Diaminopyrimidines inhibit dihydrofolate reductase, the enzyme that generates tetrahydrofolate (the active form of the vitamin) from the metabolically inactive dihydrofolate. Trimethoprim (Fig. 1), the most important antibacterial agent of this type, exhibits greater affinity for the dihydrofolate reductase of bacteria than for the corresponding mammalian enzyme; this is the basis of the selective toxicity of the compound.

Figure 1. Chemical structure of trimethoprim

Sulphonamides and trimethoprim act at different points in the same metabolic pathway interacting synergically: bacteria are inhibited by lower concentrations of the combination than by either agent alone. Trimethoprim and sulphonamides are often combined in therapeutic formulations, although trimethoprim alone is probably as effective and less toxic. The most commonly used combination is trimethoprim and sulfamethoxazole (co-trimoxazole), but combinations of trimethoprim with sulfadiazine (co-trimazine) and sulfamoxole (co-trifamole) are also available.

Trimethoprim is active at low concentration against many common pathogenic bacteria. Resistance is very high but there is high geographical variability. The drug is rapidly absorbed from the gut and excreted almost exclusively by the kidneys with a plasma half-life of about 10 h. The principal use for trimethoprim is in urinary tract infection. The combination with sulfamethoxazole is principally used in pneumonia caused by the fungus, Pneumocystis carinii. It has also been extensively used in many other clinical situations, including typhoid fever, and brucellosis. Although toxic side effects are uncommon, trimethoprim-sulphonamide combinations can give rare, but severe side effects and it is preferable to use trimethoprim alone wherever possible.

Analogues of trimethoprim, including tetroxoprim and brodimoprim, are marketed in combination with sulphonamides but offer few, if any advantages. Other diaminopyrimidines include the antimalarial agents pyrimethamine and proguanil (Chapter 5); the anti-pneumocystis agent trimetrexate; and the antineoplastic agent methotrexate.


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