Ketoprofen

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Ketoprofen
Ketoprofen.svg
Ketoprofen ball-and-stick.png
Clinical data
Trade names Oruvail, others
AHFS/Drugs.com Monograph
MedlinePlus a686014
License data
Pregnancy
category
  • AU:C
Routes of
administration 		By mouth, topical, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 99%
Elimination half-life 2–2.5 hours
Identifiers
  • (RS)-2-(3-benzoylphenyl)propanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.040.676 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H14O3
Molar mass 254.285 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • CC(c1cccc(c1)C(=O)c2ccccc2)C(=O)O
  • InChI=1S/C16H14O3/c1-11(16(18)19)13-8-5-9-14(10-13)15(17)12-6-3-2-4-7-12/h2-11H,1H3,(H,18,19) Yes check.svgY
  • Key:DKYWVDODHFEZIM-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Ketoprofen is one of the propionic acid class of nonsteroidal anti-inflammatory drugs (NSAID) with analgesic and antipyretic effects. [3] It acts by inhibiting the body's production of prostaglandin.

Contents

It was patented in 1967 and approved for medical use in 1980. [4]

Medical uses

Ketoprofen is generally prescribed for arthritis-related inflammatory pains or severe toothaches that result in the inflammation of the gums.

Ketoprofen topical patches are being used for treatment of musculoskeletal pain. [5] [6] [7]

Ketoprofen can also be used for treatment of some pain, especially nerve pain such as sciatica, postherpetic neuralgia and referred pain for radiculopathy, in the form of a cream, ointment, liquid, spray, or gel, which may also contain ketamine and lidocaine, along with other agents which may be useful, such as cyclobenzaprine, amitriptyline, acyclovir, gabapentin, orphenadrine and other drugs used as NSAIDs or adjuvant, atypical or potentiators for pain treatment.

Trials are going on for using this drug along with ibuprofen for management of lymphedema.[ citation needed ] Animal trial and some human trials have shown significant improvement over placebo control. Dr Stanley G Rockson, of Stanford University is leading these researches.[ citation needed ]

Efficacy

A 2013 systematic review indicated "The efficacy of orally administered ketoprofen in relieving moderate-severe pain and improving functional status and general condition was significantly better than that of ibuprofen and/or diclofenac." [8] A 2017 Cochrane systematic review investigating ketoprofen as a single-dose by mouth in acute, moderate-to-severe postoperative pain concluded that its efficacy is equivalent to drugs such as ibuprofen and diclofenac. [9]

There is evidence supporting topical ketoprofen for osteoarthritis but not other chronic musculoskeletal pain. [10]

Adverse effects

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in fetuses that result in low amniotic fluid. [11] [12] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. [11] [12]

Mechanism

Ketoprofen undergoes metabolism in the liver via conjugation with glucuronic acid (glucuronidation) by UGT enzymes, hydroxylation of the benzoyl ring by the CYP3A4 and CYP2C9 enzymes, and reduction of its ketone moiety (a carbonyl functional group, i.e. with carbon-oxygen double bond) [13] by carbonyl reducing enzymes (CREs). [14] [15] Ketoprofen is used for its antipyretic, analgesic, and anti-inflammatory properties by inhibiting cyclooxygenase-1 and -2 (COX-1 and COX-2) enzymes reversibly, which decreases production of proinflammatory prostaglandin precursors. [14] [16]

The patches have been shown to provide rapid and sustained delivery to underlying tissues without significantly increasing levels of drug concentration in the blood when compared to the traditional oral administration. [7] [17]

Chirality and biological activity

Ketoprofen has one stereogenic center in the side chain and hence exists as mirror-image twins. Majority of the profens are marketed as racemic mixtures. For most of the NSAIDs the pharmacological activity resides in the (S)-enantiomers with their (R)-enantiomer virtually inactive. An interesting observation about most profens including ketoprofen is that they undergo unidirectional metabolic inversion, chiral inversion, of the (R)- acid to its (S)-mirror-image version with no other change in the molecule. [18] [19] [20] There have been concerns raised that Ketoprofen can break down into the parent benzophenone molecule in skin exposed to strong summer or tropical UV light and this could pose a theoretical cancer risk. Given such a risk it is better to use other pain killers in such circumstances.

History

The earliest report of therapeutic use in humans is in 1972. [21]

Society and culture

Brand names

Brand names in Australia include Orudis and Oruvail. It is available in Japan in a transdermal patch Mohrus Tape, made by Hisamitsu Pharmaceutical. It is available in the UK as Ketoflam and Oruvail, in Ireland as Fastum Gel, in Estonia as Keto, Ketonal, and Fastum Gel, in Finland as Ketorin, Keto, Ketomex, and Orudis; in France as Profénid, Bi-Profénid, Toprec, and Ketum; in Italy as Ketodol, Fastum Gel, Lasonil, Orudis and Oki; in Greece as Okitask; in Poland as Ketonal, Ketonal active, Ketolek, in Serbia, Slovenia and Croatia as Knavon and Ketonal; in Romania as Ketonal and Fastum Gel; in Mexico as Arthril; in Norway as Zon and Orudis; in Russia as ОКИ (OKI), Fastum Gel and Ketonal; in Spain as Actron and Fastum Gel; in Albania as Oki and Fastum Gel and in Venezuela as Ketoprofeno as an injectable solution of 100 mg and 150 mg capsules.

In some countries, the optically pure (S)-enantiomer (dexketoprofen) is available; its trometamol salt is said to be particularly rapidly reabsorbed from the gastrointestinal tract, having a rapid onset of effects.

Veterinary medicine

Ketoprofen is a common NSAID, antipyretic, and analgesic used in horses and other equines. [22] It is most commonly used for musculoskeletal pain, joint problems, and soft tissue injury, as well as laminitis. It is also used to control fevers and prevent endotoxemia. It is also used as a mild painkiller in smaller animals, generally following surgical procedures.

In horses, it is given at a dose of 2.2 mg/kg/day. Studies have shown that it does not inhibit 5-lipoxygenase and leukotriene B4, [23] as originally claimed. [24] It is therefore not considered superior to phenylbutazone as previously believed, although clinical signs of lameness are reduced with its use. [25] In fact, phenylbutazone was shown superior to ketoprofen in cases of experimentally-induced synovitis when both drugs were used at labeled dosages. [26]

Ecological problems

Experiments have found ketoprofen, like diclofenac, is a veterinary drug causing lethal effects in red-headed vultures. Vultures feeding on the carcasses of recently treated livestock develop acute kidney failure within days of exposure. [27]

Related Research Articles

<span class="mw-page-title-main">Analgesic</span> Drugs used to achieve relief from pain

An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in some instances eliminate, sensation, although analgesia and anesthesia are neurophysiologically overlapping and thus various drugs have both analgesic and anesthetic effects.

<span class="mw-page-title-main">Nonsteroidal anti-inflammatory drug</span> Class of therapeutic drug for relieving pain and inflammation

Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.

An antipyretic is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in temperature. The body then works to lower the temperature, which results in a reduction in fever.

<span class="mw-page-title-main">Paracetamol</span> Common medication for pain and fever

Paracetamol (acetaminophen) is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely used over the counter medication. Common brand names include Tylenol and Panadol.

<span class="mw-page-title-main">Ibuprofen</span> Medication treating pain, fever, and inflammation

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be taken orally or intravenously. It typically begins working within an hour.

<span class="mw-page-title-main">Diclofenac</span> Nonsteroidal anti-inflammatory drug

Diclofenac, sold under the brand name Voltaren, among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout. It can be taken orally, inserted rectally as a suppository, injected intramuscularly (IM), injected intravenously (IV), or applied to the skin topically. Improvements in pain last up to eight hours. It is also available in combination with misoprostol in an effort to decrease stomach problems.

<span class="mw-page-title-main">Naproxen</span> Nonsteroidal anti-inflammatory drug (NSAID) used to treat pain

Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, and inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formulations. Onset of effects is within an hour and lasts for up to twelve hours.

<span class="mw-page-title-main">Phenylbutazone</span> Nonsteroidal anti-inflammatory drug (NSAID)

Phenylbutazone, often referred to as "bute", is a nonsteroidal anti-inflammatory drug (NSAID) for the short-term treatment of pain and fever in animals.

<span class="mw-page-title-main">Nimesulide</span> Anti-inflammatory drug

Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) with pain medication and fever reducing properties. Its approved indications are the treatment of acute pain, the symptomatic treatment of osteoarthritis, and primary dysmenorrhoea in adolescents and adults above 12 years old.

<span class="mw-page-title-main">Ketorolac</span> Nonsteroidal anti-inflammatory drug (NSAID; analgesic)

Ketorolac, sold under the brand name Toradol among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain. Specifically it is recommended for moderate to severe pain. Recommended duration of treatment is less than six days, and in Switzerland not more than two days. It is used by mouth, by nose, by injection into a vein or muscle, and as eye drops. Effects begin within an hour and last for up to eight hours.

<span class="mw-page-title-main">Flunixin</span> NSAID analgesic veterinary drug

Flunixin is a nonsteroidal anti-inflammatory drug (NSAID), analgesic, and antipyretic used in horses, cattle and pigs. It is often formulated as the meglumine salt. In the United States, it is regulated by the U.S. Food and Drug Administration (FDA), and may only be lawfully distributed by order of a licensed veterinarian. There are many trade names for the product.

<span class="mw-page-title-main">Diflunisal</span> NSAID analgesic and anti-inflammatory drug

Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971, as MK647, after showing promise in a research project studying more potent chemical analogs of aspirin. It was first sold under the brand name Dolobid, marketed by Merck & Co., but generic versions are now widely available. It is classed as a nonsteroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets.

<span class="mw-page-title-main">Flurbiprofen</span> Chemical compound

Flurbiprofen is a member of the phenylalkanoic acid derivative family of nonsteroidal anti-inflammatory drugs (NSAIDs). It is primarily indicated as a pre-operative anti-miotic as well as orally for arthritis or dental pain. Side effects are analogous to those of ibuprofen.

<span class="mw-page-title-main">Meclofenamic acid</span> Chemical compound

Meclofenamic acid is a drug used for joint, muscular pain, arthritis and dysmenorrhea. It is a member of the anthranilic acid derivatives class of nonsteroidal anti-inflammatory drugs (NSAIDs) and was approved by the US FDA in 1980. Like other members of the class, it is a cyclooxygenase (COX) inhibitor, preventing the formation of prostaglandins.

<span class="mw-page-title-main">Dexketoprofen</span> Chemical compound

Dexketoprofen is a nonsteroidal anti-inflammatory drug (NSAID). It is manufactured by Menarini, under the tradename Keral. It is available in the UK, as dexketoprofen trometamol, as a prescription-only drug and in Latin America as Enantyum, produced by Menarini. Also, in Italy and Spain it is available as an over-the-counter drug (OTC) under the trade name Enandol or Enantyum. In Hungary it is available from a pharmacy as "Ketodex". In Turkey, it is an over the counter medicine under the name "Arveles". In Latvia, Lithuania and Estonia it is available as an OTC under the tradename Dolmen. In Mexico it is available in tablet form as "Stadium" made by Menarini. It is the dextrorotatory stereoisomer of ketoprofen.

<span class="mw-page-title-main">Dexibuprofen</span> Chemical compound

Dexibuprofen is a nonsteroidal anti-inflammatory drug (NSAID). It is the active dextrorotatory enantiomer of ibuprofen. Most ibuprofen formulations contain a racemic mixture of both isomers.

Benoxaprofen, also known as Benoxaphen, is a chemical compound with the formula C16H12ClNO3. It is a non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class, and was marketed under the brand name Opren in the United Kingdom and Europe by Eli Lilly and Company (commonly referred to as Lilly), and as Oraflex in the United States of America (USA). Lilly suspended sales of Oraflex in 1982 after reports from the British government and the United States Food and Drug Administration (US FDA) of adverse effects and deaths linked to the drug.

<span class="mw-page-title-main">Fenoprofen</span> NSAID analgesic and anti-inflammatory drug

Fenoprofen, sold under the brand name Nalfon among others, is a nonsteroidal anti-inflammatory drug (NSAID). Fenoprofen calcium is used for symptomatic relief for rheumatoid arthritis, osteoarthritis, and mild to moderate pain. It has also been used to treat postoperative pain. It is available as a generic medication.

<span class="mw-page-title-main">Antiarthritics</span> Drug class

An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.

Chiral inversion is the process of conversion of one enantiomer of a chiral molecule to its mirror-image version with no other change in the molecule.

References

  1. ↑ "Health product highlights 2021: Annexes of products approved in 2021". Health Canada . 3 August 2022. Retrieved 25 March 2024.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  3. ↑ Kantor TG (1986). "Ketoprofen: a review of its pharmacologic and clinical properties". Pharmacotherapy. 6 (3): 93–103. doi:10.1002/j.1875-9114.1986.tb03459.x. PMID   3526298. S2CID   25309841.
  4. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 520. ISBN   9783527607495.
  5. ↑ Mazières B, Rouanet S, Guillon Y, Scarsi C, Reiner V (August 2005). "Topical ketoprofen patch in the treatment of tendinitis: a randomized, double blind, placebo controlled study". The Journal of Rheumatology. 32 (8): 1563–1570. PMID   16078335.
  6. ↑ Mazières B (2005). "Topical ketoprofen patch". Drugs in R&D. 6 (6): 337–344. doi:10.2165/00126839-200506060-00003. PMID   16274258. S2CID   30719197.
  7. 1 2 Sekiya I, Morito T, Hara K, Yamazaki J, Ju YJ, Yagishita K, et al. (March 2010). "Ketoprofen absorption by muscle and tendon after topical or oral administration in patients undergoing anterior cruciate ligament reconstruction". AAPS PharmSciTech. 11 (1): 154–158. doi:10.1208/s12249-009-9367-2. PMC   2850498 . PMID   20087696.
  8. ↑ Sarzi-Puttini P, Atzeni F, Lanata L, Bagnasco M (2013). "Efficacy of ketoprofen vs. ibuprofen and diclofenac: a systematic review of the literature and meta-analysis". Clinical and Experimental Rheumatology. 31 (5): 731–738. PMID   23711416.
  9. ↑ Gaskell H, Derry S, Wiffen PJ, Moore RA (May 2017). "Single dose oral ketoprofen or dexketoprofen for acute postoperative pain in adults". The Cochrane Database of Systematic Reviews. 2019 (5): CD007355. doi:10.1002/14651858.CD007355.pub3. PMC   6481461 . PMID   28540716.
  10. ↑ Derry S, Conaghan P, Da Silva JA, Wiffen PJ, Moore RA (April 2016). "Topical NSAIDs for chronic musculoskeletal pain in adults" (PDF). The Cochrane Database of Systematic Reviews. 4 (4): CD007400. doi:10.1002/14651858.cd007400.pub3. PMC   6494263 . PMID   27103611.
  11. 1 2 PD-icon.svg This article incorporates text from this source, which is in the public domain : "FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications". U.S. Food and Drug Administration (FDA) (Press release). 15 October 2020. Retrieved 15 October 2020.
  12. 1 2 PD-icon.svg This article incorporates text from this source, which is in the public domain : "NSAIDs may cause rare kidney problems in unborn babies". U.S. Food and Drug Administration. 21 July 2017. Retrieved 15 October 2020.
  13. ↑ Malátková P, Wsól V (February 2014). "Carbonyl reduction pathways in drug metabolism". Drug Metabolism Reviews. 46 (1): 96–123. doi:10.3109/03602532.2013.853078. PMID   24171394. S2CID   43774709.
  14. 1 2 Ketoprofen. (n.d.). Millennium Web Catalog. Retrieved 1 February 2010, from http://0-online.lexi.com.library.touro.edu Archived 29 August 2021 at the Wayback Machine
  15. ↑ Lemke TL, Williams DA, Roche VF, Zito SW. Foyes Principles of Medical Chemistry. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 2008.
  16. ↑ Ketoprofen. (n.d.). Micromedex. Retrieved 1 February 2010, from https://bb-tuc.touro.edu/webapps/portal/frameset.jsp?tab_id=_102_1 Archived 20 July 2011 at the Wayback Machine
  17. ↑ Gayman MD, Turner RJ, Cui M (July 2008). "Physical limitations and depressive symptoms: exploring the nature of the association". The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences. 63 (4): S219–S228. doi:10.1093/geronb/63.4.s219. PMC   2844725 . PMID   18689771.
  18. ↑ Hutt AJ, Caldwell J (November 1983). "The metabolic chiral inversion of 2-arylpropionic acids--a novel route with pharmacological consequences". The Journal of Pharmacy and Pharmacology. 35 (11): 693–704. doi:10.1111/j.2042-7158.1983.tb02874.x. PMID   6139449. S2CID   40669413.
  19. ↑ Caldwell J, Hutt AJ, Fournel-Gigleux S (January 1988). "The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences". Biochemical Pharmacology. 37 (1): 105–114. doi:10.1016/0006-2952(88)90762-9. PMID   3276314.
  20. ↑ Aboul-Enein HY, Wainer IW (1997). The impact of stereochemistry on drug development and use. New York: Wiley. ISBN   0-471-59644-2. OCLC   35262289.
  21. ↑ Gyory AN, Bloch M, Burry HC, Grahame R (November 1972). "Orudis in management of rheumatoid arthritis and osteoarthrosis of the hip: comparison with indomethacin". British Medical Journal. 4 (5837): 398–400. doi:10.1136/bmj.4.5837.398. PMC   1786628 . PMID   4564764.
  22. ↑ Forney BC (2007), Understanding equine medications: your guide to horse health care and managements, The Horse health care library (Revised ed.), Lexington, KY: Eclipse Press, OCLC   1360077554
  23. ↑ Salmon JA, Tilling LC, Moncada S (September 1984). "Benoxaprofen does not inhibit formation of leukotriene B4 in a model of acute inflammation". Biochemical Pharmacology. 33 (18): 2928–2930. doi:10.1016/0006-2952(84)90220-x. PMID   6089840.
  24. ↑ Betley M, Sutherland SF, Gregoricka MJ, Pollet RA (1991). "The analgesic effect of ketoprofen for use in treating equine colic as compared to flunixin meglumine". Equine Pract. 13: 11–16.
  25. ↑ Owens JG, Kamerling SG, Keowen ML (1994). Anti-inflammatory effects and pharmacokinetics of ketoprofen in a model of equine synovitis. Proceedings of the 6th International Congress of the EAVPT. Blackwell Scientific Publications. pp. 170–171.
  26. ↑ Owens JG, Kamerling SG, Stanton SR, Keowen ML, Prescott-Mathews JS (June 1996). "Effects of pretreatment with ketoprofen and phenylbutazone on experimentally induced synovitis in horses". American Journal of Veterinary Research. 57 (6): 866–874. doi:10.2460/ajvr.1996.57.06.866. PMID   8725815.
  27. ↑ Naidoo V, Wolter K, Cromarty D, Diekmann M, Duncan N, Meharg AA, et al. (June 2010). "Toxicity of non-steroidal anti-inflammatory drugs to Gyps vultures: a new threat from ketoprofen". Biology Letters. 6 (3): 339–341. doi:10.1098/rsbl.2009.0818. PMC   2880042 . PMID   20007163.
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