Sulfonylureas with sulfonamides

Hypoglycemia, often during the first hours of combining the two drugs, is the result of an important interaction between sulfonylureas and sulfonamides (184—187). For example, the half-life of tolbutamide was increased from 9.5 to 29 hours by chronic sulfaphenazole and from 9.2 to 26 hours by a single dose of sulfaphenazole (188). Interference by sulfonamides with the protein binding of sulfonylureas may contribute. 

Hypersensitivity, mostly rashes, which can be severe (Stevens-Johnson syndrome). Assume complete cross-allergenicity between sulfonamides and possibly with sulfonylurea hypo-glycemics. 

Coupling Processes. The coupling can be carried out as in Equation 1 by preparing a sulfonylisocyanate by treating the sulfonamide with phosgene in the presence of butyl isocyanate (BuNCO) in xylene at reflux. Frequently 1,4-diazabicyclooctane (DABCO) aids in catalyzing this reaction. The sulfonyl isocyanate which is usually an oil can be added to a solution or sus nsion of the aminoheterocycle in a solvent such as methylene chloride or acetonitrile. The desired sulfonylurea usually precipitates as a white crystalline solid. Dry conditions are essential to avoid hydrolysis of the extremely water sensitive isocyanate. 

Another route, discovered by Meyer and Fory (2), involves the heating of a phenyl carbamate of the sulfonamide with the aminoheterocycle (Equation 3) to yield the desired sulfonylurea. 

Sulfonylureas are not directly amenable to gas chromatography (GC) because of their extremely low volatility and thermal instability. GC has been used in conjunction with diazomethane derivatization, pentafluorobenzyl bromide derivatization, and hydrolysis followed by analysis of the aryl sulfonamides. These approaches have not become widely accepted, owing to poor performance for the entire family of sulfonylureas. Capillary electrophoresis (CE) has been evaluated for water analysis and soil analysis. The low injection volumes required in CE may not yield the required sensitivity for certain applications. Enzyme immunoassay has been reported for chlorsulfuron and triasulfuron, with a limit of detection (LOD) ranging from 20 to 100 ng kg (ppt) in soil and water. 

Linear descendants of the antimicrobial sulfonamides, the orally active sulfonylureas continue to be of interest as alternatives to insulin injections in patients with adult-onset diabetes. Tolpyrramide (153) is synthesized from unsymmetrical O-methylurea... 

This reaction is typical for the synthesis of sulfonylureas it is mildly exothermic and proceeds smoothly in a variety of inert aprotic solvents. The product is usually obtained in very high yield, as a fine crystalline precipitate. The sulfonyl isocyanates are readily prepared from the substituted benzene sulfonamides by reaction with phosgene, Fig. 3, in the presence of an alkyl isocyanate, for example, butyl isocyanate in an inert solvent at 120 to 140°C according to the general procedure of H. Ulrich and A. A. R. Sayigh (Ref. 3). 

Hypersensitivity to sulfonamides or chemically related drugs (eg, sulfonylureas, thiazide and loop diuretics, carbonic anhydrase inhibitors, sunscreens with PABA, local anesthetics) pregnancy at term lactation infants less than 2 months of age (except in congenital toxoplasmosis as adjunct with pyrimethamine) porphyria salicylate hypersensitivity. 

Drugs that may interact with sulfonamides include oral anticoagulants, cyclosporine, hydantoins, methotrexate, and sulfonylureas. 

Methotrexate clearance can be decreased by the coadministration of NSAIDs however, this not usually a problem with the low doses of methotrexate used to treat arthritis. Methotrexate can be displaced from plasma protein binding sites by phenylbutazone, pheny-toin, sulfonylureas, and sulfonamides and certain other antibiotics. The antifolate effects of methotrexate are additive with those of other folate-inhibitory drugs, such as trimethoprim. 

Sulfasalazine is contraindicated in individuals with hypersensitivity to salicylates, sulfonamides, sulfonylureas, and certain diuretics (furosemide, thiazides, and carbonic anhydrase inhibitors). Because it can cause kernicterus, sulfasalazine is contraindicated in infants and children under 2 years of age. Sulfasalazine passes into breast milk and is therefore contraindicated for nursing mothers. Similarly, pregnant women near term should not use this drug, although it appears to be the safest of the DMARDs during early pregnancy. 

Probenecid can impair the renal active secretion of a variety of acidic compounds, including sulfinpyrazone, sulfonylureas, indomethacin, penicillin, sulfonamides, and 17-ketosteroids. If these agents are to be given concomitantly with probenecid, their dosage should be modified appropriately. Salicylates interfere with the clinical effects of both sulfinpyrazone and probenecid and should be avoided in patients treated with uricosuric agents. Uricosuric agents also can influence the volume of distribution and hepatic metabolism of a number of drugs. 

The sulfonylurea hypoglycemic agents, as noted in Chapter 2, also trace their ancestry to the sulfonamides. It is of interest that activity is retained when a substituted 2-amino-1,3,4-thiadiazole replaces the urea function. Reaction of isobutyryl chloride (123-1) with thiosemicarbazone (123-2) leads initially to the transient 1,2-diacyUiydrazine (123-3). This apparently cyclizes spontaneously to thiadiazine (123-4) under reaction conditions. Acylation with p-methoxysulfonyl chloride (123-5) affords the oral hypoglycemic agent isobuzole (123-6) [134]. 

Tolbutamide is well absorbed but rapidly metabolized in the liver. Its duration of effect is relatively short, with an elimination half-life of 4-5 hours, and it is best administered in divided doses. Because of its short half-life, it is the safest sulfonylurea for elderly diabetics. Prolonged hypoglycemia has been reported rarely, mostly in patients receiving certain drugs (eg, dicumarol, phenylbutazone, some sulfonamides) that inhibit the metabolism of tolbutamide. 

All sulfonamides, including antimicrobial sulfas, diuretics, diazoxide, and the sulfonylurea hypoglycemic agents, have been considered to be partially cross-allergenic. Flowever, evidence for this is not extensive. The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and difficulties referable to the urinary tract (see below). Stevens-Johnson syndrome, although relatively uncommon (ie, < 1% of treatment courses), is a particularly serious and potentially fatal type of skin and mucous membrane eruption associated with sulfonamide use. Other unwanted effects include stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see below), hepatitis, and, rarely, polyarteritis nodosa and psychosis. 

Drug-induced photosensitivity reactions are divided into phototoxicity (a nonimmunologic reaction) and photoallergic reactions (an immunologic reaction). The latter form is far less common. Medications associated with photosensitivity reactions include fluoroquinolones, nonsteroidal antiinflammatory drugs, phenothiazines, antihistamines, estrogens, progestins, sulfonamides, sulfonylureas, thiazide diuretics, and tricyclic antidepressants. 

A15.1.3.1 Sulfonamides, Sulfonylureas, Epoxides, and Aziridines. Sulfonamides (RS02NR"2) are susceptible to acid hydrolysis (RS02NR"2 -1- water -1-acid RSO2OH), but not basic hydrolysis. Primary alcohols react rapidly only with A,A -disubstituted sulfonamides to yield sulfonic esters (RS02NR"2 -1-R OH -I- acid RSO2OR + NHR y. Sulfonamides are not susceptible to oxidation because the sulfur is already fuUy oxidized. 

Acute thrombocytopenia is rarely associated with the newer sulfonamides (4,93,94). The structurally related sulfonylureas and thiazide diuretics can also cause allergic thrombocytopenia (95). Although some in vitro tests have been reported to predict the occurrence of thrombocytopenia, none of these has been used routinely (96,97). Furthermore, a negative test result with a drug does not definitely exclude it as the responsible allergen. 

SIM with three compound specific ions can be applied, as for instance demonstrated by Wang and Budde [101] for sixteen carbamate, urea and thioiuea pesticides and herbicides, by Rodriguez and Orescan [51] for selected sulfonylurea, imidazolinone, and sulfonamide herbicides, and by Yu et al. [17] for 52 carbamates, thiocaibamates, and phenylureas. In the latter case, computer-controlled optimization of the MS measurement conditions is performed. The most prominent ion, either a protonated or an ammoniated molecule, is used for quantitation. The dwell time for each ion in SIM was 0.02 s with an inter-charmel delay of 0.02 s, i.e., 2 s are needed for each data point in the chromatogram. Detection limits ranged from 0.09 to 19 pg/1 with 50-pl injections. 

A typical thermospray ionization mass spectrum for a sulfonylurea contains a weak protonated molecular ion and three to four characteristic fragment ions. Figure 2 shows the thermospray positive ion mass spectrum for HARMONY. The spectrum contains a protonated molecular ion at m/z 388, the sulfonamide ammonium adduct ion at m/z 239 and the protonated triazine urea fragment ion at m/z 184. At the same time, Figure 3 shows the positive ion thermospray mass spectrum for LONDAX. It contains the protonated pyrimidine amine at m/z 156, the protonated pyrimidine urea is at m/z 199 and the sulfonamide ammonium adduct ion at m/z 247. LONDAX (bensulfuron methyl) is a sulfonylurea rice herbicide and it elutes between EXPRESS and CLASSIC if we use the LC conditions outlined in Figure 1. HARMONY and LONDAX thermospray spectra were generated with the thermospray vaporizer tip temperature at 150°C and the source block temperature at 320°C. 

The administration of total parenteral nutrition for periods greater than 1 week induces cholestatic changes and nonspecific enzyme elevations in some patients. Patients with low serum albumin concentrations may be at greater risk than patients with normal serum albumin concentrations. This reaction also has been reported to occur rarely with sulfonamides, sulfonylureas, erythromycin estolate and ethylsuccinate, captopril, fisinoprU, and other phenothiazines. ... 

Like all sulfonamides, sulfasalazine is contraindicated in patients with known hypersensitivity to other drags containing sulfur (thiazides, furosemide, or oral sulfonylureas), in patients with known hypersensitivity to salicylates, in patients with severe renal or hepatic dysfunction, or porphyria, during pregnancy, and during lactation, and in infants and children under age 2. Sulfasalazine is also contraindicated in patients with intestinal or urinary tract obstructions because of the risk of local GI irritation and of crystalluria. 

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