ibuprofen

Ibuprofen
Systematic (IUPAC) name
(RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid
Identifiers
CAS number	15687-27-1
ATC code	M01AE01
PubChem	3672
DrugBank	APRD00372
ChemSpider	3544
Chemical data
Formula	C13H18O2
Mol. mass	206.28
SMILES	eMolecules & PubChem
Physical data
Melt. point	76 °C (169 °F)
Pharmacokinetic data
Bioavailability	49–73%
Protein binding	99%
Metabolism	Hepatic (CYP2C9)
Half life	1.8–2 hours
Excretion	Renal
Therapeutic considerations
Licence data	US FDA:link
Pregnancy cat.	C(AU) D(US)
Legal status	Unscheduled(AU) GSL(UK) OTC(US)
Routes	Oral, rectal, topical, and intravenous
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Coated 200 mg ibuprofen tablets

Ibuprofen (INN) (pronounced /ˈaɪbjuːproʊfɛn/ or /aɪbjuːˈproʊfən/; from the now outdated nomenclature iso-butyl-propanoic-phenolic acid) is a non-steroidal anti-inflammatory drug (NSAID) originally marketed as Brufen, and since then under various other trademarks (see tradenames section), most notably Nurofen, Advil and Motrin. It is used for relief of symptoms of arthritis, primary dysmenorrhea, fever, and as an analgesic, especially where there is an inflammatory component. Ibuprofen is known to have an antiplatelet effect, though it is relatively mild and short-lived when compared with that of aspirin or other better-known antiplatelet drugs. Ibuprofen is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system.^[1]

History

Ibuprofen was derived from propionic acid by the research arm of Boots Group during the 1960s.^[2] It was discovered by Stewart Adams, with colleagues John Nicholson, Andrew RM Dunlop, Jeffery Bruce Wilson & Colin Burrows and was 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. Famously, it is recorded that Dr. Adams initially tested his drug on a hangover. 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.^[3]

Typical administration

Low doses of ibuprofen (200 mg, and sometimes 400 mg) are available over the counter (OTC) in most countries. Ibuprofen has a dose-dependent duration of action of approximately 4–8 hours, which is longer than suggested by its short half-life. The recommended dose varies with body mass and indication. Generally, the oral dose is 200–400 mg (5–10 mg/kg in children) every 4–6 hours, adding up to a usual daily dose of 800–1200 mg. 1200 mg is considered the maximum daily dose for over-the-counter use, though under medical direction, a maximum daily dose of 2400 mg may sometimes be used in increments of 600–800 mg.

Unlike aspirin, which breaks down in solution, ibuprofen is stable, and thus ibuprofen can be available in topical gel form which is absorbed through the skin, and can be used for sports injuries, with less risk of gastrointestinal problems.^[4]

Off-label and investigational use

Ibuprofen is sometimes used for the treatment of acne, because of its anti-inflammatory properties,^[5] and has been sold in Japan in topical form for adult acne.^[6]

As with other NSAIDs, ibuprofen may be useful in the treatment of severe orthostatic hypotension (low blood pressure when standing up).^[7]

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.^[8] Further studies are needed to confirm the results before ibuprofen can be recommended for this indication.

Ibuprofen has been associated with a lower risk of Parkinson's disease, and may delay or prevent it. Aspirin, other NSAIDs, and paracetamol had no effect on the risk for Parkinson's.^[9] Further research is warranted before recommending ibuprofen for this use.

Ibuprofen lysine

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 the medication to be administered intravenously.^[10] Ibuprofen lysine has been shown to have a more rapid onset of action compared to acid ibuprofen.^[11]

Ibuprofen lysine is indicated for closure of a patent ductus arteriosus in premature infants weighing between 500 and 1500 grams, who are no more than 32 weeks gestational age when usual medical management (e.g., fluid restriction, diuretics, respiratory support, etc.) is ineffective.^[10] With regard to this indication, ibuprofen lysine is an effective alternative to intravenous indomethacin and may be advantageous in terms of renal function.^[12]

Mechanism of action

Non-steroidal 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, indometacin, and most other NSAIDs, ibuprofen is considered a non-selective COX inhibitor—that is, it inhibits two isoforms of cyclooxygenase, COX-1 and COX-2. The analgesic, antipyretic, and anti-inflammatory activity of NSAIDs appears to be achieved mainly through inhibition of COX-2, whereas inhibition of COX-1 would be responsible for unwanted effects on platelet aggregation and the gastrointestinal tract.^[13] 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.^[14]

Adverse effects

Ibuprofen appears to have the lowest incidence of gastrointestinal adverse drug reactions (ADRs) of all the non-selective NSAIDs. However, this only holds true at lower doses of ibuprofen, so over-the-counter preparations of ibuprofen are generally labeled to advise a maximum daily dose of 1,200 mg.^[15][16]

Common adverse effects include: nausea, dyspepsia, gastrointestinal ulceration/bleeding, raised liver enzymes, diarrhea, epistaxis, headache, dizziness, priapism, rash, salt and fluid retention, and hypertension.^[17]

Infrequent adverse effects include: oesophageal ulceration, heart failure, hyperkalaemia, renal impairment, confusion, and bronchospasm.^[17]

Photosensitivity

As with other NSAIDs, ibuprofen has been reported to be a photosensitising agent.^[18][19] However, this only rarely occurs with ibuprofen and it is considered to be a very weak photosensitising agent when compared with other members of the 2-arylpropionic acid class. This is because the ibuprofen molecule contains only a single phenyl moiety and no bond conjugation, resulting in a very weak chromophore system and a very weak absorption spectrum which does not reach into the solar spectrum.

Cardiovascular risk

Along with several other NSAIDs, ibuprofen has been implicated in elevating the risk of myocardial infarction (heart attack), particularly among those chronically using high doses.^[20]

Risks in inflammatory bowel disease (IBD)

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Ibuprofen should not be used regularly in individuals with inflammatory bowel disease due to its ability to cause gastric bleeding and form ulceration in the gastric lining. Pain relievers such as paracetemol/acetaminophen or drugs containing codeine (which slows down bowel activity) are safer methods than ibuprofen for pain relief in IBD. Ibuprofen is also known to cause worsening of IBD during times of a flare-up, thus should be avoided completely.

Human toxicology

Ibuprofen overdose has become common since it was licensed for over-the-counter use. There are many overdose experiences reported in the medical literature, although the frequency of life-threatening complications from ibuprofen overdose is low.^[21] Human response in cases of overdose ranges from absence of symptoms to fatal outcome in spite of 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.^[22] 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.

There is little correlation between severity of symptoms and measured ibuprofen plasma levels. Toxic effects are unlikely at doses below 100 mg/kg but can be severe above 400 mg/kg;^[23] however, large doses do not indicate that the clinical course is likely to be lethal.^[24] It is not possible to determine a precise lethal dose, as this 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 absorbs 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.^[25] 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.^[23] Since ibuprofen has acidic properties and is also excreted in the urine, forced alkaline diuresis is theoretically beneficial. However, due to the fact ibuprofen is highly protein bound in the blood, there is minimal renal excretion of unchanged drug. Forced alkaline diuresis is therefore of limited benefit.^[26] Symptomatic therapy for hypotension, GI bleeding, acidosis, and renal toxicity may be indicated. Occasionally, close monitoring in an intensive care unit for several days is necessary. If a patient survives the acute intoxication, they will usually experience no late sequelae.

Chemistry

Ibuprofen is only very slightly soluble in water, less than 1 mg of ibuprofen dissolves in 1 ml water (< 1 mg/mL).^[27]

Stereochemistry

Ibuprofen, like other 2-arylpropionate derivatives (including ketoprofen, flurbiprofen, naproxen, etc), contains a stereocenter in the α-position of the propionate moiety. As such, there are two possible enantiomers of ibuprofen, with the potential for different biological effects and metabolism for each enantiomer.

Indeed it was found that (S)-(+)-ibuprofen (dexibuprofen) was the active form both in vitro and in vivo.

It was logical, then, that there was 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 (2-arylpropionyl-CoA epimerase) which converted (R)-ibuprofen to the active (S)-enantiomer.^[28][29][30] Thus, due to the expense and futility that might be involved in making a pure enantiomer, most ibuprofen formulations currently marketed are racemic mixtures.

(R)-ibuprofen	(S)-ibuprofen

Synthesis

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 with an intramolecular Williamson ether synthesis gave the epoxide, which was hydrolyzed to the aldehyde. Reaction with hydroxylamine gave the oxime, converted to the nitrile, then hydrolyzed to the desired acid:^[31]

An improved synthesis by BHC required only three steps. This improved synthesis won the Presidential Green Chemistry Challenge Greener Synthetic Pathways Award in 1997.^[32] After a similar acetylation, hydrogenation with Raney nickel gave the alcohol, which underwent palladium-catalyzed carbonylation:^[31]

Availability

A Bottle of Generic Ibuprofen

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 (post-approval studies), has resulted in the availability of small packages of ibuprofen over the counter in pharmacies worldwide, as well as in supermarkets and other general retailers.

North America

In the United States, the Food and Drug Administration approved ibuprofen for over the counter use in 1984.

In North America doses between 100 mg and 400 mg are available over the counter. The 600 mg and 800 mg form is only available in North America by prescription.

In 2009, the first injectable formulation of ibuprofen was approved in the United States, under the trade name Caldolor. Ibuprofen thus became the only pain and fever reliever available in the country for parenteral use.^[33]

Europe

For some time, there has been a limit on the amount that can be bought over the counter in a single transaction in the UK. Behind the counter in pharmacies this is one pack of 96 × 200 mg or 400 mg, the latter being far less common for over the counter sales. In UK non-pharmacy outlets only 200 mg tablets are allowed and they are restricted to a maximum pack of 16 tablets.

In Germany, 600 mg and 800 mg per pill packages have to be prescribed, whereas 400 mg is available over the counter in pharmacies. In Italy, Belgium and the Netherlands, 200 mg and 400 mg pills are available with no prescription.

In other countries, higher dosages of 600 mg are available.

References

External links

Wikimedia Commons has media related to: Ibuprofen

• U.S. National Library of Medicine: MedlinePlus Drug Information: Ibuprofen
• University of Bristol chemistry department page on Ibuprofen
• Nurofen UK Website