Sulfonamides and trimethoprim

Sulfonamides and trimethoprim

The sulfonamides and trimethoprim are broad-spectrum antimicrobials that have closely related mechanisms: They all disrupt the synthesis of tetrahydrofolic acid. In approaching these drugs, we begin with the sulfonamides, followed by trimethoprim, and then conclude with trimethoprim/sulfamethoxazole, an important fixed-dose combination.

Sulfonamides

Sulfonamides were the first drugs available for systemic treatment of bacterial infections. Their introduction and subsequent widespread use produced a sharp decline in morbidity and mortality from susceptible infections. Until the penicillins became generally available, sulfonamides remained the mainstay of antibacterial chemotherapy. With the advent of newer antimicrobial drugs, use of sulfonamides has greatly declined. Today, only a few remain on the market. Nonetheless, the sulfonamides still have important uses, primarily against urinary tract infections. With the introduction of trimethoprim/sulfamethoxazole in the 1970s, indications for the sulfonamides expanded.

Basic pharmacology

Similarities among the sulfonamides are more striking than the differences. Accordingly, rather than focusing on a representative prototype, we will discuss the sulfonamides as a group.

Chemistry

The general structural formula for the sulfonamides is shown in Figure 88–1. As you can see, sulfonamides are structural analogs of para-aminobenzoic acid (PABA). The antimicrobial actions of sulfonamides are based on this similarity.

Figure 88–1 Structural relationships among sulfonamides, PABA, and folic acid.

Figure 88–1 Structural relationships among sulfonamides, PABA, and folic acid.

Individual sulfonamides vary greatly with respect to solubility in water. Older sulfonamides had low solubility, and hence they often crystallized out in the urine, causing injury to the kidneys. The sulfonamides in current use are much more water soluble, and hence the risk of renal damage is low.

Mechanism of action

Sulfonamides suppress bacterial growth by inhibiting synthesis of folic acid (folate), a compound required by all cells to make DNA, RNA, and proteins. The steps in folate synthesis are shown in Figure 88–2. As indicated, sulfonamides block the step in which PABA is combined with pteridine to form dihydropteroic acid. Because of their structural similarity to PABA, sulfonamides act as competitive inhibitors of this reaction. Sulfonamides are usually bacteriostatic. Accordingly, host defenses are essential for complete elimination of infection.

Figure 88–2 Sites of action of sulfonamides and trimethoprim.
Sulfonamides and trimethoprim inhibit sequential steps in the synthesis of tetrahydrofolic acid (FAH₄). In the absence of FAH₄, bacteria are unable to synthesize DNA, RNA, and proteins.

Figure 88–2 Sites of action of sulfonamides and trimethoprim.
Sulfonamides and trimethoprim inhibit sequential steps in the synthesis of tetrahydrofolic acid (FAH₄). In the absence of FAH₄, bacteria are unable to synthesize DNA, RNA, and proteins.

If all cells require folate, why don’t sulfonamides harm us? The answer lies in how bacteria and mammalian cells acquire folic acid. Bacteria are unable to take up folate from their environment, and hence must synthesize folic acid from precursors. Sulfonamides disrupt this process. In contrast to bacteria, mammalian cells do not manufacture their own folate. Rather, they simply take up folic acid obtained from the diet, using a specialized transport system for uptake. Because mammalian cells use preformed folic acid rather than synthesizing it, sulfonamides are harmless to us.

Microbial resistance

Many bacterial species have developed resistance to sulfonamides. Resistance is especially high among gonococci, meningococci, streptococci, and shigellae. Resistance may be acquired by spontaneous mutation or by transfer of R factors. Principal resistance mechanisms are (1) reduced sulfonamide uptake, (2) synthesis of PABA in amounts sufficient to overcome sulfonamide-mediated inhibition of dihydropteroate synthetase, and (3) alteration in the structure of dihydropteroate synthetase such that binding and inhibition by sulfonamides is reduced.

Antimicrobial spectrum

The sulfonamides are active against a broad spectrum of microbes. Susceptible organisms include gram-positive cocci (including methicillin-resistant Staphylococcus aureus), gram-negative bacilli, Listeria monocytogenes, actinomycetes (eg, Nocardia), chlamydiae (eg, Chlamydia trachomatis), some protozoa (eg, Toxoplasma, plasmodia, Isospora belli), and two fungi: Pneumocystis jiroveci (formerly thought to be Pneumocystis carinii) and Paracoccidioides brasiliensis.

Therapeutic uses

Although the sulfonamides were once employed widely, their applications are now limited. Two factors explain why: (1) introduction of bactericidal antibiotics that are less toxic than the sulfonamides, and (2) development of sulfonamide resistance. Today, urinary tract infection is the principal indication for these drugs.

Urinary tract infections.

Sulfonamides are often preferred drugs for acute infections of the urinary tract. About 90% of these infections are due to Escherichia coli, a bacterium that is usually sulfonamide sensitive. Of the sulfonamides available, sulfamethoxazole (in combination with trimethoprim) is generally favored. Sulfamethoxazole has good solubility in urine and achieves effective concentrations within the urinary tract. Urinary tract infections and their treatment are discussed in Chapter 89.

Sulfonamides are useful drugs for nocardiosis (infection with Nocardia asteroides), listeria, paracoccidioidomycosis, and infection with Pneumocystis jiroveci. In addition, sulfonamides are alternatives to doxycycline and erythromycin for infections caused by C. trachomatis (trachoma, inclusion conjunctivitis, urethritis, lymphogranuloma venereum). Sulfonamides are used in conjunction with pyrimethamine to treat two protozoal infections: toxoplasmosis and malaria caused by chloroquine-resistant Plasmodium falciparum. Topical sulfonamides are used to treat superficial infections of the eye and to suppress bacterial colonization in burn patients.

One sulfonamide—sulfasalazine—is used to treat ulcerative colitis. However, benefits in this disorder do not result from inhibiting microbial growth. Ulcerative colitis is discussed in Chapter 80.

Pharmacokinetics

Sulfonamides are well absorbed following oral administration. When applied topically to the skin or mucous membranes, these drugs may be absorbed in amounts sufficient to cause systemic effects.

Sulfonamides are well distributed to all tissues. Concentrations in pleural, peritoneal, ocular, and similar body fluids may be as much as 80% of the concentration in blood. Sulfonamides readily cross the placenta, and levels achieved in the fetus are sufficient to produce antimicrobial effects and toxicity.

Sulfonamides are metabolized in the liver, principally by acetylation. Acetylated derivatives lack antimicrobial activity, but are just as toxic as the parent compounds. Acetylation may decrease sulfonamide solubility, thereby increasing the risk of renal damage from crystal formation.

Sulfonamides are excreted primarily by the kidneys. Hence, the rate of renal excretion is the principal determinant of their half-lives.

Adverse effects

Sulfonamides can cause multiple adverse effects. Prominent among these are hypersensitivity reactions, blood dyscrasias, and kernicterus, which occurs in newborns. Renal damage from crystalluria was a problem with older sulfonamides but is of minimal concern with the sulfonamides used today.

Hypersensitivity reactions.

Sulfonamides can induce a variety of hypersensitivity reactions, which are seen in about 3% of patients. Mild reactions—rash, drug fever, photosensitivity—are relatively common. To minimize photosensitivity reactions, patients should avoid prolonged exposure to sunlight, wear protective clothing, and apply a sunscreen to exposed skin.

Hypersensitivity reactions are especially frequent with topical sulfonamides. As a result, these preparations are no longer employed routinely. Rather, they are usually reserved for ophthalmic infections, burns, and bacterial vaginosis caused by Gardnerella vaginalis and a mixed population of anaerobic bacteria.

The most severe hypersensitivity response to sulfonamides is Stevens-Johnson syndrome, a rare reaction with a mortality rate of about 25%. Symptoms include widespread lesions of the skin and mucous membranes, combined with fever, malaise, and toxemia. The reaction is most likely with long-acting sulfonamides, which are now banned in the United States. Short-acting sulfonamides may also induce the syndrome, but the incidence is low. To minimize the risk of severe reactions, sulfonamides should be discontinued immediately if skin rash of any sort is observed. In addition, sulfonamides should not be given to patients with a history of hypersensitivity to chemically related drugs, including thiazide diuretics, loop diuretics, and sulfonylurea-type oral hypoglycemics—although the risk of cross-reactivity with these agents is probably low (see below, under Drug Interactions).

Hematologic effects.

Sulfonamides can cause hemolytic anemia in patients whose red blood cells have a genetically determined deficiency in glucose-6-phosphate dehydrogenase (G6PD). This inherited trait is most common among African Americans and people of Mediterranean origin. Rarely, hemolysis occurs in the absence of G6PD deficiency. Red cell lysis can produce fever, pallor, and jaundice; patients should be observed for these signs. In addition to hemolytic anemia, sulfonamides can cause agranulocytosis, leukopenia, thrombocytopenia, and, very rarely, aplastic anemia. When sulfonamides are used for a long time, periodic blood tests should be obtained.

Kernicterus.

Kernicterus is a disorder in newborns caused by deposition of bilirubin in the brain. Bilirubin is neurotoxic and can cause severe neurologic deficits and even death. Under normal conditions, infants are not vulnerable to kernicterus. Why? Because any bilirubin present in their blood is tightly bound to plasma proteins, and therefore is not free to enter the central nervous system (CNS). Sulfonamides promote kernicterus by displacing bilirubin from plasma proteins. Since the blood-brain barrier of infants is poorly developed, the newly freed bilirubin has easy access to sites within the brain. Because of the risk of kernicterus, sulfonamides should not be administered to infants under the age of 2 months. In addition, sulfonamides should not be given to pregnant women near term or to mothers who are breast-feeding.

Renal damage from crystalluria.

Because of their low solubility, older sulfonamides tended to come out of solution in the urine, forming crystalline aggregates in the kidneys, ureters, and bladder. These aggregates caused irritation and obstruction, sometimes resulting in anuria and even death. Renal damage is uncommon with today’s sulfonamides, owing to their increased water solubility. To minimize the risk of renal damage, adults should maintain a daily urine output of 1200 mL. This can be accomplished by consuming 8 to 10 glasses of water each day. Because the solubility of sulfonamides is highest at elevated pH, alkalinization of the urine (eg, with sodium bicarbonate) can further decrease the chances of crystalluria.

Drug interactions

Metabolism-related interactions.

Sulfonamides can intensify the effects of warfarin, phenytoin, and sulfonylurea-type oral hypoglycemics (eg, glipizide, glyburide). The principal mechanism is inhibition of hepatic metabolism. When combined with sulfonamides, these drugs may require a reduction in dosage to prevent toxicity.

Cross-hypersensitivity.

There is concern that people who are hypersensitive to sulfonamide antibiotics may be cross-hypersensitive to other drugs that contain a sulfonamide moiety (eg, thiazide diuretics, loop diuretics, sulfonylurea-type oral hypoglycemics). However, there are no good data to show that such cross-hypersensitivity actually exists—suggesting that patients who experience an allergic reaction when taking another sulfonamide simply have a general predisposition to drug allergy, rather than a specific cross-reactivity with sulfonamide-type drugs. In fact, clinical experience has shown that patients with documented allergy to sulfonamide antibiotics can take other sulfonamide drugs without incident. The bottom line? For most patients allergic to sulfa antibiotics, it’s safe to use other sulfonamide-type drugs, including thiazide diuretics and sulfonylurea-type oral hypoglycemics. Having said that, the proper answer on your NCLEX exam is this: Patients who are allergic to sulfonamide antibiotics should avoid all other sulfonamide-type drugs. (This answer would be consistent with Food and Drug Administration recommendations, if not with current clinical reality.)

Sulfonamide preparations

The sulfonamides fall into two major categories: (1) systemic sulfonamides and (2) topical sulfonamides. The systemic agents are used more often.

Systemic sulfonamides

In the past, we had three groups of systemic sulfonamides: short acting, intermediate acting, and long acting. Today, the long-acting agents are no longer available, owing to a high risk of Stevens-Johnson syndrome. The remaining two groups—short acting and intermediate acting—differ primarily with regard to dosing interval, which is much shorter for the short-acting drugs.

Sulfamethoxazole.

Sulfamethoxazole is the only intermediate-acting sulfonamide available. Because its effects are moderately prolonged, dosing can be done less often than with the short-acting agents. The risk of renal damage from crystalluria can be reduced by maintaining adequate hydration. Sulfamethoxazole is not available for use by itself—but is available in combination with trimethoprim (see below).

Sulfisoxazole is a short-acting sulfonamide. Prior to the introduction of trimethoprim/sulfamethoxazole, sulfisoxazole was the preferred sulfonamide for urinary tract infections. The drug is just as effective as other sulfonamides and less expensive. Moreover, owing to its high water solubility, sulfisoxazole poses a minimal risk of crystalluria. Because high plasma concentrations of sulfisoxazole can be achieved, the drug is useful against a variety of systemic infections (eg, nocardiosis, chancroid, trachoma). In the United States, only one formulation is available: an oral solution that contains sulfisoxazole combined with erythromycin.

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Tags: Pharmacology for Nursing Care

Jul 24, 2016 | Posted by admin in NURSING | Comments Off

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