Sulfonamides

Structure-activity relationship: Acetylation or conjugation with glucuronic acid takes place in the N4 amine group with the resulting acetylation derivatives being inactive.

Mechanism of action: Sulfonamides are bacteriostatic, enhancing phagocytosis of susceptible organisms. Sulfonamides compete with PABA for incorporation into folic acid. Only organisms that endogenously synthesize folate are susceptible.

Resistance:

1. Decreased permeability of cell wall;

2. Decreased enzyme affinity for sulfonamide;

3. Increase in PABA production.

Importance of folate: Folate coenzymes specifically catalyze the transfer and utilization of single carbon moieties that are necessary in the biosynthesis of purines, thymine, and AA (serine, glycine, methionine, histidine).

Pharmacokinetics:

Peak level reached in 3-4 hrs; effect lasts for 3-4 days; absorbed from duodenum; orally administered; renal excretion rate varies; good penetration (CSF 50-80% of plasma level); acetylated derivatives are more highly bound and thus more difficult to excrete  can lead to crystalluria in kidneys; alkalinization of the urine promotes excretion.

Toxicity and side effects: Hypersensitivity with Steven-Johnson syndrome (long acting sulfamethoxypyridazine and sulfadimethoxine); hemolytic anemia in individuals deficient in G6PDH; agranulocytosis; hepatitis; nausea, vomiting, diarrhea; crystalluria; reduction in gut bacteria can lead to vitamin K deficiency.

Drug interactions:

1. Sulfonamides given to mothers during delivery can precipitate kernicterus in neonates due to displacement of bilirubin;

2. Hypoglycemia when given with tolbutamide;

3. Cotrimoxazole increases warfarin levels;

4. Sulfa drugs displace thiopental so anesthesia lasts longer;

5. Vitamin K deficiency-associated bleeding;

6. Increased half-lives of some anticonvulsants (phenytoin).

Spectrum: Gram(+), gram (-), some filterable agents, trachoma, Nocardia.

Indications: UTIs, nocardiosis (agent of choice), chlamydial infections, shigellosis (nonabsorbable sulfas), trachoma/inclusion conjunctivitis (with tetracyclines).

• Sulfadiazine – short-acting, liquid suspension available.
• Sulfisoxazole – short-acting
• Sulfamethylthiadazole – short-acting
• Sulfamethoxazole – intermediate-acting, more likely to cause crystalluria, liquid suspension available.
• Mafenide – topical, used for chronic burn lesions, alpha-amino-p-toluensulfonamide.
• Succinylsulfathiazole & Salicylazosulfapyridine – poorly-absorbed, used to decrease gut flora, prodrugs.

Category: Pharmacology Notes