Sulfasalazine Explained

Sulfasalazine, sold under the brand name Azulfidine among others, is a medication used to treat rheumatoid arthritis, ulcerative colitis, and Crohn's disease. It is considered by some to be a first-line treatment in rheumatoid arthritis. It is taken by mouth or can be administered rectally.

Significant side effects occur in about 25% of people. Commonly these include loss of appetite, nausea, headache, and rash. Severe side effects include bone marrow suppression, liver problems, Stevens–Johnson syndrome, and kidney problems.[1] [2] It should not be used in people allergic to aspirin or sulfonamide.[3] Use during pregnancy appears to be safe for the baby.

Sulfasalazine is in the disease-modifying antirheumatic drugs (DMARDs) family of medications. It is unclear exactly how it works. One proposed mechanism is the inhibition of prostaglandins, resulting in local anti-inflammatory effects in the colon. The medication is broken down by intestinal bacteria into sulfapyridine and 5-aminosalicylic acid.

Sulfasalazine was approved for medical use in the United States in 1950.[4] It is on the World Health Organization's List of Essential Medicines.[5] Sulfasalazine is available as a generic medication.[4] In 2020, it was the 284th most commonly prescribed medication in the United States, with more than 1million prescriptions.[6] [7]

Medical uses

Sulfasalazine is used in the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. It is also indicated for use in rheumatoid arthritis and used in other types of inflammatory arthritis (e.g. psoriatic arthritis and reactive arthritis).[8] [9]

It is usually not given to children under two years of age.[9]

Side effects

Use of sulfasalazine is contraindicated in people with sulfa allergies and in those with urinary tract obstructions, intestinal obstructions, and severe liver or kidney problems.

Sulfasalazine metabolizes to sulfapyridine. Serum levels should be monitored every three months, and more frequently at the outset. Serum levels above 50 μg/L are associated with side effects. In rare cases, sulfasalazine can cause severe depression in young males. It can also cause oligospermia and temporary infertility. Immune thrombocytopenia has been reported.[10]

Sulfasalazine inhibits dihydropteroate synthase, and can cause folate deficiency and megaloblastic anemia.[11] [12] and various other undesirable effects.[13]

Sulfasalazine can cause hemolytic anemia in people with G6PD deficiency.[14]

Sulfasalazine can cause kidney stones.[15] Sulfasalazine may cause stomach upset, nausea, vomiting, loss of appetite, headache, dizziness, or unusual tiredness.[4] Skin and urine can become orange, with occasional allergic reactions.[16] [4]

Sulfasalazine may cause sulfhemoglobinemia.

Pharmacology

Around 90% of a dose of sulfasalazine reaches the colon, where most of it is metabolized by bacteria into sulfapyridine and mesalazine (also known as 5-aminosalicylic acid or 5-ASA). Both metabolites are active; most of the sulfapyridine is absorbed and then further metabolized, but most mesalazine is not, and remains in the colon.[9]

A mix of unchanged, hydroxylated, and glucuronidated sulfapyridine is eliminated in urine, as is acetylated mesalazine and unmetabolized sulfasalazine.[9]

The mechanism of action is not clear, but it appears that sulfasalazine and its metabolites have immunosuppressive, antibacterial, and anti-inflammatory effects.[8] [9] It also appears to inhibit the cystine-glutamate antiporter,[17] as well as sepiapterin reductase.[18]

Chemistry

It is a codrug which is a combination of sulfapyridine and 5-aminosalicylic acid coupled with an azo linkage.

Cost

In people with rheumatoid arthritis, the cost-effectiveness of sulfasalazine is improved by combining it with other drugs.[19] It is commonly used in treating inflammatory bowel disease in part due to its cost effectiveness.[20]

Research

Sulfasalazine has been studied in cirrhosis,[21] psoriasis,[22] idiopathic urticaria,[23] and amyloidosis.[24]

Notes and References

  1. Book: Hamilton R . Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. 2015. Jones & Bartlett Learning. 9781284057560. 464.
  2. Book: Davis's drug guide for nurses. Vallerand AH, Sanoski CA, Deglin JH . 978-0-8036-4085-6. Fourteenth. Philadelphia. 881473728. 5 June 2014.
  3. Book: WHO Model Formulary 2008 . 2009 . 9789241547659 . ((World Health Organization)) . Stuart MC, Kouimtzi M, Hill SR . 10665/44053 . World Health Organization . World Health Organization . free . 41, 45 .
  4. Web site: Sulfasalazine. The American Society of Health-System Pharmacists. 8 December 2016. live. https://web.archive.org/web/20161221012800/https://www.drugs.com/monograph/sulfasalazine.html. 21 December 2016.
  5. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO . free .
  6. Web site: The Top 300 of 2020 . ClinCalc . 7 October 2022.
  7. Web site: Sulfasalazine - Drug Usage Statistics . ClinCalc . 7 October 2022.
  8. Web site: Azulfidine- sulfasalazine tablet . DailyMed . 8 May 2019 . https://web.archive.org/web/20151029144549/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ddbe69f3-bd55-45f3-a64f-f60226c744c4 . 29 October 2015 . live . 24 January 2020 .
  9. Web site: Salazopyrin Tablets - Summary of Product Characteristics. electronic medicines compendium (emc) . February 2014. live. https://web.archive.org/web/20170416220909/https://www.medicines.org.uk/emc/medicine/3344. 16 April 2017.
  10. Cantarini L, Tinazzi I, Biasi D, Fioravanti A, Galeazzi M . Sulfasalazine-induced immune thrombocytopenia . Postgraduate Medical Journal . 83 . 980 . e1 . June 2007 . 17551063 . 2600053 . 10.1136/pgmj.2006.055194 .
  11. Women With Autoimmune Diseases: Medications During Pregnancy and Lactation: Sulfasalazine; Web site: Women with Autoimmune Diseases: Medications During Pregnancy and Lactation: Sulfasalazine . 8 March 2012 . live . https://web.archive.org/web/20111021082209/http://www.medscape.org/viewarticle/720225_7 . 21 October 2011 .
  12. Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA . Folic acid antagonists during pregnancy and the risk of birth defects . The New England Journal of Medicine . 343 . 22 . 1608–1614 . November 2000 . 11096168 . 10.1056/NEJM200011303432204 . free .
  13. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, Thomas AG, Gleason CE, Tatonetti NP, Slusher BS, Stockwell BR . 6 . Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis . eLife . 3 . e02523 . May 2014 . 24844246 . 4054777 . 10.7554/eLife.02523 . free .
  14. Web site: SulfaSALAzine: Drug Information Provided by Lexi-Comp . 28 July 2012 . Jan 2012 . . unfit . https://web.archive.org/web/20110829125852/http://www.merckmanuals.com/professional/lexicomp/sulfasalazine.html . 29 August 2011 .
  15. De Koninck AS, Groen LA, Maes H, Verstraete AG, Stove V, Delanghe JR . An Unusual Type of Kidney Stone . Clinical Laboratory . 62 . 1–2 . 235–239 . 2016 . 27012055 . 10.7754/Clin.Lab.2015.150605 . free . 1854/LU-6847821 .
  16. Web site: Sulfasalazine. WebMD. live. https://web.archive.org/web/20160126171655/http://www.webmd.com/drugs/2/drug-6260/sulfasalazine-oral/details. 26 January 2016.
  17. Bridges RJ, Natale NR, Patel SA . System xc⁻ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS . British Journal of Pharmacology . 165 . 1 . 20–34 . January 2012 . 21564084 . 3252963 . 10.1111/j.1476-5381.2011.01480.x .
  18. Costigan M, Latremoliere A, Woolf CJ . Analgesia by inhibiting tetrahydrobiopterin synthesis . Current Opinion in Pharmacology . 12 . 1 . 92–99 . February 2012 . 22178186 . 3288148 . 10.1016/j.coph.2011.10.019 .
  19. Benucci M, Saviola G, Manfredi M, Sarzi-Puttini P, Atzeni F . Cost effectiveness analysis of disease-modifying antirheumatic drugs in rheumatoid arthritis. A systematic review literature . International Journal of Rheumatology . 2011 . 845496 . 2011 . 22162693 . 3228304 . 10.1155/2011/845496 . free .
  20. Book: Baumgart DC . Crohn's Disease and Ulcerative Colitis: From Epidemiology and Immunobiology to a Rational Diagnostic and Therapeutic Approach. 2017. Springer. 978-3-319-33703-6. 395. en.
  21. Oakley F, Meso M, Iredale JP, Green K, Marek CJ, Zhou X, May MJ, Millward-Sadler H, Wright MC, Mann DA . 6 . Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis . Gastroenterology . 128 . 1 . 108–120 . January 2005 . 15633128 . 10.1053/j.gastro.2004.10.003 . free .
  22. Gupta AK, Ellis CN, Siegel MT, Duell EA, Griffiths CE, Hamilton TA, Nickoloff BJ, Voorhees JJ . 6 . Sulfasalazine improves psoriasis. A double-blind analysis . Archives of Dermatology . 126 . 4 . 487–493 . April 1990 . 1690970 . 10.1001/archderm.1990.01670280071013 .
  23. McGirt LY, Vasagar K, Gober LM, Saini SS, Beck LA . Successful treatment of recalcitrant chronic idiopathic urticaria with sulfasalazine . Archives of Dermatology . 142 . 10 . 1337–1342 . October 2006 . 17043190 . 10.1001/archderm.142.10.1337 .
  24. Brumshtein B, Esswein SR, Salwinski L, Phillips ML, Ly AT, Cascio D, Sawaya MR, Eisenberg DS . 6 . Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain . eLife . 4 . e10935 . November 2015 . 26576950 . 4758944 . 10.7554/eLife.10935 . free .

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