Sulfasalazine

Sulfasalazine
Names
Trade namesAzulfidine, Salazopyrin, Sulazine, others
Other namesSulphasalazine
IUPAC name
  • 2-hydroxy-5-[(E)-2-{4-[(pyridin-2-yl)sulfamoyl]phenyl}diazen-1-yl]benzoic acid
Clinical data
Drug classSulfonamide
Main usesRheumatoid arthritis, ulcerative colitis, Crohn's disease[1]
Side effectsLoss of appetite, nausea, headache, rash[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: A[2]
  • US: B (No risk in non-human studies)[2]
    Routes of
    use    		By mouth
    Defined daily dose2 grams (by mouth or rectal)[3]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa682204
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability<15%
    Elimination half-life6-17 hours[6]
    Chemical and physical data
    FormulaC18H14N4O5S
    Molar mass398.39 g·mol−1
    3D model (JSmol)
    Melting point240 to 245 °C (464 to 473 °F) (dec.)
    SMILES
    • C1=CC=NC(=C1)NS(=O)(=O)C2=CC=C(C=C2)N=NC3=CC(=C(C=C3)O)C(=O)O
    InChI
    • InChI=1S/C18H14N4O5S/c23-16-9-6-13(11-15(16)18(24)25)21-20-12-4-7-14(8-5-12)28(26,27)22-17-3-1-2-10-19-17/h1-11,23H,(H,19,22)(H,24,25) checkY
    • Key:NCEXYHBECQHGNR-UHFFFAOYSA-N checkY

    Sulfasalazine (SSZ), sold under the trade name Azulfidine among others, is a medication used to treat rheumatoid arthritis, ulcerative colitis, and Crohn's disease.[1] It is considered by some to be a first line treatment in rheumatoid arthritis.[7] For ulcerative colitis, it is largely considered after mesalazine.[8] It is taken by mouth.[1]

    Significant side effects occur in about 25% of people.[7] Commonly these include loss of appetite, nausea, headache, and rash.[1] Severe side effects include bone marrow suppression, liver problems, Stevens–Johnson syndrome, and kidney problems.[7][9][10] It can stain body fluids and contact lenses yellow.[11] It should not be used in people allergic to aspirin or sulfonamides.[7] Use during pregnancy appears to be safe for the baby; though folic acid supplements are needed.[1][11]

    Sulfasalazine is in the disease-modifying antirheumatic drugs (DMARDs) family of medications.[1] It is unclear exactly how it works.[1] One proposed mechanism is the inhibition of prostaglandins, resulting in local anti-inflammatory effects in the colon.[10] The medication is broken down in the colon by intestinal bacteria into 5-aminosalicylic acid, the active ingredient, and sulfapyridine, which is largely responsible for its side effects.[8] Of the 10-20% that is absorbed, some is excreted by the kidneys and in the bile.[6][10]

    Sulfasalazine was approved for medical use in the United States in 1950.[1] It is on the World Health Organization's List of Essential Medicines.[12] Sulfasalazine is available as a generic medication and is cost effective with respect to inflammatory bowel disease as of 2017.[1][13] Sulfadiazine is different and has in the past been prescribed in error.[11]

    Medical uses

    Sulfasalazine is used in rheumatoid arthritis, where it reduces bone destruction, and in other types of reactive arthritis, psoriatic arthritis, juvenile idiopathic arthritis and ankylosing spondylitis (AS).[6]

    It is also used in the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, gastrointestinal Behçet's disease and AS associated HLA-B27-positive anterior uveitis.[6]

    It is usually not given to children under two years of age.[14][5]

    Monitoring requirements include blood tests: a complete blood count and liver function test at the start of use and repeated monthly for the first 3 months.[11]

    Dosage

    The defined daily dose is 2 grams (by mouth) or 2 grams (rectal).[3] In rheumatoid arthritis, the dose can be upto 3 grams.[6]

    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.[10]

    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.[15]

    Sulfasalazine inhibits dihydropteroate synthase, and can cause folate deficiency and megaloblastic anemia.[16][17][18] and various other undesirable effects.[19]

    Sulfasalazine can cause hemolytic anemia in people with G6PD deficiency.[20]

    Sulfasalazine may cause stomach upset, nausea, vomiting, loss of appetite, headache, dizziness, or unusual tiredness.[1] Skin and urine can become orange, with occasional allergic reactions.[21][1]

    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.[5]

    A mix of unchanged, hydroxylated, and glucuronidated sulfapyridine is eliminated in urine, as is acetylated mesalazine and unmetabolized sulfasalazine.[5][4]

    The mechanism of action is not clear, but it appears that sulfasalazine and its metabolites have immunosuppressive, antibacterial, and anti-inflammatory effects.[14][5] It also appears to inhibit the cystine-glutamate antiporter.[22]

    Chemistry

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

    Society and culture

    Cost

    Use for rheumatoid arthritis cost about US$500 per year for sulfazalazine in the United States in 2002 versus up to $25,000 per year for TNF blocking agents.[23] This was for a 2 gm per day dose of the 500 mg tablets.[23] In the United States in 2020 the wholesale cost is US$0.16 for the 500 mg immediate release tablets and US$0.23 for the 500 mg slow release tablets.[24] The wholesale cost in 4 countries in the developing world varies from US$0.11 to US$0.24 per 500 mg tablet as of 2015.[25] A months supply in the UK costs the NHS less than £10.[11] It is commonly used in IBD in part due to its cost effectiveness.[13]

    • Sulfasalazine costs (US)
      Sulfasalazine costs (US)
    • Sulfasalazine prescriptions (US)
      Sulfasalazine prescriptions (US)

    Research

    Sulfasalazine has been studied in cirrhosis,[26] psoriasis,[27] idiopathic urticaria,[28] and amyloidosis.[29]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 "Sulfasalazine". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
    2. 1 2 "Sulfasalazine Use During Pregnancy". Drugs.com. 9 November 2018. Archived from the original on 4 December 2019. Retrieved 24 January 2020.
    3. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 20 September 2020. Retrieved 19 September 2020.
    4. 1 2 "Sulfasalazine 250mg/5ml Oral Suspension - Summary of Product Characteristics (SmPC)". electronic medicines compendium (emc). 13 September 2019. Archived from the original on 4 December 2019. Retrieved 4 December 2019.
    5. 1 2 3 4 5 "Salazopyrin Tablets - Summary of Product Characteristics". electronic medicines compendium (emc). February 2014. Archived from the original on 16 April 2017.
    6. 1 2 3 4 5 Shagroni, T.; Cazares, Ramirez; Kim, J. A.; Furst, Daniel E. (2020). "36. Nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, nonopioid analgesics, & drugs used in gout". In Katzung, Bertram G.; Trevor, Anthony J. (eds.). Basic and Clinical Pharmacology (15th ed.). New York: McGraw-Hill. p. 679. ISBN 978-1-260-45231-0. Archived from the original on 10 October 2021. Retrieved 5 November 2021.
    7. 1 2 3 4 World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 41, 45. hdl:10665/44053. ISBN 9789241547659.
    8. 1 2 Hitchings, Andrew; Lonsdale, Dagan; Burrage, Daniel; Baker, Emma (2019). The Top 100 Drugs: Clinical Pharmacology and Practical Prescribing (2nd ed.). Elsevier. pp. 46–47. ISBN 978-0-7020-7442-4. Archived from the original on 22 May 2021. Retrieved 9 November 2021.
    9. ↑ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 464. ISBN 9781284057560.
    10. 1 2 3 4 Vallerand, April Hazard (5 June 2014). Davis's drug guide for nurses. Sanoski, Cynthia A.,, Deglin, Judith Hopfer, 1950- (Fourteenth ed.). Philadelphia. ISBN 978-0-8036-4085-6. OCLC 881473728.
    11. 1 2 3 4 5 "1. Gastro-intestinal system". British National Formulary (BNF) (82 ed.). London: BMJ Group and the Pharmaceutical Press. September 2021 – March 2022. pp. 47–48. ISBN 978-0-85711-413-6.
    12. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    13. 1 2 Baumgart, Daniel C. (2017). Crohn's Disease and Ulcerative Colitis: From Epidemiology and Immunobiology to a Rational Diagnostic and Therapeutic Approach. Springer. p. 395. ISBN 978-3-319-33703-6. Archived from the original on 29 August 2021. Retrieved 13 April 2020.
    14. 1 2 "Azulfidine- sulfasalazine tablet". DailyMed. 8 May 2019. Archived from the original on 29 October 2015. Retrieved 24 January 2020.
    15. ↑ 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.
    16. ↑ Inflammatory Bowel Disease~workup at eMedicine
    17. ↑ Women With Autoimmune Diseases: Medications During Pregnancy and Lactation: Sulfasalazine; "Archived copy". Archived from the original on 21 October 2011. Retrieved 8 March 2012.{{cite web}}: CS1 maint: archived copy as title (link)
    18. ↑ 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.
    19. ↑ 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.
    20. ↑ "SulfaSALAzine: Drug Information Provided by Lexi-Comp". Merck & Co., Inc. January 2012. Archived from the original on 29 August 2011. Retrieved 28 July 2012.{{cite web}}: CS1 maint: unfit URL (link)
    21. ↑ "Sulfasalazine". WebMD. Archived from the original on 26 January 2016.
    22. ↑ 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.
    23. 1 2 Day, Richard O.; Furst, Daniel E.; Riel, Piet L. C. M. van; Bresnihan, Barry (2010). Antirheumatic Therapy: Actions and Outcomes. Springer Science & Business Media. p. 61. ISBN 978-3-7643-7726-7. Archived from the original on 29 August 2021. Retrieved 13 April 2020.
    24. ↑ "NADAC as of 2020-04-08 | Data.Medicaid.gov". Centers for Medicare and Medicaid Services. Archived from the original on 7 August 2020. Retrieved 13 April 2020.
    25. ↑ International medical products price guide (PDF) (2015 ed.). WHO and MSG. 2016. p. A-144. Archived from the original (PDF) on 18 March 2020. Retrieved 13 April 2020.
    26. ↑ 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. PMID 15633128.
    27. ↑ 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.
    28. ↑ 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.
    29. ↑ 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.
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