Sulfonamides

                               SULFONAMIDES

Introduction

 Sulfonamides were the first antimicrobial agents effective against pyogenic bacterial infections. Sulfonamido-chrysoidine (ProntosilRed) was one of the dyes included by Domagk to treat experimental streptococcal infection in mice and found it to be highly effective. Subsequently an infant was cured of staphylococcal 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.

Classification

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

                      

Anti-bacterial 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 Streptococcus pyogenes, Haemophilusinfluenzae, H. ducreyi, Calymmatobacteriumgranulomatis, Vibrio cholerae.

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 that 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 acidto 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

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 serious reactions reported with the long-acting agents. 

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

• Topical use of sulfonamides is not allowed, because of risk of contact sensitization. However, ocular use is permitted. 

• Haemolysis can occur in G-6-PD deficient individuals with high doses of sulfonamides. Neutropenia and other blood dyscrasias are rare. 

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

Interactions

Sulfonamides inhibit the metabolism (possibly displace from protein binding also) of phenytoin, tolbutamide and warfarin—enhance their action. They displace methotrexate from binding sites and decrease its renal excretion—toxicity can occur.

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 nocardiosis . Along with pyrimethamine, certain sulfonamides are used for malaria 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.