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Sulfonamides and Cotrimoxazole
Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong
Sulfonamides
• The first antimicrobial effective against Pyogenic Bacterial
infections.
• Derivatives of Sulfanilamide con...
Sulfonamides - History
• Screening of “Dyes” for their antibacterial properties in 1920s.
• Sulfonamido-chrysidine – commo...
1920’s
Investigations into the antimicrobial properties of dyes
Prontosil emerged as a viable compound
metabolized to
Para...
Sulfonamides - Classification
• Short acting: Sulfadiazine, Sulfadimidine,
Sulfacetamide
• Intermediate acting: Sulfametho...
Sulfonamides – Antibacterial Property
• Bacteriostatic against gm +ve and gm –ve bacteria
• Bactericidal in urine
• Suscep...
Sulfonamides - MOA
Woods and Fielde`s Theory:
 Bacteriae normally picks up
PABA from surroundings to
synthesize folic ac...
Sulfonamides – MOA image
Sulfonamides - Resistance
• Many strains – S. aureaus, Gonococci,
Meningococci, Strep. Pyogens, E coli and Shigella
• Mech...
Sulfonamides – Kinetics
• Rapidly and completely absorbed from GIT
• Extend of plasma protein binding differs (10 –
95%)
–...
Sulfonamides - ADRs
• Nausea, vomiting and epigastric pain
• Crystalluria – alkanization of urine
• Hypersensitivity (2 – ...
Sulfonamides - Uses
• Rarely used now a days via systemic route
• UTI: caused by E. coli and P. mirabilis: Sulfisoxazole –...
Cotrimoxazole – In 1969
Fixed drug combination of
Sulfamethoxazole and Trimethoprim
SYNERGISM
Trimethoprim
• Trimethoprim (trimethyl benzyl pyrimidine) is a
diaminopyrimidine, chemically related to Pyrimethamine
• Do...
Tetrahydropteroic acid synthetase
Dihydrofolic acid
Dihyrofolate reductase
Tetrahydrofolic acid
Purine synthesis
DNA synth...
Cotrimoxazole – general points
• Both drugs have almost similar half lives (10 Hrs)
• Optimal synergism is obtained at 20 ...
Cotrimoxazole – antibacterial
spectrum
• Similar to sulfonamides
• Additional benefits: Salmonella typhi, Serratia,
Klebsi...
Cotrimoxazole - ADRs
• All adverse effects of sulfonamides –
nausea, vomiting, stomatitis, rash etc
• Folate deficiency (m...
Cotrimoxazole - Uses
• Uncomplicated infection of the lower urinary tract infection
– Cystitis (5 tablet dose)
– chronic a...
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Sulfonamides and cotrimoxazole - drdhriti

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  1. 1. Sulfonamides and Cotrimoxazole Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
  2. 2. Sulfonamides • The first antimicrobial effective against Pyogenic Bacterial infections. • Derivatives of Sulfanilamide containing a “sufonamido “ring (SO2NH2). • Structurally and chemically related to p-aminobenzoic acid (PABA). • Structurally similar to many drugs – thiazides, acetazolamide, dapsone and sulfonylureas etc. • Physically – available as white powder, mildly acidic and form water soluble salts with bases. • However, indications and practical uses are very few these days.
  3. 3. Sulfonamides - History • Screening of “Dyes” for their antibacterial properties in 1920s. • Sulfonamido-chrysidine – commonly known as “Prontosil red” was the first one effective in streptococcal infection in mice by Domagk. – Cured his daughter • 1937: Prontosil was broken down to release “sulfanilamide” – many sulfonamides were produced. Para-amino-benzene-sulfonamide (sulfanilamide) Prontosil
  4. 4. 1920’s Investigations into the antimicrobial properties of dyes Prontosil emerged as a viable compound metabolized to Para-amino-benzene-sulfonamide (sulfanilamide)
  5. 5. Sulfonamides - Classification • Short acting: Sulfadiazine, Sulfadimidine, Sulfacetamide • Intermediate acting: Sulfamethoxazole • Long acting: Sulfamethoxypyrazine, Sulfadoxine, Sulfadimethoxine etc. • Topically used: Mafenide, Silver sulfadiazine and Sulfacetamide • Ulcerative colitis: Sulfasalazine
  6. 6. Sulfonamides – Antibacterial Property • Bacteriostatic against gm +ve and gm –ve bacteria • Bactericidal in urine • Susceptible organisms: S. pyogens, H. influenzae, H. ducreyi, Callymatobacterium grannulomatosis, V. cholerae, Chlamydia, Actinomyces etc. – Few strains of Staph aureus, gonococci, meningococci, pneumococci, E. coli and Shigella • Protozoa: – Plasmodium (Sulfadoxine + Pyrimethamine) – Toxoplasmosis (Sulfadiazine + Pyrimethamine) – PCP (Sulfamethoxazole + Trimethoprim = SXT)
  7. 7. Sulfonamides - MOA Woods and Fielde`s Theory:  Bacteriae normally picks up PABA from surroundings to synthesize folic acid  Inhibition of bacterial folic acid synthesis from PABA (enzyme folate synthase) – competitive  Essential metabolic reactions suffer Why no human affect?? Preformed folic acid by human. Evidence of MOA: PABA antagonizes Sulfonamides, only the organisms synthsizing FA Dihydropteroic acid Dihydrofolic acid Enzymes: Pteridine synthetase and Dihydrofolate synthetase
  8. 8. Sulfonamides – MOA image
  9. 9. Sulfonamides - Resistance • Many strains – S. aureaus, Gonococci, Meningococci, Strep. Pyogens, E coli and Shigella • Mechanism: – Production of increased amounts of PABA (Staph, Neisseria) – Folate synthase enzyme has low affinity to sulfonamides – Adopt alternative pathway of folate synthesis – structural changes in folate synthase (E coli) – encoded chromosomally and plasmid mediated • Resistant to one sulfonamide – resistant to all
  10. 10. Sulfonamides – Kinetics • Rapidly and completely absorbed from GIT • Extend of plasma protein binding differs (10 – 95%) – Longer acting ones are highly plasma protein bound – Widely distributed – enters in serous cavity easily • Metabolized by non microsomal acetyl transferase in liver – slow and fast acetylators • Acetylated product excreted in urine (more toxic than parent) – crystalluria • Reabsorbed in tubule
  11. 11. Sulfonamides - ADRs • Nausea, vomiting and epigastric pain • Crystalluria – alkanization of urine • Hypersensitivity (2 – 5%) • Hepatitis • Haemolysis – G-6-PD deficiency • Kernicterus
  12. 12. Sulfonamides - Uses • Rarely used now a days via systemic route • UTI: caused by E. coli and P. mirabilis: Sulfisoxazole – 1 gm 4 times daily • Malaria – sulfadoxine and pyrimethamine combination • Toxoplasmosis: sulfadiazine + pyrimethamine • Ulcerative colitis – Sulfasalazine – 1-4 gm initially and 500 mg 6 Hrly. • Locally: – Sodium sulfacetamide: 10-30% ophthalmic solution in bacterial conjunctivitis, trachoma etc. – Mafenide acetate (1% cream) and Silver sulfadiazine 1% cream): Burn dressing and chronic ulcers
  13. 13. Cotrimoxazole – In 1969 Fixed drug combination of Sulfamethoxazole and Trimethoprim SYNERGISM
  14. 14. Trimethoprim • Trimethoprim (trimethyl benzyl pyrimidine) is a diaminopyrimidine, chemically related to Pyrimethamine • Do not confuse: Cotrimoxazole is TMP –SMZ, but Sulfadoxine + Pyrimethamine is antimalarial • MOA: Sequential block of folate metabolism • Trimethoprim is 50,000 or more times more active against bacterial DHFRase enzyme than mammalian • So, no harm to human folate metabolism • Individually, both are bacteriostatic, but combination is – cidal • Maximum synergism if the organism is sensitive to both the agents
  15. 15. Tetrahydropteroic acid synthetase Dihydrofolic acid Dihyrofolate reductase Tetrahydrofolic acid Purine synthesis DNA synthesis Sulfonamides Trimethoprim MOA OF TRIMETHOPRIM-SULFAMETHOXAZOLE 1.Sulfamethoxazole inhibits dihydrofolate synthase. 2.Trimethoprim inhibits dihydrofolate reductase. PABA
  16. 16. Cotrimoxazole – general points • Both drugs have almost similar half lives (10 Hrs) • Optimal synergism is obtained at 20 (S) : 1 (T) concentration (MIC of both is reduced by 5-6 times) – This ratio is obtained at 5:1 dose ratio ( e.g. 800 mg:160 mg) – Because TMP has large Vd and enters many tissues – plasma conc. Is low • But, TMP crosses BBB and placenta and SMZ not • TMP is more rapidly absorbed than SMZ • TMP is 45% plasma protein bound but SMZ is 65% bound • TMP is partly metabolized in liver
  17. 17. Cotrimoxazole – antibacterial spectrum • Similar to sulfonamides • Additional benefits: Salmonella typhi, Serratia, Klebsiella Enterobacter, Yersinia and Pneumocystis jiroveci • Sulfonamides resistance strains of S aureus, E coli, gonococci, meningococci and H influenzae • RESISTANCE: Slow to develop – By mutational changes or plasmid mediated acquisition of a DHFRase enzyme having lower affinity for the inhibitior.
  18. 18. Cotrimoxazole - ADRs • All adverse effects of sulfonamides – nausea, vomiting, stomatitis, rash etc • Folate deficiency (megaloblastic anaemia) – patients with marginal folate levels • Blood dyscrasias • Pregnancy: teratogenic risk, Neonatal haemolysis and methaemoglobinaemia • Patients with renal disease may develop uremia • Elderly – risk of bone marrow toxicity from cotrimoxazole • Diuretics given with cotrimoxazole have produced a higher incidence of thrombocytopenia • Bone marrow hypoplasia among AIDS patients with Pneumocystis jiroveci infection
  19. 19. Cotrimoxazole - Uses • Uncomplicated infection of the lower urinary tract infection – Cystitis (5 tablet dose) – chronic and recurrent urinary tract infections (including enterobacteriaceae) – 3-10 days • Respiratory tract infection – lower and upper, chronic bronchitis, facio-maxillary infections, otitis media due to gm+ve cocci and H influenzae etc • Typhoid • Bacterial diarrhoeas & dysentery: due to campylobacter, E coli, Shigella etc. • Pneumocystis jiroveci: Severe pneumonia - Prophylactic use in AIDS patients with neutropenia. Dose – DS tablet 4-6 times 2-3 weeks • Chancroid – H. ducreyi • Alternative to penicillin in agrannulocytosis patients, scepticaemia etc.
  20. 20. Thank you
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