Folic Acid Antagonists

Structure-activity relationship of large molecule antifolates: Can make an isoteric replacement of an amino group for a hydroxyl group at C4. Leaving a hydrogen yields aminopterin while adding a methyl group yields methotrexate.

Structure-activity relationship of small molecule antifolates: Two amino groups for multiple substitutions (R1 and R2), which affect inhibitory properties. Relatively non-toxic compounds.

Mechanism of action: Inhibition of dihydrofolate reductase (pseudoirreversible).

Resistance: Genetic phenomenon leading to increased in dihydrofolate reductase.

Trimethoprim-sulfamethoxazole – TMP has a Vd of 100 L and its concentration in tissues exceeds that of plasma; the opposite is true of sulfamethoxazole; both agents are excreted in the urine in both free and metabolized form; SMX clearance is increased by high urine flow rate and urinary alkalization; TMP clearance is increased in acid urine; combined action is synergistic.

Indications: UTIs, prostatitis, otitis media, bronchitis, p. carinii, shigella, malaria & toxoplasmosis (given with pyrimethamine).

Category: Pharmacology Notes