The P-I-E-N-O Parkinsn's List Drug Database
acetaminophen, TylenolTM
Description: 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.
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.
Pharmacokinetics: 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.
CONTRAINDICATIONS/PRECAUTIONS: Patients with hepatic disease, viral hepatitis or alcoholism may be at risk for acetaminophen hepatotoxicity since conjugation of the drug can be decreased and the half-life can be increased. 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. These higher levels can increase the risk for hepatotoxicity.
Patients with anemia should be treated with caution since it can be aggravated by acetaminophen. Cyanosis may not be apparent in patients with preexisting anemia, in spite of dangerously high blood concentrations of methemoglobin.
Symptoms of acute infection (fever, pain) can be masked during treatment with acetaminophen.
Certain acetaminophen products containing aspartame (NutrasweetTM ) should be avoided in patients who have phenylketonuria or who must restrict intake of phenylalanine. These products include: TempraTM chewable tablets, Alka- SeltzerTM Advanced Formula, Children's Anacin-3TM , Junior Strength TylenolTM , Children's TylenolTM , and Double-Strength TempraTM .
DRUG INTERACTIONS: 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. Several preparations that combine acetaminophen with a barbiturate are commercially available.
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. Increases in PT usually occurred after several weeks of acetaminophen administration and both PT prolongation and clinical bleeding have been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe. Clinicians should be alert for an increased PT if acetaminophen is administered daily in large doses for longer than 10 days.
ADVERSE REACTIONS: Hepatic necrosis is the major adverse reaction of acetaminophen. Any evidence of hepatotoxicity suggests discontinuation of the drug. Hepatotoxicity can result from acute overdoses or from chronic use (i.e., several months of daily administration). Regular use of acetaminophen for periods of 5-39 months produced hepatotoxicity in 11 patients. If plasma half-life exceeds 4 hours, hepatic necrosis can occur, and if the half-life exceeds 12 hours, hepatic coma is likely to develop. When an acute overdose is suspected, 2 or 3 days pass before maximum liver damage becomes apparent. Young children appear to be at less risk of developing hepatotoxicity, possibly because of an age-related difference in the metabolism of the drug. Nausea/vomiting and abdominal pain usually occur only after the ingestion of toxic doses of the drug and within 2-3 hours after ingestion. GI bleeding can occur secondary to low prothrombin levels. In addition, poisoning can lead to mental changes, characterized by initial CNS stimulation and subsequent CNS depression. 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 with anemia, resulting 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.
PATIENT INFORMATION:
What do acetaminophen tablets, caplets, or chewable tablets do?
Acetaminophen (TylenolTM ) is an analgesic and antipyretic. This means acetaminophen can relieve mild to moderate pain and reduce fever. It is the preferred treatment for patients with aspirin allergy, ulcers, or clotting (bleeding) disorders. Patients who are having medicines to treat gout can safely take acetaminophen. There are many generic variations available for adults and children. Tablets can be plain, extended-release, or chewable. Gelcaps or geltabs are also available.
What should my doctor, dentist, or pharmacist know before I take acetaminophen?
They need to know if you have any of these conditions:
How should I take this medicine?
Acetaminophen can be taken as needed for the relief of pain or fever, or may be prescribed by the doctor on a more regular basis. Do not take more often than directed, or exceed the recommended dose. Take acetaminophen tablets, caplets or gelcaps by mouth. Follow the directions on the label. Chewable tablets can be chewed before swallowing, crushed and taken with food, or mixed in a drink. Swallow extended-release tablets whole, do not crush or chew. Drink a full glass of water either with or after taking your medicine.
Special precautions for use in children:
Do not give children more than five doses per day, unless otherwise prescribed by the doctor. Larger or more frequent doses can be dangerous.
What if I miss a dose?
If your doctor has prescribed a regular schedule and you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.
What other medicines can interact with acetaminophen?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking acetaminophen?
If you take acetaminophen as recommended, serious side effects are uncommon.
Effects of overdose include:
Call your doctor as soon as you can if you get any of these side effects.
What do I need to watch for while I take acetaminophen?
Do not treat yourself for pain for more than 10 days (5 days for children) without checking with your doctor. If you are treating a fever, check with your doctor if the fever lasts for more than 3 days. Report any possible overdose promptly to your doctor. If you have taken an overdose the effects may not be obvious for several days.
Alcohol can increase possible damage to your liver. Avoid alcoholic drinks if you are taking acetaminophen on a regular basis.
Many non-prescription medicines contain acetaminophen as an ingredient. Always read the labels carefully to avoid taking an accidental overdose, which can be dangerous.
Acetaminophen can affect the results from some blood-sugar tests used by diabetic patients. Check with your doctor before you change your diet or the dose of your diabetic medicine.
Where can I keep my medicine?
Keep out of reach of children in a container that small children cannot open. Acetaminophen can be dangerous to children.
Store at room temperature between 15 and 30C (59 and 86F). Protect from moisture and light. Throw away any unused medicine after the expiration date.
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