1. chemotherapy basics Flashcards
Selective toxicity:
- Unique targets
= target only in infectious agents - so very safe drugs
a) Inhibition of cell wall synthesis
- B-lactams (Penicilin, cephalosporin), glycopeptides (vancomycin), bacitracin
b) Fungal cell membrane component: ergosterol
- — we have cholesterol in cell membrane, so targeting Ergosterol leaves our cholesterol alone*
- Ergosterol-synthesis inhibitors: Azoles (Ketoconazole, Intraconazole, Fluconazole)
- Ergosterol-complex formers: Polienes (Nystatin)
–> it forms a complex with Ergosterol whch is in the cell membrane, its conformation alters and forms a pore in the membrane, and the cell leaks out its content.
c) Folic acid synthesis
- — folic acid is essential for DNA synthesis (in both us and bacteria)*
- PABA –> dihydroFolic acid (inactive form) –> tetrahydroFolic Acid (active form)
- enzyme responsible: Dihydropteroate-synthetase
- Sulphonamides are structural analogues of PABA
Selective toxicity:
- Unique targets: figure
Selective toxicity:
- Similar targets
= both infectious agent and host have target, but the drug has much higher affinity to the infectious agent target. in very high doses it can affect the host.
a) Dihydrogolate reductase
- inhibition, eg: Trimethoprim
b) Protein synthesis inhibitoris
- 30S and 50S ribosome subunits (these are the bact. subunits)
- aminoglycosides (30S) are the most toxic
- Phenicols (50S) have dose dependent toxicity
Selective toxicity:
- Common targets
a) Primary antineoplastic agents
- main target is: intensice cell dicidation –> inhibition
–> with this we will also inhibit our cell division processes too, the biggest side effects are seen in out highly dividing cells
- But: intestinal mucosa (SE: vomit, diarrhea), bone marrow(SE: anemia, leukopenia), hair follicle (SE: hair loss)
b) Antiparasitic drugs
- Cholinergic substanves (levimasole, organiphosphates etc.)
Category to helt control AB resistance:
1. Category A: Avoid
- drugs that are lifesaving in human med.
- only in small animals for life saving purposes
- never use in food producing animals
- eg: Vancomycin can be used against MRSA, so it is important to keep its effectivness and dont use it often, since MRSA is resistant to many ABs
2. Category B: Restrict = CIA highest priority
- fluoroquinolones
- 3-4. generation cephalosporin
- colistin
- also used as life saving drugs in human med.
- only used if Category D and C are not working!
3. Category C: Caution
4. Category D: Prudence
- eg. penicillin
Antibacterial agents
- Origin
Natural - Antibiotic (eg. penicillin)
Semisynthetic - Antibiotic (eg. amoxicillin)
Synthetic - Chemotherapeutic (eg. sulphonamides or Fluoroquinolones)
Antibacterail agents
- describing efficacy
- MIC: Minimum inhibitory concentration
- MPC: mutant prevention concentration
- MBC: minimum bactericidal concentration
Ex of Bactericidal, ex of Bacteriostatics
Bacteriocidal:
- Penicillins, Cefalosporins, Aminoglycosides, Polypeptides, Potentiated SA, Fluoroquinolones, Metronidazole
Bacteriostatic:
- Tetracyclines, macrolides, lincosamides, pleuromitilins, phenicols
What is the Postabtibiotic effect (PAE)
A delayed antibacterial effect after the concentration of the drug declined below the MIC
- eg: B-lactams, aminoglycosides, fluoroquinolones
Combinations
- ex
Bactericidal-bacteriostatic:
- usually bad to combine
- especially bad in cell wall inhibitors (eg penicillin, cephalosporins) because cell wall synthesis happens when the cell is dividing, so if you use a bacteristatic there will be no cell wall synthesis happening to act on
Additive-synergistic-antagonist
- Synergistic: excellent, they potentiate eachother
- eg. penicillin (b-lactam) + streptomycin (aminoglycoside)
- eg. lincomycin (50S inhibitor) +s pectinomycin (30S inhibitor)
- Additive: act against different bacteria
- eg. Gentamicin (Aerobic bac.) + Metronidazol (Anaerobic bact.)
- usually when you want to broaden the spectrum
- Antagonist: prohibited to give together
- eg. Erythromycin (50S inhibitor) + chloramphenicol (50S inhibitor)
Types of resistance
1. Chromosomal resistance: frequently spread vertically
- eg. MRSA
2. Plasmid encoded: horisontal and vertical
- very frequent
- eg. E.coli, Salmonellae
- Colistin mcr-1 gene
Transferring resistance genes between bacteria
1. Conjugation
- can transfer chromosomal or plasmid encoded resistance genes
2. Transduction
- resistance gene is transferred via bacteriophages
3. Transformation
- from dead bacteria
- minor siginificance
Resistance mechanisms
- Antibiotic degrading enzymes: Penicillinase
- Antibitotic transforming enzymes: eg. acetylation, adenylation (eg aminoglycosides)
- Increasing integrity of cell wall
- Increased efflux pump expression
- Modifying binding sites: fluoroquinolones (DNA topoisomerase)
