Pharmacology
Summary
Trimethoprim/Sulfamethoxazole is a combination drug that disrupts folate synthesis at two sequential steps. It consists of two medications: sulfamethoxazole, a PABA analog that inhibits the first enzymatic step (dyhydropterate synthase) and trimethoprim which blocks the second enzymatic step (dihydrofolate reductase). This combination is often the first-line treatment for urinary tract infections (UTIs) and provides substantial gram-negative gastrointestinal coverage.
Apart from UTIs, trimethoprim/sulfamethoxazole also treats meningitis, and shows activity against the gram-positive bacteria Staphylococcus aureus, including MRSA strains. The combination is also the drug of choice for treating another gram-positive bacterium, Nocardia. Furthermore, it is used for prophylaxis in treating an indolent pneumonia known as Pneumocystis jiroveci pneumonia (PJP) in HIV-infected patients with CD4 counts less than 200. At a CD4 count less than 100, it's used for prophylaxis against Toxoplasmosis. Administration of drugs that block folate production can lead to development of various cytopenias including megaloblastic anemia and are considered teratogenic, leading to neural tube defects.
Side effects of sulfonamides, which are included in the formulation, encompass allergic symptoms including rash, fever, and urticaria. If G6PD deficient, sulfonamides can provoke hemolytic anemia. Other risks include displacement of drugs from albumin, inhibition of the cytochrome P450 system leading to increased concentrations of various drugs, and Stevens-Johnson syndrome, a severe type of skin and mucous membrane eruption. Trimethoprim/sulfamethoxazole can also cause photosensitivity, interstitial nephritis, and, for fetuses in the last month of pregnancy, neonatal kernicterus due to the displacement of bilirubin bound to serum albumin.
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FAQs
TMP/SMX is a combination of antibiotics that work synergistically. SMX, a PABA analog, blocks dihydropteroate synthase, an enzyme involved in folate synthesis. TMP blocks dihydrofolate reductase, another enzyme critical in the synthesis of tetrahydrofolic acid. By inhibiting these two sequential steps in folate synthesis, this antibiotic combination effectively impairs the growth and multiplication of bacteria.
TMP/SMX is a versatile antibiotic with a wide range of applications. It is often first line treatment for urinary tract infections and acute prostatitis, and is also used to treat gastroenteritis caused by gram negative bacteria, such as Shigella and Salmonella. It has activity against both gram negative and gram positive bacteria, including Nocardia and MRSA, although it is not the first line empiric treatment for the latter. It is also the treatment of choice for Pneumocystis jirovecii pneumonia (PJP) and is used for PJP prophylaxis in individuals with a CD4 count less than 200. Finally, it is used as a prophylaxis for toxoplasmosis in individuals with a CD4 count less than 100.
Adverse effects of TMP/SMX range from common to rare but serious conditions. Frequently observed reactions include pancytopenia, megaloblastic anemia, photosensitivity, and skin reactions like rash and urticaria, which can escalate to Stevens-Johnson syndrome. It can cause hemolytic anemia in individuals deficient in G6PD. Other severe effects include interstitial nephritis and type IV renal tubular acidosis that can lead to hyperkalemia. Pregnant women particularly in their first trimester should avoid TMP/SMX as it may act as a teratogen causing neural tube defects. The use of sulfonamides in the last month of pregnancy can cause kernicterus in newborns. Rarely, TMP/SMX can also lead to drug-induced lupus.
Both TMP and SMX interfere with the pathways of folic acid synthesis. SMX is a competitive inhibitor of dihydropteroate synthase, preventing the incorporation of PABA, an intermediate in folate synthesis. TMP inhibits dihydrofolate reductase, which converts dihydrofolic acid to its active form, tetrahydrofolic acid. The combined action creates a potent blockade of folate metabolism, which is crucial for bacterial DNA synthesis. Humans, on the other hand, do not synthesize folate but obtain it through their diet, and therefore these drugs selectively affect bacterial cells.
Sulfonamides have the capacity to displace other drugs from their binding sites on albumin, leading to increased free concentrations of these drugs in the blood. Warfarin, an anticoagulant, is one such drug and displacement can enhance its anticoagulant effects, leading to over-anticoagulation and an increased risk of bleeding. In addition, TMP/SMX can inhibit the cytochrome P450 enzymes that metabolize warfarin, further elevating its levels in the blood.
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