DNA Synthesis Inhibitors

Question 1

Name the sulfonamides

Answer 1

Sulfisoxazole, sulfamethoxazole, cotrimazole, and dapsone

Question 2

Name the fluoroquinolones

Answer 2

Ciprofoxacin

Question 3

Name the urinary antiseptic agents

Answer 3

Nitrofurantoin, methenamine

Question 4

Describe the mechanism of action of sulfonamides

Answer 4

Bacteriostatic. Competitively inhibits dihydropteroate synthase by mimicking PABA (antimetabolite). This blocks folate biosynthesis, necessary for bacteria to make DNA (mammals use preformed folate from diet).

Question 5

ADME of sulfonamides

Answer 5

Taken orally, absorbed in stomach/small intestine. Widely distributed including CNS and CSF. Excreted via urine. Conjugated metabolites will precipitate in acidic urine so patient must be hydrated and alkalized (insoluble in water).

Question 6

Indications for sulfonamides

Answer 6

Sulfisoxazole and sulfamethoxazole are good for UTIs. Dapsone treats leprosy. Effective against Gram+/- bacteria in UTIs and respiratory infections.

Question 7

What’s the deal with trimethoprim and sulfonamides?

Answer 7

Trimethoprim selectively inhibits dihydrofolate reductase (DHFR) which is good for eukaryotes, bad for prokaryotes. When combined with a sulfonamide (i.e. sulfamethoxazole + trimethoprim = bactrim), the two independently bacteriostatic drugs become bactericidal together.

Question 8

Mechanism of resistance of sulfonamides

Answer 8

1. Mutation in dihydropteroate synthase
2. Impaired uptake, increased efflux
3. mutation leading to increased PABA synthesis (outcompetes sulfonamides).

Question 9

Adverse effects of sulfonamides

Answer 9

hypersensitivity (e.g. rashes, TEN, stevens-johnsons), hematopoietic toxicity (e.g. thrombocytopenia, hemolytic/aplastic anemia), crystallization in urine
*bind to albumin, displacing bilirubin which newborns can’t excrete yet so they develop kernicterus (generalized CNS syndrome)

Question 10

Contraindications of sulfonamides

Answer 10

newborns, pregnant/breastfeeding women!!

Question 11

Describe the mechanism of action of fluoroquinolones

Answer 11

Block bacterial DNA synthesis:
Inhibits DNA gyrase in Gram - (inhibits the relaxing of DNA supercoils)
Inhibits Topoisomerase IV in Gram + (prevents DNA separation for cell division)
*concentration-dependent killing

Question 12

Indications for fluoroquinolones

Answer 12

Primarily for complicated UTIs, but because of resistance not recommended as 1st for uncomplicated.

Question 13

ADME of fluoroquinolones

Answer 13

PO (Mg2+, Ca2+, Fe, and aluminum compounds impair absorption, e.g. antacids). Hepatic metabolism, urinary excretion.

Question 14

Mechanisms of resistance in fluoroquinolones

Answer 14

Mutation of DNA gyrase or topoisomerase, enhanced efflux/decreased influx

Question 15

Adverse effects of fluoroquinolones

Answer 15

typical (n/v/d, headache, dizziness), cartilage damage (e.g. tendonitis, joint swelling, etc), acute psychosis

Question 16

Contraindications for fluoroquinolones

Answer 16

People taking NSAIDs because of interactions with GABA-a receptor; inhibits the inhibitory effects of GABA leading to CNS effects

Question 17

Mechanism of action of nitrofurantoin

Answer 17

Bacteria reduce nitrofurantoin and it causes free radical damage to bacterial DNA

Question 18

Adverse effects of nitrofurantoin

Answer 18

Turns urine brown

Question 19

Indications for nitrofurantoin

Answer 19

Uncomplicated UTIs from Gram + and some Gram - bacteria

Question 20

Contraindications for nitrofurantoin

Answer 20

pregnancy, newborns, renal failure

Question 21

What drug classes are DNA synthesis inhibitors?

Answer 21

Sulfonamides, Fluoroquinolones, and urinary antiseptic agents