Analgesic – Antipyretic
Action And Clinical Pharmacology: Acetaminophen is the major metabolite of phenacetin and acetanilide. Animal and clinical studies have shown acetaminophen to have antipyretic and analgesic activity equal to that of ASA. Acetaminophen lacks anti-inflammatory effects.
Unlike the salicylates, acetaminophen does not interfere with tubular secretion of uric acid nor does it affect acid-base balance if taken in therapeutic doses. Acetaminophen does not interfere with hemostasis and, in particular does not inhibit platelet aggregation. Allergic reactions are rare and thus the drug is useful in patients who cannot tolerate salicylates and those with an allergic diathesis, including bronchial asthmatics. The rate of acetaminophen absorption from the gastrointestinal tract following oral administration is a function of stomach emptying rate and is generally rapid and complete with peak plasma concentrations of free drug being achieved in 0.5 to 1 hour following administration. The plasma half-life of unchanged drug is about 2 hours with approximately 85% of a 1 g oral dose being recovered in the urine in 24 hours. Approximately 3% is excreted unchanged with the balance being eliminated principally as the glucuronide and sulfate conjugates.
A small portion of the administered acetaminophen is converted by hepatic microsomal enzymes to a reactive metabolite. At therapeutic doses this minor metabolite is rapidly inactivated by conjugation with glutathione and eliminated by renal excretion. However, where hepatic glutathione has been depleted, covalent binding of the reactive metabolite to liver-cell macromolecules occurs and hepatic cell necrosis ensues. It has been shown that glutathione precursors such as N-acetylcysteine, cysteine, cysteamine and methionine can decrease experimental acetaminophen-induced hepatic necrosis when administered promptly after a toxic dose of acetaminophen. Rectal absorption of acetaminophen, as with most rectally administered drugs, is more erratic than absorption following oral administration. Absorption rate is generally slower. Peak blood levels of free acetaminophen are not reached until 1.5 to 3 hours following rectal administration and the peak concentration in the blood is approximately 50% of that observed following an equivalent oral dose. The percentage of a rectal dose of acetaminophen absorbed also varies giving wide variances in bioavailability. In view of these observations higher rectal doses or more frequent administration may be required to achieve and/or maintain blood concentrations of acetaminophen comparable to those obtained following oral administration.
Indications And Clinical Uses: For the treatment of mild to moderate pain and the reduction of fever.
Contra-Indications: Hypersensitivity to acetaminophen or to its nonmedicinal ingredients. tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: Acetaminophen poisoning can result in severe hepatic damage.
Precautions And Adverse Reactions: When used as directed, acetaminophen is virtually free of severe toxicity or side effects. The incidence of gastrointestinal upset is less than after salicylate administration. If a rare sensitivity reaction occurs, discontinue the drug.
Hypersensitivity to acetaminophen is usually manifested by a rash or urticaria.
Regular use of acetaminophen has been shown to produce a slight increase in prothrombin time in patients receiving oral anticoagulants but the clinical significance of this effect is not clear.
Symptoms And Treatment Of Overdose: Symptoms: In adults hepatotoxicity may occur after ingestion of a single dose of 10 to 15 g (200 to 250 mg/kg) of acetaminophen; a dose of 25 g or more is potentially fatal. In adults, nonfatal overdoses (ranging from 12.5 to 31.5 g) have been reported and 1 death after 30 g of acetaminophen had been ingested. A 13 year old child is reported to have died after ingesting 15 g.
Symptoms during the first 2 days of acute poisoning by acetaminophen do not reflect the potential seriousness of the intoxication. Nausea, vomiting, anorexia and abdominal pain occur during the initial 24 hours and may persist for a week of more. Liver injury may become manifest the second day, initially by elevation of serum transaminase and lactic dehydrogenase activity, increased serum bilirubin concentration and prolongation of prothrombin time. Alkaline phosphatase activity and serum albumin concentration may remain normal. The hepatotoxicity may progress to encephalopathy, coma and death. Liver biopsy reveals centrilobular necrosis with sparing of the periportal area. In nonfatal cases, the hepatic lesions are reversible over a period of weeks or months. Transient azotemia is apparent in most patients and acute renal failure occurs in some. Hypoglycemia may occur, but glycosuria and impaired glucose tolerance have also been reported. Both metabolic acidosis and metabolic alkalosis have been noted, cerebral edema and nonspecific myocardial depression have also occurred. Since acetaminophen is metabolized primarily by the liver, in cases of acute poisoning, prolongation of the plasma half-life beyond 3 hours may be indicative of liver injury. Hepatic necrosis should be anticipated if the half-life exceeds 4 hours, and hepatic coma is likely if the half-life is greater than 12 hours. A single determination of serum acetaminophen concentration is a less reliable predictor of hepatic injury. However, only minimal liver damage has developed when the serum concentration was below 120 Âµg/mL at 4 hours or less than 50 Âµg/mL at 12 hours after ingestion of the drug. Encephalopathy should also be anticipated if serum bilirubin concentration exceeds 4 mg/100 mL during the first 5 days.
Treatment: Early diagnosis is vital. Vigorous supportive therapy is essential when intoxication is severe. Procedures to limit continuing absorption of the drug must be initiated promptly. When the oral route of administration is used induction of vomiting or gastric lavage should be performed and should be followed by oral administration of activated charcoal (50 g). Hemodialysis, if it can be initiated within the first 12 hours, has been advocated for all patients with a plasma concentration of acetaminophen greater than 120 Âµg/mL 4 hours after drug ingestion. If administered within the first few hours after ingestion of acetaminophen, sulfhydryl compounds, which replete glutathione, have been shown to effectively prevent or reduce the hepatotoxic effects of acetaminophen. N-acetylcysteine, available commercially as a sterile 20% solution (Mucomyst), has been shown to be particularly effective and well tolerated when given orally as a 5% solution diluted with cola, fruit juice, or water. The accepted treatment regimen is a loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours for 17 doses or until plasma concentrations of acetaminophen are indicative of a low risk of hepatotoxicity.
Dosage And Administration: Adults: 650 mg every 4 to 6 hours as necessary. Maximum daily dosage recommended is 6 suppositories.
Children: Under 2 years: As recommended by the physician. 2 to 4 years: 120 mg every 4 hours. Maximum daily dosage recommended is 6 suppositories. 4 to 6 years: 325 mg every 6 hours. Maximum daily dosage recommended is 4 suppositories. 6 to 12 years: 325 mg every 4 hours. Maximum daily dosage recommended is 6 suppositories.
A physician should be consulted for treatment regimens lasting longer than 5 days. Inherent in the rectal route of administration is the possibility of erratic absorption, lower blood concentrations and lower bioavailability in some patients relative to the oral route. Therefore, more frequent rectal administration is acceptable when deemed necessary by the prescriber.
Availability And Storage: Each suppository contains: acetaminophen 120, 325 or 650 mg. Nonmedicinal ingredients: Novata. Suppositories are individually sealed in plastic moulds. Boxes of 4 and 12. Store at room temperature.
ABENOLÂ® SmithKline Beecham Acetaminophen Analgesic – Antipyretic