2. History of sulfonamides
• Domagk, Mietsch and colleagues 1938
– Working non azo dyes demonstrated efficacy of
prontosil – A dye with sulfonamide chain in
inhibiting growth of streptococci
• Nitti, Bovet and fuller
– Proved that therapeutic effect of prontosil is due
to its conversion to sulfanilamide in body
• Sulfapyridine was first sulfonamide to be
marketed in 1938
3. Chemical structure of sulfonamides
• Antimicrobial agents containing sulfonamido
group SO2NH2 group
• This group also present in
– Sulfonylureas
– Thiazide diuretics
– Furosemide
– Acetazolamide
4.
5. Classification
Used for treatment of systemic infections
Short acting Intermediate acting Long acting
Sulfadiazine
Sulfamethazine
Sulfacetamide
Sulfisoxazole
Sulfamethizole
Sulfamethoxazole
Sulfamoxazole
Sulfadoxine
Sulfametho-
pyrazine
Sufadimethoxine
Sulformethoxine
Used for treatment of ulcerative colitis
Used topically
Sulfasalazine
Mafenide, silver sulfadiazine, sulfacetamide
9. Mechanisms of resistance
• Over production of PABA
• Production of folic acid synthetase with lower
affinity for sulfonamides
• Adopt alternative pathway for folate
metabolism
10. 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
11. Individual sulfonamides
• Sulfadiazine
– Rapidly absorbed
– Rapidly excreted
– 50 % protein bound , 20 -40 % acetylated
– Crosses BBB more effectively than other
sulfonamides
– Acetylated derivative less soluble in urine
– Dose: 500 mg QID to 2 Gm TDS
12. 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
13. 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: serious
cutaneous reactions
15. Sulfacetamide
• Topical drug in ocular infections
– Neutral pH 7.4
– Non irritant
– Penetrates the ocular fluids and tissues in high
concentration
• Dose: 1-2 drops of 10 -30-% solution 3 -4 times a day
• Antagonist to inhibition of pseudomonas by
gentamicin
• Uses: Chlamydia , ophthalmia neonatorum caused
by Chlamydia occulogenitalis
• Sensitivity reactions low
16. Mafenide
• Not a typical sulfonamide
• Active in presence of pus against pseudomonas,
clostridia which are not inhibited by typical
sulfonamides
• Use:
– Burn`s dressing to prevent infection
• Adverse effect:
– Burning sensation
– Carbonic anhydrase inhibitor can alkalinize urine cause
acidosis and hyperventilation
– Allergic reaction : rashes may occur
17. Silver sulfadiazine
• Effective against large number of bacteria, fungi,
even those resistant to other sulfonamides e.g
pseudomonas
• Releases silver ions largely responsible for
antimicrobial action
• One of most effective drug for preventing
infections on burnt surfaces and chronic ulcers
• Well tolerated
• Adverse effects:
– Burning sensation
– May be absorbed systemically and produce adverse
effects
20. Drug interactions
S.No Interfering drug Effect
1 Sulfonylureas Displaced from protein binding site
probable hypoglycemia
2 Phenytoin, warfarin ↑ action of both
3 Methotrexate Displaced also ↓ excretion
toxicity may occur
4 Procaine (Contain
PABA)
Direct inhibition of sulfonamide
action
5 Phenylbutazone ,
salicylate ,
probenecid
Sulfonamide displaced from
protein binding
↑ activity of sulfonamides
21. 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 of
intestinal origin
– Has genetic predisposition
– Ulcerative colitis: colon & rectum, superficial
lesions
– Crohns disease: Small intestine & colon,
transmural involvement
23. Sulfasalazine
Sulfapyridine 5-ASA
Acetylated in liver
Absorbed rapidly in colon
Excreted in urine
Poorly absorbed
Induces remission in
ulcerative colitis
No therapeutic action
in ulcerative colitis
Inhibit COX
LOX , PAF,
Cytokines
Inhibit IL-1 &
TNF-
24. Mesalazine /Mesalamine/ 5-ASA
• 5 –ASA the active moeity in ulcerative colitis
• Delayed release preparation coated with
acrylic polymer
• Reliable for delivering 5 ASA to colon & distal
bowel
• 400 mg tab = 1 gm sulfasalazine
• Primary use: preventing relapses
• Better tolerated than sulfasalazine
• Nephrotoxic C/I in renal & hepatic impairment
25. Mesalazine preparations
Preparation Structure Dose
Sulfasalazine Mesalazine linked to sulfapyridine 2-6 gm/day
Basalazide Mesalazine linked to inert molecule 2.25 gm TDS
Osalazine Mesalazine linked to Mesalazine 1.5 TO 3 gm /
Mesalazine Time released 3-4 gm/day
Mesalazine pH sensitive coated mesalazine
released at pH > 7
2.4 -4.8 gm/d
Mesalazine
suppository
Mesalazine directly in rectum 0.5 to 1 gm
OD/BD
Mesalazine
enema
Directly in left colon 4 gm in 60 m
26.
27. 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
28. 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
30. Trimethoprim (Pharmacokinetics)
• Rapid & almost complete absorption
• 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, Placenta
• Excretion markedly ↑ with acidification of urine
31. 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 in
females
– Prostatitis: Concentrated in prostrate
• Dose: 100-200 mg BD
32. Co-trimoxazole
• WHO approved fixed dose combination of
sulfamethoxazole & trimethoprim in ratio of
5:1
• Sulfamethoxazole = 400 mg
• Timethoprim = 80 mg
• MOA:
– Sequential blockade
33. 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
34. Pharmacokinetics
• Trimethoprim & sulfomethoxazole have nearly
same t1/2 , 10 hrs
• Optimal synergy in case of most organisms
exhibited 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 as
tablet in ratio (5:1) sulfamethoxazole:
trimethoprim
37. 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 to
pneumococcus & hemophilus
• Typhoid:
– DS tablet for 2 weeks
38. 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
39. Advantages of cotrimoxazole
• Sequential blockade , supra-additive effect
• Individually bacteriostatic but combination
has bactericidal effect
• Chances of development of resistance
reduced
• Wide spectrum antibacterial drug
• Relatively safe and well tolerated
• Highly cost effective in many common
infections in practice
42. Drug interactions
• Similar to sulfonamides
– ↑action of warfarin, sulfonylureas methotrexate
– NSAIDS displace sulfa-methoxazole from protein
binding site increase its action
43. 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
Editor's Notes
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
