Sulfonamides and cotrimoxazole - drdhriti

A Power point presentation on "Sulfonamides and cotrimoxazole" suitable for undergraduate level medical student and others

1. SULFONAMIDES & COTRIMOXAZOLE Dr. D. K. Brahma Associate Professor, Pharmacology NEIGRIHMS, Shillong

2. Sulfonamides The first antimicrobials effective against Pyogenic Bacterial infections. Derivatives of Sulfanilamide containing a “sufonamido “ ring (SO 2 NH 2 ). 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. History – Sulfonamides 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. Sulfonamides - Classification Short acting: Sulfadiazine , Sulfadimidine, Sulfacetamide Intermediate acting: Sulfamethoxazole Long acting: Sulfadoxine , Sulfamethoxypyrazine , Sulfadimethoxine etc. Topically used: Mafenide, Silver sulfadiazine and Sulfacetamide Ulcerative colitis: Sulfasalazine

5. Sulfonamides – Antibacterial Property Bacteriostatic against gm +ve and gm –ve bacteria Bactericidal in urine Susceptible organisms: Str. p yogens, H. influenzae, H. ducreyi, Callymatobacterium grannulomatosis, V. cholerae, Chlamydia, Actinomyces etc. Few strains of Staph aureus, gonococci, meningococci, pneumococci, E. coli and Shigella Chlamydiae : trachoma, lymphogrnuloma venereum ., inclusion conjunctivitis. Also Actinomyces and Nocardia Protozoa: Plasmodium (Sulfadoxine + Pyrimethamine) Toxoplasmosis (Sulfadiazine + Pyrimethamine) PCP (Sulfamethoxazole + Trimethoprim = SXT)

6. 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 synthesizing FA Dihydropteroic acid Dihydrofolic acid Enzymes: Pteridine synthetase and Dihydrofolate synthetase

7. Sulfonamides – MOA image

8. Sulfonamides - Resistance Many strains – S. aureaus , pneumococci , 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 No cross resistance

9. 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 – inactive excreted in urine (but, more toxic than parent) – crystalluria Acetylated form accumulates in blood – toxic in renal faiure Reabsorbed in tubule

10. Sulfonamides - ADRs Nausea, vomiting and epigastric pain Crystalluria – alkanization of urine Hypersensitivity (2 – 5%) – rashes, urticaria , drug fever. Exfoliative dermatitis, SJ syndrome (long acting ones) Hepatitis Haemolysis – G-6-PD deficiency Kernicterus – displacement of bilirubin

11. Individual Sulfonamides Sulfadiazine: General purpose use – absorbed orally and rapidly excreted. More crystalluria . Preferred in meningitis. Sulfamethoxazole : slower absorption and lower excretion. 10 Hrs. half life. Combination with Trimethop Sulfadoxine: Ultra -long acting >1 week. High protein bound – long excretion. Not suitable for Pyogenic infections – low plasma conc.. Used in Malaria, Pneumocystis jiroveci and toxoplasmosis Sulfacetamide : Ophthalmic use – infections by bacteria, chlamydia , ophthalmia neonatorum etc Mafendie : Atypical sulfonamide. Local application – inhibits variety of bacteria – active in presence of pus – pseudomonas and clostridia Silver sulfadiazine: Bacteria, fungi, Pseudomonas. In burn cases

12. Sulfonamides - Uses Rarely used now a days systemically UTI: caused by E. coli and P. mirabilis: Sulfisoxazole – 1 gm 4 times daily Malaria: sulfadoxine and pyrimethamine combination Toxoplasmosis: sulfadiazine + pyrimethamine In Combination with Trimethoprim : Cotrimoxazole 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. Cotrimoxazole – In 1969 Fixed drug combination of Sulfamethoxazole and Trimethoprim SYNERGISM

14. Trimethoprim Trimethoprim (trimethyl benzyl pyrimidine) is a diaminopyrimidine, chemically related to Pyrimethamine Do not confuse: Clotrimazole ( antiungal ) - 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

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. Cotrimoxazole – general points Individually, both are bacteriostatic , but combination is – bactericidal Both drugs have almost similar half lives (10 Hrs) Maximum synergism if the organism is sensitive to both the agents Optimal synergism is obtained at 20 (S) : 1 (T) concentration (MIC of both is reduced by 3 - 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. 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. 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 Fever, rash and bone marrow hyperplasia 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. 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. Must Know Classification of Sulfonamides – examples of some Sulfonamides Uses of some selected Sulfonamides Cotrimoxazole – as a whole Rationale of combinations – Cotrimoxazole and Sulfadoxine + pyrimethmine

21. Take Home ……. Students (Sulfonamides) + Teachers ( Trimethoprim ) Similar half lives (10 Hrs ) – human being Both are bacteriostatic – combination is bactericidal - alone nothing - together can make difference S ynergism is obtained at 20 (S) : 1 (T) concentration (MIC of both is reduced by 3 - 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 teachers effort Optimal synergism if the organism is sensitive to both the agents – have to reciprocate each other Combination - Lesser toxic ( trimethoprim ) - have to monitor Alone ( trimethoprim ) - sometimes have to act

22. Thank you