity and nephrotoxicity are the two main effects associated with acute overdose
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of acetaminophen. Of these, death in most species is due to acute hepatic failure. LD50 values range from 350 mg kg1 to 4500 mg kg1 depending on the species and the route of acetaminophen administration, mice (LD50 350–600 mg kg1) being more far more sensitive than rats, guinea pigs, and rabbits (LD50 > 3 g kg1). Death occurs by 12 h after acetaminophen exposure. In mice after a toxic dose, general findings in addition to the severe hepatic necrosis include necrotic changes in the kidney, bronchiolar epithelium, testes, lymphoid follicles of the spleen, and small intestine. Cats are particularly susceptible to acetaminophen intoxication because of their impaired glucuronic acid conjugation mechanism and saturation of their sulfate conjugation pathway. The clinical signs associated with experimental acetaminophen administration to cats included cyanosis followed by anemia, hemoglobinuria, icterus, and facial edema. Laboratory findings in acetaminophen-poisoned cats include methemoglobinemia and an elevated serum alanine aminotransferase activity.
Human Hepatotoxicity is the primary toxic insult from acute acetaminophen overdose. Acetaminophen overdose accounts for more than 56 000 emergency room visits and is implicated in nearly 50% of all acute liver failure in the United States (U.S. Acute Liver Failure Study Group). Exposure to toxic doses of acetaminophen may be due to intentional (suicidal) or unintentional (accidental). Recent data from Parkland Hospital suggest that greater percentages of unintentional overdose victims suffer from fatal consequences compared to persons attempting suicide (with acetaminophen) primarily due to their characteristic late presentation. Data from the U.S. ALF Study Group show that unintentional overdoses (which are more frequent in liver failure cases) were also larger (median dose of 34 g) compared to suicidal doses, being consumed over several preceding days. There is no clear agreement on a maximum tolerated dose of acetaminophen. Most people tolerate 4–8 g day1 of acetaminophen without any hepatotoxic incidence. However, the risk of severe liver injury may be quite high above the 4 g day1 dose, especially in a group of individuals due to indeterminate idiosyncratic reasons. The typical clinical manifestations are secondary to hepatic damage. Plasma concentrations should be obtained to determine the probability of acetaminophen-induced hepatotoxicity. The Rumack-Matthews nomogram is used to assess the risk of hepatotoxicity. Levels in excess of 200 mg ml1 of acetaminophen at 4 h postingestion are associated with a high probability of development of hepatotoxicity. A second treatment line 25% lower than the original 200 line was added at the request of the FDA in 1976. While not yet clinically available, newer methods of detecting APAP-toxicity include detection of APAP-cysteine adducts via HPLC-EC and via metabolomic analysis of urine samples (early-intervention pharmacometabolomics). The clinical presentation follows four distinct phases. Gastrointestinal irritation, nausea, and vomiting are present in the first 24 h postingestion. The second stage (24–48 h postingestion) is characterized by the resolution of the initial symptoms, accompanied by elevations of hepatic transaminases. Cases that progress to stage three develop hypoglycemia, coagulopathies, jaundice, and symptoms
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Acetaminophen
consistent with hepatic failure. Surviving patients go through a fourth stage of recovery. As toxicity develops, half-life becomes prolonged and transaminases rise and fall. In instances where reliable history of time of ingestion is not available, calculations of body burden may be useful in deciding treatment.
Chronic Toxicity Animal In a 2-year feed study, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3000, or 6000 ppm acetaminophen for 104 weeks. There was equivocal evidence of carcinogenic activity in female F344/ N rats based on increased incidences of mononuclear cell leukemia. Overall, there is inadequate evidence in experimental animals for the carcinogenicity of acetaminophen and is not classifiable as to its carcinogenicity. Acetaminophen was nonmutagenic in the Salmonella/mammalian microsome assay at concentrations ranging from 0.1 to 50 mg per plate. In a study to examine the effect of acetaminophen on reproduction and fertility, no changes in the number of pups/litter, viability, or adjusted pup weight were found. Acetaminophen in the diet of Swiss mice reduced weight gain during nursing. Fertility endpoints (ability to bear normal numbers of normal-weight young) were generally not affected.
primary hepatocytes is blebbing of the cell membrane. However, electron microscopy has shown that toxicity is associated with progressive loss of microvilli, mitochondrial abnormalities, and appearance of myeloid bodies. Exposure of primary mouse hepatocytes to concentrations of acetaminophen above 1 mM led to significant lactate dehydrogenase leakage in as soon as 3 h. Cytotoxicity of acetaminophen has also been examined using standard liver cell lines, including, PC12 cells, HepG2 cells, and H4IIEC3G cells, among other cell lines. Immortalized hepatocyte cultures, in many cases, lose their ability to bioactivate acetaminophen and hence are resistant to toxicity. Transient or consistent overexpression of drug-metabolizing enzymes (CYP4502E1 and/or CYP4501A2) leads to increased cytotoxicity of acetaminophen. Acetaminophen is also cytotoxic in cultures of rat liver sinusoidal endothelial cells, Kupffer cells, and mouse fibroblasts.
Cytotoxicity in Other Cells The cytotoxicity of acetaminophen has been demonstrated in cultures of HeLa cells, L929 and 3T3 murine fibroblasts, chick embryo neurons, rat embryonic and skeletal muscle, peripheral blood lymphocytes, and lung and dermal cells. In addition, cytotoxicity of acetaminophen has been evaluated in the BF-2 fish cell line (see Ecotoxicology).
Clinical Management Human There is inadequate evidence in humans for the carcinogenicity of acetaminophen and it is not classifiable as to its carcinogenicity. The chronic ingestion of excessive amounts of acetaminophen may produce similar toxicity as a large acute dose but in a more insidious fashion. Age, chronic alcohol abuse, and preexisting disease may be contributing factors. The American Academy of Pediatrics considers use of acetaminophen safe during breast-feeding, and acetaminophen is classified as a category B chemical by the FDA (studies in laboratory animals have not demonstrated a fetal risk, but there are no controlled studies in pregnant women). Acetaminophen should be given with care to patients with impaired kidney or liver function. Acetaminophen should be given with care to patients taking other drugs that affect the liver.
In Vitro Toxicity Acetaminophen causes cytotoxicity in several cell types; however, the most widely studied cytotoxicity of acetaminophen is in primary hepatocytes or hepatocyte cell lines.
Cytotoxicity in Hepatic Cells Primary hepatocytes from rats, mice, hamsters, rabbits, dogs, pigs, monkeys, and humans have been shown to be susceptible to acetaminophen in vitro. The cytotoxicity of acetaminophen varies considerably depending on species, presumably due to differences in bioactivation and glutathione status. The most obvious morphological effect of acetaminophen in isolated
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-acetylcysteine (NAC) therapy. The Rumack-Matthew nomogram is utilized to identify proper course of treatment. Blood acetaminophen concentrations of 200 mg l1 (or higher) at 4 h postingestion 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. An oral loading dose of 140 mg kg1 (as a 5% solution in soft drink or juice) is followed by 70 mg kg1 given orally as a 5% solution in soft drink or juice every 4 h for an additional 17 doses. An alternative intravenous Ò dosing protocol (20 h regimen) for NAC (Acetadote ; Cumberland Pharmaceuticals) can also be used in patients where oral NAC administration is not possible. A loading dose of 150 mg kg1 NAC (in 200 ml of 5% dextrose in water) is administered over 15 min, followed by 50 mg kg1 NAC in 500 ml of 5% dextrose over the next 4 h. A final dose of 100 mg kg1 NAC is administered in 1000 ml of 5% dextrose over a 16 h period. A longer 72 h treatment regimen with intravenous NAC is recommended in the United States. An injectable form and an extended-release form of NAC are available (Acetadote) for treating patients who developed acetaminophen-induced liver injury. Basic and advanced lifesupport measures should be utilized as required by the condition of the patient. Studies have also suggested that an increase in alphafetoprotein, 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.
Acetaminophen
Environmental Fate Acetaminophen was found to be inherently biodegradable and has no bioaccumulation potential. No other information about the environmental fate of acetaminophen is currently available.
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exists when consumed following alcohol intake. In a recent review, however, Dr Barry Rumack suggests that only chronic heavy drinkers may be at greater risk following an overdose of acetaminophen and that no potentiation of toxicity occurs at therapeutic doses. However, acetaminophen use during acute or chronic alcohol exposure remains a controversial topic.
Ecotoxicology The acute toxicity of acetaminophen has been examined in several aquatic species. The LC50 value in brine shrimp (Artemia salina) examining mortality was reported to be 3820 mmol l1. The EC50 for immobility over a 24 h experiment using water flea (Daphnia magna) was 367 mmol l1. Acetaminophen is classified as not toxic or only slightly to moderately toxic in all fish (fathead minnow, Pimephales promelas) and zooplankton species tested. The crustacean fairy shrimp (Streptocephalus proboscideus) appears to be highly sensitive to acetaminophen (average LC50 of 196 mg l1).
Other Hazards Acetaminophen is stable under ordinary conditions of use and storage. In the presence of heat and water, acetaminophen will hydrolyze into acetic acid and p-aminophenol. Incineration can produce carbon monoxide, carbon dioxide, and nitrogen oxides. Flammability: As with most organic solids, fire is possible at elevated temperatures or by contact with an ignition source. Explosivity: Fine dust dispersed in air in sufficient concentrations, and in the presence of an ignition source, is a potential dust explosion hazard. The minimum concentration for explosion is 0.25 oz. per cubic feet. The recommended fireextinguishing media are water spray, dry chemical, alcohol foam, or carbon dioxide. Acetaminophen is capable of generating a static electrical charge. Processes involving dumping of acetaminophen into flammable liquid, inert atmosphere in the vessels or temperatures of flammable liquid should be maintained below its flashpoint.
Exposure Limits Therapeutic exposure: The total daily dose of acetaminophen should not exceed 4 g. Dosages of acetaminophen over 4–8 g day1 over long periods of time may be associated with higher risk of liver toxicity. Acetaminophen should not be administered for more than 10 days or to young children except upon advice of physician. Occupational exposure: Mallinckrodt recommends an airborne exposure limit of 5 mg m3.
Miscellaneous 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
See also: Mechanisms of Toxicity; Oxidative Stress.
Further Reading Bateman, D.N., 2012. Poisoning and self-harm. Clin. Med. 12 (3), 280–282. Bulku, E., Stohs, S.J., Cicero, L., et al., 2012. Curcumin exposure modulates multiple pro-apoptotic and anti-apoptotic signaling pathways to antagonize acetaminopheninduced toxicity. Curr. Neurovasc. Res. 9 (1), 58–71. Chun, L.J., Tong, M.J., Busuttil, R.W., Hiatt, J.R., 2009. Acetaminophen hepatotoxicity and acute liver failure. J. Clin. Gastroenterol. 43 (4), 342–349. DHHS/National Toxicology Program, 1993. Toxicology and Carcinogenesis Studies of Acetaminophen in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 394, NIH Publication No. 93–2849. Feucht, C.L., Patel, D.R., 2010. Analgesics and anti-inflammatory medications in sports: use and abuse. Pediatr. Clin. North Am. 57 (3), 751–774. Gunawan, B.K., Kaplowitz, N., 2007. Mechanisms of drug-induced liver disease. Clin. Liver Dis. 11 (3), 459–475. Guggenheimer, J., Moore, P.A., 2011. The therapeutic applications of and risks associated with acetaminophen use: a review and update. J. Am. Dent Assoc. 142 (1), 38–44. Hinson, J.A., Roberts, D.W., James, L.P., 2010. Mechanisms of acetaminopheninduced liver necrosis. Handbook Exp. Pharmacol. 196, 369–405. James, L.P., Letzig, L., Simpson, P.M., Capparelli, E., Roberts, D.W., Hinson, J.A., Davern, T.J., Lee, W.M., 2009. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab. Dispos. 37, 1779–1784. Jefferies, S., Saxena, M., Young, P., 2012. Paracetamol in critical illness: a review. Crit. Care Resusc. 14 (1), 74–80. Klein-Schwartz, W., Doyon, S., 2011. Intravenous acetylcysteine for the treatment of acetaminophen overdose. Expert Opin. Pharmacother. 12 (1), 119–130. Kienhuis, A.S., Bessems, J.G., Pennings, J.L., et al., 2011. Application of toxicogenomics in hepatic systems toxicology for risk assessment: acetaminophen as a case study. Toxicol. Appl. Pharmacol. 250 (2), 96–107. Malhi, H., Gores, G.J., Lemasters, J.J., 2006. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43 (2 Suppl. 1), S31–S44. Mazer, M., Perrone, J., 2008. Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestations, and management. J. Med. Toxicol. 4 (1), 2–6. Mehendale, H.M., 2012. Once initiated, how does toxic tissue injury expand? Trends Pharmacol. Sci. 33 (4), 200–206. Ozkaya, O., Genc, G., Bek, K., Sullu, Y., 2010. A case of acetaminophen (paracetamol) causing renal failure without liver damage in a child and review of literature. Ren. Fail. 32 (9), 1125–1127. Ruepp, S.U., Tonge, R.P., Shaw, J., Wallis, N., Pognan, F., 2002. Genomics and proteomics analysis of acetaminophen toxicity in mouse liver. Toxicol. Sci. 65, 135–150. Rumack, B.H., Bateman, D.N., 2012. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin. Toxicol. (Phila) 50 (2), 91–98. Starkey Lewis, P.J., Merz, M., Couttet, P., et al., 2012. Serum microRNA biomarkers for drug-induced liver injury. Clin. Pharmacol. Ther. 92 (3), 291–293. http:// dx.doi.org/10.1038/clpt.2012.101. Tujios, S., Fontana, R.J., 2011. Mechanisms of drug-induced liver injury: from bedside to bench. Nat. Rev. Gastroenterol. Hepatol. 8 (4), 202–211. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm – USFDA. Winnike, J.H., Li, Z., Wright, F.A., et al., 2010. Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans. Clin. Pharmacol. Ther. 88, 45–51. Zhao, L., Pickering, G., 2011. Paracetamol metabolism and related genetic differences. Drug Metab. Rev. 43 (1), 41–52.
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Name: Acetaminophen Chemical Abstracts Service Registry Number: 103-90-2 Synonyms: APAP, 40 -Hydroxyacetanilide, P-hydroxyacetanilide, Acetamide N-(4-hydroxyphenyl), N-acetyl-paminophenol, N-acetyl-p-aminophenol, P-acetamidophenol; 4-Acetamidophenol, 4-Acetaminophenol, Paracetamol, Tylenol Pharmaceutical Class: Acetaminophen is a synthetic nonopioid congener of acetanilide in the paraaminophenol class Molecular Formula: C8H9NO2 Chemical Structure: O CH3 HO
NH
prescription drugs, alone or in combination with other drugs. The pharmacology and toxicology of this drug have been extensively studied and reviewed. The first clinical use of acetaminophen dates back to 1893 by von Mering (and subsequently by Hinsberg and Treupel, 1894) as an effective antipyretic with comparable pharmacological effects to antipyrine and phenacetin. However, after a hiatus of almost half a century, acetaminophen was rediscovered as the major metabolite of phenacetin and acetanilide in man and was marketed in the United States as a combination with aspirin and caffeine in 1950. In the 1960s and 1970s, concerns about gastrointestinal adverse effects of aspirin and methemoglobinemia of acetanilide only led to increased popularity of acetaminophen as a generally safe antipyretic analgesic. Hepatotoxicity of acetaminophen began to be reported in the late 1960s and has been a topic of intense scientific evaluation to this day. The impact of acetaminophen-induced liver toxicity, accidental or otherwise, will be taken up in later sections.
Routes of Exposure Uses Acetaminophen is a nonnarcotic analgesic and antipyretic drug. It is used to relieve pain of moderate intensity, such as usually occurs in headache and in many muscle, joint, and peripheral nerve disorders. Headaches are one of the most common indications for the use of acetaminophen. Acetaminophen is used to treat acute tension headaches and mild to moderate migraine, especially in combination with caffeine and aspirin. Acetaminophen is indicated in chronic pain associated with rheumatoid arthritis, back or hip pain, osteoarthritis, dental pain, or acute pain due to soft-tissue injury. Acetaminophen is a suitable substitute for aspirin for its analgesic or antipyretic uses in cases where aspirin is contraindicated (gastric bleeding) or when the prolongation of bleeding time caused by aspirin would be a disadvantage. Acetaminophen has been used in studies of pain relief following obstetric and gynecological procedures, including Caesarean section, hysterectomy, tubal ligation, primary dysmenorrhea, and termination of pregnancy. Acetaminophen is also used to manage chronic pain of cancer, postpartum pain, and postoperative pain after minor surgery. In a double-blind crossover study, the analgesic oral butorphanol, and acetaminophen in combination, showed additive analgesic effects against moderate to severe pain due to metastatic carcinoma over that of the individual drug. Acetaminophen is also widely used as an antipyretic drug to reduce fever.
Background Information Acetaminophen can be found as the active ingredient in more than 100 over-the-counter products and a number of
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Acetaminophen is available in several dosage forms, including tablets, capsules, syrups, elixirs, and suppositories. Oral ingestion is the most common route for both accidental and intentional exposure to acetaminophen.
Toxicokinetics Absorption of acetaminophen occurs in the gastrointestinal tract primarily by passive nonionic diffusion and is highly dependent on several factors, including dose, presence of food and other chemicals, mucosal blood flow, age, body weight, time of day, and coexisting disease condition. At pharmacological doses, acetaminophen is absorbed rapidly, with about 75–95% of the therapeutic oral dose being recovered in the urine by 12–24 h as unchanged acetaminophen or metabolite. A large number of studies have evaluated the pharmacokinetic parameters of acetaminophen in man after oral or intravenous dosing. Most studies consistently report volume of distribution to be between 0.8 and 1 l kg1. Total clearance and plasma half-life with therapeutic doses in healthy subjects were usually 3–5 ml min kg1 and 1–3 h, respectively. After suprapharmacological or toxic doses, absorption may be delayed after producing peak blood concentrations at approximately 4 h postingestion. In humans, the majority of acetaminophen is metabolized in the liver to glucuronide and sulfate conjugates that are eliminated in the urine. Estimates in humans from urinary metabolites report 50–60% as glucuronide conjugate, 25–35% as sulfate conjugate, and between 2 and 5% of cysteine and mercapturate conjugates each. In young children, the sulfate conjugate predominates. The water-soluble glucuronide and sulfate conjugates are eliminated via the
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00215-3
Acetaminophen
kidneys. Approximately 2–5% is eliminated in the urine as unchanged acetaminophen. The half-life of therapeutic dose is 1–3 h. In overdose patients, this may be increased to more than 4 h and may even exceed 12 h in patients with severe acetaminophen-induced liver toxicity.
Mechanism of Toxicity Although a major part of the ingested dose of acetaminophen is detoxified, a very small proportion is metabolized via the cytochrome P450-mixed function oxidase pathway to a highly reactive n-acetyl-p-benzoquinoneimine (NAPQI). The toxic intermediate NAPQI is normally detoxified by endogenous glutathione to cysteine and mercapturic acid conjugates and excreted in the urine. Recent studies have shown that hepatic P450s, CYP2E1, and to a lesser extent CYP1A2 are responsible for conversion of acetaminophen to NAPQI. In acetaminophen overdose, the amount of NAPQI increases and depletes endogenous glutathione stores. Time course studies have shown that covalent binding of reactive NAPQI and subsequent toxicity occur only after cellular glutathione stores are reduced by 70% or more of normal. Mitochondrial dysfunction and damage can be seen as early as 15 min after a toxic dose in mice, suggesting that this may be a critical to cellular necrosis. The NAPQI is then thought to covalently bind to critical cellular macromolecules in hepatocytes and cause cell death. Recent proteomic studies have identified at least 20 known proteins that are covalently modified by the reactive acetaminophen metabolite. The resulting acetaminophen-cysteine (APAP-CYS) protein adducts can be quantified via a highpressure liquid chromatography coupled with electrochemical detection (HPLC-EC). 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. In the past two decades, several studies have indicated that acetaminophen is a powerful inducer of programmed cell death or apoptosis in addition to necrosis. Acetaminopheninduced apoptosis involves a complex interplay of cell signaling pathways involving the organelles mitochondria, nucleus, and cytoplasm. Key players that propel toxic events leading to various forms of cell deaths are oxidative stress (mediated by BRIs and ROS), intracellular perturbation of Ca2þ, and a complex interplay of proteolytic caspases.
Acute Toxicity Animal A large body of evidence is available examining the acute toxicity of acetaminophen in animal models. Mice and rats have been widely used to study the toxic effects of acetaminophen. Since the rat is relatively resistant, the mouse has been the most widely used species to study the mechanisms of acetaminophen toxicity and to examine chemicals that potentiate or protect from the toxicity. Hepatotoxicity and nephrotoxicity are the two main effects associated with acute overdose
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of acetaminophen. Of these, death in most species is due to acute hepatic failure. LD50 values range from 350 mg kg1 to 4500 mg kg1 depending on the species and the route of acetaminophen administration, mice (LD50 350–600 mg kg1) being more far more sensitive than rats, guinea pigs, and rabbits (LD50 > 3 g kg1). Death occurs by 12 h after acetaminophen exposure. In mice after a toxic dose, general findings in addition to the severe hepatic necrosis include necrotic changes in the kidney, bronchiolar epithelium, testes, lymphoid follicles of the spleen, and small intestine. Cats are particularly susceptible to acetaminophen intoxication because of their impaired glucuronic acid conjugation mechanism and saturation of their sulfate conjugation pathway. The clinical signs associated with experimental acetaminophen administration to cats included cyanosis followed by anemia, hemoglobinuria, icterus, and facial edema. Laboratory findings in acetaminophen-poisoned cats include methemoglobinemia and an elevated serum alanine aminotransferase activity.
Human Hepatotoxicity is the primary toxic insult from acute acetaminophen overdose. Acetaminophen overdose accounts for more than 56 000 emergency room visits and is implicated in nearly 50% of all acute liver failure in the United States (U.S. Acute Liver Failure Study Group). Exposure to toxic doses of acetaminophen may be due to intentional (suicidal) or unintentional (accidental). Recent data from Parkland Hospital suggest that greater percentages of unintentional overdose victims suffer from fatal consequences compared to persons attempting suicide (with acetaminophen) primarily due to their characteristic late presentation. Data from the U.S. ALF Study Group show that unintentional overdoses (which are more frequent in liver failure cases) were also larger (median dose of 34 g) compared to suicidal doses, being consumed over several preceding days. There is no clear agreement on a maximum tolerated dose of acetaminophen. Most people tolerate 4–8 g day1 of acetaminophen without any hepatotoxic incidence. However, the risk of severe liver injury may be quite high above the 4 g day1 dose, especially in a group of individuals due to indeterminate idiosyncratic reasons. The typical clinical manifestations are secondary to hepatic damage. Plasma concentrations should be obtained to determine the probability of acetaminophen-induced hepatotoxicity. The Rumack-Matthews nomogram is used to assess the risk of hepatotoxicity. Levels in excess of 200 mg ml1 of acetaminophen at 4 h postingestion are associated with a high probability of development of hepatotoxicity. A second treatment line 25% lower than the original 200 line was added at the request of the FDA in 1976. While not yet clinically available, newer methods of detecting APAP-toxicity include detection of APAP-cysteine adducts via HPLC-EC and via metabolomic analysis of urine samples (early-intervention pharmacometabolomics). The clinical presentation follows four distinct phases. Gastrointestinal irritation, nausea, and vomiting are present in the first 24 h postingestion. The second stage (24–48 h postingestion) is characterized by the resolution of the initial symptoms, accompanied by elevations of hepatic transaminases. Cases that progress to stage three develop hypoglycemia, coagulopathies, jaundice, and symptoms
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Acetaminophen
consistent with hepatic failure. Surviving patients go through a fourth stage of recovery. As toxicity develops, half-life becomes prolonged and transaminases rise and fall. In instances where reliable history of time of ingestion is not available, calculations of body burden may be useful in deciding treatment.
Chronic Toxicity Animal In a 2-year feed study, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3000, or 6000 ppm acetaminophen for 104 weeks. There was equivocal evidence of carcinogenic activity in female F344/ N rats based on increased incidences of mononuclear cell leukemia. Overall, there is inadequate evidence in experimental animals for the carcinogenicity of acetaminophen and is not classifiable as to its carcinogenicity. Acetaminophen was nonmutagenic in the Salmonella/mammalian microsome assay at concentrations ranging from 0.1 to 50 mg per plate. In a study to examine the effect of acetaminophen on reproduction and fertility, no changes in the number of pups/litter, viability, or adjusted pup weight were found. Acetaminophen in the diet of Swiss mice reduced weight gain during nursing. Fertility endpoints (ability to bear normal numbers of normal-weight young) were generally not affected.
primary hepatocytes is blebbing of the cell membrane. However, electron microscopy has shown that toxicity is associated with progressive loss of microvilli, mitochondrial abnormalities, and appearance of myeloid bodies. Exposure of primary mouse hepatocytes to concentrations of acetaminophen above 1 mM led to significant lactate dehydrogenase leakage in as soon as 3 h. Cytotoxicity of acetaminophen has also been examined using standard liver cell lines, including, PC12 cells, HepG2 cells, and H4IIEC3G cells, among other cell lines. Immortalized hepatocyte cultures, in many cases, lose their ability to bioactivate acetaminophen and hence are resistant to toxicity. Transient or consistent overexpression of drug-metabolizing enzymes (CYP4502E1 and/or CYP4501A2) leads to increased cytotoxicity of acetaminophen. Acetaminophen is also cytotoxic in cultures of rat liver sinusoidal endothelial cells, Kupffer cells, and mouse fibroblasts.
Cytotoxicity in Other Cells The cytotoxicity of acetaminophen has been demonstrated in cultures of HeLa cells, L929 and 3T3 murine fibroblasts, chick embryo neurons, rat embryonic and skeletal muscle, peripheral blood lymphocytes, and lung and dermal cells. In addition, cytotoxicity of acetaminophen has been evaluated in the BF-2 fish cell line (see Ecotoxicology).
Clinical Management Human There is inadequate evidence in humans for the carcinogenicity of acetaminophen and it is not classifiable as to its carcinogenicity. The chronic ingestion of excessive amounts of acetaminophen may produce similar toxicity as a large acute dose but in a more insidious fashion. Age, chronic alcohol abuse, and preexisting disease may be contributing factors. The American Academy of Pediatrics considers use of acetaminophen safe during breast-feeding, and acetaminophen is classified as a category B chemical by the FDA (studies in laboratory animals have not demonstrated a fetal risk, but there are no controlled studies in pregnant women). Acetaminophen should be given with care to patients with impaired kidney or liver function. Acetaminophen should be given with care to patients taking other drugs that affect the liver.
In Vitro Toxicity Acetaminophen causes cytotoxicity in several cell types; however, the most widely studied cytotoxicity of acetaminophen is in primary hepatocytes or hepatocyte cell lines.
Cytotoxicity in Hepatic Cells Primary hepatocytes from rats, mice, hamsters, rabbits, dogs, pigs, monkeys, and humans have been shown to be susceptible to acetaminophen in vitro. The cytotoxicity of acetaminophen varies considerably depending on species, presumably due to differences in bioactivation and glutathione status. The most obvious morphological effect of acetaminophen in isolated
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-acetylcysteine (NAC) therapy. The Rumack-Matthew nomogram is utilized to identify proper course of treatment. Blood acetaminophen concentrations of 200 mg l1 (or higher) at 4 h postingestion 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. An oral loading dose of 140 mg kg1 (as a 5% solution in soft drink or juice) is followed by 70 mg kg1 given orally as a 5% solution in soft drink or juice every 4 h for an additional 17 doses. An alternative intravenous Ò dosing protocol (20 h regimen) for NAC (Acetadote ; Cumberland Pharmaceuticals) can also be used in patients where oral NAC administration is not possible. A loading dose of 150 mg kg1 NAC (in 200 ml of 5% dextrose in water) is administered over 15 min, followed by 50 mg kg1 NAC in 500 ml of 5% dextrose over the next 4 h. A final dose of 100 mg kg1 NAC is administered in 1000 ml of 5% dextrose over a 16 h period. A longer 72 h treatment regimen with intravenous NAC is recommended in the United States. An injectable form and an extended-release form of NAC are available (Acetadote) for treating patients who developed acetaminophen-induced liver injury. Basic and advanced lifesupport measures should be utilized as required by the condition of the patient. Studies have also suggested that an increase in alphafetoprotein, 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.
Acetaminophen
Environmental Fate Acetaminophen was found to be inherently biodegradable and has no bioaccumulation potential. No other information about the environmental fate of acetaminophen is currently available.
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exists when consumed following alcohol intake. In a recent review, however, Dr Barry Rumack suggests that only chronic heavy drinkers may be at greater risk following an overdose of acetaminophen and that no potentiation of toxicity occurs at therapeutic doses. However, acetaminophen use during acute or chronic alcohol exposure remains a controversial topic.
Ecotoxicology The acute toxicity of acetaminophen has been examined in several aquatic species. The LC50 value in brine shrimp (Artemia salina) examining mortality was reported to be 3820 mmol l1. The EC50 for immobility over a 24 h experiment using water flea (Daphnia magna) was 367 mmol l1. Acetaminophen is classified as not toxic or only slightly to moderately toxic in all fish (fathead minnow, Pimephales promelas) and zooplankton species tested. The crustacean fairy shrimp (Streptocephalus proboscideus) appears to be highly sensitive to acetaminophen (average LC50 of 196 mg l1).
Other Hazards Acetaminophen is stable under ordinary conditions of use and storage. In the presence of heat and water, acetaminophen will hydrolyze into acetic acid and p-aminophenol. Incineration can produce carbon monoxide, carbon dioxide, and nitrogen oxides. Flammability: As with most organic solids, fire is possible at elevated temperatures or by contact with an ignition source. Explosivity: Fine dust dispersed in air in sufficient concentrations, and in the presence of an ignition source, is a potential dust explosion hazard. The minimum concentration for explosion is 0.25 oz. per cubic feet. The recommended fireextinguishing media are water spray, dry chemical, alcohol foam, or carbon dioxide. Acetaminophen is capable of generating a static electrical charge. Processes involving dumping of acetaminophen into flammable liquid, inert atmosphere in the vessels or temperatures of flammable liquid should be maintained below its flashpoint.
Exposure Limits Therapeutic exposure: The total daily dose of acetaminophen should not exceed 4 g. Dosages of acetaminophen over 4–8 g day1 over long periods of time may be associated with higher risk of liver toxicity. Acetaminophen should not be administered for more than 10 days or to young children except upon advice of physician. Occupational exposure: Mallinckrodt recommends an airborne exposure limit of 5 mg m3.
Miscellaneous 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
See also: Mechanisms of Toxicity; Oxidative Stress.
Further Reading Bateman, D.N., 2012. Poisoning and self-harm. Clin. Med. 12 (3), 280–282. Bulku, E., Stohs, S.J., Cicero, L., et al., 2012. Curcumin exposure modulates multiple pro-apoptotic and anti-apoptotic signaling pathways to antagonize acetaminopheninduced toxicity. Curr. Neurovasc. Res. 9 (1), 58–71. Chun, L.J., Tong, M.J., Busuttil, R.W., Hiatt, J.R., 2009. Acetaminophen hepatotoxicity and acute liver failure. J. Clin. Gastroenterol. 43 (4), 342–349. DHHS/National Toxicology Program, 1993. Toxicology and Carcinogenesis Studies of Acetaminophen in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 394, NIH Publication No. 93–2849. Feucht, C.L., Patel, D.R., 2010. Analgesics and anti-inflammatory medications in sports: use and abuse. Pediatr. Clin. North Am. 57 (3), 751–774. Gunawan, B.K., Kaplowitz, N., 2007. Mechanisms of drug-induced liver disease. Clin. Liver Dis. 11 (3), 459–475. Guggenheimer, J., Moore, P.A., 2011. The therapeutic applications of and risks associated with acetaminophen use: a review and update. J. Am. Dent Assoc. 142 (1), 38–44. Hinson, J.A., Roberts, D.W., James, L.P., 2010. Mechanisms of acetaminopheninduced liver necrosis. Handbook Exp. Pharmacol. 196, 369–405. James, L.P., Letzig, L., Simpson, P.M., Capparelli, E., Roberts, D.W., Hinson, J.A., Davern, T.J., Lee, W.M., 2009. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab. Dispos. 37, 1779–1784. Jefferies, S., Saxena, M., Young, P., 2012. Paracetamol in critical illness: a review. Crit. Care Resusc. 14 (1), 74–80. Klein-Schwartz, W., Doyon, S., 2011. Intravenous acetylcysteine for the treatment of acetaminophen overdose. Expert Opin. Pharmacother. 12 (1), 119–130. Kienhuis, A.S., Bessems, J.G., Pennings, J.L., et al., 2011. Application of toxicogenomics in hepatic systems toxicology for risk assessment: acetaminophen as a case study. Toxicol. Appl. Pharmacol. 250 (2), 96–107. Malhi, H., Gores, G.J., Lemasters, J.J., 2006. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 43 (2 Suppl. 1), S31–S44. Mazer, M., Perrone, J., 2008. Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestations, and management. J. Med. Toxicol. 4 (1), 2–6. Mehendale, H.M., 2012. Once initiated, how does toxic tissue injury expand? Trends Pharmacol. Sci. 33 (4), 200–206. Ozkaya, O., Genc, G., Bek, K., Sullu, Y., 2010. A case of acetaminophen (paracetamol) causing renal failure without liver damage in a child and review of literature. Ren. Fail. 32 (9), 1125–1127. Ruepp, S.U., Tonge, R.P., Shaw, J., Wallis, N., Pognan, F., 2002. Genomics and proteomics analysis of acetaminophen toxicity in mouse liver. Toxicol. Sci. 65, 135–150. Rumack, B.H., Bateman, D.N., 2012. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin. Toxicol. (Phila) 50 (2), 91–98. Starkey Lewis, P.J., Merz, M., Couttet, P., et al., 2012. Serum microRNA biomarkers for drug-induced liver injury. Clin. Pharmacol. Ther. 92 (3), 291–293. http:// dx.doi.org/10.1038/clpt.2012.101. Tujios, S., Fontana, R.J., 2011. Mechanisms of drug-induced liver injury: from bedside to bench. Nat. Rev. Gastroenterol. Hepatol. 8 (4), 202–211. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm – USFDA. Winnike, J.H., Li, Z., Wright, F.A., et al., 2010. Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans. Clin. Pharmacol. Ther. 88, 45–51. Zhao, L., Pickering, G., 2011. Paracetamol metabolism and related genetic differences. Drug Metab. Rev. 43 (1), 41–52.