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Universiti Technologi Mara Faculty of Medicine Module: Urinary System Pharmacology Lecturer 1

Lecture objectives. Quinolones and Fluoroquinolones. Classification, mechanism of action, antimicrobial spectrum of activity, pharmacokinetics, therapeutic uses, adverse effects, drug interactions. Urinary antiseptics (nitrofurantoin, fosfomycin). Mechanisms of action, antimicrobial spectrum, pharm

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Universiti Technologi Mara Faculty of Medicine Module: Urinary System Pharmacology Lecturer 1

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    1. Universiti Technologi Mara Faculty of Medicine Module: Urinary System Pharmacology Lecturer 1 Fluoroquinolones and Urinary antiseptics Dr. Anna V. Krasilnikova

    2. Lecture objectives Quinolones and Fluoroquinolones. Classification, mechanism of action, antimicrobial spectrum of activity, pharmacokinetics, therapeutic uses, adverse effects, drug interactions. Urinary antiseptics (nitrofurantoin, fosfomycin). Mechanisms of action, antimicrobial spectrum, pharmacokinetics, therapeutic uses, adverse effects, drug interactions. Lower and upper urinary tract infections. Risk factors and most important etiology factors of UITs. Management of lower and upper tract urinary infections.

    3. Quinolones And Fluoroquinolones The quinolones (Qs) and fluoroquinolones (FQs) are a family of broad-spectrum synthetic antimicrobial agents. The parent of the group is nalidixic acid, what was introduced in 1962. The fluoroquinolones have a fluoro group attached the central ring system.

    4. Quinolones And Fluoroquinolones Classification

    5. Quinolones And Fluoroquinolones Qs and FQs are bactericidal drugs. FQs enter into the host cells and therefore are active against intracellular pathogens such as Legionella spp., Mycoplasma spp. and Chlamydia spp.

    6. Quinolones And Fluoroquinolones Mechanism of action DNA gyrase (topoisomerase II) nikes double-stranded DNA, relaxes supercoils. Topoisomerase IV nikes and unlinks DNA for the following DNA replication. Qs and FQs inhibit both enzymes so they inhibit DNA replication.

    7. Quinolones And Fluoroquinolones Mechanism of action Gram-negative bacteria primary target is DNA gyrase. Gram-positive bacteria primary target is topoisomerase IV.

    9. Nalidixic Acid Well absorbed from GIT. Partly metabolized in liver. Poor tissue penetration and low plasma levels. Cannot be used for the treatment of systemic infections. Excreted in urine. High urine concentration.

    10. Nalidixic Acid. Clinical Use Non-complicated lower UTIs. Bacterial gastrointeritis caused by E. coli, Proteus spp, Klebsiella spp, Shigells spp.

    11. Ciprofloxacin The most potent of the fluoroquinolones for P. aeruginosa. Long post-antibiotic effect. Well absorbed from GIT. Administration: orally, iv. Excreted in urine. Potent CYP450 inhibitor

    12. Ciprofloxacine. Clinical Use UTIs Intra-abdominal infections (peritonitis) Bacterial gastrointeritis Sepsis Skin/soft tissue infections Typhoid (ciprofloxacine is the first choice in typhoid fever) Tuberculosis Gonorrhea Conjunctivitis

    13. Levofloxacin Very well absorbed from GIT. Administration: orally, iv. Excreted unchanged Long post-antibiotic effect. Long-acting (single daily dose) Mostly used for the treatment respiratory tract infections (pneumonia, COPD exacerbation).

    14. Moxifloxacin Long-acting (single daily dose). Long post-antibiotic effect. Mostly used for the treatment respiratory tract infections (pneumonia, COPD exacerbation). Used for the treatment severe bacterial infections including sepsis, peritonitis. The most potent fluoroquinolone against M. tuberculosis.

    15. Quinolones And Fluoroquinolones Adverse Effects Abnormalities of bone and cartilage formation. (Cause cartilage damage in weight bearing joints in animal studies)

    16. Quinolones And Fluoroquinolones Adverse Effects Photosensitivity (photodermatitis) Avoid sun and U.V. radiation exposure during therapy!!!

    17. Quinolones And Fluoroquinolones Adverse Effects Tendonitis/tendon rupture. A few cases of ruptures of the shoulder, hand and Achilles tendon have been reported. CNS: confusion, insomnia, fatigue, depression, somnolence, seizures. CVS: QT-prolongation.

    18. Drug Interactions Ciprofloxacin is a potent CYP450 inhibitor. Increases plasma levels and toxic effects of anticoagulants, digoxin, theophylline. FQs in combination with with class IA and class III antiarrhythmics prolong QT and may cause arrhythmias. Qs and FQs have no sinergistic effects with other antibiotic classes.

    20. Urinary antiseptics Urinary antiseptics (uroseptics) are agents that exert antibacterial activity in the urine but have little or no systemic antibacterial effect Nitrofurantoin Fosfomycin Nitroxoline They use only in the treatment of lower urinary tract infections.

    21. Nitrofurantoin Bacteriostatic or bacteriocidal?

    22. Nitrofurantoin Pharmacokinetics Nitrofurantoin is weak acid. Well absorbed from GIT. Extremely poor tissue penetration and low blood levels. Excreted unchanged in urine. Activity enhances in low urine pH. Probenicid inhibits its tubular secretion and reduces its urine concentration.

    23. Nitrofurantoin Antibacterial Spectrum High antibacterial activity E.coli Staphylococcus saprophyticus Low antibacterial activity Staphylococcus aureus Streptococcus spp. Klebsiella spp.

    24. Nitrofurantoin Clinical Use Prophylaxis and treatment of low urinary tract infections (simple cistitis) Why it is not useful for treating kidney and systemic infections?

    25. Nitrofurantoin Adverse Reactions Alergical reactions: rash, urticaria. Pulmonitis and pulmonary fibrosis (when given for long periods of time). Haemolysis and haemolytic anaemia in patients with G-6-PD deficiency. Colours urine a dark orange-brown. Antagonism with quinolones.

    26. Fosphomycin Fosphomycin is an antibiotic produced by certain Streptomyces species. It is bacteriostatic agent. Used for the treatment of uncomplicated lower urinary tract infections. Administration: orally.

    27. Fosphomycin Mechanism of action Fosphomycin inhibits the first step of the bacterial wall synthesis. The first stage takes place in the cytoplasm, where the low-molecular-weight precursor of murein is synthesized. Fosfomycin is an antimetabolite of phosphoenolpyruvate in the enzymatic synthesis of N-Acetylmuramic acid.

    29. Fosphomycin Antibacterial Spectrum Gram-negative bacteria: E.coli Salmonella Shigella Proteus spp. Most of gram-positive (Staphylococci, Streptococci), gram-negative (P.aeruginosa, Klebsiela) and anaerobic bacteria are resistant

    30. Fosphomycine Adverse Reactions CNS: headache, dizziness. Alergic reactions GIT.

    31. Urinary tract infections Urinary tract infections (UTIs) include the acute and chronic infections of kidneys, bladder, ureters and urethra. Urinary tract infections represent one of the most common bacterial infections accounting for 1- 3% of all GP visits.

    32. UTIs Classification Lower tract infections bladder (cystitis) urethra (urethritis)) Upper tract infections ureters and kidneys (pyelonephritis)

    33. UTIs Classification Acute infections are sudden inflammations. Recurent infections are persistent inflammatory process.

    34. UTIs Classification Complicated UTI with factors that predispose to ascending bacterial infection. Predisposing factors: urinary instrumentation (catheterization) anatomic abnormalities obstruction of urine flow (urinary tract stones) poor bladder emptying (prostate adenoma) Uncomplicated UTI without abnormality or impairment of urine flow.

    35. UITs Etiology

    36. Antibiotic Management Of UTIs First-line therapy Sulphametoxasol/Trimetoprim Fluoroquinolones (II generation) Urinary antiseptics Second-line therapy Penicillins Cephalosporins Fluoroquinolones (III generation)

    37. Antibiotic Management Of UTIs Penicillins Cephalosporins Carbapenems Fluoroquinolones (II-IV generations) Aminoglycosides

    38. Thank You!

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