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acetaminophen

 
American Heritage Dictionary:

a·cet·a·min·o·phen

(ə-sē'tə-mĭn'ə-fən, ăs'ə-) pronunciation
n.
A crystalline compound, C8H9NO2, used in medicine to relieve pain and reduce fever.

[ACET(O)- + AMINO- + PHEN(OL).]


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Drug used to relieve mild headache or muscle and joint pain and to reduce fever. An organic compund, it relieves pain by inhibiting prostaglandin synthesis in the central nervous system and reduces fever by acting on the temperature-regulating centre of the brain. Unlike aspirin, it has no anti-inflammatory effect. It also is much less likely to irritate the stomach and cause peptic ulcers, is not linked with Reye syndrome, and can be taken by persons using anticoagulants or allergic to aspirin. Overdosages can cause fatal liver damage. Common brand names around much of the world are Tylenol and Panadol. See also ibuprofen.

For more information on acetaminophen, visit Britannica.com.

A painkiller which, unlike aspirin, does not increase the tendency to bleed. However, paracetamol acts within the brain and not at the site of tissue damage, so it lacks the power of aspirin to reduce the inflammation associated with many sports injuries. Overdoses can cause liver failure.

Drug Info:

Acetaminophen

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Brand names: 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®, 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

Chemical formula:



Acetaminophen tablets, caplets, or chewable tablets

What are acetaminophen tablets, caplets, or chewable tablets?

ACETAMINOPHEN (Tylenol®, Panadol®, Feverall® and many others) is used to 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 taking medicines to treat gout can safely take acetaminophen. There are many generic variations available for adults and children. Tablets can be immediate-release, extended-release, or chewable. Gelcaps or geltabs are also available.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• anemia
• drink more than 3 alcohol-containing drinks per day
• infection
• kidney disease
• liver disease
• hepatitis
• phenylketonuria
• an unusual or allergic reaction to acetaminophen, aspirin, other medicines, foods, dyes or preservatives

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 prescriber or health care professional on a more regular basis. Do not take more often than directed, or more than the recommended dose. Acetaminophen tablets come in several strengths for children and adults. Make sure you are taking or giving the correct 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.

Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed. Do not administer adult acetaminophen preparations to children.

What drug(s) may interact with acetaminophen?

• alcohol
• medicines for seizures
• antacids
cimetidine
• medicines for mental problems and psychotic disturbances
warfarin

Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional 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 with your health care professional before stopping or starting any of your medicines.

What should I watch for while taking acetaminophen?

Do not treat yourself for pain for more than 10 days (5 days for children) without checking with your prescriber or health care professional. If you are treating a fever, check with your prescriber or health care professional if the fever lasts for more than 3 days.

Report any possible overdose promptly to your prescriber or health care professional as soon as possible. The effects of excessive doses may not be obvious for several days.

Avoid alcoholic drinks if you are taking acetaminophen on a regular basis. Alcohol can increase possible damage to your liver.

Many non-prescription medicines contain acetaminophen as an ingredient. Always read the labels carefully to avoid taking an accidental overdose, which can be dangerous.

Certain acetaminophen products containing the artificial sweetener aspartame (Nutrasweet®).

Acetaminophen can affect the results from some blood-sugar tests used by diabetic patients. Check with your prescriber or health care professional before you change your diet or the dose of your diabetic medicine.

If you are receiving cancer chemotherapy or other immunosuppression medicine, do not take acetaminophen with out checking with your prescriber or health care professional. Acetaminophen may hide the signs of an infection such as fever or pain.

What side effects may I notice from taking acetaminophen?

If you take acetaminophen as recommended, serious side effects are uncommon.
Side effects that you should report to your prescriber or health care professional as soon as possible:
• skin rash or hives
• unusual bleeding or bruising, pinpoint red spots on the skin
• difficulty breathing, wheezing
• bloody or black, tarry stools
• decrease in amount of urine passed
• not willing to eat
• fever or sore throat
• nausea, vomiting
• stomach cramps and pain
• unusual tiredness or weakness
• yellowing of the skin or eyes

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. Avoid accidental overdose of acetaminophen as this may result in severe effects and possibly death.

Store at room temperature between 15—30 degrees C (59—86 degrees F). Protect from moisture and light. Throw away any unused medicine after the expiration date.

Last updated: 11/25/2003 8:33:00 PM

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.


A drug that relieves pain (see analgesics) and also reduces fever (but has no anti-inflammatory activity). Paracetamol provides effective relief of mild to moderate pain, including headache, toothache, period pains, backache, and rheumatic pains, and is useful for reducing high temperatures in colds, influenza, and other feverish conditions. Unlike aspirin, it does not irritate the stomach lining and is preferred to aspirin for elderly people and young children (under 12 years old). Paracetamol is available as tablets, soluble tablets, capsules, solutions, suppositories, and a solution for intravenous infusion; there are also suspensions and solutions specially formulated for babies and young children, often as flavoured sugar-free syrups. Paracetamol can be obtained without a prescription, but because it can have serious effects in overdosage (see below) there are restrictions on the quantities of tablets or capsules that can be supplied. Packs containing 16 tablets or capsules are freely available over the counter; packs containing up to 32 (or exceptionally up to 100) tablets or capsules can only be obtained from pharmacies. Larger quantities are available on prescription only. Paracetamol is combined with aspirin, codeine, or other ingredients in a variety of compound analgesic preparations and cold remedies. See also co-codamol; co-dydramol; co-proxamol.

Side effects and precautions:
side effects of recommended doses (up to 8 tablets/capsules a day in adults) are rare, but rashes or other allergic reactions may rarely occur; pancreatitis has been reported after prolonged use. In higher than recommended doses paracetamol causes liver damage, which may not be apparent for two days or more and can be fatal unless treated immediately with the antidote (methionine or acetylcysteine). For this reason it is important not to mix preparations containing paracetamol, in case the recommended dose is accidentally exceeded, and paracetamol should be taken with caution by people with liver disease.

Proprietary preparations:
Alvedon (suppositories); Anadin Paracetamol; Boots Cold & Flu Relief Hot Blackcurrant, Hot Lemon; Boots Paracetamol Capsules/Suspension; Boots Paracetamol and Codeine Extra Capsules; Calpol; Disprol; Fennings Children's Cooling Powders; Hedex; Medinol; Paldesic; Panadol; Panadol Soluble; Perfalgan (infusion). For details of these and other preparations of which paracetamol is an ingredient, see Appendix 1.

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Definition

Acetaminophen is a medicine used to relieve pain and reduce fever.

Description

Acetaminophen is used to relieve many kinds of minor aches and pains: headaches, muscle aches, backaches, toothaches, menstrual cramps, arthritis, and the aches and pains that often accompany colds.

Description

This drug is available without a prescription. Acetaminophen is sold under various brand names, including Tylenol, Panadol, Aspirin Free Anacin, and Bayer Select Maximum Strength Headache Pain Relief Formula. Many multi-symptom cold, flu, and sinus medicines also contain acetaminophen.

Studies have shown that acetaminophen relieves pain and reduces fever about as well as aspirin. But differences between these two common drugs exist. Acetaminophen is less likely than aspirin to irritate the stomach. However, unlike aspirin, acetaminophen does not reduce the redness, stiffness, or swelling that accompany arthritis.

Precautions

Most of the precautions for acetaminophen apply to adults rather than children but may apply to some teenagers.

The primary precaution in children's therapy is to watch the dosage carefully and follow the label instructions only. Acetaminophen for children comes in two strengths. Children's acetaminophen contains low concentrations of the drug, 160 milligrams in a teaspoonful of solution. The infant drops contain a much higher concentration of acetaminophen, 100 milligrams in 20 drops, equal to 500 milligrams in a teaspoonful. The infant drops should never be given by the teaspoonful.

Parents should never give their child more than the recommended dosage of acetaminophen unless told to do so by a physician or dentist.

Patients should not use acetaminophen for more than 10 days to relieve pain (five days for children) or for more than three days to reduce fever, unless directed to do so by a physician. If symptoms do not go away or if they get worse, a physician should be contacted. Anyone who drinks three or more alcoholic beverages a day should check with a physician before using this drug and should never take more than the recommended dosage. A risk of liver damage exists from combining large amounts of alcohol and acetaminophen. People who already have kidney or liver disease or liver infections should also consult with a physician before using the drug. Women who are pregnant or breastfeeding should do the same.

Side Effects

Acetaminophen causes few side effects. The most common one is lightheadedness. Some people may experience trembling and pain in the side or the lower back. Allergic reactions do occur in some people, but they are rare. Anyone who develops symptoms such as a rash, swelling, or difficulty breathing after taking acetaminophen should stop taking the drug and get immediate medical attention. Other rare side effects include yellow skin or eyes, unusual bleeding or bruising, weakness, fatigue, bloody or black stools, bloody or cloudy urine, and a sudden decrease in the amount of urine.

Overdoses of acetaminophen may cause nausea, vomiting, sweating, and exhaustion. Very large overdoses can cause liver damage. In case of an overdose, parents should get immediate medical attention for their child.

Interactions

Acetaminophen may interact with a variety of other medicines. When this happens, the effects of one or both of the drugs may change or the risk of side effects may be greater. Among the drugs that may interact with acetaminophen are the following:

  • alcohol
  • nonsteroidal anti-inflammatory drugs (NSAIDs) such as Motrin
  • oral contraceptives
  • the antiseizure drug phenytoin (Dilantin)
  • the blood-thinning drug warfarin (Coumadin)
  • the cholesterol-lowering drug cholestyramine (Questran)
  • the antibiotic Isoniazid
  • zidovudine (Retrovir, AZT)

Check with a physician or pharmacist before combining acetaminophen with any other prescription or nonprescription (over-the-counter) medicine.

Acetaminophen is generally safe when taken as directed. Acetaminophen is commonly mixed with other ingredients as part of combinations intended for colds, influenza, and other conditions. Parents should read the labels carefully in order to avoid giving an overdose of acetaminophen to their child. They need to be particularly cautious about liquid medicines that contain acetaminophen and alcohol.

Parental Concerns

Acetaminophen is very safe when used properly. While most precautions are intended to reduce the risk of overdose, parents should not try to reduce the risk by giving a lower than normal dose. Children should not suffer pain if it can be safely treated.

See also Analgesics; Pain management.

Resources

Books

Beers, Mark H., and Robert Berkow, eds. The Merck Manual, 2nd home ed. West Point, PA: Merck & Co., 2004.

Mcevoy, Gerald, et al. AHFS Drug Information 2004. Bethesda, MD: American Society of Healthsystems Pharmacists, 2004.

Siberry, George K., and Robert Iannone, eds. The Harriet Lane Handbook, 15th ed. Philadelphia: Mosby Publishing, 2000.

Periodicals

Burillo-Putze G., et al. "Changes in pediatric toxic dose of acetaminophen." American Journal of Emergency Medicine 22, no. 4 (July 2004): 323.

Evered, L. M. "Evidence-based emergency medicine/systematic review abstract. Does acetaminophen treat fever in children?" American Journal of Emergency Medicine 41, no. 5 (May 2003): 741–3.

Goldman, Ran D., and D. Scolnik. "Underdosing of acetaminophen by parents and emergency department utilization." Pediatric Emergency Care 20, no. 2 (February 2004): 89–93.

Kociancic T., et al. "Acetaminophen intoxication and length of treatment: how long is long enough?" Pharmacotherapy 23, no. 8 (August 2003): 1052–9.

Losek, Joseph D. "Acetaminophen dose accuracy and pediatric emergency care." Pediatric Emergency Care 20, no. 5 (May 2004): 285–8.

Organizations

American Pain Society. 4700 W. Lake Ave., Glenview, IL 60025. Web site: www.ampainsoc.org/.

Web Sites

"Acetaminophen." MedlinePlus. Available online at www.nlm.nih.gov/medlineplus/druginfo/medmaster/a681004.html (accessed October 15, 2004).

[Article by: Nancy Ross-Flanigan Samuel Uretsky, PharmD]



Columbia Encyclopedia:

acetaminophen

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acetaminophen (əsēt'əmĭn'əfĭn), an analgesic and fever-reducing medicine similar in effect to aspirin. It is an active ingredient in many over-the-counter medicines, including Tylenol and Midol. Introduced in the early 1900s, acetaminophen is a coal tar derivative that acts by interfering with the synthesis of prostaglandins and other substances necessary for the transmission of pain impulses. Although its action is similar to that of aspirin, it lacks aspirin's anti-inflammatory and blood-thinning effects, is less irritating to the stomach, and can be used by people who are allergic to aspirin. Heavy use, however, has been linked to an increased incidence of liver failure, especially in heavy drinkers of alcoholic beverages and in those who are not eating enough, and overdose, especially in children, can be fatal.


or paracetamol

4-acetamidophenol; N-acetyl-p-aminophenol;N-(4-hydroxyphenyl)acetamide; a drug widely used as an analgesic and antipyretic. It inhibits formation of prostaglandins within, but not outside the brain. It is metabolized within the liver mostly to glucuronide and sulfate conjugates. A small amount is oxidized to a highly reactive intermediate, N-acetylbenzoquinoneimine, that is normally detoxified by conjugation with glutathione. If it is produced in excess of the capacity of the liver to detoxify it, hepatic necrosis can result. It can be administered with methionine, which increases glutathione in the liver. N-Acetylcysteineis administered in cases of poisoning to act as a glutathione substitute. Proprietary names include: Panadol, Tylenol.

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Mosby's Dental Dictionary:

acetaminophen

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n

trade names: Tylenol, Anacin-3; drug class: nonnarcotic analgesic; action: thought to block initiation of pain impulses by inhibition of prostaglandin synthesis; uses: mild-to-moderate pain, fever; also used in combination with narcotic analgesics.

Random House Word Menu:

categories related to 'acetaminophen'

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Random House Word Menu by Stephen Glazier
For a list of words related to acetaminophen, see:
  • PHARMACOLOGY - acetaminophen: mild analgesic without anticoagulant activity


Wikipedia on Answers.com:

Paracetamol

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Paracetamol
Systematic (IUPAC) name
N-(4-hydroxyphenyl)ethanamide
N-(4-hydroxyphenyl)acetamide
Clinical data
Trade names Aminofen (USA), Anacin Aspirin Free (USA), Apra (USA), Feverall (USA), Genapap (USA), Tylenol (USA), Crocin (India)
AHFS/Drugs.com monograph
MedlinePlus a681004
Licence data US FDA:link
Pregnancy cat. A(AU) B(US) safe
Legal status Unscheduled (AU) GSL (UK) OTC (US)
Routes Oral, rectal, intravenous
Pharmacokinetic data
Bioavailability ~100%
Metabolism 90 to 95% Hepatic
Half-life 1–4 h
Excretion Renal
Identifiers
CAS number 103-90-2 YesY
ATC code N02BE01
PubChem CID 1983
DrugBank DB00316
ChemSpider 1906 YesY
UNII 362O9ITL9D YesY
KEGG D00217 YesY
ChEBI CHEBI:116450 N
ChEMBL CHEMBL112 YesY
Chemical data
Formula C8H9NO2 
Mol. mass 151.17 g/mol
SMILES eMolecules & PubChem
Physical data
Density 1.263 g/cm³
Melt. point 169 °C (336 °F) [2][3]
Solubility in water 12.78[1] mg/mL (20 °C)
 N(what is this?)  (verify)

Paracetamol INN (play /ˌpærəˈstəmɒl/ or /ˌpærəˈsɛtəmɒl/), or acetaminophen USAN Listeni/əˌstəˈmɪnəfɨn/, is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies. In combination with opioid analgesics, paracetamol can also be used in the management of more severe pain such as post-surgical pain and providing palliative care in advanced cancer patients.[4] The onset of analgesia is approximately 11 minutes after oral administration of paracetamol,[5] and its half-life is 1–4 hours. Though acetaminophen is used to treat inflammatory pain, it is not generally classified as an NSAID because it exhibits only weak anti-inflammatory activity.

While generally safe for use at recommended doses (1,000 mg per single dose and up to 4,000 mg per day for adults),[6] acute overdoses of paracetamol can cause potentially fatal liver damage and, in rare individuals, a normal dose can do the same; the risk is heightened by alcohol consumption. Paracetamol toxicity is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia and New Zealand.[7][8][9][10]

It is the active metabolite of phenacetin, once popular as an analgesic and antipyretic in its own right, but unlike phenacetin and its combinations, paracetamol is not considered carcinogenic at therapeutic doses.[11] The words acetaminophen (used in the United States, Canada, Japan, South Korea, Hong Kong, and Iran[12]) and paracetamol (used elsewhere) both come from a chemical name for the compound: para-acetylaminophenol and para-acetylaminophenol. In some contexts, it is simply abbreviated as APAP, for acetyl-para-aminophenol.

Contents

Medical uses

Fever

Paracetamol is approved for reducing fever in people of all ages.[13] The World Health Organization (WHO) recommends that paracetamol only be used to treat fever in children if their temperature is greater than 38.5 °C (101.3 °F).[14] The efficacy of paracetamol by itself in children with fevers has been questioned[15] and a meta-analysis showed that it is less effective than ibuprofen.[16] Paracetamol has a well-established role in pediatric medicine as an effective analgesic and antipyretic.

Pain

Paracetamol is used for the relief of pains associated with many parts of the body. It has analgesic properties comparable to those of aspirin, while its anti-inflammatory effects are weaker. It is better tolerated than aspirin in patients in whom excessive gastric acid secretion or prolongation of bleeding time may be a concern. Available without a prescription, it has in recent years increasingly become a common household drug.[17]

Paracetamol can relieve pain in mild arthritis but has no effect on the underlying inflammation, redness, and swelling of the joint. It is as effective as the non-steroidal anti-inflammatory drug ibuprofen in relieving the pain of osteoarthritis of the knee.

Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics such as the NSAIDs aspirin and ibuprofen.

Regarding comparative efficacy, studies show conflicting results when compared to NSAIDs. A randomized controlled trial of chronic pain from osteoarthritis in adults found similar benefit from paracetamol and ibuprofen.[18][19]

The efficacy of paracetamol when used in a combination form with weak opioids (such as codeine) has been questioned by recent data studies; the small amount of data available have made reaching a conclusion difficult. Combination drugs of paracetamol and strong opioids like morphine have been shown to reduce the amount of opioid used and improve analgesic effect as well as discouraging overuse of addictive opioids due to APAP's potentially toxic effects.[20]

A randomized controlled trial of acute musculoskeletal pain in children found that the standard over-the-counter dose of ibuprofen gives greater pain relief than the standard dose of paracetamol.[21]

Adverse effects

In recommended doses, the side effects of paracetamol are mild to non-existent.[22] In contrast to aspirin, it is not a blood thinner (and thus may be used in patients where coagulation is a concern), and it does not cause gastric irritation.[23] Compared to Ibuprofen—which can have adverse effects that include diarrhea, vomiting, and abdominal pain—paracetamol is well tolerated with fewer side effects.[24] Prolonged daily use increases the risk of upper gastrointestinal complications such as stomach bleeding,[25] and may cause kidney or liver damage.[23][26] Paracetamol is metabolized by the liver and is hepatotoxic; side effects may be more likely in chronic alcoholics or patients with liver damage.[22][27]

Until 2010 paracetamol was believed safe in pregnancy (as it does not affect the closure of the fetal ductus arteriosus as NSAIDs can[28]). However, in a study published in October 2010 it has been linked to infertility in the adult life of the unborn.[29] Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood although recent research shows some evidence that paracetamol can ease psychological pain.[30] Unlike aspirin, it is safe for children, as paracetamol is not associated with a risk of Reye's syndrome in children with viral illnesses.[31] Paracetamol use for fever in the first year of life was associated with an increase in the incidence of asthmatic symptoms at 6–7 years, and that paracetamol use, both in the first year of life and in children aged 6–7 years, was associated with an increased incidence of rhinoconjunctivitis and eczema.[32] The authors acknowledged that their "findings might have been due to confounding by indication", i.e., that the association may not be causal but rather due to the disease being treated with paracetamol, and emphasized that further research is needed. Furthermore a number of editorials, comments, correspondence, and their replies have been published in The Lancet concerning the methodology and conclusions of this study.[33][34][35][36][37][38][39] The UK regulatory body the Medicines and Healthcare products Regulatory Agency, also reviewed this research and published a number of concerns over data interpretation, and offer the following advice for healthcare professionals, parents, and care-givers: "The results of this new study do not necessitate any change to the current guidance for use in children. Paracetamol remains a safe and appropriate choice of analgesic in children. There is insufficient evidence from this research to change guidance regarding the use of antipyretics in children. "[40]

Chronic users of paracetamol may have a higher risk of developing blood cancer.[41]

Overdose

Paracetamol hepatotoxicity is, by far, the most common cause of acute liver failure in both the United States and the United Kingdom.[10][42] Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance.[43] Signs and symptoms of paracetamol toxicity may initially be absent or vague. Untreated overdose can lead to liver failure and death within days. Treatment is aimed at removing the paracetamol from the body and replacing glutathione. Activated charcoal can be used to decrease absorption of paracetamol if the patient presents for treatment soon after the overdose. While the antidote, acetylcysteine, (also called N-acetylcysteine or NAC) acts as a precursor for glutathione, helping the body regenerate enough to prevent damage to the liver, a liver transplant is often required if damage to the liver becomes severe.[7]

There are tablets available (brand-name in the UK Paradote) that combine paracetamol with an antidote (methionine), to protect the liver in case of an overdose.

In June 2009, a U. S. Food and Drug Administration (FDA) advisory committee recommended that new restrictions should be placed on paracetamol usage in the United States to help protect people from the potential toxic effects. The maximum dosage at any given time would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and narcotic analgesics would be prohibited. Committee members were particularly concerned by the fact that the present maximum dosages of paracetamol had been shown to produce alterations in hepatic function.[44] On January 13, 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit the amount of paracetamol to no more than 325 mg per tablet or capsule and began requiring manufacturers to update the labels of these products to warn of the potential risk for severe liver damage.[45][46][47][48] Manufacturers will have three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.[46][48] The FDA also is requiring manufacturers to update labels of all prescription combination paracetamol products to warn of the potential risk for severe liver injury.[45][46][48]

In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.[49]

Classification

Paracetamol is part of the class of drugs known as "aniline analgesics"; it is the only such drug still in use today.[50] It is not considered an NSAID because it does not exhibit significant anti-inflammatory activity (it is a weak COX inhibitor).[51][52] This is despite the evidence that paracetamol and NSAIDs have some similar pharmacological activity.[53]

Mechanism of action

AM404Metabolite of paracetamol
Anandamide – Endogenous cannabinoid

To date, the mechanism of action of paracetamol is not completely understood. The main mechanism proposed is the inhibition of cyclooxygenase (COX), and recent findings suggest that it is highly selective for COX-2.[54] While it has analgesic and antipyretic properties comparable to those of aspirin or other NSAIDs, its peripheral anti-inflammatory activity is usually limited by several factors, one of which is high level of peroxides present in inflammatory lesions. However, in some circumstances, even peripheral anti-inflammatory activity comparable to other NSAIDs can be observed. An article[55] in Nature Communications from a research group in Lund, Sweden in November 2011 has found a hint to the analgesic mechanism of acetaminophen (paracetamol), being that the metabolites of acetaminophen e.g. NAPQI, act on TRPA1-receptors in the spinal cord to suppress the signal transduction from the superficial layers of the dorsal horn, to alleviate pain.

Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting thromboxanes.[54]

The COX family of enzymes are responsible for the metabolism of arachidonic acid to prostaglandin H2, an unstable molecule that is, in turn, converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories such as the NSAIDs block this step. Only when appropriately oxidized is the COX enzyme highly active.[56][57]

Paracetamol reduces the oxidized form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.[58][59] This leads to a reduced amount of Prostaglandin E2 in the CNS, thus lowering the hypothalamic set-point in the thermoregulatory centre.

Paracetamol also modulates the endogenous cannabinoid system.[60] Paracetamol is metabolized to AM404, a compound with several actions; what is most important is that it inhibits the uptake of the endogenous cannabinoid/vanilloid anandamide by neurons. Anandamide uptake would result in the activation of the main pain receptor (nociceptor) of the body, the TRPV1 (older name: vanilloid receptor). Furthermore, AM404 inhibits sodium channels, as do the anesthetics lidocaine and procaine.[61] Either of these actions by themselves has been shown to reduce pain, and are a possible mechanism for paracetamol. However, it has been demonstrated that, after blocking cannabinoid receptors with synthetic antagonists, paracetamol's analgesic effects are prevented, suggesting its pain-relieving action involves the endogenous cannabinoid system.[62] Spinal TRPA1 receptors have also been demonstrated to mediate antinociceptive effects of paracetamol and Δ9-tetrahydrocannabiorcol in mice.[63]

The exact mechanisms by which COX is inhibited in various circumstances is still a subject of discussion. Because of differences in the activity of paracetamol, aspirin, and other NSAIDs, it has been postulated that further COX variants may exist. A recently discovered COX-1 splice variant termed COX-3 was considered to explain some of the knowledge gap but newer findings do not support the hypothesis that it plays any significant role in the functioning of paracetamol.[54]

Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes and, because paracetamol's action is partially similar to aspirin's,[clarification needed] much research has focused on whether paracetamol also inhibits COX. It is now clear that paracetamol acts via at least two pathways.[50][58][64][65]

One theory holds that paracetamol works by inhibiting the COX-3 isoform of the COX family of enzymes. When expressed in dogs, this enzyme shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol.[66] However, some research has suggested that, in humans and mice, the COX-3 enzyme is without inflammatory action.[64] Another possibility is that paracetamol blocks cyclooxygenase (as in aspirin), but that is in an inflammatory environment where the concentration of peroxides is high, and the high oxidation state of paracetamol prevents its actions. This would mean that paracetamol has no direct effect at the site of inflammation, but instead acts in the CNS where the environment is not oxidative, to reduce temperature, etc.[66] The exact mechanism by which paracetamol is believed to affect COX-3 is disputed.

Structure and reactivity

Paracetamol molecule polar surface area

Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern.[67] The amide group is acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the carbonyl oxygen are all conjugated. The presence of two activating groups also make the benzene ring highly reactive toward electrophilic aromatic substitution. As the substituents are ortho,para-directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces the basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion.

Synthesis

In the laboratory, paracetamol is easily prepared by nitrating phenol with sodium nitrate, separating the desired p-nitrophenol from the ortho- byproduct, and reducing the nitro group with sodium borohydride. The resultant p-aminophenol is then acetylated with acetic anhydride.[68] In this reaction, phenol is strongly activating, thus the reaction requires only mild conditions (cf. the nitration of benzene). The industrial process is analogous, but hydrogenation is used instead of the sodium borohydride reduction.[69][70]

Synthesis of paracetamol from phenol.png

A simpler synthesis by Hoechst-Celanese involves direct acylation of phenol with acetic anhydride catalyzed by HF, conversion of the ketone to a ketoxime with hydroxylamine, followed by the acid-catalyzed Beckmann rearrangement to give the amide.[70][71]

Celanese synthesis of paracetamol.png

Demand for paracetamol in the United States was estimated at 30–35 thousand tonnes per year in 1997, equal to the demand from the rest of the world.[72]

Metabolism

Main pathways of paracetamol metabolism (click to enlarge). Pathways shown in blue and purple lead to non-toxic metabolites; the pathway in red leads to toxic NAPQI.

Paracetamol is metabolised primarily in the liver, into non-toxic products. Three metabolic pathways are notable:

  • Glucuronidation is believed to account for 40% to two-thirds of the metabolism of paracetamol.[73]
  • Sulfation (sulfate conjugation) may account for 20–40%.[73]
  • N-hydroxylation and rearrangement, then GSH conjugation, accounts for less than 15%. The hepatic cytochrome P450 enzyme system metabolizes paracetamol, forming a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzo-quinone imine).[74] NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione.[74]

All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for the toxic effects of paracetamol; this constitutes an example of toxication.

Production of NAPQI is due primarily to two isoenzymes of cytochrome P450: CYP2E1 and CYP1A2. The P450 gene is highly polymorphic, however, and individual differences in paracetamol toxicity are believed due to a third isoenzyme, CYP2D6. Genetic polymorphisms in CYP2D6 may contribute to significantly different rates of production of NAPQI. Furthermore, individuals can be classified as "extensive", "ultrarapid", and "poor" metabolizers (producers of NAPQI), depending on their levels of CYP2D6 expression. Although CYP2D6 metabolises paracetamol into NAPQI to a lesser extent than other P450 enzymes, its activity may contribute to paracetamol toxicity in extensive and ultrarapid metabolisers, and when paracetamol is taken at very large doses.[75] At usual doses, NAPQI is quickly detoxified by conjugation.[74] Following overdose, and possibly also in extensive and ultrarapid metabolizers, this detoxification pathway becomes saturated, and, as a consequence, NAPQI accumulates.

Reactions

p-Aminophenol may be obtained by the amide hydrolysis of paracetamol. p-Aminophenol prepared this way, and related to the commercially available Metol, has been used as a developer in photography by hobbyists.[76] This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, p-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an indophenol dye under oxidization by air.[77]

History

Julius Axelrod (pictured) and Bernard Brodie demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better tolerated analgesic.

Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by A. Cahn and P. Hepp in 1886.[78] But its unacceptable toxic effects, the most alarming being cyanosis due to methemoglobinemia, prompted the search for less toxic aniline derivatives.[50] Harmon Northrop Morse had already synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877,[79][80] but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on patients.[50] In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative.[81] Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company.[82] Overshadowed in part by aspirin, introduced into medicine by Heinrich Dreser in 1899, phenacetin was popular for many decades, particularly in widely advertised over-the-counter "headache mixtures", usually containing phenacetin, an aminopyrine derivative of aspirin, caffeine, and sometimes a barbiturate.[50]

Von Mering's claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and paracetamol.[82] In 1947 David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.[83] In three papers published in the September 1948 issue of the Journal of Pharmacology and Experimental Therapeutics, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed using more specific methods that paracetamol was the major metabolite of acetanilide in human blood, and established it was just as efficacious an analgesic as its precursor.[84][85][86] They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A followup paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.[87] This led to a "rediscovery" of paracetamol.[50] It has been suggested that contamination of paracetamol with 4-aminophenol, the substance von Mering synthesized it from, may be the cause for his spurious findings.[82]

Paracetamol was first marketed in the United States in 1953 by Sterling-Winthrop Co., which promoted it as preferable to aspirin since it was safe to take for children and people with ulcers.[82] The best known brand today for paracetamol in the United States, Tylenol, was established in 1955 when McNeil Laboratories started selling paracetamol as a pain and fever reliever for children, under the brand name Tylenol Children's Elixir—the word "tylenol" was a contraction of para-acetylaminophenol.[88] In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc. Panadol was originally available only by prescription, for the relief of pain and fever, and was advertised as being "gentle to the stomach," since other analgesic agents of the time contained aspirin, a known stomach irritant. In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.[80] Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of analgesic nephropathy and hematological toxicity.[50]

The U.S. patent on paracetamol has long expired, and generic versions of the drug are widely available under the Drug Price Competition and Patent Term Restoration Act of 1984, although certain Tylenol preparations were protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for "Extended release acetaminophen particles".[89]

Available forms

Tylenol 500 mg capsules
Panadol 500 mg tablets

Paracetamol is available in a tablet, capsule, liquid suspension, suppository, intravenous, and intramuscular form. The common adult dose is 500 mg to 1000 mg. The recommended maximum daily dose, for adults, is 4000 mg. In recommended doses, paracetamol generally is safe for children and infants, as well as for adults,[90] although rare cases of acute liver injury have been linked to amounts lower than 2500 mg per day.[91]

Panadol, which is marketed in Africa, Asia, Europe, Central America, and Australasia, is the most widely available brand of paracetamol, sold in over 80 countries. In North America, paracetamol is sold in generic form (usually labeled as acetaminophen) or under a number of trade names, for instance, Tylenol (McNeil-PPC, Inc.), Anacin-3, Tempra, Datril, and Ofirmev. While there is brand named paracetamol available in the UK (e.g. Panadol), unbranded or generic paracetamol is more commonly sold. Acamol, a brand name for paracetamol produced by Teva Pharmaceutical Industries in Israel, is one of the most widely used drugs in that country. In the Philippines, the largest-selling paracetamol brand is Biogesic, manufactured by the drug giant United Laboratories. Biogesic tablet sales reach nearly a billion units each year in the country alone, not including liquid suspension formats. The brand is also available in most of the ASEAN countries where the drug giant has market presence. In Europe, the most common brands of paracetamol are Efferalgan and Doliprane. In India, the most common brand of paracetamol is Crocin manufactured by Glaxo SmithKline Asia. In Bangladesh the most popular brand is Napa manufactured by Beximco Pharma. In China paracetamol is sold over the counter as Duìyǐxiān'ānjīfēn Piàn (对乙酰氨基酚片).[92] Likewise in Japan it is sold under the name Acetaminophen (アセトアミノフェン Asetoaminofen). In North Korea the DPRK-Swiss joint venture PyongSu Pharma markets the drug as PyongSu Cetamol.

In some formulations, paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN). In the United States and Canada, this is marketed under the name of Tylenol #1/2/3/4, which contain 8–10 mg, 15 mg, 30 mg, and 60 mg of codeine, respectively. In the U.S., this combination is available only by prescription, while the lowest-strength preparation is over-the-counter in Canada, and, in other countries, other strengths may be available over the counter. There are generic forms of these combinations as well. In the UK and in many other countries, this combination is marketed under the names of Tylex CD and Panadeine. Other names include Captin, Disprol, Dymadon, Fensum, Hedex, Mexalen, Nofedol, Panocod, Paralen, Pediapirin, Perfalgan, and Solpadeine. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (BAN), oxycodone or hydrocodone, marketed in the U.S. as Percocet and Vicodin, respectively. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate, sold under the brand name Darvocet. A combination of paracetamol, codeine, and the calmative doxylamine succinate is marketed as Syndol or Mersyndol. The efficacy of paracetamol/codeine combinations have been questioned by recent research.[20]

Paracetamol is commonly used in multi-ingredient preparations for migraine headache, typically including butalbital and paracetamol with or without caffeine, and sometimes containing codeine.

Veterinary use

Paracetamol is extremely toxic to cats.[93] Cats lack the necessary glucuronyl transferase enzymes to safely break paracetamol down, and minute portions of a tablet may prove fatal.[93] Initial symptoms include vomiting, salivation, and discolouration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead, methemoglobin formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation (methemoglobemia and hemolytic anemia).[94] Treatment with N-acetylcysteine,[93] methylene blue or both is sometimes effective after the ingestion of small doses of paracetamol.

Although paracetamol is believed to have no significant anti-inflammatory activity, it has been reported as effective as aspirin in the treatment of musculoskeletal pain in dogs.[95] A paracetamol-codeine product (trade name Pardale-V)[96] licensed for use in dogs is available on veterinary prescription in the UK.[96] It should be administered to dogs only on veterinary advice and with extreme caution.[96] The main effects of toxicity in dogs is liver damage, GI ulceration has been reported.[93][97][98][99] N-acetylcysteine treatment is efficacious in dogs when administered within a few hours of paracetamol ingestion.[93][95]

Paracetamol is also lethal to snakes, and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam.[100][101]

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External links


Translations:

Paracetamol

Top

Dansk (Danish)
n. - paracetamol

Français (French)
n. - paracétamol

Deutsch (German)
n. - (Med.) Parazetamol (Schmerzmittel)

Ελληνική (Greek)
n. - παρακεταμόλη

Italiano (Italian)
paracetamolo

Português (Portuguese)
n. - paracetamol (m) (Med.)

Русский (Russian)
парацетамол

Español (Spanish)
n. - paracetamol

Svenska (Swedish)
n. - smärtstillande medel

中文(简体)(Chinese (Simplified))
一种温和的止疼退热药

中文(繁體)(Chinese (Traditional))
n. - 一種溫和的止疼退熱藥

한국어 (Korean)
n. - 파라세타몰 (해열진통제)

日本語 (Japanese)
n. - パラセタモール

עברית (Hebrew)
n. - ‮אקמול (שם מסחרי)‬


 
 

 

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