Acetaminophen

(CC) Image: David E. Volk
Acetaminophen (paracetamol)

Acetaminophen, also widely called acetaminofen, paracetamol or paracetanol, is an analgesic and antipyretic drug widely used for the treatment of headaches, fever and other minor aches and pains. Many cold and flu medications and some prescription analgesics contain acetaminophen. Although it is sold under hundreds of names, it is popularly known as Tylenol®.

The drug has long been considered especially safe, and replaced aspirin for many over-the-counter uses. It does not interfere with clotting mechanisms and increase bleeding tendency, and does not produce Reye's Syndrome in children. Nevertheless, suspicions arose that it could cause liver failure in heavy users of alcohol, but more data suggests there is a more general risk to the liver. In July 2009, an advisory committee to the Food and Drug Administration recommended that the maximum dose be reduced to 650 milligrams, from 1000 milligrams in current "extra strength" preparations.

It has no mood altering effects and is not addictive although it can be combined with opioid analgesics which have these effects such as oxycodone or hydrocodone with the brand names of Percocet and Vicodin respectively. These combinations do offer some synergistic pain control, but that is not the primary purpose. Indeed, some prescribers may recommend that before increasing opioid dose, a second 300-375mg acetaminophen be taken with the combined tablet.

When the other drugs contain opioid analgesics, the primary purpose is to keep the oral dose from being diverted to recreational injection. The combination also has some therapeutic sense, because acetaminophen and opioids affect different mechanisms of pain. Unfortunately, there have been cases where raising the combined-tablet dose, usually to provide more opioid and often under medical orders, inadvertently produced acetaminophen toxicity. The FDA Advisory committee recommended, with a 20 to 17 vote, that prescription products that combine acetaminophen with other medications should be eliminated. This does not affect over-the-counter cold products that combine acetaminophen with such other agents as decongestants and cough supressants, but addresses the situation when the patient might try to increase pain relief with what would be a safe additional opioid dosage, but overdose with acetaminophen. There is little reason to take higher dose of a cold medication.

Mechanism of action

Acetaminophen inhibits cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) indirectly through a hypothesized yet unknown enzyme called COX-3, in the central nervous system and endothelial cells and thus suppresses the synthesis of prostaglandin and heightens the pain threshold. However, it does not inhibit COX enzymes in the peripheral tissues, and thus has no peripheral anti-inflammatory effects.

Metabolism

Glucuronosyltransferase is part of the phase II drug metabolism of acetaminophen.

Effectiveness

Analgesia

Acetaminophen one gram orally four times a day had similar efficacy to ibuprofen in reducing pain in randomized controlled trial of patients with mild to moderate osteoarthritis or the hip or knee.

"Diclofenac and paracetamol had the same effect on pain reduction of ankle sprains but more acute ankle edema was present in patients who were treated with diclofenac than in patients who were treated with paracetamol"according to a randomized controlled trial.

Intravenous acetaminophen one gram was as effective as morphine 0.1 mg/kg for renal colic.

Combination therapy

According to a systematic review sponsored by industry, combining acetaminophen with Non-steroidal anti-inflammatory agents may help treatment of posteroperative pain.

For lumbalgia, acetaminophen one gram orally four times a day combined with diclofenac, a non-steroidal anti-inflammatory agent, was not better than acetaminophen alone in a randomized controlled trial.

Acetaminophen has been combined with ibuprofen with uncertain results.

Fever

For reducing fever, acetaminophen combined with ibuprofen may be better than either drug alone according to a randomized controlled trial.

Toxicity and drug interactions

While it is generally safe and effective, the margin between a safe and toxic dosage is narrower than once believed. In particular, overdoses are dangerous to the liver, once to be the case only in patients with alcohol-induced hepatic damage. While not yet a firm recommendation, there is increasing sentiment that patients taking it should not drink any alcohol while being treated.

It may cause liver, blood cell, and kidney damage in a limited number of people. Alcohol intake increases its liver toxicity. The toxic effects of acetaminophen are due to a minor metabolite N-acetyl-p-benzo-quinone imine, which reacts with sulfhydryl groups. At usual doses, it is detoxified by combining with glutathione to produce a non-toxic conjugate that gets excreted by the kidneys.

The anticoagulation effects of acenocoumarol, anisindione, dicumarol and warfarin are increased when taken with acetaminophen. Increased liver toxicity occurs when used in combination with imatinib, isoniazid or alcohol.

One third of patients taking a full dose (1 gram four times a day) may have their liver function tests rise to three times the upper limit of normal.

Dosage

The Food and Drug Administration may reduce the recommended dose to 650 milligrams per dose and no more than 3250 milligrams per day.

External links

• The most up-to-date information about Acetaminophen and other drugs can be found at the following sites.
• Acetaminophen - FDA approved drug information (drug label) from DailyMed (U.S. National Library of Medicine).
• Acetaminophen - Drug information for consumers from MedlinePlus (U.S. National Library of Medicine).
• Acetaminophen - Detailed information from DrugBank.