Acetaminophen

Acephen®
Acetaminophen
Actamin®
Adprin® B
Anacin® AF
Anacin®-3 Maximum Strength
Apacet®
Apra®
Children’s Pain and Fever
Childrens Silapap®
Comtrex® Sore Throat Relief
Dolono®
Dolono® Infant
Ed-APAP®
ElixSure® Fever/Pain
Equate® Pain Reliever
Feverall®
Genapap®
Genebs®
Infantaire®
Liquiprin®
Lopap®
Mapap
Mapap Extra Strength Rapid Release
Mapap®
Mapap® Junior Strength
Mardol®
Masophen®
Neopap® Supprettes
Non-Aspirin Childrens
Non-Aspirin Infants
Pain-Eze®
Panadol®
Panadol® Jr.
Q-Pap®
Q-Pap® Childrens
Redutemp®
Ridenol®
S-T Febrol®
St. Joseph® Aspirin-Free
T-Painol®
T-Panol®
Tempra® 1
Tempra® 2
Tempra® 3
Tycolene®
Tylenol®
Tylenol® 8 Hour
Tylenol® Arthritis
Tylenol® Childrens
Tylenol® Infants
Tylenol® Junior
Tylenol® Sore Throat
Tylenol® Sore Throat Daytime
Tylophen®
Uni-Ace®
Uni-Ace® Child
Uniserts®
Vitapap®
XS® No Aspirin PR
XS® Pain Reliever

Classification:
» Analgesics

Description: Acetaminophen (APAP, paracetamol) is a para-aminophenol analgesic and is the active metabolite of phenacetin. Due to the toxic effects of phenacetin at therapeutic doses and that it is metabolized to acetaminophen, phenacetin is no longer used. Acetaminophen possesses analgesic and antipyretic activity similar to aspirin; however, acetaminophen has no peripheral antiinflammatory activity or effects on platelet function. Acetaminophen is effective in the relief of both acute and chronic pain. Acetaminophen may be preferred in elderly patients with osteoarthritis over other NSAIDs due to fewer GI and renal side effects; the American Geriatrics Society recommends acetaminophen as the analgesic of choice for minor aches and pains in patients > 50 years of age. Acetaminophen is the preferred analgesic/antipyretic for patients in whom aspirin is contraindicated (e.g., those who have a history of gastric ulcer or a coagulation disorder). Acetaminophen is the analgesic of choice for the treatment of episodic pain in patients with underlying renal disease. However, chronic use should be discouraged (see Contraindications/Precautions). In addition, acetaminophen has been recommended by the American Lung Association as the first line treatment for aches and pains associated with the flu. Acetaminophen was first used in clinical medicine in 1893, but widespread use began after its FDA approval in 1950. It is available without a prescription in several oral dosage forms, and is often found in combination non-prescription (OTC) products. Acetaminophen is also available by prescription in combination with other commonly prescribed prescription analgesics (e.g., opioid analgesics). The drug has a history of use safely and effectively by patients; however, unintentional or intentional misuse of the drug can lead to significant health risks. Taking too much acetaminophen is the number one cause of acute hepatic failure in the U.S. (see Adverse Reactions).

Mechanism of Action: Acetaminophen’s exact mechanism of action is unknown, but it is known to mediate its actions centrally. Acetaminophen is thought to act primarily in the CNS and increase the pain threshold by inhibiting cyclooxygenase, a collection of enzymes involved in prostaglandin (PG) synthesis. Acetaminophen appears to be a potent inhibitor of both isoforms of cyclooxygenase, COX-1 and COX-2, within the CNS. Unlike nonsteroidal anti-inflammatory drugs, acetaminophen does not inhibit cyclooxygenase in peripheral tissues, which is the reason for its lack of peripheral anti-inflammatory effects. Acetaminophen may also inhibit the synthesis or actions of chemical mediators that sensitize the pain receptors to mechanical or chemical stimulation. The antipyretic activity of acetaminophen is exerted by blocking the effects of endogenous pyrogen on the hypothalamic heat-regulating center by inhibiting PG synthesis. Heat is dissipated by vasodilatation, increased peripheral blood flow, and sweating.

Acephen Suppository (Supp 120 mg)
Acute acetaminophen overdose will lead to dose-dependent hepatotoxicity and possibly acute renal failure. In addition, chronic ingestion of acetaminophen may also lead to hepatotoxicity or chronic analgesic nephropathy. Acetaminophen-induced hepatotoxicity and nephrotoxicity are due to the formation of the oxidative metabolite, N-acetyl-para-benzoquinoneimine (NAPQI), in the liver and to a lesser degree in the kidney. NAPQI binds covalently to sulfhydryl groups on tissue macromolecules leading to cell necrosis. Depletion of glutathione reserves leads to hepatotoxicity. Administration of N-acetylcysteine or methionine may reduce hepatotoxicity by binding to NAPQI. However, these agents do not prevent renal toxicity. Other toxic glutathione metabolites such as aminophenol-S-conjugates may play a role in acetaminophen-induced acute renal toxicity. Chronic analgesic nephropathy is characterized by interstitial nephritis and papillary necrosis. The mechanism of chronic analgesic necrosis is due to reactive metabolites or other products that inhibit renal cyclooxygenase.

Pharmacokinetics: Acetaminophen is administered orally (oral dosage forms) or rectally (via suppository). Following oral administration, acetaminophen is rapidly and almost completely absorbed from the GI tract. Peak plasma concentrations are attained within 30 - 60 minutes, although serum concentrations and analgesia are not necessarily correlated. Binding to serum protein is about 25% after normal therapeutic dosages.

Approximately 25% of the acetaminophen dose is subject to first-pass metabolism by the liver. The plasma half-life of acetaminophen in patients with normal hepatic function is 1.25 - 3 hours. Between 85 - 90% of the normal, therapeutic acetaminophen dose is metabolized in the liver via glucuronidation and sulfate conjugation. The remaining 10 - 15% undergoes oxidative metabolism via cytochrome P450 isoenzymes (CYP) 2E1 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine (NAPQI). NAPQI is a highly reactive quinone imine that is conjugated with glutathione and excreted into urine as thioether metabolites. The P450 isoenzyme 3A4 appears to have a minor role in the metabolism of acetaminophen. Excess NAPQI may be formed when acetaminophen is given concomitantly with hepatic enzyme-inducing agents. Also, fasting shifts the metabolic pathway away from glucuronidation towards oxidation, which results in greater NAPQI amounts that need to be inactivated by conjugation with glutathione. The elimination half-life of acetaminophen is 2 - 4 hours in patients with normal liver function. After about 8 hours, only traces of the drug are detectable. Acetaminophen is renally excreted mainly as the glucuronide conjugate. About 85% of a dose appears in the urine within 24 hours of oral administration.

Special Populations: At all doses, metabolites, but not unchanged drug, can accumulate in renal impairment. The half-life of acetaminophen can be prolonged in patients with hepatic disease. In neonates and children (3 - 9 years), acetaminophen is excreted primarily as the sulfate conjugate; however there is not any age-related differences in the total clearance of acetaminophen. The difference in methods of clearance may be due to a deficiency in glucuronide formation in younger age groups.

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References
_{. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. N Engl J Med 1994;331:1675 - 9.}

. Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther 1976;19:284 - 94.

. Tolman KG. Hepatotoxicity of non-narcotic analgesics. Am J Med 1998;105:13S - 19S.

. Amadio P. Peripherally acting analgesics. Am J Med 1984;77:17 - 26.

. Manyike PT, Kharasch ED, Kalhorn TF, et al. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 2000;67:275 - 82.

. Larson AM, Polson J, Fontana RJ, et al, the Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005;42:1364 - 72.

Acetaminophen

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