Ibuprofen

Source: Wikipedia, the free encyclopedia.

Ibuprofen
(R)-ibuprofen
Clinical data
Pronunciation/ˈaɪbjuːproʊfɛn/, /aɪbjuːˈproʊfən/, EYE-bew-PROH-fən
Trade namesAdvil, Motrin, Nurofen, others
Other namesisobutylphenylpropionic acid
AHFS/Drugs.comMonograph
MedlinePlusa682159
License data
Pregnancy
category
topical, intravenous
ATC code
Legal status
Legal status
  • AU: OTC
  • CA: OTC
  • UK:
    General sales list
    (GSL, OTC)
  • US: WARNING[2]OTC / Rx-only
  • EU: Rx-only[3]
Pharmacokinetic data
Bioavailability80–100% (orally),[4] 87% (rectal)
Protein binding98%[5]
MetabolismLiver (CYP2C9)[5]
Metabolitesibuprofen glucuronide, 2-hydroxyibuprofen, 3-hydroxyibuprofen, carboxy-ibuprofen, 1-hydroxyibuprofen
Onset of action30 min[6]
Elimination half-life2–4 h[7]
ExcretionUrine (95%)[5][8]
Identifiers
  • (RS)-2-(4-(2-Methylpropyl)phenyl)propanoic acid
JSmol)
ChiralityRacemic mixture
Density1.03 g/cm3
Melting point75 to 78 °C (167 to 172 °F)
Boiling point157 °C (315 °F) at 4 mmHg
Solubility in water0.021 mg/mL (20 °C)
  • CC(C)Cc1ccc(cc1)[C@@H](C)C(=O)O
  • InChI=1S/C13H18O2/c1-9(2)8-11-4-6-12(7-5-11)10(3)13(14)15/h4-7,9-10H,8H2,1-3H3,(H,14,15) checkY
  • Key:HEFNNWSXXWATRW-UHFFFAOYSA-N checkY
  (verify)

Ibuprofen is a

premature baby.[3][9] It can be used orally (by mouth) or intravenously.[9] It typically begins working within an hour.[9]

Common

prostaglandins by decreasing the activity of the enzyme cyclooxygenase (COX).[9] Ibuprofen is a weaker anti-inflammatory agent than other NSAIDs.[10]

Ibuprofen was discovered in 1961 by

generic medication.[9] In 2021, it was the 36th-most commonly prescribed medication in the United States, with more than 17 million prescriptions.[16][17]

Medical uses

Example of some 200 mg ibuprofen tablets
A 150 ml bottle (100 mg/5 ml dosage) of ibuprofen, sold in Greece

Ibuprofen is used primarily to treat

lower back pain found that "NSAIDs are effective for short-term symptomatic relief in patients with acute low back pain".[19]

It is used for inflammatory diseases such as juvenile idiopathic arthritis and rheumatoid arthritis.[20][21] It is also used for pericarditis and patent ductus arteriosus.[3][22][23]

Ibuprofen lysine

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.[24]

Ibuprofen lysine is sold for rapid pain relief;[25] given in the form of its lysine salt, absorption is much quicker (35 minutes for the salt compared to 90–120 minutes for ibuprofen). However, a clinical trial with 351 participants in 2020, funded by Sanofi, found no significant difference between ibuprofen and ibuprofen lysine concerning the eventual onset of action or analgesic efficacy.[26][unreliable medical source]

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 g (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.[27]

Adverse effects

Adverse effects include

gastrointestinal ulceration, headache, dizziness, rash, salt and fluid retention, and high blood pressure.[21][28]

Infrequent adverse effects include esophageal ulceration,

kidney impairment, confusion, and bronchospasm.[21] Ibuprofen can exacerbate asthma, sometimes fatally.[29]

Allergic reactions, including anaphylaxis and anaphylactic shock, may occur.[30] 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 people who are hospitalized, or assist in a medicolegal death investigation. A monograph relating ibuprofen plasma concentration, time since ingestion, and risk of developing renal toxicity in people who have overdosed has been published.[31]

In October 2020, the US FDA required the drug label to be updated for all NSAID medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.[32][33]

Cardiovascular risk

Along with several other NSAIDs, chronic ibuprofen use has been found correlated with risk of progression to

heart attack and stroke risk associated with ibuprofen and related NSAIDs; the NSAID aspirin is not included in this warning.[36] The European Medicines Agency (EMA) issued similar warnings in 2015.[37][38]

Skin

Along with other NSAIDs, ibuprofen has been associated with the onset of

2-arylpropionic acid class. Like other NSAIDs, ibuprofen is an extremely rare cause of the autoimmune disease Stevens–Johnson syndrome (SJS).[41][42] Ibuprofen is also an extremely rare cause of toxic epidermal necrolysis.[43]

Interactions

Alcohol

Drinking alcohol when taking ibuprofen may increase the risk of

stomach bleeding.[44]

Aspirin

According to the FDA, "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. If ibuprofen is taken only occasionally without the recommended timing, though, the reduction of the cardioprotection and stroke prevention of a daily aspirin regimen is minimal.[45]

Paracetamol

Ibuprofen combined with paracetamol is considered generally safe in children for short-term usage.[46]

Overdose

Ibuprofen overdose has become common since it was licensed for

acute kidney failure, cyanosis, respiratory depression, and cardiac arrest have been reported.[48]
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);[49] however, large doses do not indicate the clinical course is likely to be lethal.[50] A precise lethal dose is difficult to determine, as it may vary with age, weight, and concomitant conditions of the individual person.

Treatment to address an ibuprofen overdose is based on how the symptoms present. In cases presenting early, decontamination of the stomach is recommended. This is achieved using

forced alkaline diuresis is theoretically beneficial. However, because ibuprofen is highly protein-bound in the blood, the kidneys' excretion of unchanged drug is minimal. Forced alkaline diuresis is, therefore, of limited benefit.[52]

Miscarriage

A Canadian study of pregnant women suggests that 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 medications.[53] However, an Israeli study found no increased risk of miscarriage in the group of mothers using NSAIDs.[54]

Pharmacology

NSAIDs 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

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.[55] 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.[56]

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.[57] The R-enantiomer is converted through a series of three main enzymes. These enzymes include acyl-CoA-synthetase, which converts the R-enantiomer to (−)-R-ibuprofen I-CoA; 2-arylpropionyl-CoA epimerase, which converts (−)-R-ibuprofen I-CoA to (+)-S-ibuprofen I-CoA; and hydrolase, which converts (+)-S-ibuprofen I-CoA to the S-enantiomer.[43] In addition to the conversion of ibuprofen to the S-enantiomer, the body can metabolize ibuprofen to several other compounds, including numerous hydroxyl, carboxyl and glucuronyl metabolites. Virtually all of these have no pharmacological effects.[43]

Unlike most other NSAIDs, ibuprofen also acts as an inhibitor of Rho kinase and may be useful in recovery from spinal-cord injury.[58][59] Another unusual activity is inhibition of the sweet taste receptor.[60]

Pharmacokinetics

After oral administration, peak serum concentration is reached after 1–2 hours, and up to 99% of the drug is bound to plasma proteins.[61] The majority of ibuprofen is metabolized and eliminated within 24 hours in the urine; however, 1% of the unchanged drug is removed through biliary excretion.[57]

Chemistry

Modern synthesis of ibuprofen
Modern synthesis of ibuprofen

Ibuprofen is practically insoluble in water, but very soluble in most organic solvents like ethanol (66.18 g/100 mL at 40 °C for 90% EtOH), methanol, acetone and dichloromethane.[62]

The original synthesis of ibuprofen by the Boots Group started with the compound isobutylbenzene. The synthesis took six steps. A modern, greener technique with fewer waste byproducts for the synthesis involves only three steps was developed in the 1980s by the Celanese Chemical Company.[63][64] The synthesis is initiated with the acylation of isobutylbenzene using the recyclable Lewis acid catalyst hydrogen fluoride.[65][66] The following catalytic hydrogenation of isobutylacetophenone is performed with either Raney nickel or palladium on carbon to lead into the key-step, the carbonylation of 1-(4-isobutylphenyl)ethanol. This is achieved by a PdCl2(PPh3)2 catalyst, at around 50 bar of CO pressure, in the presence of HCl (10%).[67] The reaction presumably proceeds through the intermediacy of the styrene derivative (acidic elimination of the alcohol) and (1-chloroethyl)benzene derivative (Markovnikow addition of HCl to the double bond).[68]

Stereochemistry

Ibuprofen, like other 2-arylpropionate derivatives such as ketoprofen, flurbiprofen and naproxen, contains a stereocenter in the α-position of the propionate moiety.

(R)-ibuprofen (S)-ibuprofen

The product sold in pharmacies is a racemic mixture of the S and R-isomers. The S (dextrorotatory) isomer is the more biologically active; this isomer has been isolated and used medically (see dexibuprofen for details).[62]

The isomerase enzyme, alpha-methylacyl-CoA racemase, converts (R)-ibuprofen into the (S)-enantiomer.[69][70][71]

(S)-ibuprofen, the

distomer, undergoes a unidirectional chiral inversion to offer the active (S)-enantiomer. That is, when the ibuprofen is administered as a racemate the distomer is converted in vivo into the eutomer while the latter is unaffected.[72][73][74]

History

The Royal Society of Chemistry blue plaque at BioCity Nottingham

Ibuprofen was derived from

Boots Group during the 1960s.[75] The name is derived from the 3 functional groups: isobutyl (ibu) propionic acid (pro) phenyl (fen).[76] Its discovery was the result of research during the 1950s and 1960s to find a safer alternative to aspirin.[13][77] The molecule was discovered and synthesized by a team led by Stewart Adams, with a patent application filed in 1961.[13] Adams initially tested the drug as treatment for his hangover.[78] In 1985, Boots' worldwide patent for ibuprofen expired and generic products were launched.[79]

The medication was launched as a treatment for

Queen's Award for Technical Achievement in 1985 for the development of the drug.[80]

In November 2013, work on ibuprofen was recognized by the erection of a Royal Society of Chemistry blue plaque at Boots' Beeston Factory site in Nottingham,[81] which reads:

In recognition of the work during the 1980s by The Boots Company PLC on the development of ibuprofen which resulted in its move from prescription only status to over the counter sale, therefore expanding its use to millions of people worldwide

and another at BioCity Nottingham, the site of the original laboratory,[81] which reads:

In recognition of the pioneering research work, here on Pennyfoot Street, by Dr Stewart Adams and Dr John Nicholson in the Research Department of Boots which led to the discovery of ibuprofen used by millions worldwide for the relief of pain.

Availability and administration

See also:
Ibuprofen brand names
A bottle of generic ibuprofen

Ibuprofen was made available by prescription in the United Kingdom in 1969 and in the United States in 1974.[82]

Ibuprofen is the International nonproprietary name (INN), British Approved Name (BAN), Australian Approved Name (AAN) and United States Adopted Name (USAN). In the United States, it has been sold under the brand-names Motrin and Advil since 1974[83] and 1984,[84] respectively. Ibuprofen is commonly available in the United States up to the FDA's 1984 dose limit OTC, rarely used higher by prescription.[85][failed verification]

In 2009, the first injectable formulation of ibuprofen was approved in the United States, under the brand name Caldolor.[86][87]

Ibuprofen can be taken orally (by mouth) (as a tablet, a capsule, or a suspension) and intravenously.[9]

Research

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.[88][89] As with other NSAIDs, ibuprofen may be useful in the treatment of severe orthostatic hypotension (low blood pressure when standing up).[90] NSAIDs are of unclear utility in the prevention and treatment of Alzheimer's disease.[91][92]

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.[93] 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.[94][95][96] 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.[97]

Some

red clover; and those that increase the risk of bleeding, like tamarind.[98]

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