sulphonamides and quinolones phar 12111111q1q1q1qq11.11.pptx

Sulphonamides and quinolones

1. Sulfonamides and Quinolones

2. Objectives Know about sulphonamides Types (Classification) MOA Combination with Trimethoprim or Pyrimethamine Uses ADRs, DDI, and Contraindications Special points Know about Quinolones Types (Classification) MOA Uses ADRs, DDI, and Contraindications Special points

3. Sulfonamides were the first antimicrobial agents (AMAs) effective against pyogenic bacterial infections Use limited by: rapid emergence of bacterial resistance availability of many safer and more effective antibiotics, thus utility is limited, to combination with trimethoprim (as cotrimoxazole) or pyrimethamine (for malaria). synthetic antimicrobial agents simply called sulfa drugs Primarily Bacteriostatic drugs Cellular & humoral immunity of host is essential for eradication of the infection. Spectrum covers Gram positive & Gram negative

4. Derivatives of sulfanilamide (p-aminobenzene sulfonamide). Alterations at N1 result in changes in pharmacokinetics; solubility and potency Antibacterial activity is necessitated by a free N4 position

5. Classification Agents that are absorbed & excreted rapidly Sulfisoxazole Sulfamethoxazole Sulfadiazine Agents that are absorbed very poorly when administered orally, hence active in bowel lumen Sulphasalazine

6. Agents used topically Sulfacetamide Mafenide Silver sulfadiazine Classification according to duration of action 1. Short acting (4–8 hr ): Sulfadiazine 2. Intermediate acting (8–12 hr ): Sulfamethoxazole 3. Long acting (~7 days): Sulfadoxine , Sulfamethopyrazine because it is rapidly absorbed and excreted slowly 4. Special purpose sulfonamides: Sulfacetamide sod., Mafenide, Silver sulfadiazine, Sulfasalazine

7. Mechanism of action Sulfonamides are competitive inhibitors of PABA Note that sulfonamides can't affect human cells – WHY? Drugs not effective in case of an abscess due to increased concentration of PABA

8. Folic acid is used for the synthesis of purines and thymine Required for formation of DNA Therefore, folic acid is required for replication of cellular genes. Important function of folic acid is to promote growth so in its absence organism grows very little.

9. Mechanism of resistance produce increased amounts of PABA their folate synthase enzyme has low affinity for sulfonamides adopt an alternative pathway in folate metabolism. NOTE: resistance cuts across molecules

10. Absorption, Fate & Excretion Absorbed rapidly from GIT Small intestine(major site) & stomach PPB variable, Long acting drugs more protein bound…albumin, Distributed throughout the body Readily enter pleural, peritoneal, synovial, ocular fluids Conc. 50-80% that in blood Readily cross placenta and free drug forms may be seen in CSF (antibacterial + toxic effects) Metabolised in liver , Excreted in urine Small amounts in faeces , bile , milk and other secretions .

11. Individual sulfonamides Sulfamethoxazole Close to sulfisoxazole Half-life :8-12 Hrs Fixed dose combination with trimethoprim High fraction is acetylated, which is relatively insoluble crystalluria can occur. Precautions to avoid crystalluria

12. Poorly absorbed sulfonamides Sulfasalazine poorly absorbed from GIT Active in bowel lumen Ulcerative collitis , regional enteritis Intestinal bacteria - sulfapyridine (toxic) +5 aminosalicylate (effective agent in IBD)

13. Silver Sulfadiazine Inhibits growth of nearly all pathogenic bacteria & fungi Used topically to reduce incidence of infections of wounds from burns Slowly releases silver ions -antimicrobial action DOC for prevention of infection of burns.

14. LONG ACTING SULFONAMIDES Sulfadoxine Long acting Half-life :7-9 days Combination Sulfadoxine 500mg + Pyrimethamine 25 mg Prophylaxis & treatment of malaria caused by chloroquine resistant strains of plasmodium falciparum.

15. Falciparum Malaria Pyrimethamine Inhibits Plasmodial DHFRase Supraadditive synergistic combination with pyrimethamine due to sequential block Combination acts faster Development of resistance to pyrimethamine is retarded. 3 tablets are given as a single dose (good compliance). Currently used for prevention of malaria in pregnancy

16. Mechanism of Resistance to sulfonamides Produce increased amounts of PABA Their Folate synthetase enzyme has low affinity for sulfonamides Adopt alternate pathway of folate metabolism. ADRs of Sulfonamides Crystalluria Older, less soluble sulphonamides Insoluble in acidic urine Hypersensitivity reactions Acute hemolytic anemia in G-6PD deficient patient Agranulocytosis - sulfadiazine Aplastic anemia Anorexia, nausea, vomiting

17. Drug interactions and contraindications Potentiate the effect Oral anticoagulants Sulphonylurea hypoglycaemic agents Hydantoin anticonvulsants Inhibition of metabolism of these drugs + displacement from albumin. Dosage adjustment Cautious use in patients with impaired renal functions .

18. Quinolones and Fluoroquinolones Have Quinolone structure Nalidixic acid is first member Fluorination of Quinolones - Fluoroquinolones Gram negative mainly (Plus gram positive New FQs) N to P

19. MOA- (Queen stops gyrating dancers) In gram negative – Inhibition of DNA gyrase enzyme (Inhibit negative super coiling) In gram positive – Inhibition of Topoiosmerase IV – Inhibition of nicking and separation of daughter DNA strands after DNA replication (Inhibition of Decatenation) The malformed DNA is digested by Exonucleases Why not human cells affected ? Mammalian cells have Topoiosmerase II

20. Quinolones

21. Resistance- Due to mutation in chromosomes Altered DNA gyrase and Topoisomerase IV Reduced permeability for drug Increased efflux of drug

22. Members Quinolones Nalidixic acid Fluoroquinolones New Generations Lomefloxacin Levofloxacin Prulifoxacin Sparfloxacin Gatifloxacin Gemifloxacin Moxifloxacin Trovafloxacin Alatrofloxacin Finafloxacin Fluoroquinolones First Generation Ciprofloxacin Norfloxacin Pefloxacin Ofloxacin Second Third Fourth MAN C an SPOT G ood L ife

23. Nalidixic Acid- Gram negative, (Narrow spectrum) Bactericidal, Acts by DNA gyrase inhibition, Highly protein bound, High concentration is in Urine Neurological toxicity (vertigo, visual and seizures) Haemolysis in G-6PD deficiency Used as Urinary antiseptic, Bacterial Diarrhea. Don’t give with Nitrofurantoin (Antagonism)

24. First generation FQs Ciprofloxacin - Long Post Antibiotic Effect (PAE) Less active at acidic pH Interacts with food and calcium High tissue penetrability ( Except BBB) High conc. in urine and bile CNS side effects are common, Tendonitis and tendon rupture Drug Interaction- Inhibition of metabolism of other drug, Chelation QT interval prolongation

25. USES- (Extended spectrum) CNSI, MFI, OI, ENTI, RTI, GITI, UTI, PID, STDs, SBI Nosocomial Infections Septicaemia Tuberculosis - MDR TB and XDR TB Typhoid Treatment 2 weeks Prevention of carrier state 2 months Other drugs- Other FQs Cephalosporins , Ceftriaxone (Fastest) Chloramphenicol Cotrimoxazole Ampicillin

26. Norfloxacin – Less potent, Primarily used for UTI and GIT infections, Ofloxacin - Highly active against Mycobacterium leprae Pefloxacin – Methylated derivative of Norfloxacin, Oral bioavailability is 100%

27. Second Generation FQs Lomefloxacin – Once a day dose Levofloxacin – Levo-isomer of Ofloxacin, Oral absorption is 100% Single daily dose Minimal drug interactions

28. Gatifloxacin – Prolongs Q-T interval, Unexpected Hypo or Hyperglycemia in Diabetes mellitus patients. ( Withdrawn ) Moxifloxacin – Most potent FQ against M. tuberculosis. Can prolong Q-T interval, Phototoxic Trovafloxacin – Hepatotoxic (Reserved and maximum of 15 days Tt.) Alatrofloxacin - Prodrug of Trovafloxacin Finafloxacin, Prulifoxacin, Gemifloxacin

29. Elimination of Fluoroquinolones Renal Norfloxacin Ofloxacin Ciprofloxacin Lomefloxacin Levofloxacin Gatifloxacin Hepatic Pefloxacin Moxifloxacin Trovafloxacin Sparfloxacin Gemifloxacin Fluoroquinolones safe in renal failure P efloxacin M oxifloxacin T rovafloxacin

30. Summary Sulphonamides Act by inhibition of folic acid synthesis Combined with Trimethoprim Produce Stevens Johnson Syndrome Prolonged use may produce hypothyroidism, goitre, arthritis and drug fever Quinolones Act by inhibition of DNA gyrase or Topoiosmerase IV Have extended spectrum Have chelating and enzyme inhibition property Used for multiple infective diseases

31. Revision questions Discuss the therapeutic use of quinolones Discuss mechanism of action and resistance for Co-trimoxazole. Discuss adverse drug reactions of sulfonamides