DNA & RNA Biogenesis Inhibitors

Question 1

For which 2 reactions do folate derivatives serve as sources of carbon atoms

Answer 1

dUMP  dTMP

Formation of purine aromatic ring

Question 2

Sulfa inhibits which reaction

Answer 2

Dihydropteorate

Syntase (DHPS)

Question 3

Sulfonamides (Anti-folates)

Mechanism

Answer 3

Mechanism

Analog of PABA - competitive inhibitor of dihydropteorate synthase

Question 4

Trimethoprim (TMP)

mechamism

Answer 4

Competitive inhibitor of DHFR
TMP is 50,000 times more active against the bacterial DHFR vs mammalian DHFR

Question 5

SMX/TMP

Spectrum
Clinical use
Kinetics (absorbtion & kinetics)

Answer 5

Pharmacodynamics and spectrum

• Bacteriostatic in general / can be cidal
• Some gram +ve cocci; S. pneumoniae;
• Gram -ve rods; H. Influenzae; E. Coli; Moxarella
• Pneumocystis carinii

Clinical use

• Respiratory tract infections
• Otitis
• Urinary tract infections
• Prostatitis
• MRSA skin and soft tissue

Kinetics
Well absorbed orally - impaired by food
TMP:Very high tissue & CSF concentrations (T:P 10:1)
Vd(TMP)~10Vd(SMX)
T1/2 10-12h
Hepatic metabolism and renal excretion

Question 6

SE SMX/TMP

Answer 6

Allergy: Erythema multiforme & skin rashes
Bone marrow suppression - WBC & platelets
GI upsets N/V
Hepatitis
Hyperkalemia - high doses and in the elderly
Avoid in first trimester of pregnancy

Question 7

Trimethoprim (TMP) bacterial resistance

Answer 7

(i) reduced DHFR binding affinity
(ii) overexpression of enzyme
(iii) reduced bacterial permeability to TMP

Question 8

Ciprofloxacin

Class
Mechanism
Resistance

Answer 8

Class
fluoroquonolones

Mechanism

• Irreversibly bind to DNA/enzyme complexes, intercalating in DNA
• Replication cannot proceed through these complexes

Resistance

Question 9

FLuoroquinolone resistance

Answer 9

Reduced DNA topoisomerase II and IV binding due to mutations
Impaired permeability and increased drug efflux
Protection of DNA gyrase by Qnr proteins (plasmid-mediated, new!)
Modification by AG-acetyl transferase (plasmid-mediated, new!)

Question 10

Ciprofloxacin specrum

Answer 10

Bacteriocidal
Ciprofloxacin: Poor gram +ve (resistance rapidly acquired); good gram –ve (Pseudomonas, E.coli, etc.); Legionella (& Mycobacteria avium intracellulare)
Moxi- and levofloxacins: Wide spectrum; active vs gram +ve & gram –ve
+ Chlamydia

Question 11

Fluoroquinolones kinetics

Answer 11

Good oral absorption
T1/2 = 3-5 h (ciprofloxacin); 24h (others)
CDK with prolonged PAE
Wide distribution, high conc. in tissue & CSF
Clearance (cipro): hepatic (45%) renal (55%)
Moxifloxacin and levofloxacin - low concentrations in urine

Question 12

Clincal use cipro

Answer 12

UTI, STD

Question 13

Clinical use moxiflacin & levofloxacin

Answer 13

pneumonia

Question 14

Clincal use levofloxacin

Answer 14

pneumonia & UTI

Question 15

Fluoroquinolones SE

Answer 15

Gastrointestinal upsets N/V/D
Allergy: rashes
CNS effects: seizures
Ciprofloxacin inhibits hepatic CYP450; levo- and mono- do not
Arthralgia and joint swelling in children

Rarely- bone marrow failure, hemolytic anemia, nephrotoxicity
Arthropathy in cystic fibrosis patients

Question 16

Metronidazole

Mechanmism

Answer 16

Reduced by the bacterial (anaerobes) nitroreductase

Forms a reactive nitro - anion and radicals

In anaerobic environment -nitro-anion and radicals interacts with DNA to form single strand breaks mainly at (A-T) base pairs

Radicals may also damage proteins and lipids

Question 17

Metronidazole spectrum

Answer 17

Bacteriocidal
Oral and bowel anaerobes (100% B. Fragilis)
Cl. Difficile
Protozoa (Giardia Lamblia, Entamoeba Histolytica)

Question 18

Metronidazole kinetics

Answer 18

Well absorbed from GI tract; food delays absorption
Widely distributed, enters CSF well
T 1/2 - 8h
CDK with significant PAE
Hepatic metabolism
Inhibits CYP3A and aldehyde dehydrogenase

Question 19

Metronidazole SE

Answer 19

GI upsets
Metallic taste in mouth 
CNS effects- ataxia, vertigo
Neutropenia 
Colors urine - dark
Drug interactions; inhibits CYP3A

Teratogenic

Question 20

Rifamycins (rifampin)

Mechanism

Cross resctivity with

Answer 20

Mechanism

• Binds to the beta subunit of DNA directed bacterial RNA polymerase
• Inhibits further nascent RNA production

React with
Inhibits mammalian mitochondrial RNA polymerase at much higher concentrations

Question 21

Spectrum of rifampin

Answer 21

Broad spectrum: most GP and many GN
Myco TB & other mycobacteria (static)
Staph. Aureus (cidal)
Legionella
Neisseria meningitidis  prophylaxis
Active against intracellular organisms

Question 22

Rifampin kinetics

Answer 22

Oral absorption: good, impaired by food
Large Vd, enters CSF well
T1/2 2-5h
Hepatic metabolism

Question 23

Rifampin resistance

Answer 23

Mutations of beta subunit binding site of the RNA polymerase (rpoB gene product)

Increasing problem in Myco. TB therapy;never use alone

Question 24

Rifampin SE

Answer 24

GI intolerance: N/V
Hepatitis & jaundice
Orange-pink discoloration of tears, urine

CNS effects-headaches, drowsiness
Thrombocytopenia
Drug fever -serum sickness/flu like syndrome
Induces hepatic CYP 450s- multiple drug interactions

Question 25

Cases in PPT

Answer 25

Do them!