O slideshow foi denunciado.
Utilizamos seu perfil e dados de atividades no LinkedIn para personalizar e exibir anúncios mais relevantes. Altere suas preferências de anúncios quando desejar.

2.sulfonamides

  • Entre para ver os comentários

2.sulfonamides

  1. 1. Sulfonamides
  2. 2. History of sulfonamides• Domagk, Mietsch and colleagues 1938– Working non azo dyes demonstrated efficacy ofprontosil – A dye with sulfonamide chain ininhibiting growth of streptococci• Nitti, Bovet and fuller– Proved that therapeutic effect of prontosil is dueto its conversion to sulfanilamide in body• Sulfapyridine was first sulfonamide to bemarketed in 1938
  3. 3. Chemical structure of sulfonamides• Antimicrobial agents containing sulfonamidogroup SO2NH2 group• This group also present in– Sulfonylureas– Thiazide diuretics– Furosemide– Acetazolamide
  4. 4. ClassificationUsed for treatment of systemic infectionsShort acting Intermediate acting Long actingSulfadiazineSulfamethazineSulfacetamideSulfisoxazoleSulfamethizoleSulfamethoxazoleSulfamoxazoleSulfadoxineSulfametho-pyrazineSufadimethoxineSulformethoxineUsed for treatment of ulcerative colitisUsed topicallySulfasalazineMafenide, silver sulfadiazine, sulfacetamide
  5. 5. Mechanism of action
  6. 6. Mechanism of actionPABADihydrofolic acidDihydrofolate synthetaseTetrahydrofolic acidDihydrofolate reductaseSulfonamidesTrimethoprimRNA DNA Proteins
  7. 7. Antimicrobial spectrum• Gm(+) Cocci:– Streptococcus pyogenes, Staph aureus• Gm(-) Cocci:– Gonococci, meningococci• Gm(+) bacilli:– Clostridia, bacillus anthracis• Gm(-) bacilli:– H.influenzae, H.ducreyi, cammylobacteriumgranulomatis, Vibrio cholerae• Chlamydia : LGV, psittacosis, trachoma• Actinomycosis , nocardia• In combination : Malaria, toxoplasma
  8. 8. Mechanisms of resistance• Over production of PABA• Production of folic acid synthetase with loweraffinity for sulfonamides• Adopt alternative pathway for folatemetabolism
  9. 9. Pharmacokinetics• Rapidly absorbed orally• Plasma protein binding (10-95%)– longer acting more bound• Widely distributed in body• Metabolism:– Acetylation of nitrogen at para-amino group• Excretion: By glomerular filtration– Both tubular secretion & reabsorption occurs– More lipid soluble – more reabsorbed
  10. 10. Individual sulfonamides• Sulfadiazine– Rapidly absorbed– Rapidly excreted– 50 % protein bound , 20 -40 % acetylated– Crosses BBB more effectively than othersulfonamides– Acetylated derivative less soluble in urine– Dose: 500 mg QID to 2 Gm TDS
  11. 11. Individual sulfonamides• Sulfisoxazole:– 10 times more soluble than sulfadiazine at pH 6– Not readily absorbed from renal tubules– Superior in treatment of UTI• Sulfamethoxazole:– Slower absorption & excretion– Intermediate acting– Preferred for combining with trimethoprim– Dose: 1 gm BD for 2 days then 0.5 gm BD
  12. 12. Individual sulfonamides• Sulfadoxine, sulfamethopyrazine:– Ultra long acting > 1 week– High protein binding & slow excretion– Not suitable for acute pyogenic infections– Used in combination with pyrimethamine in• Malaria• Pneumocystis jiroveci pneumonia in AIDS patients• Toxoplasmosis– Not recommended for prophylaxis: seriouscutaneous reactions
  13. 13. Topical sulfonamides• Sulfacetamide• Mafenide• Silver sulfadiazine
  14. 14. Sulfacetamide• Topical drug in ocular infections– Neutral pH 7.4– Non irritant– Penetrates the ocular fluids and tissues in highconcentration• Dose: 1-2 drops of 10 -30-% solution 3 -4 times a day• Antagonist to inhibition of pseudomonas bygentamicin• Uses: Chlamydia , ophthalmia neonatorum causedby Chlamydia occulogenitalis• Sensitivity reactions low
  15. 15. Mafenide• Not a typical sulfonamide• Active in presence of pus against pseudomonas,clostridia which are not inhibited by typicalsulfonamides• Use:– Burn`s dressing to prevent infection• Adverse effect:– Burning sensation– Carbonic anhydrase inhibitor can alkalinize urine causeacidosis and hyperventilation– Allergic reaction : rashes may occur
  16. 16. Silver sulfadiazine• Effective against large number of bacteria, fungi,even those resistant to other sulfonamides e.gpseudomonas• Releases silver ions largely responsible forantimicrobial action• One of most effective drug for preventinginfections on burnt surfaces and chronic ulcers• Well tolerated• Adverse effects:– Burning sensation– May be absorbed systemically and produce adverseeffects
  17. 17. Uses of sulfonamides• UTI: E.coli, proteus• Meningococcal meningitis• Nocardiasis, Trachoma, Chancroid• Bacillary dysentry• Topical:– Sulfacetamide: trachoma, inclusion conjunctivitis– Silversulfadiazine, mafenide : preventing infectionon burn surfaces• Sulfasalazine: ulcerative colitis
  18. 18. Adverse effects• Gastrointestinal:• Renal toxicity :– Crystaluria dose related• Hemopoetic toxicity:– Hemolysis inG6PD deficiency• Hypersensitivity• Hepatitis: non dose dependent• Kernicterus• Nervous system:• Miscellaneous:– Goitre , hypothyroidism
  19. 19. Drug interactionsS.No Interfering drug Effect1 Sulfonylureas Displaced from protein binding siteprobable hypoglycemia2 Phenytoin, warfarin ↑ action of both3 Methotrexate Displaced also ↓ excretiontoxicity may occur4 Procaine (ContainPABA)Direct inhibition of sulfonamideaction5 Phenylbutazone ,salicylate ,probenecidSulfonamide displaced fromprotein binding↑ activity of sulfonamides
  20. 20. Sulfonamide used in IBD(Sulfasalazine)• Sulfasalazine:– Treatment of mild to moderate ulcerative colitis– Crohns disease beneficial effect less predictable• Inflammatory Bowel Disease– Immunological response to bacterial antigens ofintestinal origin– Has genetic predisposition– Ulcerative colitis: colon & rectum, superficiallesions– Crohns disease: Small intestine & colon,transmural involvement
  21. 21. Sulfasalazine
  22. 22. SulfasalazineSulfapyridine 5-ASAAcetylated in liverAbsorbed rapidly in colonExcreted in urinePoorly absorbedInduces remission inulcerative colitisNo therapeutic actionin ulcerative colitisInhibit COXLOX , PAF,CytokinesInhibit IL-1 &TNF-
  23. 23. Mesalazine /Mesalamine/ 5-ASA• 5 –ASA the active moeity in ulcerative colitis• Delayed release preparation coated withacrylic polymer• Reliable for delivering 5 ASA to colon & distalbowel• 400 mg tab = 1 gm sulfasalazine• Primary use: preventing relapses• Better tolerated than sulfasalazine• Nephrotoxic C/I in renal & hepatic impairment
  24. 24. Mesalazine preparationsPreparation Structure DoseSulfasalazine Mesalazine linked to sulfapyridine 2-6 gm/dayBasalazide Mesalazine linked to inert molecule 2.25 gm TDSOsalazine Mesalazine linked to Mesalazine 1.5 TO 3 gm /Mesalazine Time released 3-4 gm/dayMesalazine pH sensitive coated mesalazinereleased at pH > 72.4 -4.8 gm/dMesalazinesuppositoryMesalazine directly in rectum 0.5 to 1 gmOD/BDMesalazineenemaDirectly in left colon 4 gm in 60 m
  25. 25. Other drugs for IBD• Glucocorticoids– Acute exacerbations of ulcerative colitis & crohns– Oral , IV , Enema form– May lead to opportunistic infections• Immunosupressive agents– Methotrexate : more useful in crohns disease– Azathioprine :– 6 mercaptopurine• Antibiotics :– Adjuncts to drugs or to treat complications– Metronidazole, ciprofloxacin
  26. 26. Trimethoprim• Diaminopyrimidine related to pyrimethamine• Spectrum of action:– Staphylococcus, streptococcus– Corynebacterium diptheriae– E.coli, salmonella, shigella, H.influenzae,– Klebsiella pnemoniae, proteus, vibriocholerae– Less effective against N.gonorrhoea &N.meningitis , Cl. Welchii, Bordetella pertusis
  27. 27. Trimethoprim (MOA)PABADihydrofolic acidDihydrofolate synthetaseTetrahydrofolic acidDihydrofolate reductaseSulfonamidesTrimethoprimRNA DNA Proteins
  28. 28. Trimethoprim (Pharmacokinetics)• Rapid & almost complete absorption• Absorption & excretion charecteristics very similar tosulfamethoxazole t1/2 = 10 hrs• Distributed more widely than sulfamethoxazole haslarger volume of distribution , attains lower plasmaconcentration.• Higher ratio 20:1 (sulfonamide:trimethoprim) inplasma than in tablets (5:1)• Trimethoprim crosses BBB, Placenta• Excretion markedly ↑ with acidification of urine
  29. 29. Adverse effects & uses• Adverse effects:– ↑ hematological toxicity of sulfamethoxazole– Megaloblastic anemia, leukopenia, granulocytopenia– These can be reverse by administration of folinic acid• Uses:– UTI: Acute as well as chronic recurrent especially infemales– Prostatitis: Concentrated in prostrate• Dose: 100-200 mg BD
  30. 30. Co-trimoxazole• WHO approved fixed dose combination ofsulfamethoxazole & trimethoprim in ratio of5:1• Sulfamethoxazole = 400 mg• Timethoprim = 80 mg• MOA:– Sequential blockade
  31. 31. Antimicrobial spectrum• Similar to sulfonamides• Additional organisms:– Salmonella, serratia, klebsiella, enterobacter– Yersinia & pneumocystis carinii• Many resistant strains to sulfonamides– Staph aureus , streptococcus pyogenes– Shigella, E.coli, H.influenzae– Gonococci & meningococci
  32. 32. Pharmacokinetics• Trimethoprim & sulfomethoxazole have nearlysame t1/2 , 10 hrs• Optimal synergy in case of most organismsexhibited in conc ratio of 20:1 (S:T)• MIC of each component reduced by 3-6 times• This ratio is obtained in plasma when given astablet in ratio (5:1) sulfamethoxazole:trimethoprim
  33. 33. Pharmacokinetics
  34. 34. Adverse effects• GIT:• Dermatological• Hematological• HIV patients :– fever ,rashes, pancytopenia• Renal toxicity:– Pt with renal disease develop uremia• Pregnancy:– Teratogenic risk , neonatal hemolysis,methaemoglobinemia
  35. 35. Uses• UTI :– Acute cystitis: 4 tab single dose therapy– DS tablet BD for 5-10 days effective for most UTI• Prostatitis :– Acute prostatitis for 3 weeks– Chronic prostatitis for 6-12 weeks• Respiratory infections:– Acute sinusitis, otitis, bronchitis due topneumococcus & hemophilus• Typhoid:– DS tablet for 2 weeks
  36. 36. Uses• Bacterial diarrhoeas/ dysentry• Nocardiasis :– DOC for pulmonary lesions or brain abcess• Sexually transmitted diseases– Chancroid: one of the drug of choice– Granuloma inguinale: alternative drug– Gonorrhea• Alternative to penicillin in agranulocytosis• Pneumocystis jiroveci pneumonia• Meliodosis
  37. 37. Advantages of cotrimoxazole• Sequential blockade , supra-additive effect• Individually bacteriostatic but combinationhas bactericidal effect• Chances of development of resistancereduced• Wide spectrum antibacterial drug• Relatively safe and well tolerated• Highly cost effective in many commoninfections in practice
  38. 38. Preparations and doseTrimethoprim sulfomethoxazoleTablet 80 mg 400 mgDouble strength 160 mg 800 mgPaediatric tablet 20 mg 100 mgSuspension /5ml 40 mg 200 mgIV injection /5ml 80 mg 400 mg
  39. 39. Drug interactions• Similar to sulfonamides– ↑action of warfarin, sulfonylureas methotrexate– NSAIDS displace sulfa-methoxazole from proteinbinding site increase its action
  40. 40. Other synergistic combinations• Cotrimazine– Combination of trimethoprim with sulfadiazine– Uses similar to cotrimoxazole– Trimethoprim = 90 mg , Sulfadiazine = 410 mg– Uses similar to cotrimoxazole– Dose = 2 tab BD for 2 days then OD• Sulfadoxine + pyrimethamine– Used in malaria – umcomplicated falciparum– Toxoplasmosis

×