Sulfonamides Pyrimethamine

A combination of pyrimethamine, sulfonamide, and qninine is the dmg of choice for acute attacks of malaria and its chloroquine-resistant forms. 

Sulfonamides in combination with dihydrofolate reductase inhibitors are of continuing value. Pyrimethamine [58-14-0] (5) in combination with sulfonamides is employed for toxoplasmosis (7), and a trimethoprim (6)-sulfamethoxa2ole preparation is used not only for urinary tract infections but also for bmceUosis, cholera, and malaria. 

Other Infections. The slowly excreted sulfonamides (eg, sulfamethoxypyrida2ine, sulfadimethoxine) are used for treatment of minor infections such as sinusitis or otitis, or for prolonged maintenance therapy. Soluble sulfonamides are sometimes used for proto2oal infections in combination with other agents. Pyrimethamine, combined with sulfonamides, has been used for toxoplasmosis or leishmaniasis, and trimethoprim with sulfonamides has been used in some types of malaria. In nocardiosis, sulfonamides have been used with cycloserine [68-41-7] (17). 

Prednisone Propranolol Spironolactone Sulfonamides Desipramine Pyrimethamine... 

Different antimalarials selectively kill the parasite s different developmental forms. The mechanism of action is known for some of them pyrimethamine and dapsone inhibit dihydrofolate reductase (p. 273), as does chlorguanide (proguanil) via its active metabolite. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p. 272). Chlo-roquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme, the latter substance being toxic for the schizonts. 

Currently, the most widely used are sulfisoxazole, sulfamethoxazole, sulfadiazine, sul-famethizole, and trisulfapyrimidine (a mixture of sulfamerazine, sulfamethazine, and sulfadiazine). The first two drugs mentioned are the most widely used. The long-lasting sulfonamide (sulfadioxin) is used only in combination with pyrimethamine (an antagonist of folic acid) for prevention and treatment of tropical fever. 

It has been shown that a few sulfones and sulfonamides may be of interest as drugs for treating malaria. Experimental research uncovered the pronounced synergism between sulfonamides and chloroguanide and pyrimethamine. 

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. 

The use of the long-acting sulfonamides such as sulfadimethoxine and sulfadoxine is limited because of a high rate of hypersensitivity reactions. Sulfadoxine in combination with pyrimethamine is indicated for chloroquine-resistant falciparum malaria. 

VI.a.2.4. Diaminopyrimidines. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum... 

Sulfonamides, such as sulfadiazine, in combination with pyrimethamine, are considered the treatment of choice of symptomatic toxoplasmosis. Patients should be well hydrated to prevent crystalluria this problem may be reduced with the use of triple sulfas (trisulfapyrimidine). Some regimens have included a sulfonamide (sul-fadoxine) in combination with pyrimethamine (Fansidar) for the treatment of chloroquine-resistant malaria caused by P. falciparum. 

Whereas the sulfonamides and sulfones inhibit the initial step whereby PABA and the pteridine moiety combine to form dihydropteroic acid (see Chapter 44), pyrimethamine and trimethoprim inhibit the conversion of dihydrofolic acid to tetrahydrofoUc acid, a reaction... 

The combined use of sulfonamides or sulfones with dihydrofolate reductase inhibitors, such as trimethoprim Bactrim, Septra) or pyrimethamine Fansidar), s, a good example of the synergistic possibilities that exist in multiple-drug chemotherapy. This type of impairment of the parasite s metabolism is termed sequential blockade. Using drugs that inhibit at two different points in the same biochemical pathway produces parasite lethality at lower drug concentrations than are possible when either drug is used alone. 

In addition to its antimalarial effects, pyrimethamine is indicated (in combination with a sulfonamide) for the treatment of toxoplasmosis. The dosage required is 10 to 20 times higher than that employed in malarial infections. 

Anti metabolite action Sulfonamides, sulfones, INFI, ethambutol, trimethoprim, PAS, pyrimethamine. 

Trimethoprim is a pyrimidine derivative (diaminopyrimidine) related to antimalarial drug pyrimethamine, which selectively inhibits bacterial dihydrofolate reductase, necessary for the conversion of dihydrofolate to tetrahydrofolic acid. Sulfonamides act by inhibiting the incorporation of PABA into dihydrofolate by bacteria. A combination of... 

Ultra long acting sulfonamides in combination with pyrimethamine are used. The effect is supraadditive due to sequential block. It may be employed as a clinical curative. Another advantage of the drug combination is that the development of resistance is retarded. 

Combination of a sulfonamide with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) provides synergistic activity because of sequential inhibition of folate synthesis (Figure 46-2). 

Sulfadoxine is the only long-acting sulfonamide currently available in the USA and only as a combination formulation with pyrimethamine (Fansidar), a second-line agent in treatment for malaria (see Chapter 52). 

Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial dihydrofolic acid reductase, which converts dihydrofolic acid to tetrahydrofolic acid, a step leading to the synthesis of purines and ultimately to DNA (Figure 46-2). Trimethoprim is about 50,000 times less efficient in inhibition of mammalian dihydrofolic acid reductase. Pyrimethamine, another benzylpyrimidine, selectively inhibits dihydrofolic acid reductase of protozoa compared with that of mammalian cells. As noted above, trimethoprim or pyrimethamine in combination with a sulfonamide blocks sequential steps in folate synthesis, resulting in marked enhancement (synergism) of the activity of both drugs. The combination often is bactericidal, compared with the bacteriostatic activity of a sulfonamide alone. 

Pyrimethamine and proguanil selectively inhibit plasmodial dihydrofolate reductase, a key enzyme in the pathway for synthesis of folate. Sulfonamides and sulfones inhibit another enzyme in the folate pathway, dihydropteroate synthase. As described in Chapter 46 and shown in Figure 46-2, combinations of inhibitors of these two enzymes provide synergistic activity. 

In many areas, resistance to folate antagonists and sulfonamides is common for P falciparum and less common for P vlvax. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of mutations leading to increasing levels of resistance. At present, resistance seriously limits the efficacy of sulfadoxine-pyrimethamine (Fansidar) for the treatment of malaria in most areas, but in Africa most parasites exhibit only moderate resistance, such that antifolates appear to continue to offer preventive efficacy against malaria. Because different mutations may mediate resistance to different agents, cross-resistance is not uniformly seen. 

Pyrimethamine may also be combined with other antimalarials such as artemisinin derivatives, but these regimens should only be used if the malarial parasites are not resistant to the specific drugs in the regimen.13 Pyrimethamine can also be combined with a sulfonamide drug such as dapsone, sulfadiazine, or sulfamethoxazole to treat protozoal infections that cause toxoplasmosis, or fungal infections that cause Pneumocystis pneumonia.These agents are administered orally. 

Mechanism of Action. Pyrimethamine blocks the production of folic acid in susceptible protozoa by inhibiting the function of the dihydrofolate reductase enzyme. Folic acid helps catalyze the production of nucleic and amino acids in these parasites. Therefore, this drug ultimately impairs nucleic acid and protein synthesis by interfering with folic acid production. The action of sulfadoxine and other sulfonamide antibacterial agents was discussed in Chapter 33. These agents also inhibit folic acid synthesis in certain bacterial and protozoal cells. 

Sulfonamides — Sulfadoxine or sulfadiazine is used with pyrimethamine. 

Sulfones — Dapsone (DDS) is used in place of or in addition to the sulfonamides and pyrimethamine. 

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