Sulfonamides (VK)


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  • Lymphogranuloma venereum 
  • Sulphamethoxazole
  • Sodium bicarbonate ,Sodium citrate
  • is inflammation of the prostate gland
  • Sulfonamides (VK)

    2. 2. FOLIC ACID ANTAGONISTS  Coenzymes containing folic acid - required for the synthesis of purines and pyrimidines (precursors of RNA and DNA) and other compounds necessary for cellular growth and replication. • In the absence of folic acid, cells cannot grow or divide.  FOLIC ACID ANTAGONISTS: 1. The sulfonamides (sulfa drugs) inhibit the synthesis of folic acid. 2. Trimethoprim - prevents the conversion of folic acid to its active, coenzyme form (tetrahydrofolic acid) 2
    3. 3. SULFONAMIDES  The antimicrobial containing a sulfonamido (sulfanilamide, SO4NH2) group are called sulfonamides. NH2 SO4-NH • Structurally related to p-aminobenzoic acid (PABA).  This group is also present in other non-antibacterial compounds like -Sulphonureas -Benzothiazids -Furosemide -Acetazolamide 3
    4. 4. CLASSIFICATION 1. Orally absorbable agents  Short acting(4-8hrs.)Sulfadiazine, Sulfisoxazole, Sulfacytine, sulfamethizole  Intermidiate acting(8-12hrs.)Sulfamethaxazole Sulfamoxole  Long acting(7days)Sulfadoxine sulfamethopyrazine Orally Non- absorbable agents  Special purpose sulfonamides2. Sulfasalazine (ulcerative colitis) Silver sulfadiazine Sulfacetamide Burn(topical) Mafenide 4
    5. 5. Antibacterial spectrum Bacteriostatic action at low conc.  Strept.pyogens, staph. Aurius, H.influenzae, H.ducreyi, calymmatobacterium granulomatis, v.cholerae.  Gonococci, meningococci, pnumococci.  E.coli, shigella.  Chlamydia- trachoma, Lymphogranuloma venereum inclusion conjunctivities.  Actinomyces, Nocardia & Toxoplasma 5
    6. 6. Folic acid synthesis Dihydropteridine + PABA Dihydropteroate synthetase Dihydropterate (+) Glutamate Dihydrofolate Dihydrofolate reductase Tetrahydrofolate DNA/RNA 6
    7. 7. Sulphonamides: inhibitors of folate synthesis Pteridine + PABA dihydrofolic acid Dihydropteroic synthetase acid synthetase sulphonamides dihydrofolic acid dihydrofolic Dihydrofolateacid reductase reductase trimethoprim tetrahydrofolic acid Purine and pyrimidine synthesis 7
    8. 8. Mechanism of action  Folic acid - synthesized from PABA, pteridine, and glutamate.  All sulfonamides are analogues of PABA. Because of their structural similarity to PABA, SA compete with this substrate for the bacterial enzyme, dihydropteroate synthetase. They thus inhibit the synthesis of bacterial folic acid.  All sulfa drugs are bacteriostatic. 8
    9. 9. Resistance to sulfonamide  Capable of developing resistance- Gonococci, meningococci, staph. aurius, E. coli & shigella  As result of mutation or by plasmid mediated 1. Alteration in the nature of folic acid synthetase (decrease affinity). 2. Decreased bacterial permeability or active efflux of drug. 3. An appearance of alternative pathway for PABA synthesis. 9
    10. 10. Pharmacokinetics  Absorbed rapidly from the GIT (except topically used ). Peak plasma levels are achieved in 2-6hrs.  widely distributed and pass through BBB as well as placental barrier.  Metabolized as acetylated conjugates in liver. Acetylated metabolites are inactive and low soluble in acidic urine, leads to ppt. of crystaluria and renal toxicity.  Excreted through the glomerular filtration in urine. 10
    11. 11. Individual sulfonamides: 1) Well absorbed orally, short-acting: Sulfadiazine, Sulfadimidine, Sulfisoxazole, Sulfamethoxazole 2) Well absorbed orally, long-acting: Sulfamethopyrazine 3) Poorly absorbed in GIT: Sulfasalazine 4) Used topically: Silver sulfadiazine 11
    12. 12. Adverse effects Blood Hemolytic and aplastic anemia (G6PD def.) Thrombocytopenia Hypersensitivity Photosensitivity Exfoliative dermatitis Stevens-Johnsons. Drug fever 12
    13. 13.  Crystalluria and renal toxicityAdequate intake of water By making urine alkaline  Kernicterus in neonatesSulfonamides displace bilirubin from protein binding sites. Free bilirubin gets diposited-toxic encephalopathy Avoided in neonates & pregnancy (last trimester)  GI Nausea, vomiting, diarrhea, pancreatitis 13
    14. 14. CONTRAINDICATIONS  Pregnancy (full term)  Newborn and infant (<2months)  Patients on Methenamine, Tolbutamide, oral anticoagulants. 14
    15. 15. SULFASALAZINE  Poorly absorbed through GIT  Reserved for treatment of chronic inflammatory bowel disease (e.g., Crohn disease or ulcerative colitis).  Intestinal flora split sulfasalazine into sulfapyridine and 5-aminosalicylate which exerts the anti-inflammatory effect..  SILVER SULFADIAZINE Effective in reducing burn-associated sepsis. 15
    16. 16. - USES Lower respiratory tract infections  Bone and joint infections  Infectious diarrhea  Urinary tract infections  Skin infectionsBurn cases-silver sulfadiazine topically.  Sexually transmitted diseasesChancroids due to H. ducreyi Lymphogranuloma venereum  Chloroquine resistant malaria 16
    17. 17. TRIMETHOPRIM  Inhibitor of bacterial dihydrofolate reductase.  Antibacterial spectrum similar to SA • Mostly compounded with sulfamethoxazole = co-trimoxazole. 17
    18. 18. Folic acid synthesis inhibitors pterdine + para-amino benzoic acid Dihydropteroate synthetase dihydropterate dihydrofolate Dihydrofolate reductase tetrahydrofolate Sulphamethoxazole (Sulphonamides) Structural analogues of PABA Trimethoprim (Diaminopyrimidines) Binding DNA/RNA 18
    19. 19. Mechanism of action  The active form of folate – tetrahydro derivative (formed by reduction of dihydrofolate by dihydrofolate reductase). • This enzymatic reaction is inhibited by trimethoprim ---• There occurs decreased availability of the tetrahydrofolate coenzymes required for purine, pyrimidine, and amino acid synthesis.  Other folate reductase inhibitors: Pyrimethamine (used with SA in parasitic infections) Methotrexate (in cancer chemotherapy). 19
    20. 20. Antibacterial spectrum  Spectrum - similar to sulfamethoxazole • Trimethoprim is 20- 50 fold more potent than SA. Resistance  Presence of altered dihydrofolate reductase with lower affinity for trimethoprim.  Overproduction of the enzyme  Decrease drug permeability. 20
    21. 21. Uses 1. Acute UTIs 2. Bacterial prostatitis 3. Bacterial vaginitis. 21
    22. 22. Pharmacokinetics  Similar to sulfamethoxazole.  But - it is a weak base - higher concentrations of Trimethoprim in relatively acidic prostatic and vaginal fluids.  It also penetrates the CSF.  It undergoes some O-demethylation, but mostly excreted unchanged through the kidney. 22
    23. 23. Adverse effects  Effects of folic acid deficiency (megaloblastic anemia, leukopenia, granulocytopenia - especially in pregnant women and pts with a poor diets)  The blood disorders . can be reversed by the simultaneous administration of folinic acid, which does not enter bacteria.  Nausea, vomiting, skin rashes 23
    24. 24. CO-TRIMOXAZOLE  Trimethoprim – mostly compounded with sulfamethoxazole.  This combination - co-trimoxazole - shows greater antimicrobial activity than equivalent quantities of either drug used alone.  Selected because of the similarity in the pharmacokinetics of the two drugs. 24
    25. 25. COTRIMOXAZOLE 1. Sulfamethaxazole + trimethoprim = FDC 5:1= 400+80mg DS 1Tab. BD  T1/2=10-11 hrs. ADV:  Synergistic, Potent.  Bactericidal 2. Sulfadoxine+Pyrimethamine- 20:1=500+25mg Indication:chloro.resistant P. falciparum, toxoplasmosis 25
    26. 26. Mechanism of action The synergistic antimicrobial activity of co-trimoxazole –  Inhibition of 2 sequential steps in the synthesis of tetrahydrofolic acid.  Sulfamethoxazole inhibits the incorporation of PABA into folic acid.  Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate.  More potent activity than sulfamethoxazole or Trimethoprim alone.  Doses of both drugs are 1/10 of those needed if drug were used alone. 26
    27. 27. Antibacterial spectrum  Broader spectrum than SA  Uses: 1. Treating UTls 2. Respiratory tract infections 3. Pneumocystis pneumonia 4. Ampicillin- or chloramphenicol-resistant systemic salmonella infections. 27
    28. 28. Pharmacokinetics  More lipid soluble than sulfamethoxazole - greater Vd.  Ratio: 20 parts sulfamethoxazole to 1 part trimethoprim – according to some authors considered optimal for the antibiotic effect.  Generally administered orally.  Trimethoprim concentrates in the relatively acidic milieu of prostatic and vaginal fluids - the use of the trimethoprimsulfamethoxazole in infections at these sites.  Both parent drugs and their metabolites are excreted in the urine 28
    29. 29. Adverse effects  Dermatological: Reactions involving the skin are very common and may be severe in the elderly.  GIT: N, V, glossitis, stomatitis - not unusual.  Hematological: Megaloblastic anemia, leukopenia, thrombocytopenia  May be reserved by administration of folinic acid (it protects the pts and does not enter the microorganism).  Hemolytic anemia - in pts with G6PD deficiency due to the sulfamethoxazole.  Pneumocystis pneumonia - frequently drug-induced fever, rashes, diarrhea, and/or pancytopenia. 29