Sulfasalazine

Sulfasalazine (SSZ), sold under the trade name Azulfidine among others, is a medication used to treat rheumatoid arthritis, ulcerative colitis, and Crohn's disease.[4] It is considered by some to be a first line treatment in rheumatoid arthritis.[5] It is taken by mouth.[4]

Sulfasalazine
Clinical data
Trade namesAzulfidine, Salazopyrin, Sulazine, others
Other namesSulphasalazine
AHFS/Drugs.comMonograph
MedlinePlusa682204
License data
Pregnancy
category
  • AU: A [1]
  • US: B (No risk in non-human studies) [1]
    Routes of
    administration    		By mouth
    Drug classSulfonamides
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability<15%
    Elimination half-life5-10 hours
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.009.069
    Chemical and physical data
    FormulaC18H14N4O5S
    Molar mass398.394 g/mol g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Significant side effects occur in about 25% of people.[5] Commonly these include loss of appetite, nausea, headache, and rash.[4] Severe side effects include bone marrow suppression, liver problems, and kidney problems.[5][6] It should not be used in people allergic to aspirin or sulfonamide.[5] Use during pregnancy appears to be safe for the baby.[4] Sulfasalazine is in the disease-modifying antirheumatic drugs (DMARDs) family of medications.[4] It is unclear exactly how it works but is broken down into sulfapyridine and 5-aminosalicylic acid.[4]

    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, the safest and most effective medicines needed in a health system.[7] Sulfasalazine is available as a generic medication.[4] The wholesale cost in the developing world is about US$9–33 a month as of 2014.[8] In the United States it costs $25–50 per month for a typical dose.[6]

    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).[9][3]

    It is usually not given to children under two years of age.[3]

    Side effects

    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][13] and various other undesirable effects.[14]

    Sulfasalazine can cause hemolytic anemia in people with G6PD deficiency.[15]

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

    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.[3]

    A mix of unchanged, hydroxylated, and glucuronidated sulfapyridine is eliminated in urine, as is acetylated mesalazine and unmetabolized sulfasalazine.[3]

    The mechanism of action is not clear, but it appears that sulfasalazine and its metabolites have immunosuppressive, antibacterial, and anti-inflammatory effects.[9][3] It also appears to inhibit the cystine-glutamate antiporter.[17]

    Chemistry

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

    Cost

    The wholesale cost in the developing world is about US$9–33 a month as of 2014.[8] In the United States the average wholesale cost is about $25–50 per month for a typical dose.[6]

    Research

    Sulfasalazine has been studied in cirrhosis,[18] psoriasis,[19] idiopathic urticaria,[20] and amyloidosis.[21]

    References
    1. Use During Pregnancy and Breastfeeding
    2. "Sulfasalazine 250mg/5ml Oral Suspension - Summary of Product Characteristics (SmPC)". (emc). 13 September 2019. Retrieved 4 December 2019.
    3. "Salazopyrin Tablets - Summary of Product Characteristics". UK Electronic Medicines Compendium. February 2014. Archived from the original on 16 April 2017.
    4. "Sulfasalazine". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
    5. WHO Model Formulary 2008 (PDF). World Health Organization. 2009. p. 41,45. ISBN 9789241547659. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
    6. Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 464. ISBN 9781284057560.
    7. World Health Organization (2019). "World Health Organization model list of essential medicines: 21st list 2019". World Health Organization (WHO). hdl:10665/325771. Cite journal requires |journal= (help)
    8. "Sulfasalazine". International Drug Price Indicator Guide. Archived from the original on 10 May 2017. Retrieved 8 December 2016.
    9. "US Sulfasalazine label" (PDF). FDA. February 2014. Archived (PDF) from the original on 16 February 2017. For updates see index page at FDA for NDA 007073 Archived 2017-04-16 at the Wayback Machine
    10. Cantarini L, Tinazzi I, Biasi D, Fioravanti A, Galeazzi M (June 2007). "Sulfasalazine-induced immune thrombocytopenia". Postgraduate Medical Journal. 83 (980): e1. doi:10.1136/pgmj.2006.055194. PMC 2600053. PMID 17551063.
    11. Inflammatory Bowel Disease~workup at eMedicine
    12. Women With Autoimmune Diseases: Medications During Pregnancy and Lactation: Sulfasalazine; "Archived copy". Archived from the original on 21 October 2011. Retrieved 8 March 2012.CS1 maint: archived copy as title (link)
    13. Hernández-Díaz, Sonia; Werler, Martha M.; Walker, Alexander M.; Mitchell, Allen A. (2000). "Folic Acid Antagonists during Pregnancy and the Risk of Birth Defects". New England Journal of Medicine. 343 (22): 1608–14. doi:10.1056/NEJM200011303432204. PMID 11096168.
    14. Dixon, Scott J; Patel, Darpan N; Welsch, Matthew; Skouta, Rachid; Lee, Eric D; Hayano, Miki; Thomas, Ajit G; Gleason, Caroline E; Tatonetti, Nicholas P (20 May 2014). "Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis". eLife. 3: e02523. doi:10.7554/eLife.02523. ISSN 2050-084X. PMC 4054777. PMID 24844246.
    15. "SulfaSALAzine: Drug Information Provided by Lexi-Comp". Merck & Co., Inc. January 2012. Archived from the original on 29 August 2011. Retrieved 28 July 2012.
    16. "Sulfasalazine". WebMD. WebMD. Archived from the original on 26 January 2016.
    17. Bridges, Richard J; Natale, Nicholas R; Patel, Sarjubhai A (1 January 2012). "System xc- cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS". British Journal of Pharmacology. 165 (1): 20–34. doi:10.1111/j.1476-5381.2011.01480.x. ISSN 0007-1188. PMC 3252963. PMID 21564084.
    18. Fiona Oakley; Muriel Meso; John P. Iredale; Karen Green; Carylyn J. Marek; Xiaoying Zhou; Michael J. May; Harry Millward-Sadler; Matthew C. Wright; Derek A. Mann (January 2005). "Inhibition of inhibitor of κB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis". Gastroenterology. 128 (1): 108–120. doi:10.1053/j.gastro.2004.10.003.
    19. Aditya K. Gupta; Charles N. Ellis; Michael T. Siegel; Elizabeth A. Duell; Christopher E. M. Griffiths; Ted A. Hamilton; Brian J. Nickoloff; John J. Voorhees (April 1990). "Sulfasalazine Improves Psoriasis A Double-blind Analysis". Arch. Dermatol. 126 (4): 487–493. doi:10.1001/archderm.1990.01670280071013.
    20. McGirt LY, Vasagar K, Gober LM, Saini SS, Beck LA (October 2006). "Successful treatment of recalcitrant chronic idiopathic urticaria with sulfasalazine". Arch Dermatol. 142 (10): 1337–1342. doi:10.1001/archderm.142.10.1337. PMID 17043190.
    21. Brumshtein B, Esswein SR, Salwinski L, Phillips ML, Ly AT, Cascio D, Sawaya MR, Eisenberg DS (November 2015). "Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain". eLife. 4: e10935. doi:10.7554/eLife.10935. PMC 4758944. PMID 26576950.
    • "Sulfasalazine". Drug Information Portal. U.S. National Library of Medicine.
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