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![The process of discovery for sulfonamides
SO2NH2
SO2NH2
NH
2
N N
CH3CONH
N
N
NaO3S
SO3Na
H2N
Prontosil Soluble
Prontosil
NH2
SO2NH2
N
N
H2N
inactive (in vitro)
SO2NH2
Liver
[H]
H2N
active(in vivo)](https://image.slidesharecdn.com/1-131015051935-phpapp02/85/1-sulfonamide-final-24-320.jpg)
Uploaded byVijay Prasad Sangisetti
1.sulfonamide final
This document provides information on sulfonamides, which were the first antimicrobial agents effective against pyogenic bacterial infections. It discusses how sulfonamides work by competitively inhibiting the bacterial enzyme dihydropteroate synthetase, blocking the synthesis of folic acid. Various sulfonamides are described based on their absorption, duration of action, and clinical uses for infections like UTIs, respiratory infections, and travelers' diarrhea. Adverse effects include crystalluria, blood disorders, and hypersensitivity reactions. Sulfonamides remain important oral antibiotics but require monitoring for toxicity.
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1.sulfonamide final
- 1.
- 2. chemotherapy A science oftreating diseases with the help of drugs. The term gradually came in to use in reference to treatment of infections, infestations, and cancers.
- 3. • Treatment ofsystemic/topical infection with drugs that have selective toxicity for an invading pathogens with out harming the host cells. • Due to analogy between the pathogenic organism and malignant cells the treatment of neoplastic diseases with drugs is also called as Chemotherapy »Contd.,
- 4. landmarks • 1877 –Louis Pasteur – “LIFE DESTROYS LIFE”Bacteria prevented growth of anthrax bacillus in urine • 1891 – Paul Erlich (FATHER OF MODERN CHEMOTHERAPY- NOBEL 1909) - methylene blue inhibited growth of bacteria • 1928 – Alexander Fleming: The fungus penicillium notatum could inhibit staphylococci in a culture plate • 1938 – Domagk – Prontosil – a dye inhibited micro-organisms – sulfonamides- sulfanilamide • 1941 – Penicillin – Fleming, Florey, Chain- Nobel
- 5. organisms • • • • • • • • • • Bacteria Fungi Viruses Spirochetes (Treponemes, Borrelia) Actinomyces Rickettsiae Chlamydiae Mycoplasma Nocardia Protozoa/parasites(ameba,giardia,trichomonas, toxoplasma) worms (Helminths) • Prions
- 6. • Obtain MO(Antibiotics) • Antimicorbials Syn in Lab, • Semisenthetic antibiotics »Contd.,
- 7. Mechanism of Action •Antibiotic action can be split into 2 mechanisms: Bacteriostatic Bacteriocidal
- 8. STATIC - implications • • • • • • NOKILLING EFFECT – long period of treatment Infection MAY NOT BE totally eradicated ORGANISMS MAY REMAIN IN A DORMANT STAGE MAY MULTIPLY LATER RELAPSE E.g. chloramphenicol for enteric fever • COMBINATION – static drug may reduce the rate of growth – a cidal agent cannot work effectively.
- 9. CIDAL - IMPLICATIONS • • • • • • KILLINGEFFECT Infection totally eradicated Less chances of relapse Example : ENTERIC FEVER (TYPHOID) Chloramphenicol (static) Cotrimoxazole, Ampi/amoxicillin, Ciprofloxacin, Ceftriaxone (cidal) • CIDAL drugs produce rapid effect – shortening of length of treatment – tuberculosis (streptomycin, INH, rifampicin, pyrazinamide) 010613 mmm
- 10. • Bacteriostatic Drugsarrest the growth and replication of bacteria and limits the spread of infection • Bacteriostatic antibiotics hamper the growth of bacteria by interfering with bacterial: Protein production DNA replication Cellular metabolism • Macrolids ,Broad spectrum antibiotics ,Sulfanamides • Trimethroprim, Clindamycin, Ethambutol
- 11. • Bacteriocidal killor irrverisible damage the multiplying bacteria • Microbe death is usually achieved by disruption of the bacterial cell membrane leading to lysis. • • • • Betalactum antibiotics Cotrimoxazole, Aminoglycoside Fluroquinolones, Vancomycin, Polymixins Rifampicin, INH, Bacitracin
- 12. Spectrum of activity •Spectrum = range of micro-organisms inhibited • Narrow spectrum • Penicillin G (Benzyl penicillin) Mainly Gm +ve • Aminoglycosides, Metronidazole – Mainly Gm –ve • Broad Spectrum Antibiotics: (BSA) • TETRACYCLINES, CHLORAMPHENICOL
- 13. Extended spectrum • Broaderthan NARROW SPECTRUM • Narrower than BROAD SPECTRUM • • • • • • Extended spectrum penicillins II and III generation cephalosporins Co-trimoxazole Sulfa drugs, trimethoprim Quinolones Macrolides
- 14. Mech • Usually ittake advantage of the biochemical and physiological differences that exist betn MO and human beings.
- 15. PROKARYOTIC EUKARYOTIC Size 1-10µm 10-100m Envelope byrigid cell wall Flexible plasma membrane Sub cellular organs absent present Ill- defined nucleus Well defined nucleus Energy metabolism bounded to cell membrane Located in mitochondria Division -- fission mitosis Ribosomes-70s– 30s & 50s 80s– 60s & 40s
- 16. Site and Mechanismof action of Antibiotics
- 17. Combination therapy • Tomake broaden spectrum activity (Pulmonary, Aerobic, anaerobic) • Increase antibacterial activity (Synergism) • To prevent resistance (TB, leprosy) • To reduce duration of therapy (MDT, leprosy) • Reduce adverse effects
- 18. 1. As resultof mutation or by plasmid mediated 1. 2. 3. Conjugation Transduction Transformation 2. Producing an enzyme that inactivate antibiotic 1. 2. 3. Betalactmase Chloramphenicol acetyltransferase Acetyl transferase, phosphotrans, adenyltransferase (aminoglycosides) 3. Decreased bacterial permeability or active efflux of drug. 4. An appearance of alternative pathway 5. Decreased affinity for target : Penicillin binding proteins
- 19. Prevention of drugresistance • • • • • Right drug Right dose Right period Prefer rapidly acting selective spectrum Combination of AMAs whenever prolong therapy
- 20. Factors affecting choiceof antimicrobial agents Age: – Chloramphenicol – Gray baby syndrome – Half life amino glycosides is prolonged in elderly – Tetracyclines – CI in below 6 years it accumulates in developing bone and teeth Pregnancy: – All antibiotics produce risk to the fetus . Penicillins, Macrolids & Cephalosproins Impaired host defenses – Bactericidal drugs are must in immunocompromised patients
- 21. • Renal function: CIin renal disease Dose reduction in renal failure cephalothin Aminoglycosides Cephaloridine Amphotericin B Nalidixic acid Vancomycin Nitrofurantoin Ethambutol • Liver function CI in liver disease Dose reduction in liver failure Tetracycline Chloramphenicol Pyrazinamide Isoniazid Pefloxacin Rifampicin Erythromycin Clindamycin
- 22. SULFONAMIDES •Sulfonamide were thefirst antimicrobial agents effective against pyogenic bacterial infections •Anti metabolites •Bacteriostatic agents •GELMO 1908 – Synthesized •Prontosil was first drug active in vivo •In liver it converting to Sulfonamide •These are synthetic agents(Antimicrobials) •Originally, sulfonamides were synthesized in Germany as azodyes.
- 23. Gerhard Domagk (1895-1964) Germanbacteriologist and pathologist who was awarded the 1939 Nobel Prize for Physiology or Medicine for his discovery (announced in 1932) of the antibacterial effects of Prontosil, the first of the sulfonamide drugs.
- 24. The process ofdiscovery for sulfonamides SO2NH2 SO2NH2 NH 2 N N CH3CONH N N NaO3S SO3Na H2N Prontosil Soluble Prontosil NH2 SO2NH2 N N H2N inactive (in vitro) SO2NH2 Liver [H] H2N active(in vivo)
- 25. SULFONAMIDES • The antimicrobialcontaining a sulfonamido (sulfanilamide, SO4NH2) group are called sulfonamides. H2N SO4-NH2 • Structurally related to p-aminobenzoic acid (PABA). SINCE THEN : * 5000 SYNTHESISED. * 150 MARKETED. * 20 IN COMMON USE. • This group is also present in other non-antibacterial compounds like -Sulphonureas -Benzothiazids -Furosemide -Acetazolamide
- 26. Mechanism of action •Folic acid - synthesized from PABA, pteridine and glutamate. • All sulfonamides are analogs of PABA. • SA compete with this substrate for the bacterial enzyme, dihydropteroate synthetase. • All sulfa drugs are bacteriostatic.
- 27. Folic acid synthesisinhibitors pterdine + para-amino benzoic acid Dihydropteroate synthetase dihydropterate Sulphamethoxazole (Sulphonamides) Structural analogues of PABA dihydrofolate Dihydrofolate reductase tetrahydrofolate (folinic acid) Trimethoprim (Diaminopyrimidines) Binding DNA/RNA
- 29. Antimicrobial effects Both G+& G- bacteria, nocardia, chlamydia trachomatis, some protozoa, some enteric bacteria (E coli, klebsiella, salmonella, shigella, & enterobacter) Sulfonamides stimulate rickettsiae in their growth.
- 30. CLASSIFICATION Orally absorbable agents •Short acting(6-9hrs.)- Sulfadiazine Sulfacytine Sulfamethizole Sulfisoxazole • Intermidiate acting(10-12hrs.)Sulfamethaxazole Sulfamoxole • Long acting(7days)Sulfadoxine sulfamethopyrazine Orally non absorbable agents Sulfasalazine Olsalazine Topical agents Silver sulfadiazine Sulfacetamide Mafenide
- 31. Pharmacokinetics • Absorbed rapidlyfrom the gastrointestinal tract (except topically used ). Peak plasma levels are achieved in 2-6hrs. • widely distributed and pass through BBB as well as placental barrier. • Never administered SC & IM (Very painful) • 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.
- 32. COTRIMOXAZOLE COMBINATION OF :Fixed dose combination SULPHAMETHAXAZOLE : TRIMETHOPRIM. 5 : 1 400 mg. 800mg : 80 mg. 160mg M. A. O. PABA F.A. SYNT. SULPHA FOLIC ACID D. H. F. R. THFA TRIMETHOPRIM - SEQUENTIAL BLOCK. - Broad spectrum bactericidal combination. - Delays the development of bacterial resistance
- 33. Clinical use Oral sulfonamides •Cotrimoxazole UTIs –Actue uncomplicated • E.coli, Proteus • 5 -10 days cotrimaxozole DS BD Prostatis• concentrated in prostatic fluid • Acute prostatis – DS tablet BD- 3weeks • Chronic – 6-12 week
- 34. Respiratory tract infections-DS tablet BD • Frequent choice for acute sinusitis, bronchitis, otitis media due to Pneumococcus and Haemophilus Thyphoid- (Ciprofloxacin DOC) • Alternative drug • DS tablet BD- 2week • 10-12 week course eradicate carrier state Salmonella typhi
- 35. Bacterial diarrhoea andDysentery (Ds tablet Bd 7 days) Gastroenteritis - Shigella & Yersinia entrocolitica Traveler's diarrhoea - E.coli Cholera - Vibrio cholerae Nocardiosis (Sulfadiazine) Pulmonary lesions or Brain abscess -DOC
- 36. STD DS tabletBD for 7-10days – Chancoroid- Haemophilus ducreyi (Chancoroiod – highly infectious nonsyphilitic venereal ulcer) – Lymphomagranuloma – Chalamydia – Gonorrhoea- Neisseria gonorrhoea Pneumonia • Prophylactic DS tablet OD • Curative – DS 4 times a day for 2-3 week Sulfadiazine + Pyrimethamine • 1st line Acute Toxoplasmosis • Folinic acid 10mg each day to minimize bone marrow suppression
- 37. • IV cotrimoxazole- 80mg Trimetho + 500mg Sulfamethoxazole in 5ml diluted in 125ml of 5% dextrose infusion over period 60-90min • Preferred for moderate to severe – Pneumocytis carinii-pneumonia – Shigellosus – Thyoid fever – Nocardiosis – Gram –ve bacterial sepsis
- 38. Sulfadoxine + Pyrimethamine combination •Sequential block in protozoal folic acid synthesis • Clinical curative for choloro qunine resistance P. Falciparum (1500mg sulfadoxine+ 75mg Pyri) sulfadoxine 500mg + Pyrimethamine 25mg (1:20) • Pyrimethamine + sulfadoxine in toxoplasmosis
- 39. Oral non absorbable •Sulfaslazine Poorly absorbed by GIT Bacterial flora 5 Aminosalicyclic acid + sulfapyridine Anti inflammatory activity Ulcerative colitis Anti bacterial agent Carrier moiety for 5AMA to reach bowel Rheumatoid arthritis
- 40. Topical agents Sodium sulfacetamide-10%, 20%, 30% • Ophthalmic solution or ointment – conjunctivitis Mafenide acetate Prevent bacterial colonization and infection of burn wounds, Silver sulfadiazine For prevention of infection of burn wounds
- 41. Adverse effects Crystalluria andrenal toxicityAdequate intake of water By making urine alkaline Blood Hemolytic and aplastic anemia (G6PD def.) Thrombocytopenia Hypersensitivity Photosensitivity Exfoliative dermatitis Eosinophelia
- 42. • Kernicterus inneonates– Sulfonamides displace bilirubin from protein binding – Free bilirubin gets diposited in basal anglia, subthalamic nuclei - toxic encephalopathy – Avoided in neonates & pregnancy (last trimi) • GI Nausea, vomiting, diarrhea, pancreatitis
- 43. • • • • • • • R- Rash A- Acetylation S-Systemic lupus erythromatus H- Heamolysis in G6PD A- Aplastic, Megaloblastic anemia B- Bilirubin displace C- Crystalluria
- 44. Resistance to Sulfonamides ①Over-production of PABA ② Produce dihydropteroate synthase with low sulfonamide affinity ③ Loss permeability to the sulfonamide ④ Use exogenous sources of folate;
- 45. CONTRAINDICATIONS • Pregnancy (fullterm) • Newborn and infant (<2months) • Patients on Methenamine, Tolbutamide, oral anticoagulants.
- 46.