Antimetabolites: Sulfonamides and trimethoprim

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Antimetabolites: Sulfonamides and trimethoprim


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Antimetabolites: Sulfonamides and trimethoprim

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Agranulocytosis p. 597

sulfa drug allergies p. 253


sulfa drug allergies as cause p. 253

Chlamydia spp. p. 146

sulfonamides for p. 191


sulfonamides as cause p. 191

Hemolytic anemia p. 429

sulfa drug allergies p. 253

Hypersensitivity reactions p. 110-111

sulfonamides p. 191


sulfonamides p. 191

Nocardia spp.

sulfonamides for p. 191

Photosensitivity (cutaneous)

sulfonamides p. 191

Stevens-Johnson syndrome p. 191, 494, 565

sulfa drug allergies p. 253

Sulfa drugs p. 253

acute pancreatitis p. 406

erythema multiforme p. 494

G6PD deficiency from p. 417

megaloblastic p. 251

rash p. 251

Sulfonamides p. 191

acute interstitial nephritis from p. 626

cytochrome P-448 and p. 253

hemolysis in G6PD deficiency p. 251

hypothyroidism p. 250

mechanism p. 184

Nocardia spp. p. 137

photosensitivity p. 251

pregnancy contraindication p. 201

trimethroprim p. 191

vitamin BNaN deficiency p. 66

Thrombocytopenia p. 415

sulfa drug allergies p. 253

Urinary tract infections (UTIs) p. 179, 625

sulfa drugs for p. 253

sulfonamides for p. 191

Urticaria p. 487, 489

sulfa drug allergies p. 253


Antimetabolites are medications that interfere with the synthesis of DNA.

Some antimetabolites are used in chemotherapy to kill cancer cells, while others are used as antibiotics since they inhibit bacterial folate synthesis.

Folate, or folic acid, also known as vitamin B9, is necessary for the synthesis of nucleic acids, which are the building blocks of DNA and RNA.

Simply put, a lack of folate results in a lack of nucleic acids, which then results in decreased DNA and RNA synthesis, leading to hindered cell division and function.

Now, a key difference between our cells and bacterial cells is that we get all of our folate through our diet, while bacteria can make their own folate from scratch.

Because of this, we can target the bacterial folate synthesis pathway to minimize the damage done to our cells.

So in order to synthesize folate, the bacteria will first use the host’s para-aminobenzoic acid, or pABA, and convert it to dihydropteroic acid via the enzyme dihydropteroate synthetase, or DHPS.

In the second step, dihydropteroic acid is converted into dihydrofolic acid by dihydrofolate synthetase.

The third step is the conversion of dihydrofolic acid into tetrahydrofolic acid via dihydrofolate reductase.

Tetrahydrofolic acid is a folic acid derivative and can be used to synthesize purines like adenine and guanine, which are used to build DNA and RNA, as well as thymidine, which is only used in DNA.

Now, the first group of antimetabolite antibiotics are the sulfonamides, which include sulfamethoxazole, or SMX, sulfisoxazole, and sulfadiazine.

These medications bind to dihydropteroate synthetase, or DHPS, in the first step of folate synthesis and prevents the bacteria from making dihydropteroic acid.

These medications can be given peroral or injected into a vein, but they need to be metabolized by the liver in order to work.

Now, they are broad spectrum and can treat a variety of gram positive and gram negative bacteria, as well as chlamydia and nocardia species.

Next we have trimethoprim, which inhibits the 3rd step of folate synthesis by inhibiting dihydrofolate reductase, or DHFR, preventing the formation of tetrahydrofolic acid.

Now humans also have dihydrofolate reductase, but the bacterial version of this enzyme is 4-5 times more sensitive to this medication.

Trimethoprim is also broad spectrum and is effective against both gram positive and gram negative bacteria.


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  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Methotrexate, and trimethoprim-sulfamethoxazole: toxicity from this combination continues to occur" Can Fam Physician (2014)
  5. "Prophylactic Trimethoprim-Sulfamethoxazole Does Not Affect Pharmacokinetics or Pharmacodynamics of Methotrexate" Journal of Pediatric Hematology/Oncology (2016)
  6. "Medication Use and the Risk of Stevens–Johnson Syndrome or Toxic Epidermal Necrolysis" New England Journal of Medicine (1995)

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