Sulfonamides gastrointestinal effects

COX-2-selective inhibitors The COX-2-selective inhibitors may have a reduced risk of gastrointestinal effects, including gastric ulcers and serious gastrointestinal bleeding. Cele-coxib is a sulfonamide and may cause a hypersensitivity reaction in patients who are allergic to other sulfonamides. 

Valdecoxib, a diaryl-substituted isoxazole, is a new highly selective COX-2 inhibitor. Pharmacokinetic characteristics and dosage in arthritis are set forth in Table 36-1. In primary dysmenorrhea, dosage is 20 mg twice daily, and the drug is as effective as nonselective NSAIDs for this indication. Gastrointestinal and other toxicities are similar to those of the other coxibs. Valdecoxib has no effect on platelet aggregation or bleeding time. Serious reactions have been reported in sulfonamide-sensitive individuals. 

Adverse effects The side effects include gastrointestinal distress. At higher doses, albuminuria, hematuria and rashes may develop. Methenamine mandelate is contraindicated in treating patients with renal insufficiency, because mandelic acid may precipitate. Sulfonamides react with formaldehyde and must not be used concomitantly with methenamine. 

Selective inhibitors of COX-II or 5-lipoxygenase (5-LO) consisting of oxazolyl-, (I), and pyrazolylbenzene sulfonamide derivatives, (II), prepared by Talley (1,2), respectively, and sulfonyl derivatives, (III), prepared by Ando (3) were effective as anti-inflammatory agents with only marginal gastrointestinal side effects. 

The sulfonamides can produce a wide variety of side effects, and an adverse reaction to one sulfonamide frequently precludes the use of other sulfonamide derivatives. The most common adverse effects are gastrointestinal disturbances, including anorexia, nausea, vomiting, and diarrhea. 

Because sulfonamides are subject to polymorphic metabolism by N-acetyltransferase (NAT2), some of the adverse effects of sulfasalazine are more common in slow acetylators. Gastrointestinal adverse reactions occur more commonly in slow acetylators, and they should use lower doses. 

The frequency and severity of the adverse effects of sulfonamides correspond to those seen with other antibacterial agents (2-5%). Dose-related effects, which tend to be more troublesome than serious, include gastrointestinal symptoms, headache, and drowsiness. Crystalluria can occur, but urinary obstruction is rare. Hematological adverse effects due to folic acid antagonism occur primarily in combination with trimethoprim. Hemolytic anemia occurs in patients with enzyme deficiencies and abnormal hemoglobins. Hypersensitivity... 

Urticarial and maculopapular rashes are the most frequent adverse reactions to sulfonamides after gastrointestinal symptoms. Although hypersusceptibility is suspected to be the mechanism for these adverse effects, type I allergic reactions, which are induced by IgE antibodies, have been confirmed only rarely. It appears that with the older sulfonamides severe reactions were more frequent. In some patients who have immediate hypersensitivity reactions to sulfonamides, IgE has been found that can bind to an N4-sulfonamidoyl determinant (N4-SM) (169). 

In general, the sulfonamides are readily absorbed from the gastrointestinal tract of non-ruminants. Absorption may be delayed when the potentiated sulfonamides are administered with feed. Initial serum concentrations are lower in a fed horse than a fasted horse but the food effect is greatly reduced by the third treatment day. The bioavailability of one formulation of pyrimethamine is 56% following p.o. administration. 

The gastrointestinal tract is a frequent site for adverse effects of antimicrobial drugs, primarily because of disruption of normal intestinal microbial populations and proliferation of enteropatho-gens. Diarrhea, often with accompanying signs of endotoxemia, is the usual clinical manifestation. Antimicrobial agents known to be, or implicated in being, associated with antimicrobial-induced diarrhea include penicillin, ceftiofur, lincomycin, tetracycline, erythromycin and the potentiated sulfonamides. Erythromycin can also promote diarrhea via its motilide activity. 

Except for drugs especially designed for local gastrointestinal (GI) effects (see Chapter 38), the sulfonamides are absorbed rapidly and well from the GI tract. Peak plasma levels are achieved in 2-6 hours, depending on the drug. Absorption from sites such as the vagina, respiratory tract, or abraded skin is unrehable, but sufficient drug may enter the body to cause toxic reactions in susceptible persons or to produce sensitization. 

Toxicity The toxic effects of sulfonamides include skin rashes, gastrointestinal distress, hemolysis, kidney damage, and drug interactions caused by competition for plasma protein binding sites. Pyrimethamine may cause folic acid deficiency when used in high doses. 

Toxicity Common adverse effects include bone marrow suppression and toxie effects on the skin and gastrointestinal mucosa (mucositis). The toxic effects of methotrexate on normal cells may be reduced by administration of fohnie aeid (leucovorin) this strategy is called leucovorin rescue. Long-term use of methotrexate has led to hepatotoxieity and to pulmonary infiltrates and fibrosis. Salicylates, NSAlDs, sulfonamides, and sulfonylureas enhance the toxicity of methotrexate. 

---