Inflammatory bowel disease sulfasalazine

Sulfasalazine Antimicrobial anti-inflammatory ulcerative colitis/inflammatory bowel diseases Suppresses NK cells impaired lymphocyte function... 

Sulfasalazine anti-inflammatory (arthritis, inflammatory bowel disease) [18,441-445]... 

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. 

Sulfasalazine (Azulfldine) was first introduced in 1940 as a treatment for rheumatoid arthritis. It was found that a number of patients with coexistent inflammatory bowel disease showed improvement of their GI symptoms, and the drug has subsequently been used for the treatment of patients with inflammatory bowel disease. 

Sulfasalazine is composed of sulfapyridine and 5-ASA molecules linked by an azo bond. Sulfapyridine has no effect on the inflammatory bowel disease, and instillation of this agent into the colon does not heal colonic mucosa. It is, however, responsible for most of sulfasalazine s side effects, including sulfa allergic reactions. 5-ASA, the active metabolite, may inhibit the synthesis of mediators of inflammation. 

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. 

Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease (see Chapter 62). 

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. 

Clinical Use. Sulfasalazine (Azulfidine, other names) has unique properties, with some antibacterial characteristics similar to sulfonamide drugs (see Chapter 33) and some of anti-inflammatory characteristics similar to the salicylates (see Chapter 15). This drug is primarily used to suppress the immune response associated with rheumatoid arthritis and inflammatory bowel disease.38,61... 

Administration Most sulfa drugs are well absorbed after oral administration. Sulfasalazine [sul fa SAL a zeen], when administered orally or as a suppository, is reserved for treatment of chronic inflammatory bowel disease (for example, Crohn s disease or ulcerative colitis), because it is not absorbed. Similarly, succinylsulfathiazole [suks in ill sul fa THI a zole] is used for the treatment of salmonella and shigella carriers. Intravenous sulfonamides are generally reserved for patients who are unable to take oral preparations. Because of the risk of sensitization, sulfas are not usually applied topically. In burn units, creams of mafenide acetate (p-aminomethylbenzensulfonamide) or silver sulfadiazine have been effective in reducing burn sepsis. However, superinfections with resistant bacteria or fungi may occur. 

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. 

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. 

An analysis of suspected serious adverse reactions reported to the Committee on Safety of Medicines in the UK in 1991-98 has failed to show a safety advantage for mesalazine over sulfasalazine in the treatment of inflammatory bowel disease (20). Pancreatitis and interstitial nephritis were significantly more common with mesalazine. 

Pericarditis in a 16-year-old boy with inflammatory bowel disease taking mesalazine resolved on withdrawal, but recurred after starting sulfasalazine 500 mg tds (24). 

Agranulocytosis is very unusual but well described with sulfasalazine, and can occur suddenly and very early in treatment (49). The risk in sulfasalazine users with arthritic disorders (6/1000 users) was about 10 times higher than that in users with inflammatory bowel disease (0.6/1000 users) (SEDA-20, 320). Agranulocjdosis is supposedly more common in slow acetylators (50). However, in one study the risk of agranulocytosis was not increased in slow acetylators (50). Leukopenia occurred in a patient taking mesalazine after a similar reaction to sulfasalazine (SEDA-17, 425). 

When chronic inflammatory bowel disease co-exists with acute intermittent porphyria, the bowel condition itself brings with it an increased risk of acute attacks of porphyria sulfasalazine can trigger such an attack in this condition (SEDA-17, 425). 

Pulmonary reactions have been described with most sulfonamides. Pyrimethamine -I- sulfadoxine, used in malaria prophylaxis and treatment, also rarely causes pulmonary reactions (17-19). The sulfapyridine moiety of sulfasalazine, used in inflammatory bowel disease, can produce adverse pulmonary reactions (20). 

Male infertility with oligospermia has been reported during treatment with sulfasalazine (199,200). However, inflammatory bowel disease can also affect the maturation of spermatozoa (201). 

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-... 

KorelitzBI, Present DH, Rubin PH, et al. Desensitization to sulfasalazine after hypersensitivity reactions in patients with inflammatory bowel disease. J Clin Gastroenterol 1984 6 27-31. 

Sulfasalazine, commonly used in the treatment of inflammatory bowel disease and rheumatoid arthritis, is selectively used as an alternative treatment, particularly in patients with concurrent psoriatic arthritis. Sulfasalazine is an anti-inflammatory agent that inhibits 5-lipoxygenase. When used as a single agent in the treatment of psoriasis, it is not as effective as is therapy with methotrexate, PUVA, or acitretin. One possible advantage of sulfasalazine therapy compared with other systemic treatments is its relatively high margin of safety. The usual dose of oral sulfasalazine is 3 to 4 g/day for 8 weeks. ... 

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