Paraaminobenzoic Acid

FIGURE 43-1 Structural formulas of selected sulfonamides and para-aminobenzoic acid. The N of the para-NH group is designated as N4; that of the amide NH2, as N1.

After systemic administration, sulfadiazine and sulfisoxazole attain concentrations in cerebrospinal fluid (CSF) that may be effective in meningitis. Sulfonamides readily cross the placenta to reach the fetal circulation, potentially exerting both antibacterial and toxic effects.

The sulfonamides are metabolized in the liver. The major derivative is the N4-acetylated sul-fonamide. Acetylation, which occurs to a varying extent with each agent, is disadvantageous because the resulting products have no antibacterial activity yet retain the toxic potential of the parent substance. Sulfonamides are eliminated partly as the unchanged drug and partly as metabolic products. The largest fraction is excreted in the urine, and the t1/2 of sulfonamides in the body thus

Pteridine + PABA

x— sulfonamides

Dihydropteroic acid .—glutamate

Dihydrofolic acid . NADPH

■ trimethoprim

Tetrahydrofolic acid

FIGURE 43-2 Steps in folate metabolism blocked by sulfonamides and trimethoprim.

depends on renal function. In acid urine, the older sulfonamides are insoluble and crystalluria may result. Small amounts are eliminated in the feces, bile, milk, and other secretions.

Pharmacological Properties of Individual Sulfonamides

The sulfonamides are classed based on the extent or rapidity with which they are absorbed and excreted: (1) agents that are absorbed and excreted rapidly, such as sulfisoxazole and sulfadiazine; (2) agents that are absorbed very poorly when administered orally and hence are active in the bowel lumen, such as sulfasalazine; (3) agents that are used mainly topically, such as sulfacetamide, mafenide, and silver sulfadiazine; and (4) long-acting sulfonamides, such as sulfadoxine, that are absorbed rapidly but excreted slowly.

RAPIDLY ABSORBED AND ELIMINATED SULFONAMIDES Sulfisoxazole

Sulfisoxazole (gantrisin, others) is rapidly absorbed and excreted. Its high solubility eliminates much of the renal toxicity inherent in the use of older sulfonamides. Sulfisoxazole is bound extensively to plasma proteins. From 28% to 35% of sulfisoxazole in the blood and ~30% in the urine is in the acetylated form. It has a serum t/2 of 5—6 hours and ~95% of a single dose is excreted by the kidney in 24 hours. Drug concentrations in urine greatly exceed those in blood and may be bactericidal. The CSF concentration is ~33% of that in the blood. Sulfisoxazole acetyl is tasteless and hence preferred for oral use in children; it is marketed in combination with erythromycin (pediazole, others) for use in children with otitis media.

The untoward effects of sulfisoxazole are similar to those of other sulfonamides. Because of its relatively high solubility, sulfisoxazole rarely produces hematuria or crystalluria (0.2-0.3%). Patients still should ingest an adequate quantity of water. Sulfisoxazole must be used with caution in patients with impaired renal function. Like all sulfonamides, sulfisoxazole may produce hyper-sensitivity reactions, some of which are potentially lethal. Sulfisoxazole generally is preferred over other sulfonamides when a rapidly absorbed and excreted sulfonamide is indicated.

Sulfamethoxazole

Sulfamethoxazole is a close congener of sulfisoxazole, but its rates of enteric absorption and urinary excretion are slower; it has a serum t/2 of 11 hours. It is administered orally and employed for both systemic and urinary tract infections. Precautions must be observed to avoid crystalluria because of the high percentage of the acetylated, relatively insoluble form of the drug in urine. The clinical uses of sulfamethoxazole are the same as those for sulfisoxazole. It also is marketed in fixed-dose combinations with trimethoprim (see below).

Sulfadiazine

Sulfadiazine given orally is absorbed rapidly, and peak blood concentrations are reached within 3-6 hours after a single dose; the serum t122 is 10 hours. About half of the drug is bound to plasma protein. Therapeutic concentrations are attained in CSF within 4 hours of a single oral dose.

Sulfadiazine is readily excreted by the kidney in both the free and acetylated forms, rapidly at first and then more slowly over a period of 2-3 days. About 15-40% of the excreted sulfadiazine is acetylated. This form is excreted more readily than the free fraction, and alkalinization of the urine accelerates the renal clearance of both forms by further diminishing their tubular reabsorption.

In adults and children who are treated with sulfadiazine, every precaution must be taken to ensure fluid intake adequate to produce a urine output of at least 1200 mL in adults and a corresponding quantity in children. If this cannot be accomplished, sodium bicarbonate may reduce the risk of crystalluria.

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Responses

  • david
    Which sulfonamide is rapidly metabolize and eliminate?
    2 years ago

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