Aminosalicylates sulfasalazine

Induction of remission of mild to moderate active CD is accomplished with oral aminosalicylates. Sulfasalazine 4 to 6 g per day is most effective for patients with colonic involvement, with response rates of 50%.2,5 Mesalamine products have... 

DIGOXIN AMINOSALICYLATES Sulfasalazine may 1 digoxin levels. The manufacturers of balsalazide also warn against the possibility of this interaction in spite of a lack of case reports Uncertain at present Watch for poor response to digoxin check levels if signs of 1 effect... 

METHOTREXATE AMINOSALICYLATES-SULFASALAZINE t risk of hepatotoxicity with sulfasalazine Additive hepatotoxic effects. Sulfasalazine also competes with methotrexate for renal elimination Monitor closely for symptoms of liver failure. Check LFTs at the beginning of treatment then weekly until stable, and repeat if there is clinical suspicion of liver disease... 

Hypersensitivity reactions Aminosalicylates (sulfasalazine and mesalazine), azathioprine/6-MP, sulfonamides... 

The prototypical aminosalicylate is sulfasalazine, which is comprised of mesalamine linked by a diazo bond to the carrier molecule sulfapyridine. This linkage prevents premature absorption of mesalamine in the small intestine. Once sulfasalazine is delivered to the colon, bacterial degradation of... 

The use of non-sulfapyridine-based aminosalicylates has led to greater tolerability. Although the adverse effects are similar to those of sulfasalazine, they occur at a much lower rate. Olsalazine, in particular, is associated with a higher incidence of secretory diarrhea. These agents can also be used safely in patients with a reported sulfonamide allergy. 

In contrast to their use in UC, sulfasalazine and the newer aminosalicylates are marginally effective in preventing CD relapse in patients with medically-induced remission, with success rates of only 10% to 20% at 1 year.26 Nevertheless, aminosalicylates are routinely used to maintain remission of CD. Some evidence does exist that the aminosalicylates may prevent or delay disease recurrence in patients with surgically-induced remisson.2,26... 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

U Klotz. Clinical pharmacokinetics of sulfasalazine, its metaboliters and other prodrugs of 5-aminosalicylic acid. Clin Pharmacokin 10 285-302, 1985. 

The answer is b. (Hardman, p 1061.) Sulfasalazine consists of sul-fapyridine with 5-aminosalicylic acid linked by an azo- bond. This bond is broken by bacteria that release the salicylic acid, which is believed to be the active agent. Sulfa drugs or salicylic acid used alone is not as effective. The mechanism of action is unknown, but it is believed to be protective action on the mucosa by inhibition of the synthesis of prostaglandins and leukotrienes. 

A four-electron reduction of the azo group leads to the cleavage of the molecule and the production of two amines (Fig. 5.10). There are few drugs that contain an azo bond but a good example is sulfasalazine, which is reductively cleaved to 4-aminosalicylic acid and sulfapyridine (18). This reduction is mediated by anaerobic bacteria in the intestine, and it leads to the formation of two agents that are pharmacologically active in the treatment of ulcerative colitis. 

Treatment of Crohn s disease is based on the administration of oral corticosteroids, to attain remission. Oral aminosalicylates, such as oral sulfasalazine. 

Drugs that may interact with folic acid include aminosalicylic acid, oral contraceptives, dihydrofolate reductase inhibitors (eg, methotrexate, trimethoprim), sulfasalazine, hydantoins. 

Pharmacology The mode of action of sulfasalazine or its metabolites, 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP), is still under investigation but may be related to the anti-inflammatory or immunomodulatory properties that have been observed in animals and in vitro, to its affinity for connective tissue, or to the relatively high concentration it reaches in serous fluids, the liver, and intestinal walls. In ulcerative colitis, the major therapeutic action may reside in the 5-ASA moiety. P.842... 

Sulfasalazine was the first of the 5-aminosalicylic acid (5-ASA) congeners that was shown to be effective in the treatment of active Crohn s disease with involvement of the colon and of ulcerative colitis. 

Maintenance therapy with sulfasalazine reduces relapse rate. However a considerable number of patients experience adverse effects which are by the sulfa component of sulfasalazine. Then preparations of 5-aminosalicylic acid can be used. 

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. 

There are oral formulations that deliver drug to the lower intestine. In mesalazine 5-amino-salicylic acid is formulated in a polymer-coated oral preparation. Olsalazine is a dimer of 5-aminosalicylate linked by an azo bond. Balsalazide is delivered to the colon where it is cleaved by bacterial azoreduction to release equimolar quantities of mesalazine and 4-aminobenzoyl-/i-alanine. The newer 5-ASA preparations were shown to be superior to placebo and tended towards therapeutic benefit over sulfasalazine. However, considering their relative costs, a clinical advantage to using the newer 5-ASA preparations in place of sulfasalazine appears unlikely. 

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. 

Newer aminosalicylate preparations appear superior to placebo but differ little in efficacy from sulfasalazine SASP. Potential advantages in reduced adverse effects from removal of the sulfa moiety nevertheless may exist. 

The systemic adverse effects of corticosteroids make them inappropriate as maintenance treatments and the first line treatments are the aminosalicylates. The original drug sulfasalazine is a chemical combination of sulfapyridine and 5 aminosalicylic acid. Following the discovery that the active... 

Sulfasalazine is a prodrug of which 70% is converted by colon bacteria to two active metabolites, sulfapyri-dine and 5-aminosalicylic acid (mesalamine). Sulfa-pyridine has antibacterial activities, and 5-aminosali-... 

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. 

Only 10-20% of orally administered sulfasalazine is absorbed, although a fraction undergoes enterohepatic recirculation into the bowel where it is reduced by intestinal bacteria to liberate sulfapyridine and 5-aminosalicylic acid (see Figure 62-8). Sulfapyridine is well absorbed while 5-aminosalicylic acid remains unabsorbed. Some sulfasalazine is excreted unchanged in the urine whereas sulfapyridine is excreted after hepatic acetylation and hydroxylation. Sulfasalazine s half-life is 6-17 hours. 

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. 

Aminosalicylates, eg, mesalamine in many formulations Mechanism uncertain t may be inhibition of eicosanoid inflammatory mediators Topical therapeutic action systemic absorption may cause toxicity Mild to moderately severe Crohn s disease and ulcerative colitis Sulfasalazine causes sulfonamide toxicity and may cause GI upset, myalgias, arthralgias, myelosuppression other aminosalicylates much less toxic... 

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. 

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