DNA & RNA Biogenesis Inhibitors Flashcards
For which 2 reactions do folate derivatives serve as sources of carbon atoms
dUMP dTMP
Formation of purine aromatic ring
Sulfa inhibits which reaction
Dihydropteorate
Syntase (DHPS)
Sulfonamides (Anti-folates)
Mechanism
Mechanism
Analog of PABA - competitive inhibitor of dihydropteorate synthase
Trimethoprim (TMP)
mechamism
Competitive inhibitor of DHFR
TMP is 50,000 times more active against the bacterial DHFR vs mammalian DHFR
SMX/TMP
Spectrum
Clinical use
Kinetics (absorbtion & kinetics)
Pharmacodynamics and spectrum
- Bacteriostatic in general / can be cidal
- Some gram +ve cocci; S. pneumoniae;
- Gram -ve rods; H. Influenzae; E. Coli; Moxarella
- Pneumocystis carinii
Clinical use
- Respiratory tract infections
- Otitis
- Urinary tract infections
- Prostatitis
- MRSA skin and soft tissue
Kinetics
Well absorbed orally - impaired by food
TMP:Very high tissue & CSF concentrations (T:P 10:1)
Vd(TMP)~10Vd(SMX)
T1/2 10-12h
Hepatic metabolism and renal excretion
SE SMX/TMP
Allergy: Erythema multiforme & skin rashes
Bone marrow suppression - WBC & platelets
GI upsets N/V
Hepatitis
Hyperkalemia - high doses and in the elderly
Avoid in first trimester of pregnancy
Trimethoprim (TMP) bacterial resistance
(i) reduced DHFR binding affinity
(ii) overexpression of enzyme
(iii) reduced bacterial permeability to TMP
Ciprofloxacin
Class
Mechanism
Resistance
Class
fluoroquonolones
Mechanism
- Irreversibly bind to DNA/enzyme complexes, intercalating in DNA
- Replication cannot proceed through these complexes
Resistance
FLuoroquinolone resistance
Reduced DNA topoisomerase II and IV binding due to mutations
Impaired permeability and increased drug efflux
Protection of DNA gyrase by Qnr proteins (plasmid-mediated, new!)
Modification by AG-acetyl transferase (plasmid-mediated, new!)
Ciprofloxacin specrum
Bacteriocidal
Ciprofloxacin: Poor gram +ve (resistance rapidly acquired); good gram –ve (Pseudomonas, E.coli, etc.); Legionella (& Mycobacteria avium intracellulare)
Moxi- and levofloxacins: Wide spectrum; active vs gram +ve & gram –ve
+ Chlamydia
Fluoroquinolones kinetics
Good oral absorption
T1/2 = 3-5 h (ciprofloxacin); 24h (others)
CDK with prolonged PAE
Wide distribution, high conc. in tissue & CSF
Clearance (cipro): hepatic (45%) renal (55%)
Moxifloxacin and levofloxacin - low concentrations in urine
Clincal use cipro
UTI, STD
Clinical use moxiflacin & levofloxacin
pneumonia
Clincal use levofloxacin
pneumonia & UTI
Fluoroquinolones SE
Gastrointestinal upsets N/V/D
Allergy: rashes
CNS effects: seizures
Ciprofloxacin inhibits hepatic CYP450; levo- and mono- do not
Arthralgia and joint swelling in children
Rarely- bone marrow failure, hemolytic anemia, nephrotoxicity
Arthropathy in cystic fibrosis patients
Metronidazole
Mechanmism
Reduced by the bacterial (anaerobes) nitroreductase
Forms a reactive nitro - anion and radicals
In anaerobic environment -nitro-anion and radicals interacts with DNA to form single strand breaks mainly at (A-T) base pairs
Radicals may also damage proteins and lipids
Metronidazole spectrum
Bacteriocidal
Oral and bowel anaerobes (100% B. Fragilis)
Cl. Difficile
Protozoa (Giardia Lamblia, Entamoeba Histolytica)
Metronidazole kinetics
Well absorbed from GI tract; food delays absorption
Widely distributed, enters CSF well
T 1/2 - 8h
CDK with significant PAE
Hepatic metabolism
Inhibits CYP3A and aldehyde dehydrogenase
Metronidazole SE
GI upsets Metallic taste in mouth CNS effects- ataxia, vertigo Neutropenia Colors urine - dark Drug interactions; inhibits CYP3A
Teratogenic
Rifamycins (rifampin)
Mechanism
Cross resctivity with
Mechanism
- Binds to the beta subunit of DNA directed bacterial RNA polymerase
- Inhibits further nascent RNA production
React with
Inhibits mammalian mitochondrial RNA polymerase at much higher concentrations
Spectrum of rifampin
Broad spectrum: most GP and many GN Myco TB & other mycobacteria (static) Staph. Aureus (cidal) Legionella Neisseria meningitidis prophylaxis Active against intracellular organisms
Rifampin kinetics
Oral absorption: good, impaired by food
Large Vd, enters CSF well
T1/2 2-5h
Hepatic metabolism
Rifampin resistance
Mutations of beta subunit binding site of the RNA polymerase (rpoB gene product)
Increasing problem in Myco. TB therapy;never use alone
Rifampin SE
GI intolerance: N/V
Hepatitis & jaundice
Orange-pink discoloration of tears, urine
CNS effects-headaches, drowsiness
Thrombocytopenia
Drug fever -serum sickness/flu like syndrome
Induces hepatic CYP 450s- multiple drug interactions
Cases in PPT
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