Sulfonamides

Sulfonamides

1. SULFONAMIDES & COTRIMOXAZOLE MR. MANGESH BANSOD ASST. PROF. SDDVCPRC PANVEL

2. 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. 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).

3. 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 SULFONAMIDES

4. ANTIBACTERIAL SPECTRUM Sulfonamides are primarily bacteriostatic against many gram-positive and gram-negative bacteria. 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. SULFONAMIDES

5. 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 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. SULFONAMIDES

6. Sulfonamides (MOA) Dihydropteridine + PABA Sulfonamides (PABA analogues) Sulfomethoxazole (Bacterial) Sulfadiazine (Bacterial) Sulfodoxine (Malarial) Dihydropteroic acid Synthetase Dihydropteroic acid Glutamate Dihydrofolic Acid Timethoprim (Bacterial) / Pyrimethamine (Malarial) Dihydrofolate Reductase Tetrahydrofolic Acid Nucleic Bases Amino Acids RNA DNA Proteins Folic Acid Dihydrofolate Reductase (Mammalian ) + Cotrimoxazole Cotrimazine Static Cidal Static

7. 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. Development of resistance has markedly limited the clinical usefulness of this class of compounds. SULFONAMIDES

8. Sulfadiazine It is the prototype of the general purpose sulfonamides that is rapidly absorbed orally and rapidly excreted in urine. Plasma protein binding is 50%, and it is 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. SULFONAMIDES

9. Sulfamethoxazole It has slower oral absorption and urinary excretion resulting in 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 SULFONAMIDES

10. 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. SULFONAMIDES

11. ADVERSE EFFECTS Adverse effects to sulfonamides are relatively common. These are: • Nausea, vomiting and epigastric pain. • Crystalluria is dose related, but infrequent now. Hypersensitivity reactions occur in 2–5% patients. These are mostly in the form of rashes, urticaria and drug fever. Photosensitization is reported. 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. 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. SULFONAMIDES

12. USES Systemic use of sulfonamides alone (not combined with trimethoprim or pyrimethamine ) is rare now. . 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. is a cheap alternative in trachoma/inclusion conjunctivitis. Topical silver sulfadiazine or mafenide are used for preventing infection on burn surfaces. SULFONAMIDES

13. COTRIMOXAZOLE The fixed dose combination of trimethoprim and sulfamethoxazole is called cotrimoxazole . Trimethoprim is related to the antimalarial drug pyrimethamine which selectively inhibits bacterial dihydrofolate reductase ( DHFRase ). Cotrimoxazole introduced in 1969 causes sequential block of folate metabolism

14. COTRIMOXAZOLE Sulfamethoxazole was selected for combining with trimethoprim because both have nearly the same t½ (~ 10 hr). Optimal synergy in case of most organisms is exhibited at a concentration ratio of sulfamethoxazole 20 : trimethoprim 1, the MIC of each component may be reduced by 3–6 times. Spectrum of action - Antibacterial spectra of trimethoprim and sulfonamides overlap considerably. Additional organisms covered by the combination are—Salmonella typhi , Serratia , Klebsiella , Enterobacter , Yersinia enterocolitica , Pneumocystis jiroveci and many sulfonamide-resistant strains of Staph. aureus , Strep. pyogenes , Shigella , enteropathogenic E. coli, H.influenzae , gonococci and meningococci .

15. Adverse effects All adverse effects seen with sulfonamides can be produced by cotrimoxazole . • Nausea, vomiting, stomatitis , headache and rashes are the usual manifestations. • Folate deficiency ( megaloblastic anaemia ) is infrequent, occurs only in patients with marginal folate levels. • Blood dyscrasias occur rarely. Cotrimoxazole should not be given during pregnancy. • Patients with renal disease may develop uremia. Dose should be reduced in moderately severe renal impairment. • A high incidence ( upto 50%) of fever, rash and bone marrow hypoplasia has been reported among AIDS patients with Pneumocystis jiroveci infection when treated with high dose cotrimoxazole . • The elderly are also at greater risk of bone marrow toxicity from cotrimoxazole . • Diuretics given with cotrimoxazole have produced a higher incidence of thrombocytopenia. COTRIMOXAZOLE

16. Uses 1. Urinary tract infections- Most acute uncomplicated infections respond rapidly. 2. Respiratory tract infections - Both upper and lower respiratory tract infections, including chronic bronchitis and facio -maxillary infections, otitis media caused by gram positive cocci and H. influenzae respond well. 3. Bacterial diarrhoeas and dysentery Cotrimoxazole may be used for severe and invasive infections by E. coli, Shigella , nontyphoid Salmonella, and Y. enterocolitica . 4. Pneumocystis jiroveci causes severe pneumonia in neutropenic and AIDS patients. 5. Chancroid Cotrimoxazole (800 + 160 mg) BD for 14 days is a 3rd choice 6. Typhoid Initially cotrimoxazole was an effective alternative to chloramphenicol . 7. Cotrimoxazole is an alternative to penicillin for protecting agranulocytosis patients and for treating respiratory or other infections in them. COTRIMOXAZOLE