SULFONAMIDES

1. SULFONAMIDES Dr. Rajendra Nath Professor

2. SULFONAMIDES First effectivechemotherapeutic agents to be employed systemically for the prevention & cure of bact. Infections in humans. The discovery of Penicillin & subsequ. of other antib.s has diminished the usefulness of the sulfonamides.

3. SULFONAMIDES -Presently sulf. occupy small place in therapeutic armamentarium of the physician . -In 1970s however the combination of Trimethoprim &Sulfmethoxazole has increased the use of sulf.s for the Tt. & prophylaxis of specific microbial

4. SULFONAMIDES diseases . History – Domagk tested the new comp. Azo- dye ( Prontosil ) & observed that mice with Streptococcal & other inf.s could be protected by prontosil ( active metabolite was sulf.) & was very useful

5. SULFONAMIDES in puerperal sepsis & in Meningococ. Infection . Subsequently Carbonic anhydrase inhi. type of diuretics & Sulfonylurea hypo- glycemic agents followed from observ. made with sulf. antibiotics . For the discovery of the therapeutic

6. SULFONAMIDES value of prontosil Domagk was awarded Nobel prizein medicine in 1938 . Chemistry : Sulf. is a generic name for derivatives of Para – aminobenzene sulf. ( Sulfanilamide )

7. SULFONAMIDES -Insoluble in water but sodium salts are soluble. -The paraNH2 gp. is essential for activity . H2N SO2 NH2

8. SULFONAMIDES Effect on Microbes: -Wide range of AM activity against both G+ve & G- ve bacteria. - But now resist. strains have become common & usefulness of these agents has diminished . - The Sulf. exert only bacteriostatic action . - Cellular & humoral defense mech. of the

9. SULFONAMIDES host are essential for final eradication of the Infection. Anti bact. Spectrum : - Resistance is increasingly a problem Still sensitive strains are- -Most of the Strept. pyogenes , Haemophilus ducrei & influenzae , Vibrio cholerae & Calymmatobacterium - granulomatis.

10. SULFONAMIDES - Few strains of Staph. aureus , pneumococci, Meningococci & gonococci , E.coli & shigella are sensitive ( most of the strains are resistant ). - Anaerobes are not sensitive - Chlamydiae (causing trachoma , lymphogranul.venereum ,inclusion conjunctivitis), Actinomyces, Nocardia & Toxoplasma are sensitive

11. SULFONAMIDES Mech. of action : Sulf.s are structural analogue & competit. antagonists of - Para- aminobenzoic acid ( PABA) .

12. SULFONAMIDES • Prevent normal bact. utilization of PABA for the synthesis of folic acid (Pterylgluta - mic acid) . • Specifically Sulf.s are competitive inhibitor of dihydropteroate synthase ( bact. enz. responsible for incorporation of PABA into dihydropteroic acid ( immed. precursor of folic acid )

13. SULFONAMIDES • Sensitive org.s are those that must synthesize their own folic acid & bact.s that utilize preformed folate are not affected . • PABA competitively counteract Sulf.’ s bacteriostatic action . (Sulf.s do not affect mammalian cells because they require preformed folic acid

14. SULFONAMIDES and can not synthesize it ) . Pteridine + PABA Dihydropteroate synth.XSULF. Dihydropteroic acid Dihydrofolic acid NADPH Glutamate Trimethoprim x DHFRNADP Tetrahydrofolic acid

15. SULFONAMIDES Synergists : Most active agent that exerts a synergistic effect with Sulf. is Trimethoprim It is a potent & selective competitive inhibitor of microbial dihydrofolate reductase ( enz that reduces dihydrofol. to tetrahydrofolate ). Simultaneous administ. of Sulf. & Trimeth. thus introduces Sequential Block in the

16. SULFONAMIDES pathway & kill the bact. Acquired bact. resist. to Sulf. : - Originate by random mutation & selection or by transfer of resist. by Plasmids ( this type of resist. is persistent & irreversible) May be due to- i) Lower affinity for Sulf. by dihydropteroate synthase .

17. SULFONAMIDES ii) ↓ bact. permeability or active efflux of the drug. iii) Alternate metabolic pathway for synthesis of essential metabolite. iv) ↑ production of essen. metabolite or drug antagonists. ↑ prod. of PABA is not a constant finding in sulf. resist.. Bacteria & resist. mutants may

18. SULFONAMIDES posses enz.s that are less readily inhibited by sulfonamides Pharmacokinetics: -They are absorbed rapidly from GIT except locally acting sulf.s . - Peak plasma levels are achieved in 2-6 hrs depending on the drug (100-200 µg / ml ). - Small intestine is the major site of abs. but

19. SULFONAMIDES Some of the drug absorbed through stomach . • Abs. from other site e.g.–vagina, resp.tract or abraded skin is variable & cause toxic reaction in susceptible person . • All sulf.s are bound to plasma protein esp. albumin & distributed throughout all tissues of the body .

20. SULFONAMIDES - They readily enter pleural , peritoneal , synovial ,ocular & similar body fluids . • After systemic abs. of adequate doses , Sulfadiazine & Sulfisoxazole attain conc. in CSF which may be effective in meningeal infection . • They reach the fetal circulation in placenta in preg. mothers & can cause toxic

21. SULFONAMIDES as well as antibacterial effect . • They undergo metabolic alteration in vivo esp. in liver . Major metabolite is N4 - acetylated sulfonamide . • Excreted from the body partly unchanched & partly as metabolic prod.s .The largest fraction excreted in urine . • In acidic urine the older Sulf.s are insol. &

22. SULFONAMIDES form crystalline deposits that can cause urinary obstruction . • Small fractions are eliminated in the feces bile , milk etc. Pharmacological properties: - They are classified into four gps on the basis of the rapidity with which they are absorbed & excreted .

23. SULFONAMIDES CLASSSULFONAMIDESERUM H-½ in Hrs 1. Absorbed & Sulfisoxazole 5-6 Excreted rapidly Sulfamethoxazole 11 Sulfadiazine 10 2. Poorly absorbed- Active in bowel lumen Sulfasalazine --- 3. Topically used Sulfacetamide --- Silver sulfadiazine --- 4. Long acting Sulfadoxine 100 - 230

24. SULFONAMIDES 1. Agents that are absorbed & excreted rapidly: e.g. Sulfisoxazole & Sulfadiazine Sulfisoxazole: - having excellent AM activity - high solubility eliminates much of the renal toxicity. - It is highly protein bound .approx. 95% of

25. SULFONAMIDES a single dose is excreted by the kidney in 24 hrs., conc. in urine thus exceeds than in blood & may be bactericidal . - 1/3rd of the blood conc. reaches . CSF Sulfamethoxazole : cong. of sulfisoxazole. Enteric abs. & renal excrt. is slower. Given orally & employed for both systemic & urinary tract inf.s .Precaution must be taken

26. SULFONAMIDES to avoid crystalluria (i.e. take plenty of water) -Also marketed in fixed dose combination with Trimethoprim. Sulfadiazine : Given orally , absorbed rapidly from GI tract & peak conc. reaches in 3-6 hrs after single dose. Fluid intake is must so that

27. SULFONAMIDES 1200 ml. urine output is maintained ( to avoid crystalluria) 2.Poorlyabsorbed Sulf.s : Sulfasalazine- poorly abs. from the GI tract therefore used in the therapy of Ulcerative colitis & Reigional Ileitis , but relapses occurs ( Corticosteroids are better but in mild to mod. form Sulfasalaz. is preferred .

28. SULFONAMIDES -It is broken down by int. bact.s into Sulfapyridine an active Sulf. + 5-aminosali-cylic acid which reaches high levels in feces -5-aminosal. is the effective agent in inflammatory bowel disease . Whereas Sulfapyridine is respons. for toxicity e.g. – Heinz body anemia , acute hemolysis in pts of G6PO4 dehyd. enz. deficiency

29. (G6PD enzyme is required for regeneration of NADPH & Which is required for reduction of oxidized glutathione. Reduced glutathione protects –SH dependent enzyme & other proteins against oxidation. Thus in presence of pro-oxidants ( e.g.- Aspirin , Nitrofurantoin, Primaquine, Chloroquine , Quinine , Sulfonamide, Vit. K etc. ) in a pt. with deficiency of G6PD , there is no protection to RBCs & so hemolysis occurs .) SULFONAMIDES

30. SULFONAMIDES agranulocytosis & may cause rev. infertility in males . 3.Sulf. For Topical use : Sulfacetamide – Sod. Salt of drug is extensively employed in ophthalmic inf.s . Advantages –high aquous conc. not irritating to eyes . - the drug penetrates in high

31. SULFONAMIDES conc. into ocular fluids & tissues . • Sensitivity react.s are rare Silver Sulfadiazine; the comp. is used topically to reduce microbial coloniz. & the incidence of wounds from burns( one of the agents of choice for the prev. of burn inf.) . other is Mafenide .

32. SULFONAMIDES 4.Longacting Sulf.s : e.g. – Sulfadoxine– having long half life ≈ 7-9 days . • It is used in comb. with Pyrimethamine ( 500 mg Sulfadoxine + 25 mg Pyrimeth.) as Fansidar in prophylaxis & Tt of Malaria caused by resist strains of Plasmodium falciparum .

33. SULFONAMIDES Sulfonamide Therapy : • Various conditions for which the sulf.s are therapeutically useful & constitute DOC has been reduced sharply . - The development of more effective AM agents & gradual increase in resist. of no. of bact. species to this class of drugs leads to rare use of these agents - The introduction of Trimethoprim &

34. SULFONAMIDES Sulfamethoxazole combinations has revived the use of sulf.s . • Urinary Tract Inf.s : Sulf.s are no longer a therapeutic choice in UTI . Preferred agents are –Trimethop. + Sulfamethoxazole , Quinolones , Trimethop. alone , Fosfomycin , Ampicillin & Cephalosporins Sulfisoxazole may be used effectively

35. SULFONAMIDES 2. Nocardiosis – good response with Sulf.s e.g.- Sulfisoxazole & Sulfadiazine Dose – 6 - 8 Gm. / day continued for several months . second antb. along with sulf. is recomme. in advanced cases e.g.- Ampicillin & Erythromycin .

36. SULFONAMIDES 3. Toxoplasmosis : Sulfadiazine( 1Gm.) + Pyrimethamine (75 mg loading & 25 mg later on) is given 6 hrly x 3-6 weeks with folic acid 10 mg orally . 4. Treatment & Prophy. of resist. Malaria : Sulfadoxine + Pyrimethamine( Fansidar)

37. SULFONAMIDES 5. Use of Sulf.s for Prophylaxis : They are as efficacious as Penicil.s in prev. Streptococcal inf.s & recurrence of Rheumatic fever . 6. Ophthalmic inf.s : topical –e.g.- Sulfacetamide . 7. Infection of Burns : e.g.- topical Silver sulfadiazine .

38. SULFONAMIDES Adverse reactions : 1. Disturbance of urinary tract – risk of crystalluria – high with older less sol. Sulf.s but very less with more sol. agents e.g.- Sulfisoxazole -Fluid intake should be sufficient – daily ensure urine out put of 1200ml. - Alkalinization of urine is desirable .

39. SULFONAMIDES 2. Disorders of Hematopoietic system : - Acute hemolytic anemia- sometimes sensitization phenomenon & in others erythrocytic def. of G6PO4 dehydrogenase - Agranulocytosis – most pts recovered spontaneously with supportive care - Aplastic anemia –complete supp. of bone marrow activity with anemia ,

40. SULFONAMIDES granulocytopenia & thrombocytopenia. 3. Hypersensitivity reactions : Skin & mucous memb. manifestations- urticarial rash , pemphigoid , perpurial & petechial rashes , erythema nodosum multiforme of Stevenson Jonhson’s type, Exfoliative derm.& photosensitivity . most often occurs after 1st wk. of therapy

41. SULFONAMIDES It can occur with fever , malaise & pruritis • Focal or diffuse necrosis of liver, fever, headach ,hepatomegaly, jaundice – leading to yellow atrophy of liver & death Misce. : Anorexia , nausia & vomiting -1-2% in new borns – free bilirubin can deposit in the basal ganglia & ant thalamic nuclei

42. SULFONAMIDES of the brain causing encephalopathy called Kern- icterus . ( Sulf.s are not given to pregnant women near term because these drugs pass through placenta & secret. in milk ). Drug interaction : with oral anticoagulant , sulfonylurea hypo- glycemic agents & hydantoin --

43. SULFONAMIDES In each case sulf.s can potentiate the effect of the other drugs by inhibition of metabolis. & possibly displacement from albumin .

44. SULFONAMIDES TRIMETHOPRIM &SULFAMETHOXA. • Constitutes important advance in the dev.of clinically effective AM agents . • If the drugs act on sequential steps in thepathway of an obligatory enzymaticreac. in bact. , the result oftheir combination -

45. SULFONAMIDES will be synergistic . This comb. is known popularly as Cotrimoxazole . - Trimethoprim also comes in single entity prepration . Chemistry : Trimethoprim is Di-aminopyrimidine

46. SULFONAMIDES Spectrum : is equivalent to Sulfamethoxazole , although Trimeth. is 20 -100 times more potent. - Most G+ve & G-ve micro-org. are sensitive ( resist. occurs when used alone ) .

47. SULFONAMIDES Pseudomonas aeruginosa ,Bact.fragilis & Enterococci are resist. Efficacy of combination : Additional micro-org. covered by this combination – Klebsiella , S. typhi , Serratia , Yersinia enterocolitica , Enterobacter, Brucella

48. SULFONAMIDES abortus, Proteus mirabils , Pseudo- monas , Klebsiella , Brucella abortus , Pneumocystis jiroveci . -Many sulfonamide resistant strains of S. pyogenes , Staph. aureus, Shigella, E.coli , H. influenzae , meningococci & gonococci becomes sensitive .

49. SULFONAMIDES Max. degree of synergism occurs when micro-org. are sensitive to both component . Mech. of action : Sequential block in Folic acid synthesis occurs. Trimeth. is selective inhibitor of DHFR enzym. of lower org.s, about 100,000

50. SULFONAMIDES times more drug is required to↓ human reductase than bact. enz. ( Optimal synergy exhibited at a conc. ratio of sulfamethoxazole 20: Trimethoprim 1 . This ratio is obtained in the plasma when the two are given in a dose ratio of 5 : 1 ) . Bact. Resist. : It is a rapidly increasing problem but lower than the resistance to either drug