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
Routes of
administration		By mouth
Drug classSulfonamides
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability<15%
Elimination half-life5-10 hours
Identifiers
IUPAC name
  • 2-hydroxy-5-[(E)-2-{4-[(pyridin-2-yl)sulfamoyl]phenyl}diazen-1-yl]benzoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.009.069
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) Y
  • Key:NCEXYHBECQHGNR-UHFFFAOYSA-N Y
 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, Stevens–Johnson syndrome, and kidney problems.[5][6][7] 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.[4] One proposed mechanism is the inhibition of prostaglandins, resulting in local anti-inflammatory effects in the colon.[7] The medication is broken down by intestinal bacteria into sulfapyridine and 5-aminosalicylic acid.[4] That which is absorbed is excreted by the kidneys and in the bile.[7]

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.[8] Sulfasalazine is available as a generic medication.[4]

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][2]

It is usually not given to children under two years of age.[3][2]

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.[7]

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 can cause kidney stones.[16] 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.[17][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.[3]

A mix of unchanged, hydroxylated, and glucuronidated sulfapyridine is eliminated in urine, as is acetylated mesalazine and unmetabolized sulfasalazine.[3][2]

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.[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]

References
  1. "Sulfasalazine Use During Pregnancy". Drugs.com. 9 November 2018. Retrieved 24 January 2020.
  2. "Sulfasalazine 250mg/5ml Oral Suspension - Summary of Product Characteristics (SmPC)". electronic medicines compendium (emc). 13 September 2019. Retrieved 4 December 2019.
  3. "Salazopyrin Tablets - Summary of Product Characteristics". electronic medicines compendium (emc). 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. 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.
  6. Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 464. ISBN 9781284057560.
  7. 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.
  8. 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.
  9. "Azulfidine- sulfasalazine tablet". DailyMed. 8 May 2019. Archived from the original on 29 October 2015. Retrieved 24 January 2020.
  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; "Women with Autoimmune Diseases: Medications During Pregnancy and Lactation: Sulfasalazine". Archived from the original on 21 October 2011. Retrieved 8 March 2012.
  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.{{cite web}}: CS1 maint: unfit URL (link)
  16. Koninck, Anne-Sophie; Groen, Luitzen-Albert; Maes, Heleen; Verstraete, Alain; Stove, Veronique; Delanghe, Joris (2016). "An Unusual Type of Kidney Stone". Clinical Laboratory. 62 (1+02/2016): 235–239. doi:10.7754/Clin.Lab.2015.150605. hdl:1854/LU-6847821. PMID 27012055.
  17. "Sulfasalazine". WebMD. Archived from the original on 26 January 2016.
  18. 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.
  19. Benucci, Maurizio; Saviola, Gianantonio; Manfredi, Mariangela; Sarzi-Puttini, Piercarlo; Atzeni, Fabiola (2011). "Cost Effectiveness Analysis of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis. A Systematic Review Literature". International Journal of Rheumatology. 2011: 845496. doi:10.1155/2011/845496. ISSN 1687-9260. PMC 3228304. PMID 22162693.
  20. 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.
  21. 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.
  22. 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. PMID 1690970.
  23. 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.
  24. 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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