Ibuprofen

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Ibuprofen
Ibuprofen-racemic-2D-skeletal.png
Ibuprofen-3544.png
Systematic (IUPAC) name
(RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid
Clinical data
Trade namesAdvil, Brufen, Motrin, Nurofen, and others
AHFS/Drugs.commonograph
MedlinePlusa682159
Licence dataUS FDA:link
Pregnancy cat.C (AU) D (US)
Legal statusUnscheduled (AU) OTC (CA) GSL (UK) RX/OTC (US)
RoutesOral, rectal, topical, and intravenous
Pharmacokinetic data
Bioavailability49–73%
Protein binding99%
MetabolismHepatic (CYP2C9)
Half-life1.8–2 h
ExcretionRenal
Identifiers
CAS number15687-27-1 YesY
ATC codeC01EB16 G02CC01 M01AE01 M02AA13
PubChemCID 3672
IUPHAR ligand2713
DrugBankDB01050
ChemSpider3544 YesY
UNIIWK2XYI10QM YesY
KEGGD00126 YesY
ChEBICHEBI:5855 YesY
ChEMBLCHEMBL521 YesY
Chemical data
FormulaC13H18O2 
Mol. mass206.29 g/mol
Physical data
Density1.03 gr/ml g/cm³
Melt. point76 °C (169 °F)
 YesY (what is this?)  (verify)
 
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Ibuprofen
Ibuprofen-racemic-2D-skeletal.png
Ibuprofen-3544.png
Systematic (IUPAC) name
(RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid
Clinical data
Trade namesAdvil, Brufen, Motrin, Nurofen, and others
AHFS/Drugs.commonograph
MedlinePlusa682159
Licence dataUS FDA:link
Pregnancy cat.C (AU) D (US)
Legal statusUnscheduled (AU) OTC (CA) GSL (UK) RX/OTC (US)
RoutesOral, rectal, topical, and intravenous
Pharmacokinetic data
Bioavailability49–73%
Protein binding99%
MetabolismHepatic (CYP2C9)
Half-life1.8–2 h
ExcretionRenal
Identifiers
CAS number15687-27-1 YesY
ATC codeC01EB16 G02CC01 M01AE01 M02AA13
PubChemCID 3672
IUPHAR ligand2713
DrugBankDB01050
ChemSpider3544 YesY
UNIIWK2XYI10QM YesY
KEGGD00126 YesY
ChEBICHEBI:5855 YesY
ChEMBLCHEMBL521 YesY
Chemical data
FormulaC13H18O2 
Mol. mass206.29 g/mol
Physical data
Density1.03 gr/ml g/cm³
Melt. point76 °C (169 °F)
 YesY (what is this?)  (verify)
Coated 200 mg ibuprofen tablets

Ibuprofen (INN) (/ˈbjuːprfɛn/ or /bjuːˈprfən/ EYE-bew-PROH-fən; from iso-butyl-propanoic-phenolic acid) is a nonsteroidal anti-inflammatory drug (NSAID) used for relieving pain, alleviating fever,[1] and reducing inflammation.

Ibuprofen has an antiplatelet effect, though it is relatively mild and somewhat short-lived compared with aspirin or prescription antiplatelet drugs. In general, ibuprofen also has a vasodilation effect.[2] Ibuprofen is a 'core' medicine in the World Health Organization's Model List of Essential Medicines necessary to meet the minimum medical needs of a basic healthcare system.[3][4][5][6]

Ibuprofen was derived from propanoic acid by the research arm of Boots Company during the 1960s[7] and patented in 1961. Originally marketed as Brufen, ibuprofen is available under a variety of popular trademarks, including Motrin, Nurofen, Advil, Nuprin and many others.[8] Generic formulations are available as well.

Medical uses[edit]

Ibuprofen is used primarily for fever, pain, dysmenorrhea and inflammatory diseases such as osteoarthritis and rheumatoid arthritis.[9][10] It is also used for pericarditis and patent ductus arteriosus.[10]

Dosage[edit]

Ibuprofen has a dose-dependent duration of action of around four to eight hours, which is longer than suggested by its short half-life. Onset of analgesia (time to effect) is 24.5 minutes using liquigel format orally.[11] The recommended dose varies with body mass and indication. A dose of 200 mg per dose and 1200 mg per day is considered the maximum amount for over-the-counter use,[citation needed] and a dose of 800 mg per dose and 3200 mg per day is considered the maximum amount for prescription use under a doctor's supervision.[citation needed] Unlike aspirin, which breaks down in solution, ibuprofen is stable, thus it can be available in topical gel form, which is absorbed through the skin, and can be used for sports injuries, with less risk of digestive problems.[12]

Ibuprofen lysine[edit]

In Europe, Australia, and New Zealand, ibuprofen lysine (the lysine salt of ibuprofen, sometimes called "ibuprofen lysinate" even though the lysine is in cationic form) is licensed for treatment of the same conditions as ibuprofen. The lysine salt increases water solubility, allowing intravenous use, and is indicated for closure of a 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 (e.g., fluid restriction, diuretics, respiratory support, etc.) is ineffective.[13]

With regard to this indication, ibuprofen lysine is an effective alternative to intravenous indomethacin, and may be advantageous in terms of kidney function.[14] Ibuprofen lysine has been shown to have a more rapid onset of action compared to acid ibuprofen.[15]

In UK Ibuprofen Lysine is marketed as express pain relief, tension headache relief and more commonly migraine relief medicine. Usually available in packing of 16 342 mg tablets the pack is marketed OTC by most superstores and pharmacies as their own branded product including, but not limited to, Asda, Tesco and Superdrug.[16]

Adverse effects[edit]

Common adverse effects include: nausea, dyspepsia, gastrointestinal ulceration/bleeding, raised liver enzymes, diarrhea, constipation, epistaxis, headache, dizziness, rash, salt and fluid retention, and hypertension.[17][citation needed] A study from 2010 has shown regular use of NSAIDs was associated with an increase in hearing loss.[18]

Infrequent adverse effects include: esophageal ulceration, heart failure, hyperkalemia, renal impairment, confusion, and bronchospasm.[17] Ibuprofen can exacerbate asthma, sometimes fatally.[19]

Ibuprofen appears to have the lowest incidence of digestive adverse drug reactions of all the nonselective NSAIDs.[citation needed] However, this holds true only at lower doses of ibuprofen, so over-the-counter (OTC) preparations of ibuprofen are, in general, labeled to advise a maximum daily dose of 1,200 mg.[20]

Ibuprofen may be quantitated 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 nomogram relating ibuprofen plasma concentration, time since ingestion, and risk of developing renal toxicity in overdose patients has been published.[21]

Cardiovascular risk[edit]

Along with several other NSAIDs, chronic ibuprofen use has been found correlated with risk of hypertension[22] and myocardial infarction (heart attack),[23] particularly among those chronically using high doses. In older hypertensive patients treated with hydrochlorothiazide, ibuprofen in doses of 1800 mg per day was found to significantly increase systolic blood pressure.[24]

Increased risk of kidney cancer[edit]

A 2011 study in the Archives of Internal Medicine reported a 51% increase in the rate of renal cell carcinoma, the most common form of kidney cancer, in nurses who regularly took ibuprofen and other NSAIDs, such as naproxen.[25]

Skin[edit]

Along with other NSAIDs, ibuprofen has been associated with the onset of bullous pemphigoid or pemphigoid-like blistering.[26] As with other NSAIDs, ibuprofen has been reported to be a photosensitising agent,[27] 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).[28][29]

Interactions[edit]

Drinking alcohol when taking ibuprofen may increase risk of stomach bleeding.[30]

According to the US Food and Drug Administration, "ibuprofen can interfere with the antiplatelet effect of low-dose aspirin (81 mg per day), 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 400-mg 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.[31]

Erectile dysfunction risk[edit]

A 2005 study linked long-term (over three months) use of NSAIDs, including ibuprofen, with a 140% higher risk of erectile dysfunction.[32][33] The study, conducted at Kaiser Permanente and published in the Journal of Urology, reported, "regular nonsteroidal anti-inflammatory drug use is associated with erectile dysfunction beyond what would be expected due to age and other conditions".[34] The director of research for Kaiser Permanente added, "There are many proven benefits of nonsteroidals in preventing heart disease and for other conditions. People shouldn't stop taking them based on this observational study. However, if a man is taking this class of drugs and has ED, it's worth a discussion with his doctor".[33]

Overdose[edit]

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.[35] 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.[36] 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);[37] however, large doses do not indicate the clinical course is likely to be lethal.[38] A precise lethal dose is difficult to determine, as it may vary with age, weight, and concomitant diseases of the individual patient.

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.[39] 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.[37] 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.[40] 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.

Miscarriage[edit]

A Canadian study published in the Canadian Medical Association Journal of thousands 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.[41] However, an Israeli study following thousands of women found no increased risk of miscarriage in the group of mothers using NSAIDs.[42]

Rhabdomyolysis[edit]

Ibuprofen has been associated also with the development of rhabdomyolysis, especially in people with high blood cholesterol, hyperlipidaemia, high blood pressure, depression.[43]

Mechanism of action[edit]

Nonsteroidal anti-inflammatory drugs such as ibuprofen work by inhibiting the enzyme cyclooxygenase (COX), which converts 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 indomethacin,[citation needed] 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, whereas inhibition of COX-1 would be responsible for unwanted effects on the gastrointestinal tract.[44] 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.[45]

To achieve the beneficial effects of ibuprofen and other NSAIDs without gastrointestinal ulceration and bleeding, selective COX-2 inhibitors were developed to inhibit the COX-2 isoform without inhibition of COX-1.[46]

Chemistry[edit]

Ibuprofen is only very slightly soluble in water. Less than 1 mg of ibuprofen dissolves in 1 ml water (< 1 mg/ml).[47]

Stereochemistry[edit]

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.[48][49][50]

R-ibuprofen-B-2D-skeletal.png
S-ibuprofen-A-2D-skeletal.png
R-ibuprofen-A-2D-skeletal.png
S-ibuprofen-B-2D-skeletal.png
Ibuprofen-3D-balls.png
(S)-ibuprofen-3D-balls.png
(R)-ibuprofen
(S)-ibuprofen

Synthesis[edit]

The synthesis of this compound is a popular case study in green chemistry. The original Boots synthesis of ibuprofen consisted of six steps, started with the Friedel-Crafts acetylation of isobutylbenzene. Reaction with ethyl chloroacetate (Darzens reaction) gave the α,β-epoxy ester, which was hydrolyzed and decarboxylated to the aldehyde. Reaction with hydroxylamine gave the oxime, which was converted to the nitrile, then hydrolyzed to the desired acid:[51][52]

Boots synthesis of ibuprofen.png

An improved synthesis by BHC required only three steps. This improved synthesis won the Presidential Green Chemistry Challenge Greener Synthetic Pathways Award in 1997.[53]

After a similar acetylation, hydrogenation with Raney nickel gave the alcohol, which underwent palladium-catalyzed carbonylation:[51][54]

BHC synthesis of ibuprofen.png

History[edit]

Ibuprofen was derived from propionic acid by the research arm of Boots Group during the 1960s.[7] It was discovered by Andrew RM Dunlop, with colleagues Stewart Adams, John Nicholson, Vonleigh Simmons, Jeff Wilson and Colin Burrows, and patented in 1961. The drug was launched as a treatment for rheumatoid arthritis in the United Kingdom in 1969, and in the United States in 1974. Adams initially tested his drug on a hangover.[55] He 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.[55]

Availability[edit]

A bottle of generic ibuprofen

Ibuprofen was made available under prescription in the United Kingdom in 1969, and in the United States in 1974.[56] In the years since, the good tolerability profile, along with extensive experience in the population, as well as in so-called phase IV trials (post-approval studies), has resulted in the availability of ibuprofen over the counter (OTC) in pharmacies worldwide, as well as in supermarkets and other general retailers.[citation needed]

North America[edit]

Ibuprofen is commonly available in the United States up to the FDA's 200 mg 1984 dose limit OTC, rarely used higher by prescription.[20]

In Canada, the OTC dose limit is 400 mg, with 600 mg and 800 mg routinely available by prescription.[citation needed]

In 2009, the first injectable formulation of ibuprofen was approved in the United States, under the trade name Caldolor.[57][58] Ibuprofen was the only parenteral for both pain and fever available in the country prior to the approval of Ofirmev (acetaminophen) injection by the FDA.[59]

Research[edit]

Ibuprofen is sometimes used for the treatment of acne, because of its anti-inflammatory properties,[60] and has been sold in Japan in topical form for adult acne.[61] As with other NSAIDs, ibuprofen may be useful in the treatment of severe orthostatic hypotension (low blood pressure when standing up).[62] In some studies, ibuprofen showed superior results compared to a placebo in the prophylaxis of Alzheimer's disease, when given in low doses over a long time.[63][64] Some of the aforementioned uses would be considered off-label uses in some countries.

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.[65] 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.[66][67][68] 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.[69]

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