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13- Anti-neoplastics & Anti-Microbials

Terms in this set (24)

Common basic principle of chemotherapy & anti-microbials
targeting the selective differences between the microbe/cancer cell and the normal host cell
Carcinogenesis steps
1. Transformation
2. Proliferation
3. Metastasis
Transformation
if DNA damage is not repaired, mutated gene can cause altered gene expression --> abnormal cell growth & proliferation
Proliferation
Increase in # of cells - Two phases important for cancer drugs: 1. S-phase 2. M-phase
- Small or rapidly dividing cells are easier to kill b/c they progress through the cell cycle (off target cells affected hair, nails, bone marrow)
-Tumor cells in Go are hard to kill via chemo usually found in the center of large tumors
Metastasis
Secondary tumors that have spread to other tissues & through rapid/aggressive cell division they may gain mutations that increase resistance to drugs
Progression: Normal cells --> Primary tumors (susceptible) --> Secondary tumors (resistant
Antineoplasticss MOA
1. Cell-cycle specific- Inhibitors of DNA synthesis (antimetabolits, folate pathway inhibitors), microtubule poisons (vincristine)
2. Cell-cycle nonspecific: DNA-alkylating agents and DNA-intercalating agents act on all phases of the cell cycle
Log Cell Kill model
-Tumor growth is exponential w/ doubling time dependent on type of cancer
- Log cell kill model is 1st order
Cancer resistances
1. Innate- mutations in the genome itself, also responsible for the cancer
2. Acquired - genomic mutations or abnormal gene expression as cancer cells evolve
Concentration and Time Dependent Effects
Minimal inhibitory concentration: Lowest [drug] that inhibits bacterial cell growth (we want this to be small)
Minimum bacteriacidal concentration- Min. [drug] that kills bacteria
Concentration-dependent killing rate- increasing [drug] = increasing kill rate
Postantibiotic effect- persistence of inhibition of cell growth after drug has been removed (we want this long/large)
Determination of MIC
Broth Dilution Test- make different dilutions of drug and see what MIC and MBC are
ABX Pharmacodynamics (effects of drug on the body)
Bactericidal drugs kill in two different ways:
1. Concentration dependent- rate of killing increases w/ increasing [drug] e.g. aminoglycosides, fluoroquinolones
2. Time-dependent-Rate of killing maximizes at certain [drug], but as long as the dose is above the MBC, killing effect persists e.g. penicillin, vancomycin

-Most bactericidal ABX also exhibit PAE
Time-Kill Curves
Exposure to Tobramycin (Aminoglycoside) vs Ticarcillin (Penicillin)- Tobramycin shows concentration-dependent dynamics while ticarcillin's bactericidal effect maxes out at ~4x MIC, showing a time-dependent dynamics
Postabx effect (PAE)
Agents w/ both concentration dependent killing and PAE can be developed into a once daily dosing
- High dose of something with good BMC + long PAE can rapidly eliminate bacteria and continue working long after drug is eliminated
Microbial Sensitivity Tests
1. Broth Dilution (went through in another card)
2. Disk diffusion- measure the zone of inhibition to determine best drug vs bacteria
3. E-test method- point of intersection b/w zone of inhibition and scale (measures MIC)
Mechanisms of microbial resistance
1. Inactivation of the drug enzyme - ß-lactamases that destroy ß-lactams
2. Decreased accumulation- increased efflux or decreased uptake
3. Reduced affinity of target to drugs- results from mutation during exposure
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