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  2. 2. <ul><li>SULFONAMIDES </li></ul>
  3. 3. SULFONAMIDES <ul><li>The first antimicrobial agents (AMAs) – Pyogenic bacterial infections. </li></ul><ul><li>Sulfonamido-chrysoidine (Prontosil dye) – by Domagk – Streptococcal infection.(septicaemia). </li></ul><ul><li>1937 – Sulfanilamide – active antibacterial agent. </li></ul>
  4. 4. Chemistry of Sulfonamides <ul><li>Sulfanilamide (p-aminobenzene sulfonamide)- its derivaties. </li></ul><ul><li>N 1 (SulfonamidoN) – solubility, potency and pharmacokinetic property. </li></ul><ul><li>Amino group in para position (N 4 ) – antibacterial. </li></ul>
  5. 6. Sulfacetamide sod., Sulfasalazine, Mafenide, silversulfadiazine. Special purpose sulfonamides 4. Sulfadoxine, Sulfamethopyrazine. Long acting (~7days) 3. Sulfamethoxazole, Sulfamoxole. Intermediate acting (8-12hr) 2. Sulfadiazine, Sulfisoxazole. Short acting (4-8hr) 1. DRUGS LIFE S.No.
  6. 7. Antibacterial Spectrum of Sulfonamides. <ul><li>Bacteriostatic - Gram +ve and Gram – ve. </li></ul><ul><li>Strepto, pyogenes, Haemophilus influenzae, H.ducreyi, Calmmatobacterium granulomatis, Vibrio cholerae. </li></ul><ul><li>Few – Staph.aureus, gonococci, meningococci, pneumococci, Escherichia coli and Shigella but majority are resistant. </li></ul><ul><li>Chlamydiae: trachoma, lymphogranuloma venereum, inclusion conjectivitis. </li></ul><ul><li>Actinomyces, Nocardia and Toxoplasma. </li></ul>
  7. 8. Mechanism of Action of Sulphonamides <ul><li>Woods and Fildes (1940) </li></ul><ul><li>Sulphonamides are structural analogue of p-aminobenzoic acid (PABA), which is essential for folic acid synthesis in bacteria. </li></ul><ul><li>Folate is require for the synthesis of the precursors of DNA and RNA in both bacteria and mammals. </li></ul><ul><li>Mammals obtain folic acid from their diet and whereas bacteria synthesize. </li></ul><ul><li>Pus and tissue extracts. </li></ul>
  8. 9. Resistance to sulfonamides <ul><li>Gonococci, pneumococci, Staph.aureus, meningococci, E.coli, Shigella and some Strep.pyogenes. </li></ul><ul><li>The resistant mutants either: </li></ul><ul><li>Produce increased amounts of PABA (or) </li></ul><ul><li>Their folate synthetase enzyme has low afinity for sulfonamides (or) </li></ul><ul><li>Adopt an alternative pathway in folate metabolism. </li></ul>
  9. 10. Pharmacokinetics of Sulphonamides <ul><li>Rapidly and nearly completely absorbed from gastro intestinal tract. </li></ul><ul><li>Sulfonamides are widely distributed in the body – enter serous cavities easily. </li></ul><ul><li>Sulfonamides are excreted mainly by the kidney through glomerular filtration. Both renal tubular secretion and reabsorption also occur. The more lipid soluble members are highly reabsorbed in the tubule, therefore are longer acting. </li></ul>
  10. 11. <ul><li>Sulfadiazine: rapidly absorbed orally and repidly excreted in urine. </li></ul><ul><li>It is 50% plasma protein bound and 20- 40% acetylated. </li></ul><ul><li>The acetylated derivative is less soluble in urine, crystalluria is likely. </li></ul><ul><li>It has good penetrability in brain and CSF – was is the preferred compound for meningitis. </li></ul><ul><ul><li>Dose: 0.5 g QID ( Latin: quater in die) to 2g TDS (tab) ( Latin, ter die sumendus). </li></ul></ul>
  11. 12. <ul><li>Sulfisoxazole (Sulfafurazole) : </li></ul><ul><li> highly soluble (free as well as acetylated form) </li></ul><ul><li>Even in acidic urine – crystalluria is less likely. </li></ul><ul><li>2/3 is excreted unchanged in urine: has a shorter t1/2. </li></ul><ul><li>Useful for Urinary tract infection </li></ul><ul><li>Dose: 0.5g QID to 2g TDS: Gantrisin 0.5g tab. </li></ul>
  12. 13. <ul><li>Sulfamethoxazole: </li></ul><ul><li>It has slower oral absorption and urinary excretion. </li></ul><ul><li>Intermediate duration of action. </li></ul><ul><li>T1/2 in adults averages 10hrs. </li></ul><ul><li>Combining with trimethoprim </li></ul><ul><li>Dose: 1g BD (Latin: bis in die) then 0.5.g BD; Gantanol 0.5 g tab. </li></ul>
  13. 14. <ul><li>Sulfamoxole: </li></ul><ul><li>is employed when a sulfonamide alone has to be used for respiratory or urinary tract infection. </li></ul><ul><li>Dose: 1g BD on first day, then 0.5g BD </li></ul><ul><li> Sulfuno 0.5g tab. </li></ul>
  14. 15. <ul><li>Sulfadoxine, Sulfamethopyrazine: </li></ul><ul><li>Ultralong acting compounds action lasting > 1 week because of high plasma protein binding and slow renal excretion (t1/2 5-9 days). </li></ul><ul><li>Used in combination with pyrimethamine in the treatment of malaria </li></ul>
  15. 16. <ul><li>Sulfacetamide sod.: </li></ul><ul><li>Highly soluble compound yielding neutral solution </li></ul><ul><li>Only mildly irritating to the eye in conc. Up to 30%. </li></ul><ul><li>Topically for ocular infection – chlamydia. </li></ul><ul><li>Ophthalmia neonatorum – ch.oculogenitalis. </li></ul><ul><li>Locula, Albucid 10%,20%,30% eye drops, 6% eye oint. </li></ul><ul><li>Sulfasalazine used in ulcerative colitis and rheumatoid arthritis. </li></ul>
  16. 17. <ul><li>Mafenide: </li></ul><ul><li>Topically – inhibits – gram +ve and gram – ve. </li></ul><ul><li>Active in the presence of pus and against Pseudomonas, clostridia as well. </li></ul><ul><li>Burn dressing to prevent infection. </li></ul><ul><li>But burning sensation and severe pain when applied to raw surface, metabolized and excreted in urine. </li></ul><ul><li>Mafenide and its metabolite are carbornic anuhydrase inhibitors. </li></ul><ul><li>Allergic reactions, particularly rashes also occur. </li></ul><ul><li>Sulfamylon 1% cream for surface application. </li></ul>
  17. 18. <ul><li>Silver Sulfadiazine: </li></ul><ul><li>Topically as 1% cream, bacteria and fungi </li></ul><ul><li>Active if resistant to other sulfonamides, e.g. Pseudomonas. </li></ul><ul><li>Slowly releases silver ions which appear to be largely responsible for the antimicrobial acton. </li></ul><ul><li>Most effective drugs – infection of burnt surfaces and chronic ulcers. </li></ul><ul><li>Silvirin 1% cream, Argenex 1% cream with chlorhexidine 0.2%. </li></ul><ul><li>Local side effects are – burning sensation on application and itch. </li></ul>
  18. 19. ADVERSE EFFECTS OF SULPHONAMIDES <ul><li>Nausea, vomiting and epigastric pain. </li></ul><ul><li>Crystalluria, Renal irritation, haematuria are rare now. </li></ul><ul><li>Hypersensitivity reaction occur in 2-5% patients. (rashes, urticaria and drug fever). Arthritis, serum sickness like syndrome. </li></ul><ul><li>Bone marrow depression. </li></ul><ul><li>Hepatitis unrelated to dose occurs in 0.1% patients. </li></ul><ul><li>Sulfonamides cause haemolysis, dose dependent manner. Neutropenia and other blood dyscrasias are rare. </li></ul>
  19. 20. Uses of Sulphonamides <ul><li>Widely used in combination with trimethoprim but may be use alone. </li></ul><ul><li>Urinary tract infections : specially acute cystitis – high and bactericidal concentration in urine. </li></ul><ul><li>Streptococcal pharyngitis and gum infections: Though penicillins are preferred, sulfonamides may be used as cheaper alternatives. Used for prophylaxis of rheumatic fever in patients allergic to penicillin. </li></ul><ul><li>Trachoma and inclusion conjunctivitis: Sulfacetamide sod. 10%-30% for 4 weeks as eye drops or ointment is a cheap and effective alternative to topical tetracycline. Additional systemic therapy with a sulfonamide or tetracycline is required for eradication of the disease. Control of secondary bacterial. </li></ul>
  20. 21. <ul><li>4. Lymphogranuloma venereum: sulfonamides are second choice to tetracyclines. </li></ul><ul><li>5. Malaria : A long acting sulfonamides combinated with pyrimethamine is used for treatment of chloroquine resistant malaria. </li></ul><ul><li>6.Toxoplasmosis: Sulfadiazine + pyrimethamine given for 4-6 weeks is the therapy of choice for toxoplasmosis. </li></ul><ul><li>7. Nocardiosis: Long term (months) treatment with high does of a sulfonamide is required. Trimethoprim, ampicillin or erythromycin may be given in addition. </li></ul><ul><li>8. Burns: Topical silver sulfadiazine or mafenide are used primarily for preventing the raw surfaces getting infected. </li></ul>
  21. 22. <ul><li>ANTITUBERCULAR </li></ul>
  22. 23. <ul><li>Streptomycin </li></ul><ul><li>P-aminosalicylic acid (PAS) </li></ul><ul><li>Isoniazid (isonicotinylhydrazide) (INH) </li></ul><ul><li>Isonicotinic acid hydrazine (INAH). </li></ul>
  26. 27. CH 3 CH 2 CHNH(CH 2 ) 2 NHCHCH 2 CH 3 CH 2 OH CH 2 OH .2HCL ETHAMBUTOL
  27. 28. <ul><li>Tuberculosis treatment: </li></ul><ul><li>Initial Phase: combination of three drugs. </li></ul><ul><li>Continuation phase: combination of two drugs. </li></ul><ul><li>Front-line drugs are isoniazid, rifampicin, streptomycin and ethambutol. </li></ul><ul><li>Pyrazinamide – good meningeal penetration. </li></ul><ul><li>Isoniazid – effect on mycobacteria. </li></ul>
  28. 29. <ul><li>Secondary antitubercular drugs: </li></ul><ul><li>Capreomycin </li></ul><ul><li>Cycloserine </li></ul><ul><li>Macrolides (azithromycin, clarithromycin) </li></ul><ul><li>4-quinolones (ciprofloxacin, ofloxacin) and prothonamide. </li></ul><ul><li>Isonicotinic acid – Prothonamide, pyrazinamide and ethionamide ( The British National Formular ) </li></ul><ul><li>Thiacetazone – not used nowadays. </li></ul>
  29. 30. <ul><li>NITROFURANS </li></ul>o Furan o NO 2 CHO 5-nitrofurfural
  30. 31. <ul><li>Azomethine group, -CH=N-, is attached at C-2 and a nitrogroup at C-5. Less important nitrofurans have vinyl group, -CH=CH-, at C-2 </li></ul>
  31. 33. <ul><li>Furazolidone – enterobacteriaceae – for diarrhoe and gastrointestinal disturbance. </li></ul><ul><li>Nitrofurantoin – urinary tract infection </li></ul><ul><li>Nitrofurazone – burns and wounds and ear infections. </li></ul>
  34. 36. <ul><li>Active on Gram –ve and fluorinated compound on Gram +ve also. </li></ul><ul><li>Niladixic acid: - 1960s. </li></ul><ul><li>against gram negative (E.coli, Proteus, Klebsiella, Enterobacter, Shigella but not Pseudomonas). </li></ul><ul><li>Inhibit bacterial DNA gyrase. </li></ul><ul><li>Bactericidal. </li></ul><ul><li>Dose: 0.5 – 1g TDS or QID: </li></ul><ul><li>Gramoneg, Wintomylon, Urodic, 0.5 g tab, 0.3g/5 ml syrup. </li></ul>
  35. 37. <ul><li>Adverse Effects: </li></ul><ul><li>Upset and rashes. </li></ul><ul><li>Neurological – headache, drowsiness, vertigo, visual disturbance. </li></ul><ul><li>Prolonged use - leucopenia and biliary stasis. </li></ul><ul><li>Haemolysis </li></ul><ul><li>Use: </li></ul><ul><li>Urinary antiseptic. </li></ul><ul><li>Diarrhoea caused by Proteus, E.coli, Shigella or Salmonella. </li></ul>
  36. 38. <ul><li>Fluoroquinolones: Quinolone with fluorine substitutes. (CIPROFLOXACIN) </li></ul><ul><li>Rapidly bactericidal activity and high potency. </li></ul><ul><li>Relatively long post-antibiotic effect on enteriobacteriaceae, Pseudomonas and Staph. </li></ul><ul><li>Low frequency to mutational resistance. </li></ul><ul><li>Low propensity to select plasmid type resistant mutants. </li></ul><ul><li>Protective intestinal streptococci and anaerobes are spared. </li></ul><ul><li>Active against many β -lactam and aminoglycoside resistant bacteria </li></ul><ul><li>Less active at acidic PH. </li></ul>
  37. 39. <ul><li>Highly susceptible: </li></ul><ul><li>E.coli, </li></ul><ul><li>K.penumoniae, </li></ul><ul><li>Enterobacter, </li></ul><ul><li>Salmonella typhi, </li></ul><ul><li>Other salmonella, </li></ul><ul><li>Shigella, </li></ul><ul><li>Proteus, </li></ul><ul><li>Neisseria gonorrhoea, </li></ul><ul><li>N.meningitidis, </li></ul><ul><li>H.influenzae, </li></ul><ul><li>H.ducreyi, </li></ul><ul><li>Campylobacter jejuni, </li></ul><ul><li>Yersinia enterocolitica, </li></ul><ul><li>Vibrio cholerae. </li></ul><ul><li>Moderately susceptible: </li></ul><ul><li>Pseudomonas aeruginosa, </li></ul><ul><li>Pseudomonas aeruginosa, </li></ul><ul><li>Staph.aureus, </li></ul><ul><li>Staph.epidermidis, </li></ul><ul><li>Branhmella catarrhalis, </li></ul><ul><li>Legionella, </li></ul><ul><li>Brucella, </li></ul><ul><li>Listeria, </li></ul><ul><li>Mycobact.tuberculosis. </li></ul><ul><li>Low/Variable susceptibility: Strep.pyogenes, Strep.faecalis, Strep.pneumoniae, Mycoplasma, Chlamydia, Mycobact.kansasi, Mycobact.avium. </li></ul>
  38. 40. <ul><li>Adverse Effect: </li></ul><ul><li>Gastrointestinal </li></ul><ul><li>CNS </li></ul><ul><li>Skin/hypersensitivity </li></ul><ul><li>Uses: </li></ul><ul><li>Urinary tract infections </li></ul><ul><li>Gonorrhoea </li></ul><ul><li>Bacterial gastroenteritis </li></ul><ul><li>Typhoid </li></ul><ul><li>Bone, soft tissue, gynaecological and would infections. </li></ul><ul><li>Respiratory infections </li></ul><ul><li>Tuberculosis </li></ul><ul><li>Gram negative septicaemias </li></ul><ul><li>Meningitis </li></ul><ul><li>Prophylaxis </li></ul><ul><li>Conjuctivitis </li></ul>
  39. 41. <ul><li>First generation Fluroquinolones: </li></ul><ul><li>Norfloxacin </li></ul><ul><li>Ciprofloxacin </li></ul><ul><li>Ofloxacin </li></ul><ul><li>Pefloxacin </li></ul><ul><li>Second generation Fluroquinolones: </li></ul><ul><li>Lomefloxacin </li></ul><ul><li>Sparfloxacin </li></ul><ul><li>Fleroxacin </li></ul><ul><li>Amifloxacin </li></ul>
  40. 42. <ul><li>IMIDAZOLES </li></ul>METRONIDAZOLES
  41. 46. <ul><li>Come back </li></ul>MAJID MOHIUDDIN