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Acetaminophen is the active metabolite of phenacetin. Acetaminophen possesses analgesic and antipyretic activity, however, some clinicians consider acetaminophen a poor analgesic. Since acetaminophen has no peripheral antiinflammatory activity, its efficacy as an analgesic may indeed be less than aspirin's in situations in which this action is desirable. Acetaminophen is preferred over aspirin as an analgesic/antipyretic for patients in whom aspirin is contraindicated, such as those who have a history of gastric ulcer or a coagulation disorder. Also, acetaminophen does not interfere with the actions of uricosuric agents as aspirin can. 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 as an individual agent in several dosage forms, and in combination with a variety of other drugs, although there is little evidence to show that therapeutic agents are more effective when combined with acetaminophen. Recently, acetaminophen has been implicated as a cause of renal disease. sustained-release product, "Feverall Extended Release", was submitted for FDA approval 12/30/97.
Tylenol® Regular Strength Tablets or Caplets-
Tylenol® Extra Strength Tablets, Caplets, Gelcaps and Geltabs-
Tylenol® Extended Relief Caplets-
Tylenol® Junior Strength Coated Caplets and Chewable Tablets-
Children's Tylenol® Suspension-
Children's Tylenol® Chewable Tablet-
NOTE: Acetaminophen is available in a number of combination products: see combination drugs index.
Mechanism of Action:
Acetaminophen's exact mechanism of action is unknown. Unlike aspirin, acetaminophen is primarily centrally acting, has no effects on platelet aggregation, and is a reversible inhibitor of cyclooxygenase, an enzyme involved in prostaglandin (PG) synthesis. The antipyretic activity is exerted by blocking the effects of endogenous pyrogen on the hypothalamic heat-regulating center, possibly by inhibiting PG synthesis. Heat is dissipated by vasodilation, increased peripheral blood flow, and sweating. An analgesic effect may be produced by a direct action on the pain threshold. This effect is believed to be due to inhibition of PG synthesis or inhibition of the synthesis or actions of chemical mediators or other substances that sensitize the pain receptors to mechanical or chemical stimulation. Acetaminophen does not possess peripheral antiinflammatory activity.
Chronic ingestion of acetaminophen may lead to hepatotoxicity or nephrotoxicity. The mechanism of either toxicity may be similar. An acetaminophen metabolite, p-aminophenol concentrates in the hypertonic renal papillae. Oxidized metabolites of p-aminophenol bind covalently to sulfhydryl groups on tissue macromolecules leading to cell necrosis. Binding to sulfhydryl groups can occur in either the liver or kidney. Subsequent depletion of glutathione reserves can lead to hepatotoxicity or nephrotoxicity.
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.
Between 90-95% of the acetaminophen dose is metabolized in the liver via glucuronidation and sulfate conjugation. At normal therapeutic doses, 94% of acetaminophen is excreted in the urine as glutathione conjugates and only 2% as metabolites. After an acute overdose, conjugation of the hepatotoxic metabolite with glutathione is overwhelmed and hepatotoxicity occurs. At all doses, metabolites, but not unchanged drug, can accumulate in renal impairment. Plasma half-life is between 1-2.5 hours in normal, healthy patients. After about 8 hours, only traces of the drug are detectable. Half-life can be prolonged in patients with hepatic disease, and, conversely, a prolonged half-life during an acute overdose can predict the subsequent development of hepatic necrosis.
WARNING: Acute overdoses of acetaminophen are extremely toxic and potentially fatal. Furthermore, acetaminophen and other OTC (over the counter) medications are too weak for addressing moderate or severe Migraine pain and MUST be avoided as this practice can lead to painful Rebound headaches. Rebound headache a trigger, or re-trigger Migraines leading to chronic daily headache. Do not exceed recommended daily dosage. In addition, ingestion of normal doses daily for many months has also been associated with hepatotoxicity.
NOTE: If acetaminophen is not effective for you Migraine, discuss a more appropriate pain management medication.
For the treatment of mild pain or fever:
Oral or rectal dosage:
Adults and adolescents: 325-650 mg PO or PR every 4-6 hours, as needed. Alternatively, 1000 mg PO or PR, three or four times per day can be given. Maximum dose should not exceed 4 g per day. Dosage for long-term therapy should not exceed 2.6 g per day.
Children and infants: 10-15 mg/kg PO or PR every 4-6 hours. Do not exceed 5 doses in 24 hours.
Neonates: 10-15 mg/kg PO or PR every 4-6 hours as needed.
Patients with renal impairment:
Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available.
Patients with hepatic disease, viral hepatitis or alcoholism may be at risk for acetaminophen hepatotoxicity since conjugation of the drug can be decreased. Depletion of hepatic glutathione reserves limits the ability of the liver to conjugate acetaminophen which predisposes the patient to further hepatic injury. Although it is always prudent to use the smallest dose of acetaminophen for the shortest duration necessary, short courses of normal adult doses have been administered safely to patients with stable chronic liver disease. Since acetaminophen and its conjugated metabolites are excreted primarily by the kidneys, serum concentrations of both can increase in patients with renal impairment(dosage adjustment). Higher serum concentrations of acetaminophen can increase the risk for hepatotoxicity.
Acetaminophen should be used cautiously in patients with anemia since this condition can be aggravated. Cyanosis may not be apparent in patients with preexisting anemia, in spite of dangerously high blood concentrations of methemoglobin.
Acetaminophen should be used cautiously in asthmatic patients who also have aspirin hypersensitivity. A single-blind prospective study of 50 aspirin-sensitive asthmatic subjects and 20 other asthmatics who were not aspirin-sensitive revealed that 17 of 50 aspirin-sensitive subjects reacted to acetaminophen while no subject in the other group reacted. Acetaminophen was administered in doses of 1000 mg and 1500 mg. The majority of the reactions were mild bronchospasm and were easily reversed. The authors concluded that high doses of acetaminophen (e.g., >1000 mg) should be avoided in patients with aspirin-sensitivity who are also asthmatic.
Symptoms of acute infection (e.g., fever, pain) can be masked during treatment with acetaminophen.
Certain acetaminophen products containing aspartame (Nutrasweet®) should be avoided in patients who have phenylketonuria or who must restrict intake of phenylalanine. These products include: Tempra® chewable tablets, Alka-Seltzer® Advanced Formula, Children's Anacin-3®, Junior Strength Tylenol®, Children's Tylenol®, and Double-Strength Tempra®.
Antacids or food can delay and decrease the oral absorption of acetaminophen.
Phenothiazines can interfere with thermoregulation. Concomitant use of acetaminophen with phenothiazines can produce hypothermia if acetaminophen is given in large doses and the patient is exposed to cold ambient temperatures.
The risk of developing hepatotoxicity from acetaminophen appears to be increased in patients who regularly consume ethanol. In these patients, hepatotoxicity is possible even at normal, therapeutic dosages of acetaminophen. Administration of acetaminophen should be limited or avoided altogether in alcoholics or patients who consume ethanol regularly.
In rats, cimetidine decreases acetaminophen binding to hepatic microsomal proteins and cimetidine has been shown to improve survival after acetaminophen overdose. In healthy volunteers, cimetidine decreases the clearance of the toxic acetaminophen metabolite more than the conjugated metabolite. The impact of these findings in the prevention of acetaminophen hepatotoxicity is uncertain; more studies are needed to evaluate this role of cimetidine in acetaminophen toxicity.
At least one case has been reported of phenobarbital enhancing acetaminophen hepatotoxicity. Despite the use of only moderate doses of acetaminophen, the patient had been consuming acetaminophen regularly for 3 months. While chronic acetaminophen use should be discouraged during phenobarbital therapy, intermittent use of acetaminophen is probably safe. Clinicians should note that several preparations that combine acetaminophen with a barbiturate are commercially available.
Sulfinpyrazone can induce hepatic microsomal enzymes that metabolize acetaminophen and this, in turn, may increase the risk of acetaminophen hepatotoxicity due to the formation of increased amounts of toxic acetaminophen metabolites. The risk of acetaminophen hepatotoxicity in patients taking sulfinpyrazone increases with larger acetaminophen doses, particularly overdoses.
Although acetaminophen is routinely considered safer than aspirin when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion can increase PT (now referred to as INR) in a dose-related fashion. Both INR prolongation and clinical bleeding have been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered daily in large doses for longer than 10 days.
Acetaminophen can be hepatotoxic. In most cases, acetaminophen hepatotoxicity occurs as a result of an acute overdose, however, moderately excessive doses, if taken chronically, can also produce hepatotoxicity. Regular use of acetaminophen for periods of 5-39 months produced hepatotoxicity in 11 patients. If plasma acetaminophen half-life exceeds 4 hours, hepatic necrosis can occur, and if the half-life exceeds 12 hours, hepatic coma is likely to develop. After acute overdose, 2 or 3 days pass before maximum liver damage becomes apparent. Nausea/vomiting and abdominal pain usually occur within 2-3 hours after ingestion of toxic doses. Elevated hepatic enzymes and hypoprothrombinemia are seen. GI bleeding can occur secondary to low prothrombin levels. Hepatic necrosis is the major adverse reaction of acetaminophen. In addition, poisoning can lead to mental changes, characterized by initial CNS stimulation and subsequent CNS depression. Young children appear to be at less risk of developing hepatotoxicity, possibly because of an age-related difference in the metabolism of the drug. Both cimetidine and ethanol can affect the severity of acetaminophen hepatotoxicity (see Drug Interactions). It has also been suggested that recent fasting is associated with hepatotoxicity in patients taking higher than recommended doses.
Acetaminophen can cause acute renal tubular necrosis and renal papillary necrosis in patients receiving high doses (e.g., 2.5-10 g/day) chronically or after acute overdose. The risk of renal complications appears to be higher in alcoholic patients. Recently, acetaminophen has been implicated as a contributing factor in the decline of renal function in patients with underlying renal disease, including diabetic nephropathy.
Methemoglobinemia can occur after acute overdoses of acetaminophen and can lead to hemolysis thereby causing hemolytic anemia. This can result in cyanosis of the fingernails, skin, and mucosa. Children develop methemoglobinemia more readily than do adults. Other hematologic reactions reported with acetaminophen include neutropenia, leukopenia, thrombocytopenia, and pancytopenia.
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