Trimethoprim sequential blocking

Figure 7.12 Sequential blocking using sulphamethoxazole and trimethoprim...

Trimethoprim exerts a synergistic effect with sulfonamides. It potently and selectively inhibits microbial dihydrofolate reductase, the enzyme that reduces dihydrofolate to tetrahydrofolate—the form required for one-carbon transfer reactions. Coadministration of a sulfonamide and trimethoprim thus introduces sequential blocks in the biosynthetic pathway for tetrahydrofolate (Figure 43-2). 

Trimethoprim is most used in medical practice in conjunction with a sulfonamide, with the aim of achieving sequential blocking (Section 9.6). All anti-folic drugs are used with caution during pregnancy to avoid damage to the foetus. 

Sequential blocking offers very practical advantages in antibacterial chemotherapy also. The synergistic effect of trimethoprim 9.32) with sulfadiazine, shown in Fig. 9.5, is evident. In medical practice, the most striking and... 

Sulphamethoxazole ( Gantanol 3-p-aminobenzenesulphonamido-5-me-thylisoxazole) has been selected for use with trimethoprim for sequential blocking (Section 9.5), because both drugs have similar distribution and duration. 

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

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. 

Another frequently employed combination is that of a sulfonamide and an inhibitor of dihydrofolate reductase, such as trimethoprim this combination is synergistic because the drugs block sequential steps in microbial folate synthesis. 

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