Nucleic Synthesis Flashcards
What are 5 ways to interfere with nucleic acid synthesis?
- Alteration of base-pairing properties of the template
- Inhibition of either DNA or RNA polymerase
3.Direct effects on DNA itself - Inhibition of DNA gyrase
- Inhibition of nucleotide synthesis
How do Acridines work?
Intercalating agents - Produce frameshift mutations by sandwiching themselves between adjacent bases in DNA
Prevents bacterial reproduction
What are they used against?
Topical against gram +ve bacteria
Surface disinfectant & superficial wounds
What is an example of an acridine?
Proflavine - very toxic
How does Actinomycin work?
Intercalates in minor groove of double helix between guanine cytosine base pairs
Interferes with RNA polymerase
Causes hairpin loops
How is Actinomycin D administered?
I.V.
How is actinomycin D distributed?
Widely bar BBB
Where is actinomycin D absorbed?
poorly absorbed from GIT
Limited plasma binding
crosses placenta
How is actinomycin D metabloised?
Minimally by the liver
How is actinomycin excreted?
Via the biliary routes and urine
What does actinomycin D inhibit?
Gram +ves/-ves and some fungi
What are actinomycin D’s clinical uses?
Treatment of Wilm’s tumour
Combination chemotherapy
High antibacterial activity
What are the adverse effects of Actinomycin D?
Hepatotoxicity, carcinogenicity, hematological toxicity, GIT distress and motility, hypersensitivity
What is metronidazole?
Alkylating agent - forms covalent bonds with bases in DNA
Prevents replication and has cytotoxic effects
What is an example of a metronidazole?
Falgyl (prodrug)
What is metronidazole’s mode of action?
Reductive activation by intracellular trasnport proteins
Forms reduced cytotoxic compounds which binds to DNA
Loss of helical DNA structure and strand breakage - prevents nucleic acid synthesis
What does metronidazole act against?
Anaerobic infections
Antiprotozoal infections
What are metronidazole’s clinical uses?
Combination therapy against Helicobacter pylori
Oral infections
Amoebic dysentery
How is metronidazole administered?
Oral
I.V.
How is metronidazole absorbed?
Rapidly absorbed after oral admin.
How is it distributed?
Bioavailability of almost 100%
How is metronidazole metabolised?
Hepatic metabolism
How is metronidazole excreted?
Kidneys in urine
some faecal elimination
What are the side effects of metronidazole?
GIT distress and motility
Dermatological effects
Neurotoxicity
Stevens-Johnson syndrome
What are the mechanisms of resistance proposed?
Specific resistance genes
Reduced drug uptake
Efflux systems
Decreased activation
What are Fluoroquinilones?
Bacterial enzyme (topoisomerases)
What are fluoroquinolone’s mechanism of action?
Catalyses ATP-dependent negative supercoiling of double stranded closed-circular DNA
G-ve - inhibits DNA gyrase
G+ve - inhibits topoisomerase IV
Induce synthesis of exonucleases - breakdown of DNA
What is an example of a fluoroquinolone?
Ciprofloxacin
What does V act fluoroquinolone act against?
G-ve/+ organisms
How are fluoroquinolones administered?
Oral
I.V.
Topical
How are fluoroquinolones absorbed?
Well absorbed from GIT in oral admin
How are fluoroquinolones distributed?
All tissues and body fluids
Ofloxacin crosses BBB
How are fluoroquinolones metabolised?
Hepatic metabolism - can inhibit cytochrome p450 enzymes
How are fluoroquinolones excreted?
Renal excretion
Some biliary elimination
What are fluoroquinolones clinical uses?
Ciprofloxacin - G-ve organisms, UTIs, chlamydia
Morfloxacin - UTIs
What are common fluoroquinolones side effects?
GIT upset
Alleregic reactions
CNS effects
Renal impairment
What resistance mechanisms are used against fluoroquinolones?
Altered target - chromosomal mutations in bacterial genes
Efflux pumps and porin channels cause decreased accumulation
