Inflammatory bowel disease aminosalicylates

Yamada, T., Volkmer, C. and Grisham, M.B. (1990). Antioxidant properties of 5-aminosalicylic acid, potential mechanism for its anti-inflammatory activity. In Trends in Inflammatory Bowel Disease Therapy , (ed. C.J. Williams) pp. 73-84. Kluwer Academic Publishers, Lancaster. 

TABLE 16-1. Aminosalicylates for Treatment of Inflammatory Bowel Disease... 

Nugent, S. G., Kumar, D., Rampton, D. S., Evans, D. F., Intestinal luminal pH in inflammatory bowel disease possible determinants and implications for therapy with aminosalicylates and other drugs, Gut 2001, 48, 571-577. 

Sulfasalazine is absorbed in the proximal intestine and is then excreted unchanged in the bile. In consequence most of orally administred sulfasalzine reaches the colon as such. It is then split by the intestinal flora into its components sulfapyridine, a sulfonamide antimicrobial agent, and 5-aminosalicylic acid (5-ASA). It has been proven that in inflammatory bowel disease 5-ASA is responsible for the beneficial effects while the sulpha component only contributes to the adverse reaction profile. Although some 5-ASA is absorbed and excreted in urine with a half-life of 0.5-1.5 hours, most is eliminated unchanged in the faeces. Sulfapyridine is to a major extend reabsorbed, metabolized in the liver and excreted in the urine with a half-life, depending on the acetylator phenotype, between 5 and 15 hours. 

Sulfasalazine has been used for the management of RA and ankylosing spondylitis with apparently similar effectiveness as penicillamine and with less toxicity. While 5-aminosalicylic acid is the active agent in inflammatory bowel disease, it is believed that sulfapyridine is mostly responsible for the antirheumatoid effects. Gastrointestinal complaints, dizziness and photosensitivity are the most frequently observed adverse events. With levamisole and also with sulfasalazine and olsalazine a delay of 2-3 months is to be expected before positive responses will be observed. 

Xin H-W, Fischer C, Schwab M et al. Effects of aminosalicylates on thiopurine 5-methyltransferase activity an ex vivo study in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2005 21 1105-1109. 

Sulfasalazine is metabolized to sulfapyridine and 5-aminosalicylic acid, and it is thought that the sulfapyridine is probably the active moiety when treating rheumatoid arthritis (unlike inflammatory bowel disease, see Chapter 62). Some authorities believe that the parent compound, sulfasalazine, also has an effect. In treated arthritis patients, IgA and IgM rheumatoid factor production are decreased. Suppression ofT-cell responses to concanavalin and inhibition of in vitro -cell proliferation have also been documented. In vitro studies have shown that sulfasalazine or its metabolites inhibit the release of inflammatory cytokines, including those produced by monocytes or macrophages, eg, interleukins-1, -6, and -12, and TNF-a. These findings suggest a possible mechanism for the clinical efficacy of sulfasalazine in rheumatoid arthritis. 

Therapeutic pyramid approach to inflammatory bowel diseases. Treatment choice is predicated on both the severity of the illness and the responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. Drugs may be used alone or in various combinations. Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn s colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn s colitis or Crohn s perianal disease), or budesonide (Crohn s ileitis). Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with oral corticosteroids to promote disease remission immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with severe Crohn s disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used primarily for patients with severe ulcerative colitis who have failed a course of intravenous corticosteroids. TNF, tumor necrosis factor. 

Drugs that contain 5-aminosalicylic acid (5-ASA) have been used successfully for decades in the treatment of inflammatory bowel diseases (Figure 62-8). 5-ASA differs from salicylic acid only by the addition of an amino group at the 5 (meta) position. Aminosalicylates are believed to work topically (not systemically) in areas of diseased gastrointestinal mucosa. Up to 80% of unformulated, aqueous 5-ASA is absorbed from the small intestine and does not reach the distal small bowel or colon in appreciable quantities. To overcome the rapid absorption of 5-ASA from the proximal small intestine, a number of formulations have been designed to deliver 5-ASA to various distal segments of the small bowel or the colon. These include sulfasalazine, olsalazine, balsalazide, and various forms of mesalamine. 

Sulfasalazine. Salicylazosulfapyridine or Azulfadine [599-79-1] (2-hydroxy-5-[[4[(2-pyridylamino)sulfonyl]-phenyl]azo] benzoic acid) (15) is a light brownish yellow-to-bright yellow fine powder that is practically tasteless and odorless. It melts at ca 255°C with decomposition, is very slightly soluble in ethanol, is practically insoluble in water, diethyl ether, chloroform, and benzene, and is soluble in aqueous solutions of alkali hydroxides. Sulfasalazine may be made by the synthesis described in Reference 13. It is not used as an antidiarrheal as such, but is indicated for the treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn s disease. Its action is purported to result from the breakdown in the colon to 5-aminosalicylic acid [89-57-6] (5-AS A) and sulfapyridine [144-83-2]. It may cause infertility in males, as well as producing idiosyncratic reactions in some patients these reactions have been attributed to the sulfa component of the compound. The mechanism of 5-ASA is attributed to inhibition of the arachidonic acid cascade preventing leukotriene B4 production and the ability to scavenge oxygen free radicals. The active component appears to be 5-aminosalicylic acid. 

Metabolism The sulfas are acetylated at N4, primarily in the liver. The product is devoid of antimicrobial activity, but it retains the toxic potential to precipitate at neutral or acidic pH, causing crys-talluria ( stone formation ) and therefore potential damage to the kidney (Figure 29.4). Sulfasalazine is effective in the treatment of inflammatory bowel disease because local intestinal flora split the drug into sulfapyridine and 5-aminosalicylate. The latter exerts the antiinflammatory effect. Absorption of sulfapyridine can lead to toxicity in patients who are slow acetylators. 

Riley SA and Turnberg LA (1990) Sulphasalazine and the aminosalicylates in the treatment of inflammatory bowel disease. Quarterly Journal of Medicine, New Series 75 551-562. 

Sulfasalazine (salicylazosulfapyxidine) is used in inflammatory bowel disease (see p. 649) in effect the sulfapyridine component acts as a carrier to release the active 5-aminosalicylic add in the colon (see also rheumatoid cirthritis, p. 292). 

The sulfasalazine molecule comprises sulfa-piridine and 5-aminosalicylic acid linked by an azo-bond which is split by colonic bacteria, releasing the component parts. Sulfapiridine, as a sulphonamide, has an antifolate action which is believed to benefit rheumatoid arthritis, while it is the salicylate moiety that is thought to be effective in inflammatory bowel disease a fuller description appears on page 64. Sulfasalazine is used as a DMARD for rheumatoid arthritis, spondyloarthropathy with peripheral joint involvement, and psoriatic arthritis. 

Klotz U. The role of aminosalicylates at the beginning of the new millennium in the treatment of chronic inflammatory bowel disease. Eur J Qin Pharmacol 2000 56(5) 353-362. 

Schreiber S, Hamling J, Zehnter E, Howaldt S, Daerr W, Raedler A, Kruis W. Renal tubular dysfunction in patients with inflammatory bowel disease treated with aminosalicylate. Gut 1997 40(6) 761-6. 

De Broe ME, Stolear JC, Nouwen EJ, Elseviers MM. 5-Aminosalicylic acid (5-ASA) and chronic tubulo-interstitial nephritis in patients with chronic inflammatory bowel disease is there a link Nephrol Dial Transplant 1997 12 1839-1841. 

Gisbert JP, Gonzalez-Lama Y, Mate J. 5-Aminosalicylates and renal function in inflammatory bowel disease a systematic review. Inflamm Bowel Dis 2007 13(5) 629-638. 

Eiseviers MM, D Haens G, Lerebours E, Plane C, Stolear JC, Riegler G, Capasso G, Van Outryve M, Mishevska-Mukaetova P, Djuranovic S, Peickmans P, De Broe ME, forthe 5-ASA study group. Renal impairment in patients with inflammatory bowel disease association with aminosalicylate therapy Clin Nephrol 2004 61 (2) 83-91. 

Sulfonamides were first reported as causative agents in users of sulfanilamide vaginal cream. para-Aminosalicylic acid frequently produced the syndrome in tuberculosis patients being treated with this agent. There have been nine reported cases associated with sulfasalazine use in inflammatory bowel disease. The drug as-... 

Apart from classic analgesic nephropathy, this chapter will also handle the possible nephrotoxic role of 5-aminosalicylic acid (5-ASA) used in patients with chronic inflammatory bowel disease (IBD). During the last decade, 5-ASA replaced sulfasalazine as first-line therapy for mildly to moderately active IBD. For decades, sulphasalazine, an azo-compound derived from sulphapyridine and 5-aminosalicylic acid (5-ASA), has been the only valuable non-corticosteroid drug in the treatment of inflammatory bowel disease. Azad Kahn et al. [25] showed that the pharmacologically active moiety in sulphasalazine for the treatment of these diseases was 5-ASA. Consequently, this resulted in a number of new 5-ASA formulations (mesalazine, olsalazine, balsalazine) for topical and oral use. Since the metabolite sulphapyridine was largely responsible for the side effects of sulfasalazine, the primary advantage of the newer 5-ASA agents is their improved adverse effect profile. 

Figure 4. Case report of nephrotoxicity of 5-aminosalicylic acid (5-ASA) in inflammatory bowel disease.

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