Sulindac

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Sulindac
Sulindac structure.svg
Names
Trade namesClinoril, others
  • {(1Z)-5-fluoro-2-methyl-1-[4-(methylsulfinyl)benzylidene]-1H-indene-3-yl}acetic acid
Clinical data
Main usesPain, inflammation, gout[1]
Side effectsNausea, diarrhea, rash, headache, upset stomach[2]
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
use
By mouth
Onset of action1 hr[3]
Duration of actionUp to 16 hr[3]
Typical dose200 mg BID[1]
External links
AHFS/Drugs.comMonograph
US NLMSulindac
MedlinePlusa681037
Legal
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetics
BioavailabilityApproximately 90% (Oral)
Metabolism?
Elimination half-life7.8 hours, metabolites up to 16.4 hours
ExcretionKidney (50%) and fecal (25%)
Chemical and physical data
FormulaC20H17FO3S
Molar mass356.41 g·mol−1
3D model (JSmol)
Melting point182 to 185 °C (360 to 365 °F) (decomp.)
  • O=S(c1ccc(cc1)\C=C3/c2ccc(F)cc2\C(=C3C)CC(=O)O)C
  • InChI=1S/C20H17FO3S/c1-12-17(9-13-3-6-15(7-4-13)25(2)24)16-8-5-14(21)10-19(16)18(12)11-20(22)23/h3-10H,11H2,1-2H3,(H,22,23)/b17-9- checkY
  • Key:MLKXDPUZXIRXEP-MFOYZWKCSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammation.[2] This includes in conditions like attacks of gout, osteoarthritis, and rheumatoid arthritis.[1] It is taken by mouth.[1] Effects begin in about an hour and last for up to 16 hours.[3]

Common side effects may include nausea, diarrhea, rash, headache, and an upset stomach.[2] Other side effects may include liver problems, pancreatitis, allergic reactions, kidney problems, stomach bleeding, and heart failure.[2] It should not be used in the later half of pregnancy.[2] It works by blocking COX-1 and COX-2.[2]

Sulindac was patented in 1969 and approved for medical use in 1976.[4] It is available as a generic medication.[1] In the United Kingdom 56 tablets of 200 mg costs the NHS about £40.[1] In the United States this amount costs about 15 USD.[5]

Medical uses

Like other NSAIDs, it is useful in the treatment of acute or chronic inflammatory conditions.

It has also been used in familial adenomatous polyposis to decrease the formation of polyps.[2]

Dosage

Its usual dosage is 200 milligrams twice per day.[1] It may be used for up to 10 days.[1]

Side effects

It should not be used by persons with a history of major allergic reactions (urticaria or anaphylaxis) to aspirin or other NSAIDs, and should be used with caution by persons having pre-existing peptic ulcer disease. Sulindac is much more likely than other NSAIDs to cause damage to the liver or pancreas, though it is less likely to cause kidney damage than other NSAIDs.

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.[6][7] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.[6][7]

Mechanism of action

Sulindac is a prodrug, derived from sulfinylindene, that is converted in the body to the active NSAID. More specifically, the agent is converted by liver enzymes to a sulfide that is excreted in the bile and then reabsorbed from the intestine. This is thought to help maintain constant blood levels with reduced gastrointestinal side effects. Some studies have shown sulindac to be relatively less irritating to the stomach than other NSAIDs except for drugs of the COX-2 inhibitor class[citation needed]. The exact mechanism of its NSAID properties is unknown, but it is thought to act on enzymes COX-1 and COX-2, inhibiting prostaglandin synthesis.

Society and culture

Imbaral (not to be confused with mebaral) is another name. Its name is derived from sul(finyl)+ ind(ene)+ ac(etic acid)

Cost

This medication in the U.S. has a cost of $13 (USD) for 10 tablets (200 mg) [8]

Litigation

In September 2010 a federal jury in New Hampshire awarded $21 million to Karen Bartlett, a woman who developed Stevens–Johnson syndrome/Toxic epidermal necrolysis as a result of taking a generic brand of sulindac manufactured by Mutual Pharmaceuticals for her shoulder pain. Ms. Bartlett suffered severe injuries including the loss of over 60% of her surface skin and permanent near-blindness. The case had been appealed to the United States Supreme Court, where the main issue was whether federal law preempts Ms. Bartlett's claim.[9] On June 24, 2013, the Supreme Court ruled 5-4 in favor of Mutual Pharmaceuticals, throwing out the earlier $21 million jury verdict.[10] [11]

Synthesis

Sulindac synthesis:[12][13][14][15]

Rxn of p-fluorobenzyl chloride (1) with the anion of diethylmethyl malonate (2) gives intermediate diester (3), saponification of which and subsequent decarboxylation leads to 4. {Alternatively it can be formed by Perkin reaction between p-fluorobenzaldehyde and propionic anhydride in the presence of NaOAc, followed by catalytic hydrogenation of the olefinic bond using a palladium on carbon catalyst.}

Polyphosphoric acid (PPA) cyclization leads to 5-fluoro-2-methyl-3-indanone (4). A Reformatsky reaction with zinc amalgam and bromoacetic ester leads to carbinol (5), which is then dehydrated with tosic acid to indene 6. {Alternatively ths step can be performed in a Knoevenagel condensation with cyanoacetic acid, which is then further decarboxylated.}

The active methylene group is condensed with p-methylthiobenzaldehyde, using sodium methoxide as catalyst, and then saponified to give Z (7) which in turn oxidized with sodium metaperiodate to sulfoxide 8, the antiinflammatory agent sulindac.

Research

Sulindac seems to have a property, independent of COX-inhibition, of reducing the growth of polyps and precancerous lesions in the colon, especially in association with familial adenomatous polyposis, and may have other anti-cancer properties.[16][17]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 1213. ISBN 978-0-85711-369-6.CS1 maint: date format (link)
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Sulindac Monograph for Professionals". Drugs.com. Retrieved 15 October 2021.
  3. 3.0 3.1 3.2 Aschenbrenner, Diane S.; Venable, Samantha J. (2009). Drug Therapy in Nursing. Lippincott Williams & Wilkins. p. 411. ISBN 978-0-7817-6587-9.
  4. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 517. ISBN 9783527607495.
  5. "Sulindac Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 15 October 2021.
  6. 6.0 6.1 "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. Public Domain This article incorporates text from this source, which is in the public domain.
  7. 7.0 7.1 "NSAIDs may cause rare kidney problems in unborn babies". U.S. Food and Drug Administration. 21 July 2017. Retrieved 15 October 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  8. "Sulindac Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 8 April 2021.
  9. Thomas, Katie (2013-03-04). "Justices to Take Up Case on Generic Drug Markers' Liability". New York Times. Retrieved 4 March 2013.
  10. Kendall, Brent. "Supreme Court Again Limits Product-Liability Suits on Generic Drugs". Wall Street Journal. Retrieved 24 June 2013.
  11. Bartlett v. Mut. Pharm. Co., Inc., 678 F.3d 30 (D.C. Cir. March 19, 2013).
  12. Shuman, R. F.; Pines, S. H.; Shearin, W. E.; Czaja, R. F.; Abramson, N. L.; Tull, R. (1977). "A sterically efficient synthesis of (Z)-5-fluoro-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid and its S-oxide, sulindac". The Journal of Organic Chemistry. 42 (11): 1914. doi:10.1021/jo00431a019.
  13. R.B. Greenwald, E.B. Witzel, DE 2039426  (1971).
  14. J.B. Conn, D.F. Hinkley,U.S. Patent 3,647,858 (1972).
  15. R.B. Greenwald, H. Jones, U.S. Patent 3,654,349 (1972).
  16. Scheper MA, Nikitakis NG, Chaisuparat R, Montaner S, Sauk JJ (March 2007). "Sulindac induces apoptosis and inhibits tumor growth in vivo in head and neck squamous cell carcinoma". Neoplasia. 9 (3): 192–9. doi:10.1593/neo.06781. PMC 1838577. PMID 17401459. Archived from the original on 2012-09-05.
  17. Shiff SJ, Qiao L, Tsai LL, Rigas B (July 1995). "Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells". J. Clin. Invest. 96 (1): 491–503. doi:10.1172/JCI118060. PMC 185223. PMID 7615821.

External links

Identifiers: