Sulfonamide, potentiated

Trepanier, L.A., Idiosyncratic toxicity associated with potentiated sulfonamides in the dog. J. Vet. Pharmacol. Ther., 27, 129, 2004. 

Dorzolamide contains two chiral centers, and is therefore capable of existing in four diastereomers. The stereochemistry at the C-6 position of the starting material is preserved during the various chemical reactions which take place during the synthesis. The stereochemistry at the C-4 position (absolute configuration being 5) results from the Ritter substitution reaction (Scheme 1, Steps I-II) used to transform the alcohol to an acetamide. The Ritter reaction yields mostly the rra j-diastereomer, and the c/s-diastereomers are easily separated as their maleate salts. The potential sulfonamide positional isomer (3-sulfonamide) has not been observed at levels greater than 0.1% in HPLC analyses. 

Chloramphenicol and florfenicol 33 Potentiated sulfonamides 35 Tetracyclines 38 Fluoroquinolones 40 Macrolides 43 Rifampin 44 Metronidazole 45 Vancomycin 45 References 46... 

The sulfonamides are a group of organic compounds with chemotherapeutic activity they are antimicrobial agents and not antibiotics. They have a common chemical nucleus that is closely related to PABA, an essential component in the folic acid pathway of nucleic acid synthesis. The sulfonamides are synergistic with the diaminopyrim-idines, which inhibit an essential step further along the folate pathway. The combination of a sulfonamide and a diaminopyrimidine is advantageous because it is relatively non-toxic to mammalian cells (less sulfonamide is administered) and is less likely to select for resistant bacteria. Only these so-called potentiated sulfonamides are used in equine medicine. These drugs are formulated in a ratio of one part diaminopyrimidine to five parts sulfonamide, but the optimal antimicrobial ratio at the tissue level is 1 20, which is achieved because the diaminopyrimidines are excreted more rapidly than the sulfonamides. 

Resistance to the diaminopyrimidines usually occurs by plasmid-encoded production of diaminopyrimidine-resistant DHFR. Excessive bacterial production of DHFR and a reduction in the ability of the drug to penetrate the bacterial cell wall also results in resistance. There is less resistance to the potentiated sulfonamides than to the individual agents. 

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 potentiated sulfonamides have been associated with producing diarrhea in horses. In one study, changes in coliforms and clostridia were not seen following p.o. administration of trimethoprim/sulfadiazine. However, in a study of hospitalized horses, the risk of diarrhea was significantly increased when horses had been given a potentiated sulfonamide and procaine benzyl-penicillin (procaine penicillin) concurrently. 

The injectable formulations of potentiated sulfonamides are suspensions consequently, rapid i.v. administration causes hypotension and collapse. Fatal dysrhythmias are associated with the potentiated sulfonamides administered i.v. concurrently with the a2-adrenergic agonist deto-midine. It is suspected that the potentiated sulfonamide formulation potentiates the cardiac changes produced by detomidine. This adverse reaction has not been reported for the other ci2-adrenergic agonists xylazine and romifidine. 

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. 

In the past, EPM was treated using a trimethoprim-containing potentiated sulfonamide in combination with pyrimethamine, mainly because of the difficulty in finding sulfonamide formulations without trimethoprim. However, trimethoprim adds little to the antisarcocystis activity but is believed to increase the risk of hematological toxicity (Fenger et al 1997). Currently, there are numerous veterinary pharmacies in the USA that will compoimd pyrimethamine with sulfadiazine for the treatment of horses with EPM. 

It warrants mention that resistance to a particular antimicrobial agent in vitro may not preclude successful treatment with the drug as long as high concentrations are achieved in urine. Similarly, demonstrable susceptibility in vitro does not always guarantee a successful response to treatment. For example. Enterococcus spp. is often found to be susceptible to the potentiated sulfonamide combinations in vitro however, this pathogen is inherently resistant to these combinations in vivo (Jose-Cunilleras Hinchcliff 1999, Schott 1998). Antimicrobial therapy should be continued for at least 1 week for the treatment of lower UTIs and for 2-6 weeks for upper UTls in horses. Ideally, a voided, midstream urine sample should be submitted for bacterial culture 2-4 days after the initiation of therapy and again 1-2 weeks after treatment has been discontinued. 

The cephalosporins and tetracyclines are commonly used for treatment of UTIs in other species. However, in horses, the cephalosporins are rarely more advantageous than the penicillins or potentiated sulfonamides. However, ceftiofur has broad-spectrum antimicrobial activity and may be indicated when urinary pathogens are resistant to... 

Although the horse appears to be refractory to the hepatic effects of most NSAIDs, their hepato-toxic potential should be considered, especially when they are concomitantly administered with other potentially hepatotoxic agents, such as fluoroquinolones, potentiated sulfonamides or anabolic steroids. In addition, many herbal preparations are potential hepatotoxic agents and clients may administer these compounds concurrently with prescribed NSAIDs without consulting their veterinarian. Echinacea and kava kava products, for example, are reported to be potential hepatotoxins and both are used in herbal remedy products that claim to produce calming or sedating effects in horses (Abebe 2002). 

Even though the synergism observed with antifolate-sulfonamide combinations appears real, whether or not the mechanism is truly a sequential blockade is questionable. For example, it was shown that a potent DHFR inhibitor, 2,4-diaminopteroyl aspartate, is not synergistic with sulfamethoxazole. In addition, it was found that DHFR isolated from E. coli could be inhibited by sulfonamides, suggesting a multiple simultaneous inhibition of DHFR by both drugs. Curiously, it was also found that the TM potentiates sulfonamides that alone are resistant to the bacterium tested. 

D. Toxicity Massive sodium diuresis with hyponatremia is an uncommon but dangerous early effect of thiazides. Chronic therapy is often associated with potassium wasting, since an increased sodium load is presented to the collecting tubules. Diabetic patients may have significant hyperglycemia. Serum uric acid and lipid levels are also increased in some individuals. Thiazides are sulfonamides and share potential sulfonamide allergenicity. 

The sulfonamide class contains a large number of antibacterial drugs, including sulfadiazine, sulfamethazine (sulfadimidine), sulfathiazole, sulfamethoxazole, and many more. Potentiated sulfonamides, in which a sulfonamide and an antibacterial diaminopyrimidine such as trimethoprim are combined, demonstrate improved efficacy compared with sulfonamides alone. Relatively few sulfonamides are currently (as of 2011) approved for use in food-producing species. This is attributed to numerous factors, including toxicological concerns associated with some sulfonamides and the lack of contemporary data to support the historical uses of other sulfonamides. 

Papich MG, Riviere JE, Sulfonamides and potentiated sulfonamides, in Riviere JE, Papich MG, eds., Veterinary Pharmacology and Therapeutics, 9th ed., Wiley-Blackwell, Iowa State Univ. Press, Ames, 2009 pp. 835-864. 

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