Sulfonamides Methotrexate

Sulfonamides, methotrexate, methoxyfiurane, giafenin, triamterene, ticrynafen, acyciovir, ethyiene glycoi, protease inhibitors, cidoforvir, adeforvia. ... 

Crystal deposition Particularly important with acyclovir and indinavir, but also noted with sulfonamides, methotrexate and triamterene. This mechanism is becoming more recognized due to the rise in the incidence of tumor-lysis syndrome with AKI. Acute kidney injury caused by tubular obstruction can also occur with a number of drugs (Table 2), due to intratubular precipitation of the... 

Examples sulfonamides, methotrexate, oxalic acid, acyclovir Tubulointerstitial nephritis... 

Sulfonamides, methotrexate, methoxyflurane, glafenin, triamterene, ticrynafen, acyclovir, ethylene glycol, protease... 

When a sulfonamide is administered with an oral anticoagulant, the action of the anticoagulant may be enhanced. The risk of bone marrow suppression may be increased when a sulfonamide is administered with methotrexate When a sulfonamide is administered with a hydantoin, the serum hydantoin level may be increased. 

Sulfasalazine is an antiinflammatory agent that inhibits 5-lipoxygenase. It is used selectively as an alternative treatment, particularly in patients with concurrent psoriatic arthritis. When used alone, it is not as effective as methotrexate, PUVA, or acitretin. However, it has a relatively high margin of safety. The usual oral dose is 3 to 4 g/day for 8 weeks. Its adverse effects are similar to other sulfonamide antibiotics. 

Methotrexate Sulfonamides Glomerular disease Gold Nonsteroidal antiinflammatory drugs, cyclooxygenase-2... 

Drugs that may be affected by probenecid include acyclovir allopurinol barbiturates benzodiazepines clofibrate dapsone dyphylline methotrexate NSAIDs pantothenic acid penicillamine rifampin sulfonamides sulfonylureas zidovudine salicylates. 

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

Drugs that may affect methotrexate include oral aminoglycosides, charcoal, chloramphenicol, folic acid, NSAIDs, PCNs, probenecid, salicylates, sulfonamides, TCN, trimethoprim. 

Drugs that may be affected by methotrexate include sulfonamides, digoxin, phenytoin, theophylline, and thiopurines (eg, azathioprine). 

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. 

Salicylates, probenecid, and sulfonamides inhibit the renal tubular secretion of methotrexate and may displace it from plasma proteins. Asparaginase inhibits protein synthesis and may protect cells from methotrexate cytotoxicity by delaying progression from Gj-phase to S-phase. Methotrexate may either enhance or inhibit the action of fluorouracil, depending on its sequence of administration. 

See Chapters 34 and 40 in Lippincott s Illustrated Reviews Pharmacology (3rd Ed.) and Chapters 29 and 38 (2nd Ed) for a discussion of sulfonamides, trimethoprim, and methotrexate... 

Another dihydrofolate inhibitor trimethoprim is an important antibacterial drug, usually given together with a sulfonamide. Although it is not as close a structural analog of folic acid as is methotrexate, it is... 

Another group of inhibitors prevents nucleotide biosynthesis indirectly by depleting the level of intracellular tetrahydrofolate derivatives. Sulfonamides are structural analogs of p-aminobenzoic acid (fig. 23.19), and they competitively inhibit the bacterial biosynthesis of folic acid at a step in which p-aminobenzoic acid is incorporated into folic acid. Sulfonamides are widely used in medicine because they inhibit growth of many bacteria. When cultures of susceptible bacteria are treated with sulfonamides, they accumulate 4-carboxamide-5-aminoimidazole in the medium, because of a lack of 10-formyltetrahydrofolate for the penultimate step in the pathway to IMP (see fig. 23.10). Methotrexate, and a number of related compounds inhibit the reduction of dihydrofolate to tetrahydrofolate, a reaction catalyzed by dihydrofolate reductase. These inhibitors are structural analogs of folic acid (see fig. 23.19) and bind at the catalytic site of dihydrofolate reductase, an enzyme catalyzing one of the steps in the cycle of reactions involved in thymidylate synthesis (see fig. 23.16). These inhibitors therefore prevent synthesis of thymidylate in replicating... 

Normal metabolites with which indirect inhibitors of nucleotide metabolism compete. Methotrexate and trimethoprim compete with folate and, more importantly, with dihydrofolate (fig. 23.16) sulfonamides (sulfa drugs) compete with p-aminobenzoate. 

The active form of folate is the tetrahydro-derivative that is formed through reduction by dihydrofolate reductase. This enzymatic reaction (Figure 29.5) is inhibited by trimethoprim, leading to a decrease in the folate coenzymes for purine, pyrimidine, and amino acid synthesis. Bacterial reductase has a much stronger affinity for trimethoprim than does the mammalian enzyme, which accounts for the drug s selective toxicity. [Note Examples of other folate reductase inhibitors include pyrimethamine, which is used with sulfonamides in parasitic infections (see p. 353), and methotrexate, which is used in cancer chemotherapy (see p. 378).]... 

One attraction of SHW is that it can be used for reversed-phase separations and is therefore readily applicable to a wide range of pharmaceutical compounds including barbiturates, sulfonamides, analgesics and steroids (Table 18-2), and anticancer drugs, including 5-fluorouracil, methotrexate, and... 

Obstruction (intratubular precipitation) Acyclovir, methotrexate, sulfonamides, triamterene, indinavir, foscarnet, gancyclovir Sediment might be benign despite obstruction... 

Methotrexate + sulfonamides Potentiation of methotrexate with high risk of toxicity Displacement from protein binding (sulfafurazole reduces methotrexate binding from 70% to 28%) Owing to severity of methotrexate toxicity, sulfonamides that are protein-bound should never be administered... 

Clinically important, potentially hazardous interactions with allopurinol, bromelain, chloramphenicol, demeclocydine, doxycydine, erythromycin, imipenem/cilastatin, methotrexate, minocycline, oxytetracycline, sulfonamides, tetracycline... 

Clinically important, potentially hazardous interactions with acitretin, antacids, cholestyramine, dapsone, furazolidone, halofantrine, hydroxychloroquine, methotrexate, methoxsalen, mivacurium, nilotinib, penicillamine, sulfonamides... 

Clinically important, potentially hazardous interactions with anticoagulants, antidiabetics, barbiturates, chlorpheniramine, corticosteroids, digoxin, gliclazide, lithium, methotrexate, methylphenidate, phenytoin, rifampin, sulfonamides... 

Clinically important, potentially hazardous interactions with amphotericin B, benzodiazepines, doripenem, ertapenem, fludoxacillin, furosemide, glibenclamide, ketoprofen, ketorolac, methotrexate, NSAIDs, pemetrexed, penicillamine, penicillin G, penicillin V, salicylates, sulfamethoxazole, sulfonamides, torasemide, torsemide... 

Pulmonary infiltrates with eosinophilia (Loeffler s syndrome) have been associated with nitrofurantoin,para-aminosalicytic acid, methotrexate, sulfonamides, tetracycline, chlorpropamide, phenytoin, NSAIDs, and imipramine (Table 29-5). The disorder is characterized by fever, nonproductive cough, dyspnea, cyanosis, bilateral pulmonary infiltrates, and eosinophilia in the blood. Lung biopsy has revealed perivasculitis with infiltration of eosinophils, macrophages, and proteinaceous edema fluid in the alveoli. The symptoms and eosinophilia generally respond rapidly to withdrawal of the offending drug. 

Figure 9 (a) Dihydropteroate synthase inhibitors as antibacterial agents. 30, Sulfonamide core structure 31, sulfadiazine 32, sulfisoxazole 33, prontosil 34, sulfamethoxazole (SMX) and (b) inhibitors of dihydrofolate reductase. 35, Trimethoprim (TMP) 36, brodimoprim 37, tetroxoprim 38, iciaprim 39, methotrexate. ... 

Drug interactions Competition with warfarin and methotrexate for plasma protein binding transiently increases the plasma levels of these drugs. Sulfonamides can displace bilirubin from plasma proteins, with the risk of kemicterus in the neonate if used in the third trimester of pregnancy. 

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. 

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