Chemistry Structure and Mechanism of Action

Trimethoprim (Trimpex, Proloprim) is a structural analogue of the pteridine portion of dihydrofolic acid. It differs from the sulfonamides in that it acts at a second step in the folic acid synthetic pathway; that is, it competitively inhibits dihydrofolate reductase. This is the enzyme that catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid, the active form of folate. Dihydrofolate reductase is present in both mammalian tissue and bacteria, but 20,000 to 60,000 times more drug is required to inhibit the mammalian enzyme; this accounts for its selective toxicity against bacteria.

Trimethoprim-sulfamethoxazole (TMP-SMX) was introduced as a fixed dose combination in 1968. Tri-methoprim was added to sulfamethoxazole to synergisti-cally and sequentially inhibit bacterial synthesis of tetrahydrofolic acid. The combination was also designed to delay development of bacterial resistance. Sulfameth-oxazole was selected in part because it is a congener of the frequently used sulfisoxazole but exhibits slower enteric absorption and urinary excretion. Sulfamethoxazole has a half-life similar to that of trimethoprim.

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