Sulfonamides

This ppt deals with the sulfonamide group of drugs with classification, mechanism, spectrum, resistance, uses and adverse effects discussed in detail. It also discusses in detail about Cotrimoxazole

1. Sulfonamides By: Dr. Shruthi Rammohan Final Year PG Pharmacology RRMCH

2. Introduction The first antimicrobial agent effective against pyogenic bacterial infections PRONTOSIL RED A dye used to treat experimental streptococcal infections in mice Was found to be HIGHLY EFFECTIVE Used to cure infants with staphylococcal septicemias ( Sulfonamido – chrysoidine )

3. Introduction In 1937: Prontosil was broken down in the body to release sulfanilimide The active antibacterial agent

4. After this, a large number of synthetic sulfonamides were produced Bacteriostatic Extensively used in following years to come HOWEVER Use of sulfonamides became limited Introduction Rapid emergence of BACTERIAL RESISTANCE Availability of safe & more effective drugs

5. *EXCEPTION COTRIMOXAZOLE – (Combination with Trimethoprim) Combination with Pyrimethamine (Malaria) Introduction

6. Components: p-aminobenzene ring N1 substitution – solubility, potency and PK property N4 free amino group – required for antibacterial activity Structure

7. Structure *Structural Analogue of PABA*

8. Classification The sulfonamides still of clinical interest A. SHORT ACTING (4-8 HOURS) Sulfa diazine B. INTERMEDIATE ACTING (8-12 HOURS) Sulfa methoxazole C. LONG ACTING (~ 7 DAYS) Sulfa doxine Sulfa methopyrazine D. SPECIAL PURPOSE Sulfacetamide sodium Silver sulfadiazine Sulfasalazine Mafenide (Tripathi)

9. Classification The sulfonamides still of clinical interest A. Orally Absorbable 1. Short Acting (4-8 hrs) Sulfa diazine Sulfacytine Sulfamethizole Sulfisoxazole 2. Intermediate Acting (8-12hrs) Sulfa methoxazole Sulfamoxole 3. Long Acting (~7 days) Sulfa doxine Sulfa methopyrazine B. Orally Non- Absorbable Sulfa salazine Olsalazine Balsalazine C. Topical Agents Silver sulfadiazine Mafenide Sulfacetamide sodium (Sharma)

10. Mechanism of Action Leakage from Cell Membrane Broadly put, sulfonamides inhibit Nucleic Acid synthesis Specifically, sulfonamides inhibit the synthesis of folates in bacterial organisms

11. PTERIDINE PABA + DIHYDROPTEROIC ACID DIHYDROFOLIC ACID TETRAHYDROFOLIC ACID DIHYDROPTEROIC ACID SYNTHASE (Folic Acid Synthase) + GLUTAMATE DIHYDROFOLATE REDUCTASE RNA DNA Proteins FOLIC ACID DIHYDROFOLATE REDUCTASE (mammalian) SULFONAMIDES = Bacteria Man

12. Mechanism of Action Folic Acid is very essential for the growth of bacteria as it is crucial for nucleic acid synthesis . Many bacteria synthesize their own folic acid from PABA Sulfonamides are structural analogues of PABA  enters the sequence in place of PABA Sulfonamides compete for enzyme dihydropteroic acid synthase to create a non-functional analogue of folic acid This is of no use to bacteria hence    GROWTH CEASES (BACTERIOSTATIC ACTION)

13. Mechanism of Action * Humans absorb folic acid directly from diet, hence sulfonamides are SELECTIVELY TOXIC TO THE BACTERIA ONLY and not to the host cells!

14. A – Rapidly and well absorbed orally D - Widely distributed in the body - Crosses BBB and placenta - Accumulates in prostatic fluid - Extent of plasma protein binding differs  Longer acting agents are highly protein bound M – Acetylation in the Liver  acetylated metabolites are inactive but still contribute to S/E Less soluble in ACIDIC URINE  Precipitation of CRYSTALLURIA  RENAL TOXICITY E – Kidney by glomerular filtration * More lipid soluble agents are highly reabsorbed  longer acting Pharmacokinetics

15. Antibacterial Spectrum Primarily bacteriostatic Bactericidal concentrations can be attained in the URINE Effective against Gram positive + Gram negative bacteria

16. Antibacterial Spectrum Sensitive Organisms S. pyogenes H. influenzae H. ducreyi C. granulomatis V. cholera Chlamydiae species Actinomyces Nocardia Toxoplasma Resistant Organisms Gonococci Staphylococci Meningococci Streptococci E. coli Shigella Mechanism of Resistance Due to mutations causing: Overproduction of PABA Altered nature of dihydropteroic acid synthetase Loss of permeability of sulfonamides through bacterial membrane Appearance of an alternative pathway

17. Clinical Uses Orally Absorbable Drugs Acute uncomplicated UTI Third Choice Drug Nocardiosis Chancroid (H. ducreyi ) Lymphogranuloma (Chlamydia) Oral Non-Absorbable Drugs Sulfasalazine is the drug of choice for ulcerative colitis Sulfasalazine is also used in Rheumatoid Arthritis Systemic use of sulfonamides ALONE is RARE now Topical Agents Sodium sulfacetamide  Ophthalmic solution/ointment - Trachoma – Chlamydia trachomatis - Bacterial Conjunctivitis Silver sulfadiazine  Least toxic, preferred over mafenide * Slowly releases silver ions  additional antimicrobial action - Prophylaxis/Infections in Burns - Active against Pseudomonas

18. Adverse Effects Crystalluria + Renal Toxicity Dose Related Acetylated metabolites are less soluble in acidic urine Precipitates in kidney and renal tubules Causes crystalluria and renal obstruction Risk can be minimized: Taking plenty of fluids Alkalinizing urine

19. Adverse Effects Hypersensitivity Reactions Rashes – especially at mucocutaneous junctions Steven’s Johnson’s Syndrome – erythema multiforme, ulcerations of mucous membranes, malaise Eosinophelia Drug Fever Exfoliative dermatitis

20. Adverse Effects Hemolysis Can occur in patients with G6PD deficiency Neutropenia, Agranulocytosis and thrombocytopenia can occur Kernicterus in Neonates Can be precipitated especially in premature infants since their blood brain barrier is not fully developed SULFONAMIDES Displaces bilirubin from protein binding site Bilirubin passes through BBB Deposited in Basal Ganglia + Subthalamic nuclei

21. Adverse Effects Nausea, Vomiting, Epigastric Pain Hepatitis

22. Cotrimoxazole

23. Introduction (Cotrimoxazole) Introduced in 1969 It is a RATIONAL fixed drug dose combination Sulfamethoxazole + Trimethoprim This combination is BACTERICIDAL (Both drugs are bacteriostatic when given alone)

24. Trimethoprim vs. Sulfamethoxazole (Cotrimoxazole) TRIMETHOPRIM SULFAMETHOXAZOLE Diaminopyrimadine related to antimalarial drug PYRIMETHAMINE Intermediate acting PABA structural analogue MOA: Inhibits bacterial dihydrofolate reductase ( DHFRase ) MOA: Inhibits folate synthase HUMAN FOLATE METABOLISM IS NOT INTERFERED WITH Bacteriostatic Bacteriostatic Combination is BACTERICIDAL against many organisms Pharmacokinetics: A – More rapidly absorbed D – 40% plasma protein bound M – Partly metabolized in Liver E – Excreted in urine Pharmacokinetics: A – Rapidly absorbed D – 65% plasma protein bound M – Acetylation in Liver E – Renal excretion by glomerular filtration

25. Rationale (Cotrimoxazole) Both compounds have a similar half life (~10 hours) Two bacteriostatic drugs produces bactericidal action when combined The combination has a wider antibacterial spectrum The combination delays the development of bacterial resistance The MIC of each component can be reduced 3-6 times Trimethoprim enters many tissues and has a larger volume of distribution

26. Mechanism of Action (Cotrimoxazole) Cotrimoxazole inhibits Nucleic Acid Synthesis by… …. causing SEQUENTIAL BLOCKADE of Folic Acid Synthesis in bacterial organisms

27. PTERIDINE PABA + DIHYDROPTEROIC ACID DIHYDROFOLIC ACID TETRAHYDROFOLIC ACID DIHYDROPTEROIC ACID SYNTHETASE (Folic Acid Synthase) + GLUTAMATE DIHYDROFOLATE REDUCTASE RNA DNA Proteins FOLIC ACID DIHYDROFOLATE REDUCTASE (mammalian) SULFAMETHOXAZOLE = Bacteria Man TRIMETHOPRIM =

28. Spectrum of Action (Cotrimoxazole) All organisms sensitive for sulfonamides Additional organisms: S. typhi, Klebsiella, P. jiroveci Sulfonamide resistant strains Mechanism of Resistance: Resistance to Trimethoprim is mostly through plasmid mediated acquisition of DHFRase *Resistance to the combination is slow to develop compared to the drugs alone!

29. Uses (Cotrimoxazole) Urinary Tract Infections Acute uncomplicated infections respond rapidly  1 tablet twice daily X 3-10 days Acute Cystitis  Single dose therapy with 4 tablets Prostatitis Acute  1 tablet twice daily X 3 weeks Chronic  1 tablet twice daily X 6-12 weeks * If patient is allergic to sulfonamides , trimethoprim can be given alone * Cotrimoxazole is still used now … however, its popularity has decreased in the treatment of systemic infections

30. Uses (Cotrimoxazole) Respiratory Tract Infections URTI + LRTI Chronic Bronchitis Especially infections caused by Gram positive cocci and Sinusitis Hemophilus species Otitis Media  One DS tablet twice a day

31. Uses (Cotrimoxazole) Bacterial Diarrheas + Dysentery Acute gastroenteritis Traveller’s Diarrhea E. coli, Shigella, non-typhoid Salmonella, Yersinia Cholera  One DS tablet twice a day X 7 days * Fluourquinolones are the drugs of choice, however Cotrimoxazole is a valuable alternative

32. Uses (Cotrimoxazole) Pneumocystis jiroveci (Pneumonia in Neutropenic/AIDS patient) High doses Cotrimoxazole is prophylactic as well as therapeutic Drug of choice for pneumonia due to P. jiroveci Treatment  One DS tablet four times a day X 2-3 weeks Prophylaxis  One DS tablet daily * Adverse effects necessitates discontinuation in 20% cases

33. Uses (Cotrimoxazole) Sexually transmitted Diseases Chancroid – Cotrimoxazole is the 3 rd choice drug  One DS tablet twice daily X 14 days Non-specific urethritis Lymphogranuloma Gonorrhea

34. Uses (Cotrimoxazole) Nocardiosis Drug of choice for pulmonary lesions/brain abscesses due to Nocardia Melioidosis Typhoid Was initially effective and an alternate drug for typhoid. Now it is unreliable and seldomly used

35. Intravenous (Cotrimoxazole) IV Cotrimoxazole in 5% Dextrose is preferred to treat moderate to severe P. jiroveci pneumonia Shigellosis typhoid fever nocardiosis septicemia

36. Adverse Effects (Cotrimoxazole) All the adverse effects seen with Sulfonamides can be seen with Cotrimoxazole Nausea, Vomiting, Headache, Stomatitis Rashes Folate deficiency ONLY in patients with marginal folate levels Blood dyscrasias (RARE)

37. Contraindications (Cotrimoxazole) AVOID IN PREGNANCY Trimethoprim is an antifolate  Theoretical teratogenic risk Given near term  methemoglobinemia and neonatal hemolysis Uremia in renal disease Greater risk of bone marrow toxicity in the elderly Fever, Rash and bone marrow hypoplasia among AIDS patients with P. jiroveci infection

38. Interactions (Cotrimoxazole) Diuretics + Cotrimoxazole  Higher incidence of THROMBOCYTOPENIA

39. Recent Advances ( Ictaprim ) Ictaprim Recently introduced in August 2008 Trimethoprim analogue ROA: IV More effective and better tolerated than Trimethoprim Equally effective as Linezolid in MRSA skin and soft tissue infections Highly active against VRSA *Phase III trials are being conducted to explore whether the same efficacy is retained if administered orally

40. Sulfadoxine + Pyrimethamine

41. Introduction ( Sulfadoxine + Pyrimethamine) It is a RATIONAL fixed drug dose combination Synergistic Sulfadoxine + Pyrimethamine

42. Rationale ( Sulfadoxine + Pyrimethamine) Both drugs have ultra long plasma half life (> 95 hrs) Acts faster in combination Curative for Chloroquine resistant P. falciparum malari a Toxoplasmosis

43. Mechanism of Action ( Sulfadoxine + Pyrimethamine) Sequential Block in protozoal folic acid synthesis * Pyrimethamine blocks dihydrofolate reductase but has greater activity against protozoal dihydrofolate reductase * Pyrimethamine unfortunately has some activity against mammalian dihydrofolate reductase - Administer folinic acid (Citrovorum factor) during therapy

44. Adverse Effects ( Sulfadoxine + Pyrimethamine) Serious cutaneous reactions

45. THANK YOU!!