Drugs that affect Nucleic acid synthesis

Question 1

Drugs that affect Nucleic acid synthesis

Answer 1

“Find Three Sulfur Nukes”
Fluoroquinolones
Sulfonamides
Trimethoprim

Question 2

Fluoroquinolones (generations)

Answer 2

1st Generation:
Nalidixic acid (quinolone)
2nd Gen:
Ciprofloxacin (synergistic with B lactams)
3rd Generation:
Levofoxacin (excellent activity against S. pneumoniae)
4th Generation:
Gemifloxacin, Moxifloxacin 

lower gens excellent with gram -ve
higher gens better with gram +ve

Question 3

Fluoroquinolones MOA

Answer 3

• Broad spectrum, bactericidal drugs
• Enter bacterium via porins
• Inhibit bacterial DNA replication via interference w/ topoisomerase II (DNA gyrase) and IV*

Question 4

In which gen. did resistance emerge quickest

and in which bugs?

Answer 4

Gen 2.- c.jejuni, gonococci, Gram positive cocci, P. aeruginosa and serratia

• due to chromosomal mutation that:
  i. encode subunits of DNA gyrase (eg. gonococci resistance) and topo IV
  ii. regulate expression of efflux pumps (eg, S. aureus, S. pneumonia, M. tuberculosis)

Cross-resistance between drug occurs

Question 5

Fluoroquinolones Clinical applications:

1st Generation:

Answer 5

1st Generation:
Nalidixic acid (quinolone): Uncomplicated UTI's (E.coli)

4th Generation:
Gemifloxacin, Moxifloxacin:
Community acquired pneumonia

Question 6

Fluoroquinolones Clinical applications:

2nd Gen:

Answer 6

2nd Gen:
Ciprofloxacin (synergistic with B lactams):
- Travelers diarrhea (E.coli)
- Pseudomonas aeruginosa (CF patients)
- Prophylaxis against meningitis
(alternative to ceftiaxone and rifampin)

Question 7

Fluoroquinolones Clinical applications:

3rd Gen:

Answer 7

3rd Generation:
Levofoxacin (excellent activity against S. pneumoniae):
- Prostatitis (E.coli)
- STD’s (not syphilis)
- Skin infections
- Acute sinusitis, bronchitis, TB
- Community acquired pneumonia*( in patient treatment)

Question 8

Fluoroquinolones Clinical applications:

4th Gen:

Answer 8

4th Generation:
Gemifloxacin, Moxifloxacin:
Community acquired pneumonia*
- in patient treatment

Question 9

Fluoroquinolones AE

Answer 9

• Connective tissue problems (tendon rapture ) - avoid in pregnancy, nursing mother, under 18)- BLACK BOX WARNING!!
• QT prolongation (moxifloxacin, gemifloxacin, levofloxacin)- torsades
• High risk of causing superinfections ( C. difficile, C. albicans, streptococci).
• GI distress
• CNS, rash, photosensitivity.

Question 10

What enhances toxicity of fluoroquinolones?

Which generations raise conc. of WARFARIN, CAFFEINE AND CYCLOSPORINE?

Answer 10

Theophylline, NSAIDs and corticosteroids

3rd and 4th gen.

Question 11

Sulfonamides

MOA?

Answer 11

Sulfamethoxazole, Sulfadiazine, Sulfasalazine
- Structural analogs of p-aminobenzoic acid (PABA)
- Bacteriostatic against Gram-positive and Gram -ve
MOA:
- inhibit bacterial folic acid synthesis (Dihydropteroate synthase)

Question 12

Sulfonamides resistance

Answer 12

Plasmid transfers random mutations:

• altered dihydropteroate synthase
• decreased cellular permeability
• Enhanced PABA production
• Decreased intracellular drug accumulation

Question 13

Sulfonamides clinical applications

PK?

Answer 13

Infrequently use as single agents (resistance)

• topical agents (ocular, burn infections)
• Oral agents (simple UTI’s)
• Sulfasalazin (oral) = ulcerative colitis, enteritis, IBD

PK:
Oral or topical
can accumulate in renal failure
acetylated in live. Can precipitate at neutral or acidic pH
--> kidney damage.

Question 14

Sulfonamides AE?

Answer 14

Crystalluria (neophrotoxicity)
Hypersensitivity reactions
Hematopoietic disturbances (esp. patients w/ G6PD def.)
Kernicterus (in newborns and infants

Question 15

Sulfonamides drug Interactions

What accumulates and why?

Answer 15

CYP 450 inhibitor
Accumulation of: 
Warfarin 
phenytoin
methotrexate

Question 16

What structure is trimethoprim similar to?

Whats its effect on bacteria when used alone compared to when used with sulfonamide?

Answer 16

similar to Folic acid

• Bacteriostatic against Gram +ve and -ve bacteria when used alone
• bactericidal w/ sulfonamide against the same

Question 17

Trimethoprim MOA

Answer 17

Potent inhibitor of dihidrofolate reductase

- inhibits purine, pyrimidine and amino acid synthesis

Question 18

Trimethoprim clinical applications?
PK- is it changed when excreted and how is it removed?
AE?

Answer 18

UTI’s
Bacterial prostatitis
Bacterial Vaginitis

PK: Excreted unchanged through Kidney
- reaches high concentrations in prostatic and vaginal fluids (good for tx.)

AE: Antifolate effects (CI in pregnancy)
- Skin rash, pruritis

Question 19

Bactericidal drug that is a combination of both trimethoprim and sulfamethoxazole?
MOA?
PK?

Answer 19

Cotrimoxazole
BACTERICIDAL

MOA:
- synergistic: inhibition of sequential steps in tetrhydrofolic acid synthesis

PK?

• Oral admin. Can be given IV
• well distributed (including CSF)

Question 20

Cotrimoxazole Clinical applications

DOCs ?

Answer 20

Uncomplicated UTI (DOC)
PCP (DOC)
Nocardiosis (DOC)
Toxoplasmosis (alternative drug)
Respiratory, ear, sinus infections (H. Influenzae, M. Catarrhalis)

Question 21

Cotrimoxazole AE?

Answer 21

Dermatologic (common)
GI
Hematologic (hemolytic anemia)
AIDs patients = higher incidence
Contraindicated in pregnancy (esp. 1st trimester)