What are the undesirable effects of sulfonamides and what can result from these effects?

Sulfonamides (Sulfa Drugs)

Beside penicillins, sulfonamide antibiotics are the second most common cause of drug-induced allergic reactions. They commonly cause a delayed maculopapular/morbilliform eruption. Acute urticarial reactions (IgE mediated) to sulfamethoxazole (SMX) or trimethoprim (TMP) are relatively infrequent; the incidence of skin rash resulting from SMX-TMP (Bactrim) in healthy subjects is estimated to be 3%. Sulfonamides are also the most common cause of SJS and TEN.

Patients with HIV have the greatest risk of sulfonamide-induced allergic reactions. The typical reaction to SMX-TMP in patients with HIV is a generalized maculopapular eruption that occurs during the second week of treatment and is usually accompanied by pruritus and fever. Because SMX-TMP is the drug of choice for a number of HIV-associated infections such asPneumocystis carinii pneumonia and spontaneous bacterial peritonitis, several methods of desensitization have been devised to administer SMX-TMP to patients with HIV with a history of allergic reaction to the drug.

There are three classes of sulfonamides based on chemical structure: sulfonylarylamines (including sulfa antibiotics), nonsulfonylarylamines, and sulfonamide-moiety-containing drugs. A sulfonylarylamine has a sulfonamide moiety directly attached to a benzene ring with an amine (–NH2) moiety at the N4 position. A nonsulfonylarylamine also has a sulfonamide moiety attached to a benzene ring, but it does not have an amine group at the N4 position. A sulfonamide-moiety–containing drug has a sulfonamide group that is not connected to a benzene ring.Table 2 presents a list of sulfonamide-containing drugs based on their chemical structure.

The N4 amine is critical for the development of delayed reactions to sulfa antibiotics. Given the important chemical differences between drugs containing sulfa antibiotics and sulfa in nonantibiotics, the risk of cross-reactivity is extremely unlikely. A retrospective cohort study by Strom and colleagues showed that approximately 90% of patients with sulfa antibiotic allergy did not have a reaction to a sulfonamide nonantibiotic. Patients with allergic reactions to sulfa antibiotics are also more likely to experience allergic reactions to the other types of sulfonamides, but this is not because of cross-sensitivity. There is no reliable skin test to rule out or confirm sulfa allergy. Some experts recommend avoiding all classes of sulfonamides in patients with serious reactions such as SJS, TEN, or anaphylaxis to any one sulfonamide.

Most diuretics are sulfonamide derivatives. The only diuretics that are not in this group are the potassium-sparing diuretics (triamterene [Dyrenium], spironolactone [Aldactone], amiloride [Midamor]) and ethacrynic acid (Edecrin). Dapsone is a sulfone that is chemically unrelated to sulfonamides.It should also be noted that sulfates, sulfur, and sulfites are chemically unrelated to sulfonamides and do not cross-react.

Pre-Clinical Research

The sulfonamides are broad spectrum antimicrobial agents that inhibit the growth of gram-positive and gram-negative bacteria, Actinomycetes, Chlamydiae, and of some protozoa, such as Toxoplasma and Plasmodia. Resistance to sulfonamides has increased among many of these organisms. While most gram-positive cocci and bacilli are still sensitive to sulfonamides, enterococci are resistant. Gram-negative bacteria such as Escherichia coli, Enterobacter, Klebsiella, Proteus, Salmonella and Shigella are sulfonamide sensitive, as are Neisseria and Haemophilus influenzaeScholar and Pratt (2000), Kucers et al (1997), Petri (2001).

Skin

Rashes are common during sulfonamide administration, and the rate increases with duration of therapy. Maculopapular reactions are most common and occur in about 1–3% of patients [137–141]. In a survey of 5923 pediatric records, 3.46% of prescriptions for sulfonamides were followed by the development of a rash, although none was severe enough to require hospitalization [142].

Urticaria, fixed drug eruptions [140,143–146], linear A bullous dermatosis [147], erythema nodosum [148], photosensitivity reactions [149], and generalized skin reactions involving light-exposed areas [149–151] are less common. Topical silver sulfadiazine cause local reactions, consisting of rash, pruritus, or a burning sensation in 2.5% of patients [5,53].

Generalized cutaneous depigmentation after sulfamide therapy occurred in a 41-year-old man [152]. Melanocytes were not seen on electron microscopy, but there were clear cells with the characteristics of Langerhans cells along the basal layer.

Other eruptions seen with sulfonamides include erythema multiforme and Stevens–Johnson syndrome [153] and exfoliative dermatitis [154]. In erythema multiforme, linear depositions of IgA at the dermoepidermal junction have been suggested to play a pathogenic role [141].

Linear IgA dermatosis with erythema multiforme-like clinical features has been reported in a 19-year-old man several days after completion of a 5-day-course treatment with sulfadimethoxine (500 mg bd) for a flu-like syndrome [147]. Treatment with methylprednisolone (150 mg) with gradual dosage reduction was started. Slow improvement was followed by a flare-up after reduction to 80 mg/day. Therapy was changed to dapsone 100 mg/day, and there was a dramatic improvement.

The most severe skin reactions associated with sulfonamides are the severe forms of erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis [154–161]. In a study from Cameroon, eight of ten patients with toxic epidermal necrolysis had taken sulfonamides (five sulfadoxine, three sulfamethoxazole); two patients died after taking sulfadoxine [162].

Mortality in drug-induced toxic epidermal necrolysis has been estimated to be about 20–30% [163,164], and in Stevens–Johnson syndrome 1–10% [34,153,156,157,160]. Some severe skin reactions start with a maculopapular rash or generalized erythema. The culprit drug is often either a long-acting formulation or a short-acting drug that has been continued over a long period. In both toxic epidermal necrolysis and Stevens–Johnson syndrome immediate withdrawal of the sulfonamide and all other non-essential drugs is required, as well as adequate supportive therapy with fluids, proteins, and electrolytes, in order to prevent renal insufficiency and respiratory distress syndrome [163,164]. Occasionally, toxic epidermal necrolysis must be distinguished from staphylococcal scalded skin syndrome (Lyell’s syndrome) by histology. In toxic epidermal necrolysis, there is subepidermal cleavage of the skin at the level of the basal cells, resulting in full-thickness denudation, whereas in scalded skin syndrome the split occurs in the upper epidermis near the granular layer just beneath the stratum corneum [165].

Urinary tract

Renal complications that occur in relation to sulfonamide administration include crystalluria, tubular necrosis, interstitial nephritis, and glomerular lesions as part of a vasculitis syndrome.

Sulfonamides and their metabolites are excreted in large amounts in the urine. They are relatively insoluble in the acid environment and tend to precipitate in the collecting tubules, calyces, and pelvis of the kidney, and possibly in the ureters. The course is typically benign but adequate hydration and alkalinization may be required [119]. Nephrocalcinosis can cause hematuria, renal colic, or acute renal insufficiency [120]. Urinary obstruction with anuria/oliguria was seen primarily with the earlier, less soluble sulfonamides. With the newer and more soluble sulfonamides crystal formation is rare, as is acute renal insufficiency due to other mechanisms. During recent years renal complications have been seen more often in patients with AIDS, because of the use of large doses of sulfonamides combined with trimethoprim against infection with Pneumocystis jirovecii (formerly Pneumocystis carinii) or Toxoplasma encephalitis. Reduced fluid intake and low urinary pH favor crystal formation, and so both adequate fluid intake (about 2 l/day for adults) and urine alkalinization are encouraged when larger doses of sulfonamides are used [62,120–125]. For the diagnosis of sulfonamide crystalluria, the Lignin test is recommended. At room temperature crystals can even be found in the urine of patients taking sulfamethoxazole, which is readily soluble [126].

A 48-year-old man with untreated HIV infection developed confusion and dyspnea. He had a history of ischemic heart disease and hepatitis C infection [127]. His CD4 count was 50 x 106/l (reference range 400–1320). He was found to have Pneumocystis jirovecii pneumonia and cerebral toxoplasmosis and was given oral co-trimoxazole (320/1600 qds) for the Pneumocystis pneumonia and sulfadiazine (1.5 g qds) for the toxoplasmosis. Baseline renal function was normal. Later, the co-trimoxazole was withdrawn because of concurrent sulfadiazine treatment. On day 7, he developed macroscopic hematuria and profuse crystalluria. Renal function was normal, but 2 days later his creatinine rose to 250 μmol/l. Despite vigorous intravenous hydration the serum creatinine increased to 401 μmol/l. Renal tract ultrasound was normal but morphological examination of crystals confirmed the presence of a sulfonamide. Sulfadiazine was withdrawn and he recovered uneventfully within 1 month.

Sulfadiazine is a weak acid that will precipitate as crystals in the tubular lumen at a urine pH below 5.5; patients taking doses over 4 g/day should maintain a high oral fluid intake or receive adequate intravenous hydration.

Bilateral flank pain and progressive oliguria developed over 3 weeks in a 47-year-old woman who took sulfadiazine for toxoplasmosis retinitis [128]. Only in a second CT scan (an unenhanced helical scan with very low attenuation for stones) was urolithiasis detected; sulfonamide crystals were found in the urine.

Other renal complications reported with sulfonamides are:

acute tubular necrosis or tubulointerstitial nephritis [122,129];

interstitial nephritis [130], in some cases combined with granulomatous lesions [131,132];

acute vasculitis [133];

acute renal insufficiency in association with a serum sickness-like syndrome, generalized vasculitis, or rashes in combination with hepatic damage [114].

Acute anuria or oliguria is often the first symptom, not only in patients with tubular necrosis or tubulointerstitial nephritis, but also in those with allergic vasculitis. Non-oliguric renal insufficiency can also occur. It is not yet clear whether tubular necrosis in association with sulfonamides is a toxic, collateral, or hypersusceptibility reaction. The unstable hydroxylamine metabolites of some sulfonamides can act as direct renal toxins.

In a French analysis of 22 510 urinary calculi performed by infrared spectroscopy, drug-induced urolithiasis was divided into two categories: first, stones with drugs physically embedded (n = 238; 1.0%), notably indinavir monohydrate (n = 126; 53%), followed by triamterene (n = 43; 18%), sulfonamides (n = 29; 12%), and amorphous silica (n = 24; 10%); secondly, metabolic nephrolithiasis induced by drugs (n = 140; 0.6%), involving mainly calcium/vitamin D supplementation (n = 56; 40%) and carbonic anhydrase inhibitors (n = 33; 24%) [134]. Drug-induced stones are responsible for about 1.6% of all calculi in France. Physical analysis and a thorough drug history are important elements in the diagnosis.

An HIV-positive patient with toxoplasmic encephalitis developed acute renal failure after treatment with sulfadiazine; renal ultrasound showed echogenic areas presumed to be sulfa crystals [135]. Crystalluria occurs in 45% of patients taking sulfonamides and acute renal insufficiency in 0.4–29% [136]. Hydration and urinary alkalinization can prevent and resolve crystal formation.

Topical Sulfonamides

Mafenide acetate (para-aminomethylbenzene sulfonamide) is available for use in the topical treatment of burns. Its use has been limited, however, by metabolic acidosis caused by carbonic anhydrase inhibition. Silver sulfadiazine has fewer side effects and is used for burns,4 although other silver compounds are being introduced.5 In these formulations, the sulfonamide acts primarily as a vehicle for release of silver ions that exert an antibacterial effect. Outbreaks of silver-resistant infections in burn units ultimately may limit its usefulness.6 Various combinations of other sulfonamides are available as vaginal creams or suppositories. A variety of ophthalmic ointments and solutions of sulfacetamide sodium USP (a highly soluble sulfonamide) are available for use in the treatment of conjunctivitis caused by susceptible bacteria and as adjunctive therapy for trachoma. Sulfacetamide is also used as an antiinflammatory and antimicrobial agent in the treatment of acne, rosacea, and seborrheic dermatitis.

Erythrocytes

Sulfonamides rarely have adverse effects on erythrocytes. However, there are various mechanisms by which sulfonamide-induced hemolytic anemia can occur (61):

abnormally high blood concentrations, due to large doses or reduced excretion of the drug in patients with renal disease (62)

acquired hypersusceptibility, as reflected by the development of a positive Coombs’ test (63,64)

genetically determined abnormalities of erythrocyte metabolism, for example deficiency of glucose-6-phosphate dehydrogenase or of diaphorase (65,66)

the presence of an abnormal, so-called “unstable”, hemoglobin in the erythrocyte, for example hemoglobin Zürich (67,68), hemoglobin Torino (69), hemoglobin Hasharon (70), and hemoglobins H and M (66).

Simple and readily available in vitro methods have been used to demonstrate the pathogenetic mechanisms, including Coombs’ test, Harris’s test (71), a quantitative assay or screening for glucose-6-phosphate dehydrogenase activity after recovery (72,73), a test for Heinz bodies, the buffered isopropanol technique (74) to detect abnormal hemoglobins, and hemoglobin electrophoresis (61,66). The direct antiglobulin (Coombs’) test can be negative in spite of an immune mechanism. If such a mechanism is suspected and the direct Coombs’ test is negative, the indirect Coombs’ test on the patient’s serum with the addition of the suspected sensitizing agent can be of diagnostic value (75). Heinz bodies in the erythrocytes can be important for early differentiation of a sulfonamide-induced reaction, which could further progress to hemolytic anemia (76). This result can also be of help in distinguishing this from other kinds of anemia.

Sulfonamides are not directly associated with folate deficiency and megaloblastic anemias. Sulfasalazine can affect the absorption of folates, but inflammatory bowel disease can also be responsible for reduced folate absorption. Only in combination with trimethoprim are sulfonamides thought to deplete folate stores in patients with pre-existing deficiency of folate or vitamin B12 (77).

Publisher Summary

This chapter of the book Advances in Synthetic Organic Chemistry features detailed discussion on sulfonamides. The classification of the chemical agents mentioned in this book is done according to both their functional group type and product utility designation. This kind of classification makes it easy for the reader to get the information easily. This chapter describes sulfonamides with the help of a US patent. The patent discussed in this chapter is thioaryl sulfonamide hydroxamic acid compounds, authored by D.P. Getman and others. The chapter provides other relevant basic details of the patent including the assignee and the utility designation. The assignee of this patent is Pharmacia Corporation and the utility designation is proteinase inhibitors for treatment of matrix metalloproteinase disorders. It also mentions reactions related to this organic compound, which is provided to further emphasize the details. The experimental details follow the reaction to explain the entire process. This is followed by some explanatory notes. The last section of the chapter consists of some references. These are US patents that have been used here.

Drug Interactions

Sulfonamides may displace from albumin-binding sites drugs such as warfarin, increasing the effective activity of the displaced drug. Anticoagulant dosage should be reduced during sulfonamide therapy. Sulfonamides also displace methotrexate from its bound protein, increasing methotrexate toxicity. An increased hypoglycemic effect of chlorpropamide and tolbutamide may occur during sulfonamide therapy, possibly because of the same mechanism or structural similarities. Sulfonamides may compete for binding sites with some anesthetic agents such as thiopental, and reduced barbiturate doses might be necessary. Sulfonamides may potentiate the action of some thiazide diuretics, phenytoin, and uricosuric agents. Conversely, sulfonamides themselves can be displaced from binding sites by indomethacin, phenylbutazone, salicylates, probenecid, and sulfinpyrazone, resulting in increased sulfonamide activity. Cyclosporine levels may be reduced by sulfonamides. Oral contraceptive failure during sulfonamide therapy has been noted rarely.25

The activity of sulfonamides may be decreased by procaine and other local anesthetics derived from PABA. Methenamine compounds should not be used with sulfonamides because of the formation of insoluble urinary precipitates. Sulfonamides may decrease protein-bound iodine and 131I uptake and may produce false-positive Benedict test results for urine glucose and false-positive sulfosalicylic acid test results for urine proteins.

Antibacterial spectrum (Fig. 8.21)

Sulfonamides on their own are bacteriostatic. When combined with trimethoprim, they may be bactericidal. Potentiated sulfonamides are now generally used more commonly than sulfonamides alone, especially in small animal medicine, and the following discussion relates especially to sulfonamide-trimethoprim.

Sulfonamide-trimethoprim inhibits:

Gram-negative and Gram-positive aerobic bacteria, especially Nocardia, for which they are the preferred choice

anaerobes? Opinions vary. If necrotic tissue is present, thymidine and PABA antagonize their antibacterial effect

some protozoa.

Synergism between trimethoprim and the sulfonamide results in up to 40% of bacteria that are resistant to one component being susceptible to the combination.

When sulfonamides are combined with pyrimethamine they have greater antiprotozoal activity against Toxoplasma and Neospora, for example.

Sulfonamide-trimethoprim is not effective against Pseudomonas aeruginosa or Proteus.

Different sulfonamides may show quantitative but not necessarily qualitative differences in activity.

Trimethoprim-sulfonamide may be the treatment of choice for Pneumocystis pneumonia.

Mycobacterium, Mycoplasma, Rickettsia and spirochetes are resistant.

Chemical Structure

Sulfonamides such as sulfamethoxazole (Figure 137-18a) are derived from p-amino-benzene-sulfonamide, which is a structural analog of p-aminobenzoic acid, a factor required by bacteria for folic acid synthesis. A free amino group at position 4 and a sulfonamide group at position 1 are required for antibacterial activity. Heterocyclic or aromatic rings substituting the sulfonamide enhance this activity by modifying absorption and gastrointestinal tolerance.

Diaminopyrimidines such as trimethoprim and pyrimethamine (Figure 137-18b) are pyrimidines substituted at position 5 by an aromatic group (pyrimethamine has an additional ethyl substituent at position 6).