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Questions and Answers
What is a common adverse effect of cotrimoxazole?
What deficiency can be caused by trimethoprim in patients with poor diets?
Which drug can reverse the adverse effects of megaloblastic anemia caused by trimethoprim?
What condition is not treated with sulfasalazine?
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How are sulfonamides primarily eliminated from the body?
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In which fluids do trimethoprim concentrate due to its properties?
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What effect do sulfa drugs have on warfarin and methotrexate serum levels?
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Which potential adverse effect of trimethoprim could be fatal?
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What is the primary mechanism of action of sulfonamides?
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Which of the following is an intermediate-acting sulfonamide?
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What type of infections can be treated with cotrimoxazole?
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Which infection is primarily treated using trimethoprim alone?
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What can cause sulfamethoxazole resistance in bacteria?
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Which topical agent is specifically indicated for burn wounds?
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What differentiates trimethoprim from sulfonamides in terms of potency?
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Which adverse effect is specifically associated with sulfonamides?
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The sulfonamide associated with the treatment of burns is?
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What mechanism contributes to trimethoprim resistance in bacteria?
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Which of the following does NOT represent a structural analog of PABA?
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Cotrimoxazole is effective in a broader spectrum of infections due to the combination of which two agents?
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What is a common hematopoietic disturbance associated with sulfonamide use in G6PD deficiency patients?
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Which of the following is NOT a condition effectively treated by trimethoprim?
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Why is adequate hydration important when using sulfonamides?
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What kind of organism is primarily treated with cotrimoxazole?
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Study Notes
Sulfonamides & p-aminobenzoic acid (PABA)
- Sulfonamides are structural analogs of PABA.
- Sulfonamides are bacteriostatic.
Mechanism of Action
- Humans obtain folic acid from the diet.
- Many bacteria synthesize folate derivatives because their cell walls are impermeable to folic acid.
- Sulfonamides compete with PABA for the bacterial enzyme dihydropteroate synthetase.
- This inhibits the synthesis of bacterial dihydrofolic acid and essential cofactors.
- Humans do not have this pathway.
- Trimethoprim inhibits dihydrofolate reductase, which inhibits tetrahydrofolic acid synthesis.
- Tetrahydrofolic acid is required for purine, pyrimidine, and amino acid synthesis.
- Trimethoprim has a stronger affinity for bacterial dihydrofolate reductase than human dihydrofolate reductase (this is why it is selective).
Antibacterial Spectrum
- Sulfonamides are seldom prescribed alone.
- Inhibit nocardia infections and enterobacteriaceae in the urinary tract.
- Trimethoprim can be used alone to treat urinary and respiratory infections; prostatitis, shigellosis, invasive salmonella infections (20 to 50 times more potent than sulfonamides).
- Cotrimoxazole has a broader spectrum than sulfonamides alone.
- Cotrimoxazole treats UTIs, respiratory tract infections, Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis, and ampicillin- or chloramphenicol-resistant salmonella infections.
- Cotrimoxazole is also effective against community-acquired skin and soft tissue infections caused by MRSA.
- Cotrimoxazole 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.
- Bacteria obtain folate from the environment.
- Resistance can occur due to altered dihydropteroate synthetase (altered target).
- Decreased drug permeability or increased PABA can also lead to resistance.
- Trimethoprim resistance can occur due to altered dihydrofolate reductase (low affinity towards the drug).
- Efflux pumps, decreased drug permeability, and altered dihydrofolate reductase are all mechanisms of resistance.
- Cotrimoxazole resistance occurs less commonly but is known to occur in E. coli and MRSA.
Topical Agents
- Sodium sulfacetamide ophthalmic solution or ointment is effective in the treatment of bacterial conjunctivitis and as adjunctive therapy for trachoma.
- Mafenide acetate is used topically (but produces pain).
- Mafenide acetate can be absorbed from burn sites, increasing the risk of acid-base imbalance.
- Silver sulfadiazine is the drug of choice for burn wounds (less toxic).
Adverse Effects
- Sulfonamides:*
- Crystalluria (nephrotoxicity): Adequate hydration and alkalinization of urine can prevent this (decreases the drug's concentration and promotes ionization).
- Hypersensitivity: Rashes, angioedema, Stevens-Johnson syndrome.
- Hematopoietic disturbances: Hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients; granulocytopenia, thrombocytopenia, agranulocytosis, aplastic anemia, and other blood dyscrasias.
- Kernicterus: Occurs in newborns. Sulfa drugs displace bilirubin from serum albumin, which allows free bilirubin to enter the CNS (BBB is not fully developed in newborns).
- Drug potentiation: Increased serum levels of warfarin and methotrexate (sulfa drugs displace the drugs from serum albumin).
- Trimethoprim*
- Folic acid deficiency: Megaloblastic anemia, leukopenia, and granulocytopenia (especially in pregnant and malnourished patients). Administration of folinic acid (10 mg) can reverse this, because it does not enter bacteria.
- Cotrimoxazole*
- Skin rash (common)
- Nausea and vomiting (most common)
- Megaloblastic anemia, leukopenia, and thrombocytopenia can occur (fatal cases reported). Administration of folinic acid can often reverse these effects.
- Hemolytic anemia in patients with G6PD deficiency.
- Drug potentiation: Increased serum levels of warfarin and methotrexate (sulfa drugs displace the drugs from serum albumin).
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 generally applied topically (sensitization).
- However, creams of silver sulfadiazine/mafenide acetate are used to reduce burn-associated sepsis.
- IV form given for patients who cannot swallow.
- Protein bound.
- Distributed widely throughout the body fluid, including CSF even in the absence of inflammation.
- Acetylated and conjugated in the liver.
- Metabolites have no antimicrobial activity but can be toxic at neutral/acidic pH (Causes crystalluria).
- Eliminated by glomerular filtration and secretion.
- Trimethoprim:*
- Rapid oral absorption.
- Wide distribution including the CSF.
- Weak base (concentrate in acidic prostatic and vaginal fluids).
- 60-80% is excreted unchanged via the kidneys.
- Cotrimoxazole*
- Oral (preferred) or IV (for severe pneumonia caused by PCP).
- Wide distribution including the CSF.
- Both parent drugs and metabolites are excreted in the urine.
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Description
Test your knowledge on sulfonamides, their mechanism of action, and how they relate to p-aminobenzoic acid (PABA). Understand the antibacterial spectrum and the significance of folate synthesis in bacteria. This quiz will help reinforce your understanding of these important pharmacological concepts.
