DNA Replication and Folic Acid Synthesis Inhibitors Flashcards
2nd gen fluoroquinolones
ciprofloxacin and ofloxacin
3rd gen fluoroquinolones
levofloxacin
4th gen fluoroquinolones
gemifloxacin and moxifloxacin
Antifolate drugs
sulfacetamide, sulfadiazine, sulfamethoxazole, trimethoprim, cotrimoxazole/bactrim= trimethoprim + sulfamethoxazole
What is bactrim?
old name cotrimoxazole, combination of trimethoprim and sulfamethoxazole
What drug class inhibits DNA synthesis via DNA gyrase and topoisomerase IV?
fluoroquinolones
What drug classes inhibit DNA synthesis via folic acid?
trimethoprim and sulfonamides
What is the predecessor to fluoroquinolones?
naladixic acid – fluoroquinolones discovered in the 1960s
What is the MOA of fluoroquinolones?
inhibit replication of DNA by interfering with DNA gyrase AND topoisomerase IV
How do fluoroquinolones enter bacteria?
passive diffusion
What do fluoroquinolones treat?
relative broad spectrum, gram - and + coverage with dual mechanism giving added protection against resistance
Are fluoroquinolones bacteriostatic or bactericidal?
bactericidal, more pronounced as concentration increases
What gram (-) organisms are treated by fluoroquinolones?
pseudomonas, H. influenzae, moraxella, chlamydia
T/F earlier generations of fluoroquinolones have increased gram (+) coverage?
false the later generations are more broad spectrum
Which fluoroquinolone is most effective against pseudomonas?
ciprofloxacin
Which fluoroquinolone is the drug of choice for anthrax?
ciprofloxacin
Which fluoroquinolone does not concentrate in urine and is therefore not indicated for UTIs?
moxifloxacin
Which two fluoroquinolones have the longest half-lives?
levofloxacin and moxifloxacin, allow for once a day dosing
What interferes with fluoroquinolone absorption?
antacids, iron, zinc, calcium
Which fluoroquinolone is excreted by the liver instead of the kidney?
moxifloxacin
What are the adverse reactions of fluoroquinolones?
GI, CNS toxicity, phototoxicity, connective tissue problems, new FDA warning for hypoglycemia
What are the contraindications for fluoroquinolones?
patients with arrhythmia, avoid in pregnancy, nursing mothers and children under 18
Why can’t pregnant women and young children be given fluoroquinolones systemically?
shown to cause cartilage erosion, topical drugs okay
What drug interactions do ciprofloxacin and ofloxacin have?
increase theophylline levels
What drug interactions do fluoroquinolones have?
increase levels of warfarin, caffeine and cyclosporine
What factors do DNA and RNA synthesis depend on?
folate derived cofactors
How do humans get folic acid?
diet
How do bacteria get folic acid?
make their own, many bacteria are impermeable to folic acid
T/F sulfa drugs are seldom given alone
true
What is the MOA of sulfa drugs?
sulfonamides are structural analogues of PABA and compete with dihydropteroate synthetase and inhibit folate production
What do sulfonamides treat?
wide antibacterial spectrum, not active against anaerobes, pseudomonas is resistant
How does sulfonamide resistance come about?
organisms that can obtain folic acid from the environment are not sensitive and there can be acquired resistance
How do sulfonamides acquire resistance?
altered enzyme, decreased cellular permeability, enhanced production of PABA
What is the absorption of sulfonamides?
most absorbed from the small intestine, not usually applied topically because of risk of sensitization
What is true of the distribution of sulfonamides?
bound to serum albumin, penetrate well into CSF, can pass placenta
Where are sulfonamides metabolized?
in the liver, metabolites can be toxic
How are sulfonamides excreted?
eliminated through glomerular filtration and breast milk
What are the adverse effects of sulfonamides?
crystalluria, hypersensitivity, hemopoietic disturbances, kernicterus, drug potentiation
What is crystalluria?
precipitate at neutral or acidic pH that can cause nephrotoxicity
What is the result of a hemopoietic disturbance?
anemia
What is kernicterus?
increased bilirubin in the CNS, occurs in newborns
What do sulfonamides do to warfarin?
increases circulating warfarin levels
What is the MOA of trimethoprim?
inhibits dihydrofolate reductase, preventing conversion of dihydrofolic acid to tetrahydrofolic acid
T/F the antibacterial spectrum of trimethoprim is similar to sulfonamides but much more potent
true
How does resistance to trimethoprim occur?
develops in gram (-) bacteria due to presence of altered enzyme
What are the pharmacokinetic properties of trimethoprim?
drug is a weak base (accumulates in more acidic environments), penetrates CSF, excreted via kidney
What is the adverse effect of trimethoprim?
folic acid deficiency, especially in pregnant patients or those with poor diets, can co-administer with folinic acid
What is cotrimoxazole/bactrim?
combination of trimethoprim and sulfamethoxazole, has greater activity and similar half life to each drug alone
T/F bactrim (trimethoprim and sulfamethoxazole) have a broader spectrum than sulfa drugs
true
What does bactrim (trimethoprim and sulfamethoxazole) treat?
UTIs, respiratory tract infections, pneumocystis jiroveci, MRSA (especially skin and soft tissue infections)
T/F resistance is a problem in trimethoprim + sulfamethoxazole
false, less frequent resistance
How is bactrim administered and excreted?
orally and via kidney
What are adverse effects of bactrim?
skin rash, nausea and vomiting, anemias or thrombocytopenia, adverse effect in immunocompromised patients
What drugs can bactrim react with?
warfarin, phenytoin, methotrexate
