Ibuprofen, from isobutylphenylpropanoic acid, is a drug in the nonsteroidal anti-inflammatory drug (NSAID) class used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. About 60% of people improve with any given NSAID, and it is recommended that if one does not work then another should be tried. It may also be used to close a patent ductus arteriosus in a premature baby. It can be used by mouth or intravenously. It typically begins working within an hour.
Common side effects include heartburn and a rash. Compared to other NSAIDs it may have fewer side effects such as gastrointestinal bleeding. It increases the risk of heart failure, kidney failure, and liver failure. At low doses, it does not appear to increase the risk of myocardial infarction; however, at higher doses it may. Ibuprofen can also result in worsened asthma. While it is unclear if it is safe in early pregnancy, it appears to be harmful in later pregnancy and therefore is not recommended. Like other NSAIDs, it works by inhibiting the making of prostaglandins by decreasing the activity of the enzyme cyclooxygenase. Ibuprofen might be a weaker anti-inflammatory than other NSAIDs.
Ibuprofen was discovered in 1961 by Stewart Adams and marketed as Brufen. It is available under a number of trade names, including Advil, Motrin, and Nurofen. It was first marketed in 1969 in the United Kingdom and in the United States in 1974. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system. It is available as a generic medication. The wholesale cost in the developing world is between 0.01 and 0.04 USD per dose. In the United States it costs about 0.05 USD per dose.
Ibuprofen is used primarily to treat fever (including postimmunisation fever), mild to moderate pain (including pain relief after surgery), painful menstruation, osteoarthritis, dental pain, headaches, and pain from kidney stones. About 60% of people respond to any NSAID; those who do not respond well to a particular one may respond to another.
In some countries, ibuprofen lysine (the lysine salt of ibuprofen, sometimes called "ibuprofen lysinate") is licensed for treatment of the same conditions as ibuprofen; the lysine salt is used because it is more water-soluble. In 2006, ibuprofen lysine was approved in the US by the Food and Drug Administration (FDA) for closure of patent ductus arteriosus in premature infants weighing between 500 and 1,500 grams (1 and 3 lb), who are no more than 32 weeks gestational age when usual medical management (such as fluid restriction, diuretics, and respiratory support) is not effective.
Ibuprofen may be quantified in blood, plasma, or serum to demonstrate the presence of the drug in a person having experienced an anaphylactic reaction, confirm a diagnosis of poisoning in hospitalized patients, or assist in a medicolegal death investigation. A monograph relating ibuprofen plasma concentration, time since ingestion, and risk of developing renal toxicity in overdose patients has been published.
Along with several other NSAIDs, chronic ibuprofen use has been found correlated with risk of hypertension and myocardial infarction (heart attack), particularly among those chronically using high doses. In older hypertensive patients treated with hydrochlorothiazide, ibuprofen at a high daily dose was found to significantly increase systolic blood pressure. On 9 July 2015, the US FDA toughened warnings of increased heart attack and stroke risk associated with ibuprofen and related NSAIDs; the NSAID aspirin is not included in this warning.
Along with other NSAIDs, ibuprofen has been associated with the onset of bullous pemphigoid or pemphigoid-like blistering. As with other NSAIDs, ibuprofen has been reported to be a photosensitising agent, but it is considered a weak photosensitising agent compared to other members of the 2-arylpropionic acid class. Like other NSAIDs, ibuprofen is an extremely rare cause of the autoimmune disease Stevens-Johnson syndrome (SJS).
Drinking alcohol when taking ibuprofen may increase the risk of stomach bleeding.
According to the US Food and Drug Administration, "ibuprofen can interfere with the antiplatelet effect of low-dose aspirin, potentially rendering aspirin less effective when used for cardioprotection and stroke prevention." Allowing sufficient time between doses of ibuprofen and immediate-release (IR) aspirin can avoid this problem. The recommended elapsed time between a dose of ibuprofen and a dose of aspirin depends on which is taken first. It would be 30 minutes or more for ibuprofen taken after IR aspirin, and 8 hours or more for ibuprofen taken before IR aspirin. However, this timing cannot be recommended for enteric-coated aspirin. But, if ibuprofen is taken only occasionally without the recommended timing, the reduction of the cardioprotection and stroke prevention of a daily aspirin regimen is minimal.
Ibuprofen overdose has become common since it was licensed for OTC use. Many overdose experiences are reported in the medical literature, although the frequency of life-threatening complications from ibuprofen overdose is low. Human response in cases of overdose ranges from absence of symptoms to fatal outcome despite intensive-care treatment. Most symptoms are an excess of the pharmacological action of ibuprofen, and include abdominal pain, nausea, vomiting, drowsiness, dizziness, headache, tinnitus, and nystagmus. Rarely, more severe symptoms, such as gastrointestinal bleeding, seizures, metabolic acidosis, hyperkalaemia, hypotension, bradycardia, tachycardia, atrial fibrillation, coma, hepatic dysfunction, acute renal failure, cyanosis, respiratory depression, and cardiac arrest have been reported. The severity of symptoms varies with the ingested dose and the time elapsed; however, individual sensitivity also plays an important role. Generally, the symptoms observed with an overdose of ibuprofen are similar to the symptoms caused by overdoses of other NSAIDs.
Correlation between severity of symptoms and measured ibuprofen plasma levels is weak. Toxic effects are unlikely at doses below 100 mg/kg, but can be severe above 400 mg/kg (around 150 tablets of 200 mg units for an average man); however, large doses do not indicate the clinical course is likely to be lethal. A precise lethal dose is difficult to determine, as it may vary with age, weight, and concomitant conditions of the individual person.
Therapy is largely symptomatic. In cases presenting early, gastric decontamination is recommended. This is achieved using activated charcoal; charcoal adsorbs the drug before it can enter the systemic circulation. Gastric lavage is now rarely used, but can be considered if the amount ingested is potentially life-threatening, and it can be performed within 60 minutes of ingestion. Emesis is not recommended. The majority of ibuprofen ingestions produce only mild effects and the management of overdose is straightforward. Standard measures to maintain normal urine output should be instituted and renal function monitored. Since ibuprofen has acidic properties and is also excreted in the urine, forced alkaline diuresis is theoretically beneficial. However, because ibuprofen is highly protein-bound in the blood, renal excretion of unchanged drug is minimal. Forced alkaline diuresis is, therefore, of limited benefit. Symptomatic therapy for hypotension, gastrointestinal bleeding, acidosis, and renal toxicity may be indicated. On occasion, close monitoring in an intensive-care unit for several days is necessary. A patient who survives the acute intoxication usually experiences no late sequelae.
A study of pregnant woman suggests those taking any type or amount of NSAIDs (including ibuprofen, diclofenac and naproxen) were 2.4 times more likely to miscarry than those not taking the drugs. However, an Israeli study found no increased risk of miscarriage in the group of mothers using NSAIDs.
Mechanism of action
Nonsteroidal anti-inflammatory drugs such as ibuprofen work by inhibiting the cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes to several other prostaglandins (which are mediators of pain, inflammation, and fever) and to thromboxane A2 (which stimulates platelet aggregation, leading to the formation of blood clots).
Like aspirin and indometacin, ibuprofen is a nonselective COX inhibitor, in that it inhibits two isoforms of cyclooxygenase, COX-1 and COX-2. The analgesic, antipyretic, and anti-inflammatory activity of NSAIDs appears to operate mainly through inhibition of COX-2, which decreases the synthesis of prostaglandins involved in mediating inflammation, pain, fever, and swelling. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Inhibition of COX-1 instead would be responsible for unwanted effects on the gastrointestinal tract. However, the role of the individual COX isoforms in the analgesic, anti-inflammatory, and gastric damage effects of NSAIDs is uncertain and different compounds cause different degrees of analgesia and gastric damage.
Ibuprofen is administered as a racemic mixture. The R-enantiomer undergoes extensive interconversion to the S-enantiomer in vivo. The S-enantiomer is believed to be the more pharmacologically active enantiomer.
It is an optically active compound with both S and R-isomers, of which the S (dextrorotatory) isomer is the more biologically active; this isomer has also been isolated and used medically (see dexibuprofen for details).
Ibuprofen is produced industrially as a racemate. The compound, like other 2-arylpropionate derivatives (including ketoprofen, flurbiprofen, naproxen, etc.), does contain a chiral center in the α-position of the propionate moiety. So two enantiomers of ibuprofen occur, with the potential for different biological effects and metabolism for each enantiomer. Indeed, the (S)-(+)-ibuprofen (dexibuprofen) was found to be the active form both in vitro and in vivo.
It was logical, then, to consider the potential for improving the selectivity and potency of ibuprofen formulations by marketing ibuprofen as a single-enantiomer product (as occurs with naproxen, another NSAID). Further in vivo testing, however, revealed the existence of an isomerase (alpha-methylacyl-CoA racemase), which converted (R)-ibuprofen to the active (S)-enantiomer.
Ibuprofen was derived from propionic acid by the research arm of Boots Group during the 1960s. Its discovery was the result of research during the 1950s and 1960s to find a safer alternative to aspirin. It was discovered by a team led by Stewart Adams and the patent application was filed in 1961. Adams initially tested the drug as treatment for his hangover. The drug was launched as a treatment for rheumatoid arthritis in the United Kingdom in 1969, and in the United States in 1974. Later, in 1983 and 1984, it became the first NSAID (other than aspirin) to be available over the counter (OTC) in these two countries. Dr. Adams was subsequently awarded an OBE in 1987. Boots was awarded the Queen's Award for Technical Achievement for the development of the drug in 1987.
Ibuprofen was made available under prescription in the United Kingdom in 1969, and in the United States in 1974. In the years since, the good tolerability profile, along with extensive experience in the population, as well as in so-called phase-IV trials (postapproval studies), have resulted in the availability of ibuprofen OTC in pharmacies worldwide, as well as in supermarkets and other general retailers. Ibuprofen is its INN, BAN, AAN and USAN approved name. Advil is manufactured by Pfizer and has been on the market since 1984.
Ibuprofen is commonly available in the United States up to the FDA's 1984 dose limit OTC, rarely used higher by prescription. In 2009, the first injectable formulation of ibuprofen was approved in the United States, under the trade name Caldolor.
Ibuprofen is sometimes used for the treatment of acne because of its anti-inflammatory properties, and has been sold in Japan in topical form for adult acne. As with other NSAIDs, ibuprofen may be useful in the treatment of severe orthostatic hypotension (low blood pressure when standing up). In some studies, ibuprofen showed superior results compared with a placebo in the prevention of Alzheimer's disease, when given in low doses over a long time.
Ibuprofen has been associated with a lower risk of Parkinson's disease, and may delay or prevent it. Aspirin, other NSAIDs, and paracetamol (acetaminophen) had no effect on the risk for Parkinson's. In March 2011, researchers at Harvard Medical School announced in Neurology that ibuprofen had a neuroprotective effect against the risk of developing Parkinson's disease. People regularly consuming ibuprofen were reported to have a 38% lower risk of developing Parkinson's disease, but no such effect was found for other pain relievers, such as aspirin and paracetamol. Use of ibuprofen to lower the risk of Parkinson's disease in the general population would not be problem-free, given the possibility of adverse effects on the urinary and digestive systems.
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