Pharmacology: Sulfonamides and PABA

Sulfonamides and p-aminobenzoic acid (PABA)

• Sulfonamides are structural analogs of PABA.
• They are used for bacterial infections.
• They are divided into three categories: short-acting, intermediate-acting, and long-acting.

Mechanism of action

• Humans obtain folic acid from their diet to synthesize tetrahydrofolic acid.
• Bacteria synthesize folate derivatives because their cell walls are impermeable to folic acid and other folates.
• Sulfonamides compete with PABA for the bacterial enzyme dihydropteroate synthetase, inhibiting bacterial dihydrofolic acid synthesis.
• This inhibits the synthesis of essential cofactors that humans do not have.
• Trimethoprim inhibits dihydrofolate reductase, inhibiting the synthesis of tetrahydrofolic acid necessary for purine, pyrimidine, and amino acid synthesis.
• Trimethoprim has stronger affinity for bacterial dihydrofolate reductase than for human dihydrofolate reductase.
• Both sulfonamides and trimethoprim are bacteriostatic.

Antibacterial spectrum

• Sulfonamides are seldom prescribed alone.
• They are effective against nocardia infections and enterobacteriaceae in the urinary tract.
• Trimethoprim can be used alone to treat urinary and respiratory tract infections, prostatitis, shigellosis, and invasive salmonella infections.
• It is 20 to 50 times more potent than sulfonamides.
• Cotrimoxazole has a broader spectrum than sulfonamides alone.
• It is used to treat UTIs, respiratory tract infections, Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis, and ampicillin- or chloramphenicol-resistant salmonella infections.
• It is effective against community-acquired skin and soft tissue infections caused by MRSA.
• It is the drug of choice for infections caused by susceptible Nocardia species and Stenotrophomonas maltophilia.

Resistance

• Sulfonamide resistance can occur through plasmid transfer or random mutations.
• Resistance mechanisms include:
  • Bacteria obtaining folate from the environment.
  • Altered dihydropteroate synthetase (altered target).
  • Decreased drug permeability.
  • Increased PABA production.
• Trimethoprim resistance mechanisms include:
  • Altered dihydrofolate reductase (low affinity towards the drug).
  • Efflux pumps.
  • Decreased drug permeability.
• Cotrimoxazole resistance is less common but has been reported in E. coli and MRSA.

Topical agents

• Sodium sulfacetamide ophthalmic solution or ointment is effective in treating bacterial conjunctivitis and as adjunctive therapy for trachoma.
• Mafenide acetate is used topically but can cause pain.
• It can be absorbed from burn sites, increasing the risk of acid-base imbalance.
• Silver sulfadiazine is the drug of choice for burn wounds and is less toxic.

Adverse effects

• Sulfonamides:

  • Crystalluria (nephrotoxicity): Adequate hydration and alkalinization of urine can prevent this problem.
  • Hypersensitivity: Rashes, angioedema, Stevens-Johnson syndrome.
  • Hematopoietic disturbances: Hemolytic anemia in G6PD deficient patients, granulocytopenia, thrombocytopenia, agranulocytosis, aplastic anemia, and other blood dyscrasias.
  • Kernicterus: Occurs in newborns. Sulfa drugs displace bilirubin from serum albumin, allowing it to enter the CNS. The blood-brain barrier is not fully developed in newborns.
  • Drug potentiation: Increases serum levels of warfarin and methotrexate by displacing them from serum albumin.

• Trimethoprim:

  • Folic acid deficiency: Megaloblastic anemia, leukopenia, and granulocytopenia, especially in pregnant or poorly nourished patients.
  • This can be reversed by administering folinic acid (10 mg), which does not enter bacteria.

• Cotrimoxazole (trimethoprim + sulfamethoxazole):

  • Skin rash (common).
  • Nausea and vomiting (most common).
  • Megaloblastic anemia, leukopenia, and thrombocytopenia can occur and have been fatal.
    • This can be reversed by administration of folinic acid.
  • Hemolytic anemia in patients with G6PD deficiency.
  • Drug potentiation: Increases serum levels of warfarin and methotrexate.

Pharmacokinetics

• Sulfonamides:

  • Well absorbed orally, except for sulfasalazine.
  • Oral sulfasalazine is reserved for chronic inflammatory bowel disease (e.g., ulcerative colitis) as its metabolites (sulfapyridine and 5-aminosalicylate) exert anti-inflammatory effects.
  • Not applied topically due to sensitization. However, creams of silver sulfadiazine/mafenide acetate can reduce burn-associated sepsis by preventing bacterial colonization.
  • IV form is used for patients unable to swallow.
  • Protein bound and widely distributed throughout the body fluids, including CSF even in the absence of inflammation.
  • Acetylated and conjugated in the liver; metabolites have no antimicrobial activity but are toxic at neutral/acidic pH (causing crystalluria).
  • Eliminated by glomerular filtration and secretion.

• Trimethoprim:

  • Rapid oral absorption.
  • Wide distribution, including the CSF.
  • Weak base that concentrates in acidic prostatic and vaginal fluids.
  • 60-80% is excreted unchanged via the kidneys.

• Cotrimoxazole:

  • Oral (preferred) and IV (for severe pneumonia caused by PCP) routes.
  • Wide distribution, including the CSF.
  • Both parent drugs and their metabolites are excreted in the urine.