Chemistry:Mefenamic acid

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Short description: Chemical compound
Mefenamic acid
Mefenamic acid2DACS.svg
Mefenamic-acid-from-xtal-3D-bs-17.png
Clinical data
Trade namesPonstel, Ponstan, many others
AHFS/Drugs.comMonograph
MedlinePlusa681028
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration		By mouth, suppositories
ATC code
Legal status
Legal status
  • AU: S2 (Pharmacy medicine)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability90%
Protein binding>90%
MetabolismHepatic (CYP2C9)
Elimination half-life2 hours
ExcretionUrine (52–67%), faeces (20–25%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC15H15NO2
Molar mass241.290 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Mefenamic acid is a member of the anthranilic acid derivatives (or fenamate) class of nonsteroidal anti-inflammatory drugs (NSAIDs), and is used to treat mild to moderate pain.[1][2]

Its name derives from its systematic name, dimethylphenylaminobenzoic acid. It was discovered and brought to market by Parke-Davis as Ponstel in the 1960s. It became generic in the 1980s and is available worldwide under many brand names such as Meftal.[3]

Medical uses

Mefenamic acid is used to treat pain and inflammation in rheumatoid arthritis and osteoarthritis, postoperative pain, acute pain including muscle and back pain, toothache and menstrual pain, as well as being prescribed for menorrhagia.[4][5][6]

There is evidence that supports the use of mefenamic acid for perimenstrual migraine headache prophylaxis, with treatment starting two days prior to the onset of flow or one day prior to the expected onset of the headache and continuing for the duration of menstruation.[2]

Mefenamic acid is recommended to be taken with food.[7]

Contraindications

Mefenamic acid is contraindicated in people who have shown hypersensitivity reactions such as urticaria and asthma to this drug or to other NSAIDs (e.g. aspirin); those with peptic ulcers or chronic inflammation of the gastrointestinal tract; those with kidney or liver disease; heart failure; after coronary artery bypass surgery; and during the third trimester of pregnancy.[5][8]

Side effects

Known mild side effects of mefenamic acid include headaches, nervousness, and vomiting. Potentially serious side effects may include diarrhea, gastrointestinal perforation, peptic ulcers, hematemesis (vomiting blood), skin reactions (rashes, itching, swelling; in rare cases toxic epidermal necrolysis) and rarely blood cell disorders such as agranulocytosis.[9][5] It has been associated with acute liver damage.[10]

In 2008 the US label was updated with a warning concerning a risk of premature closure of the ductus arteriosus in pregnancy.[11]

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 unborn babies that result in low amniotic fluid.[12][13] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.[12][13]

In its November 2023 monthly drug safety alert under the Pharmacovigilance Programme of India (PvPI), the Indian Pharmacopoeia Commission flagged a risk of DRESS Syndrome due to use of mefenamic acid.[14]

Overdose

Symptoms of overdosing include kidney failure, gastrointestinal problems, bleeding, rashes, confusion, hallucinations, vertigo, seizures, and loss of consciousness. It is treated with induction of vomiting, gastric lavage, bone char, and control of electrolytes and vital functions.[5]

Interactions

Interactions are broadly similar to those of other NSAIDs. Mefenamic acid interferes with the anti–blood clotting mechanism of Aspirin. It increases the blood thinning effects of warfarin and phenprocoumon because it displaces them from their plasma protein binding and increases their free concentrations in the bloodstream. It adds to the risk of gastrointestinal ulcera associated with corticosteroids and selective serotonin reuptake inhibitors. It can increase the risk for adverse effects of methotrexate and lithium by lowering their excretion via the kidneys. It can increase the kidney toxicity of ciclosporin and tacrolimus. Combination with antihypertensive drugs such as ACE inhibitors, sartans and diuretics can decrease their effectiveness as well as increase the risk for kidney toxicity.[5][6]

Pharmacology

Mechanism of action

Like other members of the anthranilic acid derivatives (or fenamate) class of NSAIDs, it inhibits both isoforms of the enzyme cyclooxygenase (COX-1 and COX-2). This prevents formation of prostaglandins,[10][15] which play a role in pain sensitivity, inflammation and fever, but also in hemostasis, kidney function, sustaining of pregnancy, and protection of the gastric mucosa.[16]

Pharmacokinetics

Mefenamic acid (top) and its 3'-hydroxymethyl- and 3'-carboxy-metabolites (middle and bottom, respectively). The carboxy groups at the bottom right of each substance can be glucuronidized.

Mefenamic acid is rapidly absorbed from the gut and reaches highest concentrations in the blood plasma after one to four hours. When in the bloodstream, over 90% of the substance are bound to plasma proteins. It probably crosses the placenta, and is found in the breast milk in small amounts.[5][8]

It is metabolized by the liver enzyme CYP2C9 to the only weakly active 3'-hydroxymethylmefenamic acid. 3'-carboxymefenamic acid has also been identified as a metabolite, as well as carboxy glucuronides of all three substances. Mefenamic acid and its metabolites are excreted via the urine (52–67%) and the faeces (20–25%, or less than 20% following another source). The parent substance has a biological half-life of two hours; the half-life of its metabolites may be longer.[5][6][8]

History

Scientists led by Claude Winder from Parke-Davis invented mefenamic acid in 1961, along with fellow members of the class of anthranilic acid derivatives, flufenamic acid in 1963 and meclofenamate sodium in 1964.[17] U.S. Patent 3,138,636 on the drug was issued in 1964.[18][19]

It was approved in the UK in 1963 as Ponstan, in West Germany in 1964 as Ponalar and in France as Ponstyl, and the US in 1967 as Ponstel.[10][19]

Chemistry

Synthesis

Analogous to fenamic acid, this compound may be made from 2-chlorobenzoic acid and 2,3-dimethylaniline.[20]

Conformational flexibility

Mefenamic acid, a member of the fenamate, is a chemical compound derived from anthranilic acid . This derivative is created by substituting one of the hydrogen atoms attached to the nitrogen atom with a 2,3-dimethylphenyl fragment. The result is a structurally complex molecule with fascinating conformational properties.

The mefenamic acid molecule exhibits conformational lability, meaning it can exist in various shapes or conformers. This flexibility arises from changes in the position of the carboxylic acid group and the 2,3-dimethylphenyl fragment about the anthranil moiety. Specifically, the arrangement of the substituted benzene fragments relative to each other plays a crucial role in determining the different polymorphic forms of mefenamic acid.[21]

Recent experimental studies have unveiled two additional hidden conformers of mefenamic acid.[22] These conformers result from alterations in the positions of hydroxyl groups within the molecule. This discovery adds to our understanding of the compound's structural diversity.

External factors, including temperature, pressure, and the surrounding medium, highly influence the conformational state of mefenamic acid. Researchers have conducted extensive investigations into its spatial structure not only in organic solvents[23] but also in supercritical fluids,[24][25] aerogels,[26] and lipid bilayers.[27][28] These studies have helped elucidate the impact of different environments on the molecule's conformation.

Society and culture

Availability and pricing

Mefenamic acid is generic and is available worldwide under many brand names.[3]

In the US, wholesale price of a week's supply of generic mefenamic acid has been quoted as $426.90 in 2014. Brand-name Ponstel is $571.70.[29] By contrast, in the UK, a weeks supply is £1.66, or £8.17 for branded Ponstan.[30]

Research

While studies have been conducted to see if mefenamic acid can improve behavior in transgenic mouse models of Alzheimer's disease[31][32] there is little evidence that mefenamic acid or other NSAIDs can treat or prevent Alzheimer's in humans; clinical trials of NSAIDs other than mefenamic acid for treatment of Alzheimer's have found more harm than benefit.[33][34][35] A small controlled study of 28 human subjects showed improved cognitive impairment using mefenamic acid non-steroidal anti-inflammatory therapy.[36]

See also

References

  1. ↑ "Ponstel Label". U.S. Food and Drug Administration. 19 February 2008. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/015034s040lbl.pdf. 
  2. ↑ 2.0 2.1 "Acute treatment and prevention of menstrually related migraine headache: evidence-based review". Neurology 70 (17): 1555–1563. April 2008. doi:10.1212/01.wnl.0000310638.54698.36. PMID 18427072. 
  3. ↑ 3.0 3.1 "International listings for mefenamic acid". Drugs.com. https://www.drugs.com/international/mefenamic-acid.html. 
  4. ↑ (in en-GB) Digital Medicines Information Suite. doi:10.18578/bnf.855907230. https://about.medicinescomplete.com/. Retrieved 2020-04-18. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 (in de) Austria-Codex. Vienna: Österreichischer Apothekerverlag. 2020. Parkemed 500 mg-Filmtabletten. 
  6. ↑ 6.0 6.1 6.2 "mediQ: Mefenaminsäure". https://www.mediq.ch/. 
  7. ↑ "Side effects for Mefenamic Acid". Medline Plus. National Institutes of Health. https://www.nlm.nih.gov/medlineplus/druginfo/meds/a681028.html#side-effects. 
  8. ↑ 8.0 8.1 8.2 Cerner Multum. "Mefenamic Acid". Drugs.com. https://www.drugs.com/mtm/mefenamic-acid.html. 
  9. ↑ eyler's Side Effects of Analgesics and Anti-inflammatory Drugs. Amsterdam: Elsevier Science. 2010. p. 334. ISBN 978-0-08-093294-1. 
  10. ↑ 10.0 10.1 10.2 "Mefenamic Acid". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. January 2020. https://www.ncbi.nlm.nih.gov/books/n/livertox/MefenamicAcid/. Retrieved 28 November 2019. 
  11. ↑ "Safety Labeling Changes: Ponstel (mefenamic acid capsules, USP)". Center for Drug Evaluation and Research (CDER). U.S. Food and Drug Administration. March 2008. https://www.fda.gov/safety/medwatch/safetyinformation/safety-relateddruglabelingchanges/ucm116459.htm. 
  12. ↑ 12.0 12.1 "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. This article incorporates text from this source, which is in the public domain.
  13. ↑ 13.0 13.1 "NSAIDs may cause rare kidney problems in unborn babies". 21 July 2017. https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic.  This article incorporates text from this source, which is in the public domain.
  14. ↑ "Monthly Drug Safety Alert". 30 November 2023. https://ipc.gov.in/8-category-en/1089-drug-alerts-2023.html. 
  15. ↑ "Differential sensitivity and mechanism of inhibition of COX-2 oxygenation of arachidonic acid and 2-arachidonoylglycerol by ibuprofen and mefenamic acid". Biochemistry 48 (31): 7353–7355. August 2009. doi:10.1021/bi900999z. PMID 19603831. 
  16. ↑ Arzneimittelwirkungen. Wissenschaftliche Verlagsgesellschaft Stuttgart. 2013. pp. 205–206, 444. ISBN 978-3-8047-2898-1. 
  17. ↑ "Drugs to treat inflammation: a historical introduction". Current Medicinal Chemistry 4 (25): 707–729 (718). 2009. doi:10.2174/092986705774462879. ISBN 978-1-60805-207-3. PMID 16378496. 
  18. ↑ Scherrer RA, US patent 3,138,636, issued 23 June 1964, assigned to Parke Davis and Co LLC
  19. ↑ 19.0 19.1 "Mefenamic acid". Pharmaceutical Manufacturing Encyclopedia. 1 (Second ed.). Noyes Publications. 1988. pp. 918–919. http://files.rushim.ru/books/lekarstva/pharmaceutical-encyclopedia.pdf. 
  20. ↑ "Mefenamic acid — A Nonsteroid Antiinflammatory Agent". Pharmaceutical Chemistry Journal 11 (12): 1706–1711. 1977. doi:10.1007/BF00778304. 
  21. ↑ "Conformational Polymorphism in a Non-steroidal Anti-inflammatory Drug, Mefenamic Acid" (in en). Crystal Growth & Design 12 (8): 4283–4289. August 2012. doi:10.1021/cg300812v. ISSN 1528-7483. 
  22. ↑ "The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy". Pharmaceutics 14 (11): 2276. October 2022. doi:10.3390/pharmaceutics14112276. PMID 36365095. 
  23. ↑ "Determination of preferred conformations of mefenamic acid in DMSO by NMR spectroscopy and GIAO calculation". AIP Conference Proceedings. 2063. AIP Publishing.. January 2019. pp. 040007. doi:10.1063/1.5087339. 
  24. ↑ "Conformational Analysis of Mefenamic Acid in scCO2-DMSO by the 2D NOESY Method" (in en). Russian Journal of Physical Chemistry B 16 (7): 1191–1199. December 2022. doi:10.1134/S1990793122070028. ISSN 1990-7931. Bibcode: 2022RJPCB..16.1191B. 
  25. ↑ "Does DMSO affect the conformational changes of drug molecules in supercritical CO2 Media?" (in en). Journal of Molecular Liquids 384: 122230. August 2023. doi:10.1016/j.molliq.2023.122230. 
  26. ↑ "Exploring the Conformational Equilibrium of Mefenamic Acid Released from Silica Aerogels via NMR Analysis". International Journal of Molecular Sciences 24 (8): 6882. April 2023. doi:10.3390/ijms24086882. PMID 37108046. 
  27. ↑ "Structural details on the interaction of fenamates with lipid membranes" (in en). Journal of Molecular Liquids 367: 120502. December 2022. doi:10.1016/j.molliq.2022.120502. 
  28. ↑ "Conformational State of Fenamates at the Membrane Interface: A MAS NOESY Study". Membranes 13 (6): 607. June 2023. doi:10.3390/membranes13060607. PMID 37367811. 
  29. ↑ "Drugs for Osteoarthritis". The Medical Letter 56 (1450): 80–84. September 2014. PMID 25157683. 
  30. ↑ "Access leading drug and healthcare references". https://www.medicinescomplete.com/mc/bnf/current/PHP6487-mefenamic-acid-non-proprietary.htm. 
  31. ↑ "Mefenamic acid shows neuroprotective effects and improves cognitive impairment in in vitro and in vivo Alzheimer's disease models". Molecular Pharmacology 69 (1): 76–84. January 2006. doi:10.1124/mol.105.015206. PMID 16223958. 
  32. ↑ "Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models". Nature Communications 7: 12504. August 2016. doi:10.1038/ncomms12504. PMID 27509875. Bibcode: 2016NatCo...712504D. 
  33. ↑ "Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer's disease: a systematic review and meta-analysis of treatment effect". Drugs & Aging 32 (2): 139–147. February 2015. doi:10.1007/s40266-015-0239-z. PMID 25644018. 
  34. ↑ "Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease". The Cochrane Database of Systematic Reviews (2): CD006378. February 2012. doi:10.1002/14651858.CD006378.pub2. PMID 22336816. 
  35. ↑ "Anti-inflammatory drugs and risk of Alzheimer's disease: an updated systematic review and meta-analysis". Journal of Alzheimer's Disease 44 (2): 385–396. 2015. doi:10.3233/JAD-141506. PMID 25227314. 
  36. ↑ "Improve cognitive impairment using mefenamic acid non-steroidal anti-inflammatory therapy: additional beneficial effect found in a controlled clinical trial for prostate cancer therapy". American Journal of Translational Research 13 (5): 4535–4543. 2021. PMID 34150033. 

Further reading



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