Sulfonamides

SULFONAMIDES

Sulfonamides were the first antimicrobial agents (AMAs) effective against pyogenic bacterial infections. Sulfonamido-chrysoidine (Prontosil Red) was one of the dyes included by Domagk to treat experimental streptococcal infection in mice and found it to be highly effective. He subsequently cured his daughter of streptococcal septicaemia (which was 100% fatal at that time) by prontosil. By 1937, it became clear that prontosil was broken down in the body to release sulfanilamide which was the active antibacterial agent. A large number of sulfonamides were produced and used extensively in the subsequent years, but because of rapid emergence of bacterial resistance and the availability of many safer and more effective antibiotics, their current utility is limited, except in combination with trimethoprim (as cotrimoxazole) or pyrimethamine (for malaria).

Chemistry

All sulfonamides may be considered to be derivatives of sulfanilamide (p-aminobenzene sulfonamide). Individual members differ in the nature of N1 (Sulfonamido N) substitution, which governs solubility, potency and pharmacokinetic property. A free amino group in the para position (N4) is required for antibacterial activity.

Sulfonamides that are still of clinical interest are:

1.    Short acting (4–8 hr): Sulfadiazine

2.    Intermediate acting (8–12 hr): Sulfamethoxazole

3.    Long acting (~7 days): Sulfadoxine, Sulfamethopyrazine

4. Special purpose sulfonamides: Sulfacetamide sod., Mafenide, Silver sulfadiazine, Sulfasalazine

ANTIBACTERIAL SPECTRUM

Sulfonamides are primarily bacteriostatic against many gram-positive and gram-negative bacteria. However, bactericidal concentrations may be attained in urine. Sensitivity patterns among microorganisms have changed from time-to-time and place-to-place. Those still sensitive are:

many Strepto. pyogenes, Haemophilus influenzae, H. ducreyi, Calymmatobacterium granulomatis, Vibrio cholerae. Only a few Staph. aureus, gonococci, meningococci, pneumococci, Escherichia coli, and Shigella respond, but majority are resistant. Anaerobic bacteria are not susceptible.

Chlamydiae: trachoma, lymphogranuloma venereum, inclusion conjunctivitis, are sensitive, as are Actinomyces, Nocardia and Toxoplasma.

Mechanism Of Action

Many bacteria synthesize their own folic acid (FA) of which p-aminobenzoic acid (PABA) is a constituent, and is taken up from the medium. Woods and Fildes (1940) proposed the hypothesis regarding sulfonamide action. Sulfonamides, being structural analogues of PABA, inhibit bacterial folate synthase → FA is not formed and a number of essential metabolic reactions suffer. Sulfonamides competitively inhibit the union of PABA with pteridine residue to form dihydropteroic acid which conjugates with glutamic acid to produce dihydrofolic acid. Also, being chemically similar to PABA, the sulfonamide may itself get incorporated to form an altered folate which is metabolically injurious.

Human cells also require FA, but they utilize preformed FA supplied in diet and are unaffected by sulfonamides. Evidences in favour of this mechanism of action of sulfonamides are:

a)      PABA, in small quantities, antagonizes the antibacterial action of sulfonamides.

b)  Only those microbes which synthesize their own FA, and cannot take it from the medium are susceptible to sulfonamides.

Pus and tissue extracts contain purines and thymidine which decrease bacterial requirement for FA and antagonize sulfonamide action. Pus is also rich in PABA.

Resistance To Sulfonamides

Most bacteria are capable of developing resistance to sulfonamides. Prominent among these are gonococci, pneumococci, Staph. aureus, meningococci, E. coli, Shigella and some Strep. pyogenes, Strep. viridans and anaerobes. The resistant mutants either:

a)      produce increased amounts of PABA, or

b)      their folate synthase enzyme has low affinity for sulfonamides, or

c)       adopt an alternative pathway in folate metabolism.

Resistance developed in vivo is quite persistent. Sensitivity patterns have changed depending on the extent of use. When an organism is resistant to one sulfonamide, it is resistant to them all. No cross resistance between sulfonamides and other AMAs has been noted. Development of resistance has markedly limited the clinical usefulness of this class of compounds.

Pharmacokinetics

Sulfonamides are rapidly and nearly completely absorbed from g.i.t. Extent of plasma protein binding differs considerably (10–95%) among different members. The highly protein bound members are longer acting. Sulfonamides are widely distributed in the body—enter serous cavities easily. The free form of sulfadiazine attains the same concentration in CSF as in plasma. They cross placenta freely.

The primary pathway of metabolism of sulfonamides is acetylation at N4 by non-microsomal acetyl transferase, primarily in liver. There are slow and fast acetylators, but the difference is mostly insufficient to be clinically significant. The extent of metabolism differs for different members. The acetylated derivative is inactive, but can contribute to the adverse effects. It is generally less soluble in acidic urine than the parent drug—may precipitate and cause crystalluria. The acetylated form accumulates in blood in patients with renal failure along with the parent drug—toxicity increases.

Sulfonamides are excreted mainly by the kidney through glomerular filtration. Both renal tubular secretion and reabsorption also occur. The more lipidsoluble members are highly reabsorbed in the tubule, therefore are longer acting.

Sulfadiazine

It is the prototype of the general purpose sulfonamides that is rapidly absorbed orally and rapidly excreted in urine. It is 50% plasma protein bound and 20–40% acetylated. The acetylated derivative is less soluble in urine, crystalluria is likely. It has good penetrability in brain and CSF—was the preferred compound for meningitis.

Dose: 0.5 g QID to 2 g TDS; SULFADIAZINE 0.5 g tab.

Sulfamethoxazole

It has slower oral absorption and urinary excretion—intermediate duration of action, t½ in adults averages 10 hours. It is the preferred compound for combining with trimethoprim because the t½ of both is similar. However, a high fraction is acetylated, which is relatively insoluble—crystalluria can occur.

Dose: 1 g BD for 2 days, then 0.5 g BD.

GANTANOL 0.5 g tab.

Sulfadoxine, Sulfamethopyrazine

These are ultralong acting compounds, action lasting > 1 week because of high plasma protein binding and slow renal excretion (t½ 5–9 days). They attain low plasma concentration (of free form) and are not suitable for treatment of acute pyogenic infections. They are used in combination with pyrimethamine in the treatment of malaria, (especially chloroquine resistant P. falciparum ; See Ch. No. 59), Pneumocystis jiroveci pneumonia in AIDS patients and in toxoplasmosis. Because they have caused serious cutaneous reactions, largescale use of the combination for prophylaxis of malaria is not recommended.

Sulfacetamide sod.

It is a highly soluble compound yielding neutral solution which is only mildly irritating to the eye in concentrations up to 30%. It is used topically for ocular infections due to susceptible bacteria and chlamydia, including ophthalmia neonatorum caused by Ch. No. oculogenitalis. It attains high concentrations in anterior segment and aqueous humour after topical instillation. The incidence of sensitivity reactions with ocular use of sulfacetamide sod. has been low; but it must be promptly stopped when they occur.

LOCULA, ALBUCID 10%, 20%, 30% eye drops, 6% eye oint.

Mafenide

It is not a typical sulfonamide, because a — CH₂— bridge separates the benzene ring and the amino group. It is used only topically—inhibits a variety of gram-positive and gram-negative bacteria. In contrast to typical sulfonamides, it is active in the presence of pus and against Pseudomonas, clostridia which are not inhibited by typical sulfonamides. It has been mainly employed for burn dressing to prevent infection, but not to treat already infected cases.

The biggest limitation is that mafenide produces burning sensation and severe pain when applied to raw surface. It is rapidly absorbed from the raw surface, metabolized and excreted in urine. Mafenide and its metabolite are carbonic anhydrase (CAse) inhibitors— alkalinize urine, can cause acidosis and hyperventilation: must not be applied over large areas. Allergic reactions, particularly rashes also occur.

SULFAMYLON 1% cream for surface application.

Silver Sulfadiazine

Used topically as 1% cream, it is active against a large number of bacteria and fungi, even those resistant to other sulfonamides, e.g. Pseudomonas. It slowly releases silver ions which appear to be largely responsible for the antimicrobial action. It is considered to be one of the most effective drugs for preventing infection of burnt surfaces and chronic ulcers and is well tolerated. However, it is not good for treating established infection. SILVIRIN 1% cream, ARGENEX 1% cream with chlorhexidine 0.2%.

Local side effects are—burning sensation on application and itch.

Released sulfadiazine may be absorbed systemically and produce its own adverse effects.

Sulfasalazine used in ulcerative colitis and rheumatoid arthritis.

Adverse Effects

Adverse effects to sulfonamides are relatively common. These are:

·        Nausea, vomiting and epigastric pain.

·        Crystalluria is dose related, but infrequent now. Precipitation in urine can be minimized by taking plenty of fluids and by alkalinizing the urine in which sulfonamides and their acetylated derivatives are more soluble.

·   Hypersensitivity reactions occur in 2–5% patients. These are mostly in the form of rashes, urticaria and drug fever. Photosensitization is reported. Stevens-Johnson Syndrome and exfoliative dermatitis are more common with long-acting agents.

·        Hepatitis, unrelated to dose, occurs in 0.1% patients.

·     Topical use of sulfonamides is not recommended because of risk of contact sensitization. However, ocular use is permitted.

·          Sulfonamides cause haemolysis in a dose-dependent manner in individuals with G6PD deficiency. Neutropenia and other blood dyscrasias are rare.

·         Kernicterus may be precipitated in the newborn, especially premature, by displacement of bilirubin from plasma protein binding sites and more permeable blood-brain barrier.

Interactions

Sulfonamides inhibit the metabolism (possibly displace from protein binding also) of phenytoin, tolbutamide and warfarin— enhance their action.

They displace methotrexate from binding and decrease its renal excretion—toxicity can occur.

Fixed dose combinations of sulfonamides with penicillin are banned in India.

Uses

Systemic use of sulfonamides alone (not combined with trimethoprim or pyrimethamine) is rare now. Though they can be employed for suppressive therapy of chronic urinary tract infection, for streptococcal pharyngitis and gum infection; such uses are outmoded.

Combined with trimethoprim (as cotrimoxazole) sulfamethoxazole is used for many bacterial infections, P. jiroveci and nocardiasis (see below). Along with pyrimethamine, certain sulfonamides are used for malaria (see Ch. No. 59) and toxoplasmosis.

Ocular sulfacetamide sod. (10–30%) is a cheap alternative in trachoma/inclusion conjunctivitis, though additional systemic azithromycin or tetracycline therapy is required for eradication of the disease. Topical silver sulfadiazine or mafenide are used for preventing infection on burn surfaces.