Antimetabolites: Sulfonamides and trimethoprim

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Antimetabolites: Sulfonamides and trimethoprim

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A 27-year-old woman presents to the emergency department with shortness of breath, chest pain, and blue discoloration of lips. The patient reports that symptoms started a few hours after she took double the dose of the drug prescribed to her by a dermatologist for intensely pruritic erythematous papules and vesicles on elbows and knees. Past medical history is significant for celiac disease managed by strictly following a gluten-free diet. Oxygen saturation on pulse oximetry is 85% on ambient air. A 100% oxygen by nasal cannula is administered but fails to improve pulse oximetry readings or the cyanosis. Physical examination shows bluish discoloration of lips and fingertips. Results of urgent laboratory investigation are shown below. Which of the following medications most likely contributed to this patient’s condition?  

 Laboratory value  Result 
 Arterial blood gas 
 pH  7.39 
 PaO2  142 mm Hg 
 PaCO2  34 
 Oxygen saturation  99% 

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Agranulocytosis p. 591

sulfa drug allergies p. 251

Anemia

sulfa drug allergies as cause p. 251

Chlamydia spp. p. 146

sulfonamides for p. 191

Hemolysis

sulfonamides as cause p. 191

Hemolytic anemia p. 427

sulfa drug allergies p. 251

Hypersensitivity reactions p. 110-111

sulfonamides p. 191

Nephrotoxicity

sulfonamides p. 191

Nocardia spp.

sulfonamides for p. 191

Photosensitivity (cutaneous)

sulfonamides p. 191

Stevens-Johnson syndrome p. 191, 490, 560

sulfa drug allergies p. 251

Sulfa drugs p. 251

acute pancreatitis p. 404

erythema multiforme p. 490

G6PD deficiency from p. 415

megaloblastic p. 249

rash p. 249

Sulfonamides p. 191

acute interstitial nephritis from p. 620

cytochrome P-444 and p. 251

hemolysis in G6PD deficiency p. 249

hypothyroidism p. 248

mechanism p. 184

Nocardia spp. p. 137

photosensitivity p. 249

pregnancy contraindication p. 200

trimethroprim p. 191

vitamin BNaN deficiency p. 66

Thrombocytopenia p. 413

sulfa drug allergies p. 251

Urinary tract infections (UTIs) p. 179, 619

sulfa drugs for p. 251

sulfonamides for p. 191

Urticaria p. 483, 485

sulfa drug allergies p. 251

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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.

Sources

  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  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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