Quinolones, Folic Acid Antagonists & Urinary Antiseptics Flashcards
What are the DNA synthesis inhibitors?
- Fluoroquinolones
- Folate Acid Antagonists
- Urinary Antiseptics - Nitrofurantoin
What are Fluroquinolones?
Broad spectrum ABs w lots of adverse effects
- mostly active against gram negs & enteric coliform
Fluoroquinolones are derivatives of..
Nalidixic acid
Fluoroquinolone AB targets..
Targets..
1. DNA gyrase, primarily in gram -ve bacteria
2. Topoisomerase IV in gram +ve bacteria
=> inhibit DNA replication, eventually killing bacteria
Name the 3 Fluoroquinolones.
- Ciprofloxacin (1st gen)
Respiratory quinolones:
2. Levofloxacin
3. Moxifloxacin
Administration of Fluoroquinolones
- high oral bioavailability, thus, can be administered via
1. Oral
2. Intravenous
3. Local e.g. ophthalmic
Fluoroquinolones cannot be ingested with milk. Why?
- fluoroquinolones chelate w Ca2+, or other divalent cations such as Al or Mg containing antacids or dietary supplements
=> reduce absorption
Best taken on empty stomach as it can interact w food. (2hrs b4 or 6hrs aft food)
How are Fluoroquinolones metabolised?
Generally metabolised by kidney (cipro & levo)
-> dose adjustment in px w renal failure
Moxifloxacilin is metabolised by liver
-> dose adjustment necessary in px w hepatic failure
Adverse effects of Fluoroquinolones
- Increased risk of tendon rupture*
- Arthropathy (joint problems) in infants & children (<18 yrs of age)
- Peripheral Neuropathy (may persist even after drug is stopped)
- Prolonged QT interval, shd not be used in pxs w arrhythmias
- Phototoxicity
- C.diff colitis
- GI discomfort: nausea, vomiting, diarrhoeat (most common)
Anti microbial spectrum and clinical indications of the fluoroquinolones (ciprofloxacins)
- Most active against gram negs & enteric coliforms (including penicillin, cephalosporin & aminoglycoside-resistant strains)
- High active against P. Aeruginosa (only oral agent avail)
- Traveller’s diarrhoea caused by E. Coli /food poisoning by all enterobacteriaceae (E.coli, Salmonella, Shigella) & Campylobacter jejuni
- Typhoid fever caused by Salmonella typhi
- UTI (but not first line, only for resistant strains)
- Against Anthrax caused by bacillus anthracis
Name the 3 Anti-Folate drugs
- Sulfonamides
- Trimethoprim
- Cotrimoxazole (combi of the above 2)
What do Sulfonamides competitively inhibit?
Inhibits dihydropteroate synthase
- bacterial enzyme responsible for incorporation of paraaminobenzoic acid into dihydropteroic acid(immediate precursor of folic acid)
- higher up the chain
- mammalian cells not sensitive to this drug cuz it doesnt have this enzyme
What does Trimethoprim inhibit?
Potent inhibitor of bacterial dihydrofolate reductase
- lower down the chain
- dihydrofolate reductase also needed in humans => can lead to adverse effects
What is Cotrimoxazole?
Drug combination of Trimethoprim+Sulfamethoxazole (1:5 ratio)
=> synergistic antimicrobial activity due to inhibition of 2 sequential steps in synthesis of tetrahydrofolic acid
Why should we advice pxs to take a full cup of water when taking Sulfonamides or Cotrimoxazole?
Avoid Crystalluria
- sulfa drugs acetylated and conjugated primarily in the liver
- metabolic products has toxic potential to precipitate out & form crystals at neutral or acidic pH
- hydration & alkalinisation can prevent problem by reducing conc of drug & promoting its ionization
What should be administered to reverse effects of folic acid deficiency due to Trimethoprim?
Folinic acid
- derivative that is readily intra-converted to tetradhydrofolic acid(what we need)
- not dihydrofolic acid (since dihydrofolate reductase alr deactivated)
What is Nitrofurantoin used for?
- for prevention & treatment of simple lower UTIs
- esp cuz it gets cleared to bladder rly quickly, achieves very high urinary conc. while limiting systemic exposure (due to rapid clearance) => thus, target tx for UTIs
What is the most key Sulfonamide?
Sulfamethoxazole. Component in Cotrimoxazole.
Briefly list the 4 adverse effects of Sulfonamides.
- Crystalluria
- Hypersensitivity
- Hematopoietic disturbances
- Kernicterus
Why can Sulfonamides cause hypersensitivity & how can it present?
- sulfur allergies
- can cause rashes, andioedema(swelling of deep layers of skin) or Stevens-Johnson syndrome(painful rash that spreads n blisters, rare & serious).
Why and how can Sulfonamides cause hematopoietic disturbance?
Hemolytic anemia in pxs w G6PD deficiency. (Low RBC count due to RBC lysis)
- could cause thrombocytopenia too
How:
- sulfonamides cause lots of free radicals/rxtive oxygen species
- G6PD enzyme is the main antioxidant defense system in RBCs
- G6PD enzyme responsible for maintaining high levels of GSH & NADPH to protect cell from oxidative damage
What is Kernicterus?
- occurs in newborns when mums in late pregnancy take Sulfonamides.
- sulfa drugs displace bilirubin from binding sites on serum albumin
- bilirubin free to pass into CNS => neurotoxic, passes thru baby’s BBB
Thus, avoid Sulfonamides in 3rd trimester & newborns of less than 2 mths
What is an adverse effect of Trimethoprim?
effects of Folic acid deficiency which include 1. Megaloblastic anemia 2. Leukopenia & 3. Granulocytopenia, esp in pregnant pxs & those w very poor diets
- cuz trimethoprim inhibits dihydrofolate reductase, which humans need to make tetrahydrofolic acid
- tetrahydrofolic acid is then used in the synthesis of amino acids, purine & thymidine (precursors for DNA, RNA & protein synthesis)
