2.sulfonamides

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  • Sulfonamides were first AMA agents to be effective in pyogenic infections Domagk first used prontosil red to treat experimental streptococcal infection in mice , subsequently cured his daughter of streptococcal septicaemia 100 % fatal at that time Sulfanilamide was prepared by gilmo as early as 1908 but 30 years elapsed before its therapeutic value was discovered
  • Non antibacterial compounds Sulfonamides are white powders Mildly acidic in nature Form water soluble salts with bases Sodium salts have high pH (Alkainity ) IM damage to tissues
  • Human cells are freely permeable to folic acid but bacterial cells are not hence bacteria has to synthesize its own folic acid and humans acquire it from diet. Structuraaly folic acid made of 3 components – pteridine + PABA+ Glutamic acid Sulfonamides due to their structurakresemblence to PABA compete with it and substitute it in bacterial metabolism (Wood fields theory) The active form of folic acid is important coenzyme responsible for synthesis of bacterial proteins, RNA & DNA Structurally the folic acid consists of 3 components
  • Sulfonamides compete with PABA for enzyme folic acid synthetase which is involved in conversion of PABA to folic acid Inhibition of folic acid synthetase by sulfonamides causes folic acid deficiency resulting in injury to bacterial cell , such an injured or disrupted bacterial cell easily phagocytosedWhy NOT in humans: human cells also require folic acid but they utilize pre formed folic acid supplied in diet and are unaffected by sulfonamides Evidence supporting MOA of sulfonamides:PABA in small quantities antagonizes the antibacterial action of sulfonamides Only those microbes which synthesize their own folic acid are susceptible to sulfonamides Sulfonamides are ineffective in presence of pus and tissue breakdown products which contain large amount of PABA, purines & thymidine (decrease FA requirement) Sulfonamide resistant bacteria usually show increased PABA synthesis This theory however can not explain the Antibacterial action of mafenide HCL the antibacterial action of mafenide not antagonized by PABA
  • Bacteriostatic primarily but bactericidal concentration can be achieved in urine E coli , shigella majority resistant In combination with drugs that inhibit folic acid synthesis Clinical efficacy & potency of sulfonamides much less than other antibiotics
  • When organism is resistant to one sulfonamide it is resistant to all sulfonamides No cross resistance seen between sulfonamides & other AMAResistance has limited the use of sulfonamides
  • 70 -90 % bioavailability , main site of absorption is small intstine , absorption from skin vagina , rsp system is variable but sufficient quantities may be absorbed to cause sensitization & toxicity , so topical preparations not to be used except ocular Why is protein binding so important: More binding less bacteriostatic activity Cannot pass to tissue fluids & CSF LESS PENETRATION Not abailable for renal excretion , prolonged duration of action slow excretion High plasma protein bound drugs not effective in acute infections because of low plasma levels of free sulfonamide Widely distributed in body: enter serus cavities easily , free form attains same concentration as in plasma , cross placenta secreted in milk Sulfacetamide and sulfadiazine cross cornea penetrate the aqueos humor Acetylation: by non microsomal acetyl transferase primarily in liver 2 distinct groups fat acetylators , slow acetylators , extent of metabolism different in different members nut not of clinical significance , the acetylated form is devoid of antibacterial activity , posses toxic potentiality of original drug Certain acetylated products are poorly soluble in acidic urone may ppt and cause crystalluria and renal complications
  • Sulfadiazine: prototype of general purpose sulfonamides
  • Sulfamethoxazole : high fraction acetylated, which is relatively insoluble , crystalluria can occur
  • Less conc reached
  • Water soluble Chief use is in ocular infections Non irritant in contrast to strong alkalinity of other sulfonamides Used in ocular infections due to susceptible bacteria
  • Not a typical sulfonamide CH2 group separates benzene ring and amino group Inhibits variety of Gm+ and Gm- bacteriaShould not be used in already infected cases Adverse effect: Burning sensation biggest limitation when applier to raw area , on raw surface rapidly absorbed metabolized and excreted in urine Carbonic anhydrase inhibitor can alkalinize urine cause acidosis and hyperventilation must not be applied on large surface Allergic reaction : rashes may occur 1 % cream for application
  • 1% cream for topical use Not good for treatment of established infections
  • Used particularly in UTIs as bactericidal concentration reached in urine Meningococcal meningitis used as Co-trimoxazolePoorly absorbed sulfonamides can be used as intestinal asepsis Combined with trimethoprim : cotrimoxazole used in many bacterial infections Pjiroveci and nocardiasisAlong with pyrimethamine: malaria, toxoplasmosis Topical addition of tetracycline or azithromycin may be required for eradication of disease
  • Nausea, vomiting, epigastric pain Renal toxicity:In acidic urine acetylated form may precipitate in collecting tubules and calyces so urinary obstruction and precipitation of urinary colic may occur , also crystaluria, albuminuria, hematuria may occur Minimized by adequate water intake > 1200 ml urine out put Alkalinize urine to increase solubilty of conjugation products Sulfasoxizole use , metqabloites soluble in acidic urine also Renal damage with tubular necrosis may occur as in allergic reaction Haemopoetic toxicity:Thrombocytopenia, agranulocytosis, aplastic anemia rarely Sulfonamides tend to oxidize Hb to methaemoglobinG6pd defiency – hemolysis sulfonamides, furazolidine,nitrofurantoin, chloramphenicol, FQ,DDS, primaquine, quinine, salicylatesHypersensitivity: 2-5% Rashes , urticaria, drug fever, photosensitization, , Sj Syndrome, exfoliative dermatitis may ccur with longeracting sulfonamides Hepatitis: non dose related 0.1 % cases Kernicterus: Sulfonamides compete with bilirubin for albumin binding sites adminstered during late pregnancy, may displace bilirubin from albumin binding sites in foetusThe free bilirunin may cross BBB pernmeable only in foetus and infants and causes kernicterus so contraindicated in new born, and pregnancy Nervous system:confusion, depression, ataxia, tinnitus, fatigue
  • Sulfasalazine: Treatment of mild to moderate ulcerative colitis induce and maintain remission in ulcerative colitisBenefecial effect in crohns disease is less predictable Acute exacerbations :GC, cases resistant to both should be treated with immunosupressants or infliximab only 2/3 respond. Inflammatory Bowel Disease Immunological response to bacterial antigens of intestinal origin Has genetic predisposition Ulcerative colitis: colon & rectum, superficial lesionsCrohns disease: Small intestine & colon, transmural involvement Clinical features of IBD:Diarrhoeawith blood in stools, weight loss may develop into toxic colitis with ulcerated mucosa
  • Sulfasalazine is sufapyridine linked o 5 ASA by an azo bond One of the first drugs which when given orally reached the colon unaltered and it is split their by colonic bacteria into its constituents
  • 5 –ASA exerts local antiinflammatory actions inhits both COX& LOX , so decreases both PG & LT especially LTB4Cytokines and PAF production in GUT decreased Inhibits IL-1 AND TNF alpha Migration of infalmmatory cells into bowel wall is interfered and mucous secretrion is reduced Dose = 3-4 gm /day for few weeks till remission then 1.5 to 2 gm /day after remission Sulfapyridinemoeity only serves to carry the 5ASA to colon without being absorbed proximaly , however part of released sulfapyridine absorbed in colon is responsible for the adverse events like rashes, fever, joint pain hemolysis , blood dyscrasias, folate deficiency – 1 mg/day folate supplements Sulfasalazine used as DMARDs in rheumatoid arthritis also , the absorbed sulfapyridine appears to be responsible for the therapeutic effect contrast to ulcerative colitis- generation of superoxide radicals and cytokine elaboration by inflammatory cells may be supressed
  • But not effective orally as majority absorbed in small intestine , so given along with sulfapyridineDose = 2.4 gm daily Treatment of mild to moderate exacerbationBetter tolerated than sulfasalazineNausea, diarrhoea, abdominal pin rashes hypersensitivity is rare Bone marrow depression & decreased sperm count do not occur Nephrotoxic C/I in renal & hepatic impairment
  • Basalazide: 5 ASA linked to 4 Amino benzoylalanine as carrier 5 asa released in colon and carrier is poorly absorbed Osalazine: 2 molecules of 5 ASA coupled together by azo bond no separate carrier moeity required , most reliable preparation for delivery of asa to the colon
  • Discontinued after remission Methotrexate -15 to 25 mg once a week
  • Trimethoprim is a diaminipyrimidine related to antimalarial drug pyrimethamine , effective against common pathogenic bacteria , bacteriostatic in nature Not effective against Mycobacteria and pseudomonas Action may be inhibited in necrotic wounds . Containing pus and other cellular debris as they contain thymine and thymidine
  • Trimethoprim has 50,000 times more selectivity for bacterial dihydrofolatereductase than mammalian enzyme , higher animals they utilize preformed folic/folinic acid so immune to harmful effects of trimethoprimDepressant effect on human folate metabolism can be countered by feeding exogenous folateResistance: Altered DHFR : Low affinity to drug Plasmid mediated or mutational
  • Rapid & almost complete absorption more rapid than sulfamethoxazoleTmax = 1.5 to 3.5 hrs Absorption & excretion charecteristics very similar to sulfamethoxazole t1/2 = 10 hrs Distributed more widely than sulfamethoxazole has larger volume of distribution , attains lower plasma concentration. Higher ratio 20:1 (sulfonamide:trimethoprim) in plasma than in tablets (5:1) Trimethoprim crosses BBB, PlacentaExcretion markedly ↑ with acidification of urine : weak basic in nature
  • It has been argued that in certain situations trimethoprim alone may be useful in some condtions than combination , as majority of adverse events are due to sulfa methoxazole ,
  • Introduced in late 1960s still one of commonly used
  • Nausea, vomiting, stomatitis, headache & rashes are usual manifestations Dermatological manifestations skin rashes Hematological: megalob;qastic anemia, leukopenia, thrombocytopenia, reversed by adding folinic acid Hemolytic anemia in G6PD deficiency When creatininelevelsfall below 30 ml/min increase interval of dosing from 12 hrly to 24 hrly< 15 ml/min stop drug Elderly are at more risk for bone marrow toxicity diuretics with cotrimoxazole increase incidence of thrombocytopenia
  • Uti: ,ostly for uncomplicated uti , UTI most commonly caused by E.coli, proteusmiarabilis, usually susceptible to septranProstatitis: valuable for chronic and recurrent cases of prostatitis , because gets concentrated in prostatic fluid , if patient allergic to sulfonamides give only trimethoprimRspiratory tract infections: Frequent choice of treatment of acute sinusitis, bronchitis , and otitis media due to pneumococcus and hemophilus species 1 tab DS BD , BOTH LOWER and upper RTI including chronic bronchitis and faciomaxillary infectionsTyphoid: 1 tab DS BD for 2 weeks eradictes carrier state provided gall bladder is not involved
  • Bacterial diarrhoea: frequently uses AMA for many severe invasive infections caused by campylobacter, E.coli, shigella, and yersiniaenterocolitica , response rate lower , FQ drug of choice Can be used in ampicillin resistant cases dose = DS BD for 7 days
  • Dose= 2 BD for 2 days then 1 BD Infant =2.5 ml BD Children 1-5 yrs = 5 ml BD 6-12 yrs = 10 ml BD IV cotrimoxazole = dissolve in 5 % dextrose solution 125 ml 5 ml of solution and give it over 60 -90 min
  • Pyrimethamine is a Dihydrofolatereductase inhibitor high affinity for plasmodial DHFR VERY POOR action on bacterial DHFR, HIGH DOSES INHIBIT TOXOPLASMA GONDII Sulfonamides are not particularly effective antimalarial drugs in their own right have some negative influence on the erythrocytic phase of plasmodium falciparum They form supra-additive synergistic combination with pyrimethamine due to sequential blockade , though both are slow acting thecombination is faster acting Efficacy more against falciparum , less against vivaxSulfadoxine 500 mg + 25 mgpyrimethamineAs clinical curative 3 tab statLonger acting Combination has potential to cause aDVERSE EVENTS, EXFOLIATIVE DERMATITIS, SJ syndrome Treatment of choice for toxoplasmosis in immunocompromised patient
  • 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

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