Quinolones, Folic Acid Antagonists & Urinary Antiseptics

Question 1

What are the DNA synthesis inhibitors?

Answer 1

1. Fluoroquinolones
2. Folate Acid Antagonists
3. Urinary Antiseptics - Nitrofurantoin

Question 2

What are Fluroquinolones?

Answer 2

Broad spectrum ABs w lots of adverse effects
- mostly active against gram negs & enteric coliform

Question 3

Fluoroquinolones are derivatives of..

Answer 3

Nalidixic acid

Question 4

Fluoroquinolone AB targets..

Answer 4

Targets..
1. DNA gyrase, primarily in gram -ve bacteria
2. Topoisomerase IV in gram +ve bacteria

=> inhibit DNA replication, eventually killing bacteria

Question 5

Name the 3 Fluoroquinolones.

Answer 5

1. Ciprofloxacin (1st gen)

Respiratory quinolones:
2. Levofloxacin
3. Moxifloxacin

Question 6

Administration of Fluoroquinolones

Answer 6

• high oral bioavailability, thus, can be administered via
  1. Oral
  2. Intravenous
  3. Local e.g. ophthalmic

Question 7

Fluoroquinolones cannot be ingested with milk. Why?

Answer 7

• 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)

Question 8

How are Fluoroquinolones metabolised?

Answer 8

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

Question 9

Adverse effects of Fluoroquinolones

Answer 9

1. Increased risk of tendon rupture*
2. Arthropathy (joint problems) in infants & children (<18 yrs of age)
3. Peripheral Neuropathy (may persist even after drug is stopped)
4. Prolonged QT interval, shd not be used in pxs w arrhythmias
5. Phototoxicity
6. C.diff colitis
7. GI discomfort: nausea, vomiting, diarrhoeat (most common)

Question 10

Anti microbial spectrum and clinical indications of the fluoroquinolones (ciprofloxacins)

Answer 10

1. Most active against gram negs & enteric coliforms (including penicillin, cephalosporin & aminoglycoside-resistant strains)
2. High active against P. Aeruginosa (only oral agent avail)
3. Traveller’s diarrhoea caused by E. Coli /food poisoning by all enterobacteriaceae (E.coli, Salmonella, Shigella) & Campylobacter jejuni
4. Typhoid fever caused by Salmonella typhi
5. UTI (but not first line, only for resistant strains)
6. Against Anthrax caused by bacillus anthracis

Question 11

Name the 3 Anti-Folate drugs

Answer 11

1. Sulfonamides
2. Trimethoprim
3. Cotrimoxazole (combi of the above 2)

Question 12

What do Sulfonamides competitively inhibit?

Answer 12

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

Question 13

What does Trimethoprim inhibit?

Answer 13

Potent inhibitor of bacterial dihydrofolate reductase

• lower down the chain
• dihydrofolate reductase also needed in humans => can lead to adverse effects

Question 14

What is Cotrimoxazole?

Answer 14

Drug combination of Trimethoprim+Sulfamethoxazole (1:5 ratio)

=> synergistic antimicrobial activity due to inhibition of 2 sequential steps in synthesis of tetrahydrofolic acid

Question 15

Why should we advice pxs to take a full cup of water when taking Sulfonamides or Cotrimoxazole?

Answer 15

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

Question 16

What should be administered to reverse effects of folic acid deficiency due to Trimethoprim?

Answer 16

Folinic acid

• derivative that is readily intra-converted to tetradhydrofolic acid(what we need)
• not dihydrofolic acid (since dihydrofolate reductase alr deactivated)

Question 17

What is Nitrofurantoin used for?

Answer 17

• 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

Question 18

What is the most key Sulfonamide?

Answer 18

Sulfamethoxazole. Component in Cotrimoxazole.

Question 19

Briefly list the 4 adverse effects of Sulfonamides.

Answer 19

1. Crystalluria
2. Hypersensitivity
3. Hematopoietic disturbances
4. Kernicterus

Question 20

Why can Sulfonamides cause hypersensitivity & how can it present?

Answer 20

• sulfur allergies
• can cause rashes, andioedema(swelling of deep layers of skin) or Stevens-Johnson syndrome(painful rash that spreads n blisters, rare & serious).

Question 21

Why and how can Sulfonamides cause hematopoietic disturbance?

Answer 21

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

Question 22

What is Kernicterus?

Answer 22

• 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

Question 23

What is an adverse effect of Trimethoprim?

Answer 23

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)