Sulfonamides toxic effects

Age Renal or hepatic elimination processes are often poorly developed in newborns, making neonates particularly vulnerable to the toxic effects of chloramphenicol (see p. 320) and sulfonamides (see p. 289). Young children should not be treated with tetracyclines (see p. 311) which affect bone growth, or fluoroquinolones (see p. 323), which interfere with cartilage growth. 

In addition to the acceptable clinical side effects of many sulfonamides, some severe toxic effects were observed. In 1942, Marcel Janbon, the head of the medical faculty at Montpellier University, investigated an isopropylthiadiazole derivative of... 

Risk of toxic effect by adversely affecting serum levels of other medication 0 Sulfonamides given with ... 

Changing the nature of the group R" has also helped to reduce the toxicity of some sulfonamides. The primary amino group of sulfonamides are acetylated in the body and the resulting amides have reduced solubility which can lead to toxic effects. For example, the metabolite formed from sulfathiazole (an early sulfonamide) (Fig. 10.9) is poorly soluble and can prove fatal if it blocks the kidney tubules. 

Other toxic effects of NSAIDs include hypersensitivity reactions, rash, and central nervous system complaints of drowsiness, dizziness, headaches, depression, confusion, and tinnitus. Although NSAIDs are generally avoided in patients with asthma who are aspirin-intolerant, studies indicate that celecoxib and rofecoxib are well tolerated in aspirin-sensitive asthma, providing a viable option for these patients. Celecoxib and valdecoxib are sulfonamides and are thus contraindicated for those with sulfa allergies. 

The early history of Ehrlich s work with organic arsenicals was mentioned (Chapter 2). Arsenicals were important in the treatment of tropical protozoal diseases as well as syphilis until the advent of the sulfonamides in 1935. Today they are utilized mainly in trypanosomiasis. They are among the least well-tolerated drugs in use today and usually require hospitalization to manage toxic effects. 

Renal lesions may be due to the precipitation of sulfonamides and their acetyl derivatives in the urinary tract. Renal damage may also be attributable to a direct toxic effect of sulfonamides on the kidney tubules. 

After systemic administration, sulfadiazine and sulfisoxazole attain concentrations in cerebrospinal fluid (CSF) that may be effective in meningitis. Sulfonamides readily cross the placenta to reach the fetal circulation, potentially exerting both antibacterial and toxic effects. 

Toxicity Loop diuretics usually induce hypokalemic metabolic alkalosis. Because large amounts of sodium are presented to the collecting tubules, wasting of potassium (which is excreted by the kidney in an effort to conserve sodium) may be severe. Because they are so efficacious, the loop diuretics can cause hypovolemia and cardiovascular complications. Ototoxicity is an important toxic effect of the loop agents. The sulfonamides in this group may cause typical sulfonamide allergy. 

List the major clinical uses of sulfonamides and trimethoprim, singly and in combination, and describe their pharmacokinetic properties and toxic effects. 

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. 

Sulfonamides may adversely affect the level of some medications causing a toxic effect. Avoid using sulfonamides with anticoagulants such as coumarin or indanedione derivatives and anticonvulsants (hydantoin) as well as oral antidiabetic agents and methotrexate. 

From the clinical point of view the most important side effect is renal damage. Besides the crystallizing of the sulfonamides in the renal tubules, allergic lower nephron nephrosis appears this complication is extremely serious, but very rare. It is still not clear if it is a direct toxic effect or an idiosyncratic reaction. 

In some sulfonamides too (sulfamidine, sulfapyridine, and salazopyrine), it was found that there are quick and slow acetylators. After salazopyrine, cyanosis and hemolysis can occur in the slow acetylators, and might be toxic effects (Meyer and Meier 1982). 

Sulfonylureas. The hypoglycemic effect of sulfonylureas was first noted in the early 1940s when several patients died in hypoglycemic coma after testing glyprothia2ole, a synthetic sulfonamide used to treat typhoid. Chemical modifications which enhanced activity and lowered toxicity led to the development of the first-generation sulfonylureas. Carbutamide [339-43-5] the first commercial sulfonylurea, came onto the European... 

Although the antibacterial spectmm is similar for many of the sulfas, chemical modifications of the parent molecule have produced compounds with a variety of absorption, metaboHsm, tissue distribution, and excretion characteristics. Administration is typically oral or by injection. When absorbed, they tend to distribute widely in the body, be metabolized by the Hver, and excreted in the urine. Toxic reactions or untoward side effects have been characterized as blood dyscrasias crystal deposition in the kidneys, especially with insufficient urinary output and allergic sensitization. Selection of organisms resistant to the sulfonamides has been observed, but has not been correlated with cross-resistance to other antibiotic families (see Antibacterial AGENTS, synthetic-sulfonamides). 

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