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Sulfonamides, trimethoprim & quinolones

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Sulfonamides, trimethoprim & quinolones

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Sulfonamides, trimethoprim & quinolones

  1. 1. Sulfonamides, Trimethoprim and FluoroquinolonesFluoroquinolones Dr. Deepak Kumar Gupta
  2. 2. Introduction • 1st antimicrobial agent • Effective against pyogenic bacterial infections • Used extensively in past, but its avoide now due to increased side effect and resistantdue to increased side effect and resistant • Limited used, except in the combination of trimethoprim (cotrimoxazole) or pyrimethamine (malaria)
  3. 3. Chemistry • Derived from sulfanilamide – structural simialarity to - aminobenzoic acid (PABA) • produced by - attaching substituents to the amidosubstituents to the amido group (–SO2 –NH–R) or the amino group (–NH2 ) to the sulfanilamide nucleus • soluble at alkaline than at acid pH • sodium salts - intravenous administration
  4. 4. Classification • Short acting (4-8 hr) : Sulfadiazine • Intermediate acting ( 8-12 hrs) : Sulfamethoxazole • Long Acting ( 7 day) : Sulfadoxine,• Long Acting ( 7 day) : Sulfadoxine, sulfamethopyrazine • Special Purpose Sulfonamindes : Mafenide, Silver sulfadiazine, sulfasalazine
  5. 5. Mechanism of Action • MCO susceptible to supfonamide – cannot use exogenous folate. • So it utilizes PABA to form folate and subsequently purinespurines • structural analogs of PABA – inhibit folate synthesis. • Combination with an inhibitor of dihydrofolate reductase - trimethoprim or pyrimethamine - synergistic activity
  6. 6. Antibacterial Spectrum • Both gram-positive and gram-negative bacteria • Nocardia sp, Chlamydia trachomatis, Escherichia coli, Klebsiella pneumoniae, Salmonella , Shigella , and Enterobacter sp. and some protozoa. • Activity is poor against anaerobes. • Rickettsiae – not inhibited instead stimulated in their growth • Pseudomonas aeruginosa is intrinsically resistant
  7. 7. Resistance • Sulfonamide resistance may occur as a result of mutations that – cause overproduction of PABA, – cause production of a folic acid-synthesizing– cause production of a folic acid-synthesizing enzyme that has low affinity for sulfonamides, or – impair permeability to the sulfonamide
  8. 8. Pharmacokinetics • Sulfonamides can be divided into three major groups – Oral absorbable; – Oral nonabsorbable; – topical. • absorbed from the stomach and small intestine and distributed widely to tissues and body fluids, placenta,distributed widely to tissues and body fluids, placenta, and fetus • Protein binding varies from 20% to over 90% • A portion of absorbed drug is acetylated or glucuronidated in the liver. • Excreted into the urine, mainly by glomerular filtration. • In significant renal failure, the dosage of sulfonamide must be reduced.
  9. 9. Clinical Use • Sulfonamides are infrequently used as single agents. • The fixed-drug combination of trimethoprim- sulfamethoxazole - drug of choice forsulfamethoxazole - drug of choice for infections such as pneumonia, toxoplasmosis, nocardiosis, and occasionally other bacterial infections.
  10. 10. Clinical Use : Oral Absorbable Agents • Sulfisoxazole and sulfamethoxazole – urinary tract infections : adult dosage is 1 g of sulfisoxazole four times daily or 1 g of sulfamethoxazole two or three times daily • Sulfadiazine in combination with pyrimethamine is first-line therapy for treatment of acute • Sulfadiazine in combination with pyrimethamine is first-line therapy for treatment of acute toxoplasmosis. – 1 g four times daily, with pyrimethamine given as a 75-mg loading dose followed by a 25-mg once-daily dose. – Folinic acid, 10 mg orally each day, should also be administered to minimize bone marrow suppression
  11. 11. Clinical Use : Oral Absorbable Agents • Sulfadoxine – long-acting sulfonamide – combination formulation with pyrimethamine – a second-line agent in the treatment of malaria– a second-line agent in the treatment of malaria
  12. 12. Clinical Use : Oral Nonabsorbable Agents • Sulfasalazine (salicylazosulfapyridine) – Ulcerative colitis, – enteritis, – other inflammatory bowel disease– other inflammatory bowel disease
  13. 13. Clinical Use : Topical Agents • Sodium sulfacetamide ophthalmic solution or ointment – effective in the treatment of bacterial conjunctivitis and as adjunctive therapy forconjunctivitis and as adjunctive therapy for trachoma. • Silver sulfadiazine • infection of burn wounds
  14. 14. Adverse Reactions • Allergenic – Fever – Skin rashes, – exfoliative dermatitis, – photosensitivity, – urticaria,– urticaria, – Nausea & vomiting, – diarrhea, – difficulties referable to the urinary tract – In extreme case it may cause - Stevens-Johnson syndrome • It may also cause • stomatitis, conjunctivitis, arthritis, hematopoietic disturbances, hepatitis, rarely polyarteritis nodosa and psychosis
  15. 15. Adverse Reactions • Urinary Tract Disturbances – Crystalluria (large doses), hematuria, or even obstruction. – nephrosis and in allergic nephritis • Hematopoietic Disturbances – hemolytic or aplastic anemia, granulocytopenia,– hemolytic or aplastic anemia, granulocytopenia, thrombocytopenia, or leukemoid reactions – provoke hemolytic reactions in patients with glucose- 6- phosphate dehydrogenase deficiency – End of pregnancy increase the risk of kernicterus in newborns
  16. 16. Trimethoprim, Pyrimethamine • Selectively inhibits bacterial dihydrofolic acid reductase - converts dihydrofolic acid to tetrahydrofolic acid. • 50,000 times less efficient• 50,000 times less efficient - inhibition of mammalian dihydrofolic acid reductase. • Pyrimethamine - selectively inhibits dihydrofolic acid reductase of protozoa.
  17. 17. Resistance • reduced cell permeability • overproduction of dihydrofolatedihydrofolate reductase • production of an altered reductase with reduced drug binding • mutation
  18. 18. Pharmacokinetics • Usually given orally alone or in combination with sulfamethoxazole • Can also be given intravenously • Well absorbed from the gut - distributed widely in body fluids and tissues, including cerebrospinal fluidbody fluids and tissues, including cerebrospinal fluid • Trimethoprim is more lipid-soluble than sulfamethoxazole – 1 part of trimethoprim is given with 5 parts of sulfamethoxazole • Concentrates in prostatic fluid and in vaginal fluid - more antibacterial activity in prostatic and vaginal fluids
  19. 19. Clinical Uses • Oral Trimethoprim – Given alone (100 mg twice daily – Acute urinary tract infections • Oral Trimethoprim-Sulfamethoxazole – Wide variety of infectionsWide variety of infections – Empiric therapy of upper urinary tract infections or pneumonia. – One double-strength tablet : trimethoprim 160 mg plus sulfamethoxazole 800 mg - every 12 hours • effective treatment for urinary tract infections and prostatitis – One single-strength tablet : ½ of former dose • prophylaxis in recurrent urinary tract infections - women
  20. 20. Clinical Uses • Intravenous Trimethoprim-Sulfamethoxazole – Solution - 80 mg trimethoprim plus 400 mg sulfamethoxazole per 5 mL – intravenous infusion over 60–90 minutes – moderately severe to severe pneumocystis pneumonia – gramnegative bacterial sepsis– gramnegative bacterial sepsis – multidrugresistant species - shigellosis; typhoid fever; or urinary tract infection – leishmaniasis and toxoplasmosis • Oral Pyrimethamine with Sulfonamide – leishmaniasis and toxoplasmosis – falciparum malaria
  21. 21. Adverse Effects • Untoward reactions associated with sulfonamides • Nausea and vomiting, • Drug fever• Drug fever • Vasculitis, • Renal damage, and central nervous system
  22. 22. FLUOROQUINOLONES
  23. 23. Introduction • Quinolone structure • Active primarily against gram- negative bacteria - excellent for lower UTI only • Addition of Fluorine - Fluoroquinolones – active against gram positive bacteria active against gram positive bacteria – High potency – Expanded spectrum. – Better tissue penetration – Good tolerability • Ex: Nalidixic acid, • 1st gen: Norfloxacin, Ciprofloxacin, Ofloxacin • 2nd gen: Lomefloxacinm, Gatifloxacin, Moxifloxacin
  24. 24. Mechanism of Action • block bacterial DNA synthesis by inhibiting – Bacterial topoisomerase II (DNA gyrase) – Topoisomerase IV – prevents the relaxation of positively supercoiled DNA – required for normal transcription and replication
  25. 25. Antibacterial Activity • Since quinolones were 1 of the best drug for gram(-) bacteria – there was a need to increase its spectrum – FLUOROQUINOLONES • Norfloxacin – least effective fluoroquinolones • Ciprofloxacin, enoxacin, lomefloxacin, levofloxacin, ofloxacin, and pefloxacin – Methicillin-susceptible strains of S aureu - susceptible– Methicillin-susceptible strains of S aureu - susceptible – methicillin-resistant strains of staphylococci - resistant – most active agent of this group against gram-negative organisms, P aeruginosa in particular – Atypical pneumonia (eg, mycoplasmas and chlamydiae) – Legionellapneumophila – mycobacteria, (Mycobacterium tuberculosis and Mycobacterium avium complex)
  26. 26. Resistance • one of every 107 –109 organisms. • staphylococci, P aeruginosa , and Serratia marcescens • Point mutations in the quinolone binding• Point mutations in the quinolone binding region of the target enzyme • permeability of the organism. • Resistance to one fluoroquinolone - cross- resistance to all other members of this class
  27. 27. Pharmacokinetics • oral administration – well absorbed : bioavailability of 80–95% – distributed widely in body fluids – Serum half-lives : 3 to 10 hour – long half-lives of levofloxacin, gemifloxacin,– long half-lives of levofloxacin, gemifloxacin, gatifloxacin, and moxifloxacin - once-daily dosing – impaired by divalent and trivalent cations, including those in antacids – 2 hours before or 4 hours – eliminated by renal mechanisms - either tubular secretion or glomerular filtration
  28. 28. Clinical Use • Fluoroquinolones (other than moxifloxacin): urinary tract infections including P. aeruginosa • bacterial diarrhea caused by Shigella, Salmonella, toxigenic E coli and Campylobacter.toxigenic E coli and Campylobacter. • Fluoroquinolones (except norfloxacin) – Infections of soft tissues, bones, and joints – Intra-abdominal infection – Respiratory tract infections,
  29. 29. Clinical Use • Effective against multidrug-resistant (MDR) organisms such as Pseudomonas and Enterobacter. • Ciprofloxacin - drug of choice for prophylaxis• Ciprofloxacin - drug of choice for prophylaxis and treatment of anthrax • Gonococcal infection • Chlamydial urethritis or cervicitis • Ciprofloxacin, levofloxacin or moxifloxacin : treatment of tuberculosis.
  30. 30. Clinical Use • Eradication of meningococci • Prophylaxis of infection in neutropenic cancer patients • Respiratory fluoroquinolones : levofloxacin,• Respiratory fluoroquinolones : levofloxacin, gatifloxacin, gemifloxacin, and moxifloxacin – upper and lower respiratory tract infections – enhanced gram-positive activity and activity against atypical pneumonia agents (chlamydiae, Mycoplasma and Legionella )
  31. 31. Adverse Effects • generally well tolerated • most common effects are nausea, vomiting, and diarrhea. • Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests. • Occasionally, headache, dizziness, insomnia, skin rash, or abnormal liver function tests. • May damage growing cartilage and cause an arthropathy - not routinely recommended for patients under 18 years of age. • Tendonitis - a rare but serious complication
  32. 32. Summary
  33. 33. Summary
  34. 34. References • Basic & Clinical Pharmacology Bertram G. Katzung, Twelfth Edition • Essential of Medical Pharmacology, K.D. Tripathi, 6th edition • Basic Principles of Pharmacology with Dental• Basic Principles of Pharmacology with Dental Hygiene Applications • Rang and Dales Pharmacology 6th Ed 2007 • Color Atlas Of Pharmacology, 2Nd Ed (Lüllmann, Thieme 2000)

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