Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease
- Adam S Cheifetz, MD
Adam S Cheifetz, MD
- Associate Professor of Medicine
- Harvard Medical School
- Garret J Cullen, MD
Garret J Cullen, MD
- Consultant Gastroenterologist
- St. Vincent's University Hospital, Dublin
- Clinical Lecturer, University College Dublin School of Medicine and Medical Science
Salicylazosulfapyridine (sulfasalazine) was originally proposed as a treatment for rheumatoid arthritis. It was subsequently discovered that sulfasalazine was also efficacious in treating inflammatory bowel disease, particularly ulcerative colitis. The 5-aminosalicylic acid (5-ASA) medications were developed because many patients were intolerant of or allergic to sulfasalazine.
This topic will review the pharmacology of sulfasalazine and 5-ASAs, mechanism of action in inflammatory bowel disease, and side effects. The role of sulfasalazine and 5-ASAs in the treatment of inflammatory bowel disease and rheumatoid arthritis are discussed in detail separately. (See "Overview of the medical management of mild to moderate Crohn disease in adults" and "Management of mild to moderate ulcerative colitis in adults" and "Management of severe ulcerative colitis in adults" and "Sulfasalazine in the treatment of rheumatoid arthritis".)
Sulfasalazine is a prodrug composed of 5-aminosalicylic acid (5-ASA) linked to sulfapyridine through an azo bond (figure 1). Sulfasalazine is partially absorbed in the jejunum after oral ingestion. The remainder passes into the colon, where it is reduced by coliform bacterial enzyme, azoreductase, to sulfapyridine and 5-ASA .
The majority of absorbed sulfasalazine is excreted into bile; only a small fraction is excreted in the urine. 5-ASA is poorly absorbed from the colon and is largely excreted in the stool. Sulfapyridine is rapidly absorbed from the colon, metabolized by the liver, and excreted in the urine with only small amounts remaining in the stool.
5-ASA is primarily responsible for the efficacy of sulfasalazine, while sulfapyridine accounts for many of its side effects. Unconjugated 5-ASA (mesalamine) does not have the side effects associated with sulfapyridine, but is rapidly absorbed in the jejunum, allowing only 20 percent to reach the terminal ileum and colon. Therefore, a number of 5-ASA compounds have been developed to prevent absorption of 5-ASA in the proximal gastrointestinal tract, and thereby increase delivery to the colon (table 1).
- Peppercorn MA, Goldman P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J Pharmacol Exp Ther 1972; 181:555.
- Ordás I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet 2012; 380:1606.
- Sandborn WJ, Hanauer SB. Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Aliment Pharmacol Ther 2003; 17:29.
- Sutherland L, Macdonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2006; :CD000543.
- Feagan BG, Macdonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2012; 10:CD000544.
- Zhu Y, Tang RK, Zhao P, et al. Can oral 5-aminosalicylic acid be administered once daily in the treatment of mild-to-moderate ulcerative colitis? A meta-analysis of randomized-controlled trials. Eur J Gastroenterol Hepatol 2012; 24:487.
- Tong JL, Huang ML, Xu XT, et al. Once-daily versus multiple-daily mesalamine for patients with ulcerative colitis: a meta-analysis. J Dig Dis 2012; 13:200.
- Ford AC, Khan KJ, Sandborn WJ, et al. Once-daily dosing vs. conventional dosing schedule of mesalamine and relapse of quiescent ulcerative colitis: systematic review and meta-analysis. Am J Gastroenterol 2011; 106:2070.
- D'Haens G, Hommes D, Engels L, et al. Once daily MMX mesalazine for the treatment of mild-to-moderate ulcerative colitis: a phase II, dose-ranging study. Aliment Pharmacol Ther 2006; 24:1087.
- Lichtenstein GR, Kamm MA, Boddu P, et al. Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol 2007; 5:95.
- Kamm MA, Sandborn WJ, Gassull M, et al. Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology 2007; 132:66.
- Sandborn WJ, Kamm MA, Lichtenstein GR, et al. MMX Multi Matrix System mesalazine for the induction of remission in patients with mild-to-moderate ulcerative colitis: a combined analysis of two randomized, double-blind, placebo-controlled trials. Aliment Pharmacol Ther 2007; 26:205.
- Kane S, Huo D, Magnanti K. A pilot feasibility study of once daily versus conventional dosing mesalamine for maintenance of ulcerative colitis. Clin Gastroenterol Hepatol 2003; 1:170.
- Peyrin-Biroulet L, Beisner J, Wang G, et al. Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc Natl Acad Sci U S A 2010; 107:8772.
- Yamamoto-Furusho JK, Peñaloza-Coronel A, Sánchez-Muñoz F, et al. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression is downregulated in patients with active ulcerative colitis. Inflamm Bowel Dis 2011; 17:680.
- Fiocchi C, Podolsky DK. Cytokines and growth factors in inflammatory bowel disease. In: Inflammatory Bowel Disease, 4th ed, Kirsner JB, Shorter RG (Eds), Lea & Febriger, Philadelphia 1995. p.252.
- Rousseaux C, Lefebvre B, Dubuquoy L, et al. Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med 2005; 201:1205.
- Cominelli F, Zipser RD, Dinarello CA. Sulfasalazine inhibits cytokine production in human mononuclear cells: A novel anti-inflammatory mechanism. Gastroenterology 1992; 96:A96.
- Shanahan F, Niederlehner A, Carramanzana N, Anton P. Sulfasalazine inhibits the binding of TNF alpha to its receptor. Immunopharmacology 1990; 20:217.
- Bantel H, Berg C, Vieth M, et al. Mesalazine inhibits activation of transcription factor NF-kappaB in inflamed mucosa of patients with ulcerative colitis. Am J Gastroenterol 2000; 95:3452.
- Sharon P, Ligumsky M, Rachmilewitz D, Zor U. Role of prostaglandins in ulcerative colitis. Enhanced production during active disease and inhibition by sulfasalazine. Gastroenterology 1978; 75:638.
- Hawkey CJ, Boughton-Smith NK, Whittle BJ. Modulation of human colonic arachidonic acid metabolism by sulfasalazine. Dig Dis Sci 1985; 30:1161.
- Ligumsky M, Karmeli F, Sharon P, et al. Enhanced thromboxane A2 and prostacyclin production by cultured rectal mucosa in ulcerative colitis and its inhibition by steroids and sulfasalazine. Gastroenterology 1981; 81:444.
- Miller DK, Gillard JW, Vickers PJ, et al. Identification and isolation of a membrane protein necessary for leukotriene production. Nature 1990; 343:278.
- Stenson WF, Lobos E. Sulfasalazine inhibits the synthesis of chemotactic lipids by neutrophils. J Clin Invest 1982; 69:494.
- Zingarelli B, Squadrito F, Graziani P, et al. Effects of zileuton, a new 5-lipoxygenase inhibitor, in experimentally induced colitis in rats. Agents Actions 1993; 39:150.
- Bell RL, Lanni C, Malo PE, et al. Preclinical and clinical activity of zileuton and A-78773. Ann N Y Acad Sci 1993; 696:205.
- Rask-Madsen J, Bukhave K, Laursen LS, Lauritsen K. 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease. Agents Actions 1992; Spec No:C37.
- Craven PA, Pfanstiel J, Saito R, DeRubertis FR. Actions of sulfasalazine and 5-aminosalicylic acid as reactive oxygen scavengers in the suppression of bile acid-induced increases in colonic epithelial cell loss and proliferative activity. Gastroenterology 1987; 92:1998.
- Ahnfelt-Rønne I, Nielsen OH, Christensen A, et al. Clinical evidence supporting the radical scavenger mechanism of 5-aminosalicylic acid. Gastroenterology 1990; 98:1162.
- Grisham MB, Granger DN. 5-Aminosalicylic acid concentration in mucosal interstitium of cat small and large intestine. Dig Dis Sci 1989; 34:573.
- Burress GC, Musch MW, Jurivich DA, et al. Effects of mesalamine on the hsp72 stress response in rat IEC-18 intestinal epithelial cells. Gastroenterology 1997; 113:1474.
- Stevens C, Lipman M, Fabry S, et al. 5-Aminosalicylic acid abrogates T-cell proliferation by blocking interleukin-2 production in peripheral blood mononuclear cells. J Pharmacol Exp Ther 1995; 272:399.
- MacDermott RP, Schloemann SR, Bertovich MJ, et al. Inhibition of antibody secretion by 5-aminosalicylic acid. Gastroenterology 1989; 96:442.
- Rhodes JM, Bartholomew TC, Jewell DP. Inhibition of leucocyte motility by drugs used in ulcerative colitis. Gut 1981; 22:642.
- Neal TM, Winterbourn CC, Vissers MC. Inhibition of neutrophil degranulation and superoxide production by sulfasalazine. Comparison with 5-aminosalicylic acid, sulfapyridine and olsalazine. Biochem Pharmacol 1987; 36:2765.
- Rubinstein A, Das KM, Melamed J, Murphy RA. Comparative analysis of systemic immunological parameters in ulcerative colitis and idiopathic proctitis: effects of sulfasalazine in vivo and in vitro. Clin Exp Immunol 1978; 33:217.
- Gadangi P, Longaker M, Naime D, et al. The anti-inflammatory mechanism of sulfasalazine is related to adenosine release at inflamed sites. J Immunol 1996; 156:1937.
- Box SA, Pullar T. Sulphasalazine in the treatment of rheumatoid arthritis. Br J Rheumatol 1997; 36:382.
- Dougados M. Sulfasalazine. In: Therapy of Systemic Rheumatic Disorders, van de Putte LBA, Furst DE, Williams HJ, van Riel PLCM (Eds), Marcel Dekker, New York 1998. p.165.
- Azulfidine, EN-Tabs. In: Physicians Desk Reference, 52nd ed, Medical Economics Company, Montvale, NJ 1998. p.2239.
- Jacobson IM, Kelsey PB, Blyden GT, et al. Sulfasalazine-induced agranulocytosis. Am J Gastroenterol 1985; 80:118.
- Jick H, Myers MW, Dean AD. The risk of sulfasalazine- and mesalazine-associated blood disorders. Pharmacotherapy 1995; 15:176.
- Jansen G, van der Heijden J, Oerlemans R, et al. Sulfasalazine is a potent inhibitor of the reduced folate carrier: implications for combination therapies with methotrexate in rheumatoid arthritis. Arthritis Rheum 2004; 50:2130.
- Rao SS, Cann PA, Holdsworth CD. Clinical experience of the tolerance of mesalazine and olsalazine in patients intolerant of sulphasalazine. Scand J Gastroenterol 1987; 22:332.
- Giaffer MH, O'Brien CJ, Holdsworth CD. Clinical tolerance to three 5-aminosalicylic acid releasing preparations in patients with inflammatory bowel disease intolerant or allergic to sulphasalazine. Aliment Pharmacol Ther 1992; 6:51.
- Hanauer SB, Smith M. Critical drug appraisal: Olsalazine. Drug Ther Bull 1991; 21:57.
- Woltsche M, Woltsche-Kahr I, Roeger GM, et al. Sulfasalazine-induced extrinsic allergic alveolitis in a patient with psoriatic arthritis. Eur J Med Res 2001; 6:495.
- Gisbert JP, González-Lama Y, Maté J. 5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 2007; 13:629.
- World MJ, Stevens PE, Ashton MA, Rainford DJ. Mesalazine-associated interstitial nephritis. Nephrol Dial Transplant 1996; 11:614.
- Van Staa TP, Travis S, Leufkens HG, Logan RF. 5-aminosalicylic acids and the risk of renal disease: a large British epidemiologic study. Gastroenterology 2004; 126:1733.
- Khosla R, Willoughby CP, Jewell DP. Crohn's disease and pregnancy. Gut 1984; 25:52.
- Bell CM, Habal FM. Safety of topical 5-aminosalicylic acid in pregnancy. Am J Gastroenterol 1997; 92:2201.
- Marteau P, Tennenbaum R, Elefant E, et al. Foetal outcome in women with inflammatory bowel disease treated during pregnancy with oral mesalazine microgranules. Aliment Pharmacol Ther 1998; 12:1101.
- Beard CM, Noller KL, O'Fallon WM, et al. Cancer after exposure to metronidazole. Mayo Clin Proc 1988; 63:147.
- 5-ASA formulations
- MECHANISM OF ACTION
- Inhibition of cytokine synthesis
- Inhibition of prostaglandin and leukotriene synthesis
- Free radical scavenging
- Immunosuppressive activity
- Impairment of white cell adhesion and function
- SIDE EFFECTS
- 5-aminosalicylic acid (5-ASA)
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS