Sulfonamides - Antifolate Drugs

ANTIFOLATE DRUGS

SULFONAMIDES

Chemistry

The basic formulas of the sulfonamides and their structural similar-ity to p-aminobenzoic acid (PABA) are shown in Figure 46–1. Sulfonamides with varying physical, chemical, pharmacologic, and antibacterial properties are produced by attaching substituents to the amido group (–SO₂–NH–R) or the amino group (–NH₂) of the sulfanilamide nucleus. Sulfonamides tend to be much more soluble at alkaline than at acid pH. Most can be prepared as sodium salts, which are used for intravenous administration.

Mechanism of Action & Antimicrobial Activity

Sulfonamide-susceptible organisms, unlike mammals, cannot use exogenous folate but must synthesize it from PABA. This pathway (Figure 46–2) is thus essential for production of purines and nucleic acid synthesis. As structural analogs of PABA, sulfon-amides inhibit dihydropteroate synthase and folate production. Sulfonamides inhibit both gram-positive and gram-negative bacteria, Nocardia sp, Chlamydia trachomatis, and some protozoa. Some enteric bacteria, such as Escherichia coli, Klebsiella pneumo-niae, Salmonella, Shigella, and Enterobacter sp are also inhibited. Itis interesting that rickettsiae are not inhibited by sulfonamides but are instead stimulated in their growth. Activity is poor against anaerobes. Pseudomonas aeruginosa is intrinsically resistant to sulfonamide antibiotics.

Combination of a sulfonamide with an inhibitor of dihydro-folate reductase (trimethoprim or pyrimethamine) provides syn-ergistic activity because of sequential inhibition of folate synthesis (Figure 46–2).

Resistance

Mammalian cells (and some bacteria) lack the enzymes required for folate synthesis from PABA and depend on exogenous sources of folate; therefore, they are not susceptible to sulfonamides. Sulfonamide resistance may occur as a result of mutations that cause overproduction of PABA, (2) cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides, or (3) impair permeability to the sulfonamide. Dihydropteroate synthase with low sulfonamide affinity is often encoded on a plas-mid that is transmissible and can disseminate rapidly and widely. Sulfonamide-resistant dihydropteroate synthase mutants also can emerge under selective pressure.

Pharmacokinetics

Sulfonamides can be divided into three major groups: (1) oral, absorbable; (2) oral, nonabsorbable; and (3) topical. The oral, absorbable sulfonamides can be classified as short-, intermediate-, or long-acting on the basis of their half-lives (Table 46–1). They are absorbed from the stomach and small intestine and distributed widely to tissues and body fluids (including the central nervous

system and cerebrospinal fluid), placenta, and fetus. Protein bind-ing varies from 20% to over 90%. Therapeutic concentrations are in the range of 40–100 mcg/mL of blood. Blood levels generally peak 2–6 hours after oral administration.A portion of absorbed drug is acetylated or glucuronidated in the liver. Sulfonamides and inactive metabolites are then excreted into the urine, mainly by glomerular filtration. In significant renal failure, the dosage of sulfonamide must be reduced.

Clinical Uses

Sulfonamides are infrequently used as single agents. Many strains of formerly susceptible species, including meningococci, pneu-mococci, streptococci, staphylococci, and gonococci, are now resistant. The fixed-drug combination of trimethoprim-sulfamethox-azole is the drug of choice for infections such as Pneumocystisjiroveci (formerly P carinii) pneumonia, toxoplasmosis, nocardiosis,and occasionally other bacterial infections.

A. Oral Absorbable Agents

Sulfisoxazole and sulfamethoxazole are short- to medium-acting agents used almost exclusively to treat urinary tract infections. The usual adult dosage is 1 g of sulfisoxazole four times daily or 1 g of sulfamethoxazole two or three times daily.Sulfadiazine in combination with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. The combination of sulfadiazine with pyrimethamine, a potent inhibitor of dihydrofo-late reductase, is synergistic because these drugs block sequential steps in the folate synthetic pathway blockade (Figure 46–2). The dosage of sulfadiazine is 1 g four times daily, with pyrimethamine given as a 75-mg loading dose followed by a 25-mg once-daily dose. Folinic acid, 10 mg orally each day, should also be adminis-tered to minimize bone marrow suppression.

Sulfadoxine is the only long-acting sulfonamide currently available in the USA and only as a combination formulation with pyrimethamine (Fansidar), a second-line agent in the treatment of malaria .

B. Oral Nonabsorbable Agents

Sulfasalazine (salicylazosulfapyridine) is widely used in ulcerative colitis, enteritis, and other inflammatory bowel disease .

C. Topical Agents

Sodium sulfacetamide ophthalmic solution or ointment is effec-tive in the treatment of bacterial conjunctivitis and as adjunctive therapy for trachoma. Another sulfonamide, mafenide acetate, is used topically but can be absorbed from burn sites. The drug and its primary metabolite inhibit carbonic anhydrase and can cause metabolic acidosis, a side effect that limits its usefulness. Silver sulfadiazine is a much less toxic topical sulfonamide and is pre-ferred to mafenide for prevention of infection of burn wounds.

Adverse Reactions

All sulfonamides, including antimicrobial sulfas, diuretics, diazox-ide, and the sulfonylurea hypoglycemic agents, have been consid-ered to be partially cross-allergenic. However, evidence for this is not extensive. The most common adverse effects are fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, nausea, vomiting, diarrhea, and difficulties referable to the urinary tract . Stevens-Johnson syndrome, although relatively uncom-mon (< 1% of treatment courses), is a particularly serious and potentially fatal type of skin and mucous membrane eruptionassociated with sulfonamide use. Other unwanted effects include stomatitis, conjunctivitis, arthritis, hematopoietic disturbances , hepatitis, and, rarely, polyarteritis nodosa and psychosis.

A. Urinary Tract Disturbances

Sulfonamides may precipitate in urine, especially at neutral or acid pH, producing crystalluria, hematuria, or even obstruction. This is rarely a problem with the more soluble sulfonamides (eg, sulfisoxazole). Sulfadiazine when given in large doses, particularly if fluid intake is poor, can cause crystalluria. Crystalluria is treated by administration of sodium bicarbonate to alkalinize the urine and fluids to increase urine flow. Sulfonamides have also been implicated in various types of nephrosis and in allergic nephritis.

B. Hematopoietic Disturbances

Sulfonamides can cause hemolytic or aplastic anemia, granulocy-topenia, thrombocytopenia, or leukemoid reactions. Sulfonamides may provoke hemolytic reactions in patients with glucose-6-phosphate dehydrogenase deficiency. Sulfonamides taken near the end of pregnancy increase the risk of kernicterus in newborns.