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Sulfonamides
Sulfonamides
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Sulphonamides

  1. 1. SULPHONAMIDES GUIDE: Mrs. T. PRABHA ASISSITANT PROFESSOR DEPARTMENT OF PHARMACEUTICAL ANALYSIS NANDHA COLLEGE OF PHARMACY ERODE-52 AMEERA.N III PHARM D NANDHA COLLEGE OF PHARMACY ERODE-52
  2. 2.  Sulfonamides derived from p-amino benzene sulfonamide.  It is the first chemotherapeutic agents implied systematically for prevention of bacterial infections. HISTORY:  Screening of ‘dyes’ for their actibacterial properties in 1920s.  Sulfonamido-chrysidine-commonly known as “prontosil red” was the first one effective in streptococcal infection in mice by Domagk.  cured his daughter.  1937-prontosil was broken down to release “sulfanilamide”-many sulfonamides were produced.
  3. 3. CHEMISTRY OF SULPHONAMIDES: ■ Recognised since 1932. ■ In clinical usage since 1935. ■ First compound found to be effective antibacterial agents in safe dose ranges. ■ Chemically,it is a molecule containing sulfonamide(sulfanilamide , SO2NH2) functional group attached to an analine. ■ Structurally related to p-amino benzoic acid (PABA). ■ This group is also present in other non-antibacterial compound like sulphonureas , benzothiazids , furosemide , acetazolamide.
  4. 4. NOMENCLACTURE OF THE SULFONAMIDES: ■ Sulfonamides is a generic term that denotes 3 different cases: 1. Antibacterials that are analine-substituted sulfonamides (sulfanilamides) 2. Prodrug that react to generate active sulfanilamides(sulfasalazine) 3. Nonanaline sulfonamides (mefenide acetate)
  5. 5. SYNERGISM OF SULFONAMIDE AND FOLATE REDUCTASE INHIBITORS: ■ If biosynthesis of bacterial folate coenzymes is blocked at more than one point in the pathway , the result will be a synergistic antimicrobial effect. ■ This is beneficial because the microbe will not develop resistance as readily as it would with a singly blocked pathway. ■ The synergistic approach is used widely in antibacterial therapy with the combination of sulfamethoxazole and trimethoprim ■ In antimalarial therapy with pyrimethamine plus a sulfonamide or quinine .
  6. 6. THE PROBLEM OF CRYSTALLURIA ■ Sulfonamides are mostly excreted in urine as acetylated metabolite. ■ They are relatively water insoluble mainly due to the formation of acetylated metabolites. ■ The acetylated metabolite is non-ionizable under the PH conditions of the urine(~7) that increase the possibility of precipitation and the formation of crystals in the urine. How to minimize the possibility of crystalluria formation with sulfonamides:  Increase the urine flow.  Increase the PH of the urine to increase the ionization of sulfonamides and the formation of water soluble salts.
  7. 7. ■ Lowering the Pka of the sulfonamide group which will help to increase the ionization under the acidic conditions . This can be done by adding electron withdrawing group on the sulfonamide side chain.
  8. 8. CLASSIFICATION c)Agents which are employed topically ■ Mefenide ■ Sodium sulfacetamide ■ Silver sulfadiazole ON THE BASIS OF:  PHARMACOKINETIC PROPERTIES: a)Agents which are rapidly absorbed and excreted: ■ Sulfamethaxazole ■ Sulfisoxazole ■ Sulfapyridine ■ sulfadiazine b)Agents which are poorly absorbed in GIT (local): ■ Sulfasalazine ■ Phthalyl sulfathiazole
  9. 9. STRUCTURALACTIVITY RELATIONSHIP: ■ The amino and sulfonyl radicle on benzene ring are essential for the activity and should be in 1 ,4 position. ■ The 4 amino group should be modified to produce prodrug which are converted into 3-amino functional group invivo. eg: phthalyl sulfathiazole succinyl sulfathiazole ■ Replacement of benzene ring by another ring system or the introduction of additional subsituent on benzene ring will decrease the activity. ■ Exchange of sulfonyl group (-SO2NH2) by other group like SO2C6H4(-P-NH2) ,CONH2, CONHR, COC6H4R, to retain the activity.
  10. 10. ■ Subsitution of hectrocyclic aromatic nuclei at 1st position yield highly potent compound. ■ 1st position disubsitution in general leads to inactive compound because one hydrogen is needed for ionization. ■ The pi charge of first position activity greater the charge greater the activity. ■ The protein binding like arginine, histidine, lysine, on basic center of sulfonamide will affect the activity,because protein binding appear to modulate the bioavailability of drug and its t1/2.
  11. 11. MECHANISM OF ACTION OF SULFONAMIDES:
  12. 12. ■ Sulfonamides and sulfones in antibacterial agents act as a competitive inhibitor for incoperation of PABA to form dihydropteroic acid. ■ The 1st position substitution in sulphonamide compete for site on enzyme surface reserved for glutamate residue. ■ It compete for linking of PABA glutamate with pteridine derivative. ■ Trimethoprim is a structural analogue of dihydrofolic acid.It is a selective competitive inhibitor of microbial folate reductase,the enzyme that reduces dihydrofolate to tetrahydrofolate. ■ Simultaneous administration of sulphonamides and trimethoprim block the pathway of synthesis of tetrahydrofolate and producing synthetic antimicrobial effect.
  13. 13. SULFADIAZINE STRUCTURE
  14. 14. SULFASALAZINE STRUCTURE
  15. 15.  DOSE: 3-4g / day in divided doses.  DOSAGE: 500 mg Tablet  ADVERSE EFFECT: Gastric distress , oligospermia , anorexia , headache .  USES: Used in the treatment of ulcerative colitis and inflammatory bowel disease. STRUCTURE SULFAMETHOXAZOLE
  16. 16. SYNTHESIS DOSE: Orally 2 g followed by 1 g 8 hour. DOSAGE: Oral 500mg or 1g tablet
  17. 17.  ADVERSE EFFECTS:  mental/mood changes  extreme drowsiness  sweating  fast heartbeat  USES: • Used in the treatment of bacterial infection. • Used in lower urinary tract and systemic infections caused by E.coli and p.Mirabilis. • Used in combination with trimethoprim is used in treatment of several infections including AIDS. • It is also used to prevent and treat a certain type of pneumonia.
  18. 18. SULFAMETHIZOLE SYNTHESIS STRUCTURE
  19. 19.  DOSE : 500-1000mg 3-4 times daily  DOSAGE: 500 mg tablet  USES: Gram-Negative Bacterial infection Gram-Positive Bacterial Infections. Urinary Tract Infections. SILVER SULFADIAZINE STRUCTURE
  20. 20.  DOSAGE: 1% cream.  USES: Used to prevent skin infections after burns . Used to treat infected leg ulcers or pressure sores. SYNTHESIS
  21. 21. SULFACETAMIDE SODIUM SYNTHESIS STRUCTURE
  22. 22.  DOSAGE: Ophthalmic solution : 10% , 15% , 30% Ointment :10%.  ADVERSE EFFECT: Hypersensitivity reactions , myopia , burning conjunctivitis , corneal ulcers , irritation, stinging.  USES: Used to treat bacterial eye infection like conjuctivitis. DAPSONE STRUCTURE
  23. 23.  DOSE: 50 mg daily  DOSAGE: 25mg and 100mg tablets SYNTHESIS
  24. 24.  ADVERSE EFFECT: unusually fast heartbeat, bluish lips/skin, chest pain, mental/mood changes, muscle weakness, difficulty urinating.  USES: used to treat a certain type of skin disorder (dermatitis herpetiformis). It is also used with other drugs to treat Hansen's disease. . SULFASOXAZOLE STRUCTURE
  25. 25.  DOSE: 4-6g daily 2-3 divided doses  DOSAGE: 500mg tablet  ADVERSE EFFECT: Stomach pain , dizziness , rashes , headache , diarrhea  USES: Used to treat a certain type of bowel diseases called ulcerative colitis. SULPHAMETHAZINE STRUCTURE
  26. 26.  DOSE: 3-4 g daily in divided dose  DOSAGE: 500mg tablet  ADVERSE EFFECT: Gastric distress , headache , nausea , oligospermia , vomiting , anorexia.  USES: Used for treatment of bacterial infections causing bronchitis , prostatitis and urinary tract infection. Used for pneumococcal ,staphylococcal and streptococcal infections. Used in sepsis , gonorrhea and other infectious disease.
  27. 27.  DOSE: 250mg-1g 4 times aday for dermatitis herpetiform.  DOSAGE: 250mg capsule  ADVERSE EFFECT: Fever , crystalluria ,blood dyscariasis , thyroid function disturbances , hypersensitivity.  USES: Used for the treatment of dermatitis herpetiformis,pemphigoid,bullous and pyoderma gangrenosum. SULFAPYRIDINE STRUCTURE
  28. 28.  DOSE: 5% solution of mefenide chloride or mefenide propionate for topical use.  DOSAGE: Mefenide actetate cream  ADVERSE EFFECT: Allergic reactions , bleeding or oozing of skin , metabolic acidosis.  USES:  Used alone or with combination with other medication to prevent or treat wound infections. Used in the treatment and cure of gas gangrene . Also effective against clostridium welchii on topical application . MEFENIDE ACETATE STRUCTURE
  29. 29.  DOSE: 2g per day in equally divide dose  DOSAGE: 500 mg tablet  ADVERSE EFFECT: Decreased appetite , stomach upset or stomach pain , aching of joints , headache , photosensitivity, rashes.  USES: Used to treat certain type of bowel disease called ulcerative colitis. Delayed –release tablets of sulfasalazine used to treat rheumatoid arthritis SULFASALAZINE STRUCTURE
  30. 30.  ADVERSE EFFECT: Headache , loss of appetite , stomach upset , nausea and vomiting .  USES: Used as antileprotic drug .It is less potent than dapsone and is used when there is a gastric intolerance of dapsone. SOLAPSONE STRUCTURE
  31. 31. MIXED SULFONAMIDES  TRISULFAPYRIMIDINES,ORAL SUSPENSION: The oral suspension of trisulfapyrimidne contains equal weight of sulfadiazine , sulfamerazine and sulfamethazine either with or without an agent to raise the PH of urine.  TRISULFAPYRIMIDINES,TABLET: Trisulfapyrimidine tablet contain essentially equal quantities of sulfadiazine , sulfamerazine and sulfamethizine .  SULFADOXINE AND PYRIMETHAMINE: The mixture of sulfadoxine and pyrimethamine is used to treat of P.falciparum malaria in patients in whom chloroquine resistance is suspected . It is also used for malaria prophylaxis for travelers to areas where chloroquine- resistant malaria is endemic.
  32. 32. REFERENCE: ■ TEXTBOOKOF MEDICINALCHEMISTRY BY V.ALAGARSAMY. ■ MEDICINALCHEMISTRY BY ASHUTOSH KAR ■ https://www.researchgate.net/publication/321938118_Sulfonamides.

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