Pharmacology 32: Antimicrobial and Antineoplastic Pharmacology
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Treatment of infection and cancer similar because target selective difference between
microb/cancer cell and normal host cell
Lower respiratory infections, diarrheal disease, HIV/AIDs, tuberculosis, malaria = major infection
disease mortality
Most deadly cancers = lung, colon, breast, pancreatic, and prostate cancers
Public health and vaccination programs aim for prevention (reduction in smoking and
carcinogens, cancer screening, pap smears)
o Depend on socioeconomic factors
Selective toxicity = inhibit pathways or targets critical for pathogen or cancer cell
survival/replication at drug [] lower than those affecting host
o Attack targets unique to pathogen or cancer, those similar (not identical) to those in
host or those shared by host but vary in importance
o Antineoplastic drugs more toxic to host than antimicrobials
Therapeutic index = ratio of toxic dose to therapeutic dose
o Indicates how selective drug is in producing desired effect
o Penicillin high therapeutic index, methotrexate (anticancer) low index
Imantinib = highly specific anticancer agent -> targets product of gene rearrangement in chronic
myelogenous leukemia
Unique drug targets:
o Bacterial peptidoglycan cell wall (unique) -> penicillin and β-lactams inhibit
transpeptidase that cross-link
o β-(1,3)-D-glucan in fungal cell wall -> echinocandins inhibit
o Ergosterol -> sterol moiety in fungal cell -> azoles block biosynthesis, polyenes
(amphotericin) chelates (both alter membrane permeability)
Selective inhibition of similar targets:
o Therapeutic indices smaller
o DHFR and bacterial protein synthesis inhibitors
 DHFR important in nucleotide synthesis
 Methotrexate, trimethoprim, and pyrimethamine inhibit DHFR
Common Targets:
o Target processes involved in DNA synthesis, mitosis, and cell cycle progression
Bacteria
o Drugs interrupt bacterial DNA replication and repair, transcription and translation, and
cell wall synthesis
o Bacteriostatic = drugs that inhibit growth (no death)
 Protein synthesis inhibitors
 Rely on host immune system
o Bactericidal = drugs kill bacteria
 cell wall synthesis inhibitors (lyse)
 good for immunocompromised
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the combination of bacteriostatic drug with a bactericidal drug can result in antagonistic
effects
 ex. tetracycline (bacteriostatic) antagonizes penicillin (bacteriocidal)
o the combination of two bactericidal drugs can be synergistic
 ex. penicillin-aminoglycoside combo
Fungi and Parasites
o Fungi have nucleus, membrane bound organelles, plasma membrane like eukaryotes so
harder to target
o Immunocompromised pts more susceptible to infection by fungi and parasites
o Malaria transmitted when Anopheles mosquito deposits Plasmodia sporozoites in
human bloodstream -> schizonts develop in liver -> rupture and release merozoites ->
infect RBCs -> mature to trophozoites -> mature schizonts (fever)
Viruses
o Noncellular w/ nucleic acid core of RNA or DNA in capsid
o Rely on host to synthesize proteins
o Virus-specific processes targeted by antiviral drugs
o HIV protease = cleaves viral precursor proteins to generate proteins/enzymes necessary
for vius maturation
 HIV protease inhibitors mimic substrates of protease byt contain noncleavable
bond
Cancer Cells
o Carcinogenesis = transformation, proliferation, and metastasis
 Transformation = change in phenotype to dysregulated growth
 Mutations can be inherited, spontaneous, or from environment -> can
activate growth-promoting genes and inactivate growth-inhibiting
genes, etc
 Proliferation = can become quiescent (G0), enter the cell cycle, or die
 S phase (DNA synthesis) and M phase (division)
 Cyclins and cyclin-dependent kinases (CDKs) govern progression through
phases
 Growth fraction = # proliferating/total # of tumor cells (avg ~20%)
 Quiescent state not easily killed by chemotherapy (growing cancer
respond more)
o Antineoplastic drugs may kill normal tissue with high growth
fraction (bone marrow, and GI mucosa)
 Metastasis = must have mutations that allow invasion, seeding, spread, and
growth
o Most cancers initially clonal but become heterogeneous with new mutations
o Tumor cells secrete (EGR), create fibrous CT stroma (palpable), induce angiogenesis
(solid tumors)
o Tumors most senstitve when growing rapidly
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Metabolically active cells susceptible to drugs that interfere with cell growth and
division = mitotoxicity hypothesis
 Chemotherapeutic agents cause apoptosis of cancer cells
o Some antineoplastic drugs interfere with cell cycle at particular phase = cell-cycle
specific
o Other drugs act independent of cell cycle = cell-cycle nonspecific
o Cancers expressing wild-type p53 (leukemia, lymphoma, testicular cancer) highly
responsive to chemo while those with mutation in p53 are minimally responsive
Log cell kill model = tumor growth exponential (doubling time according to type); cell
destruction caused by cancer chemotherapy is first-order (each dose kills constant fraction of
cells)
o Intermittent cycles used to avoid toxicity (growth and resistance of cancer may develop)
Mechanisms of drug resistance
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Multidrug resistance (MDR)
New classes of antibiotics = oxazolidinones (linezolid), lipopeptides (daptomycin),
pleuromutilins (retapamulin), streptogramins (quinupristin/dalfopristin), and glycylcyclines
(tigecycline)
Genetic mechanisms of resistance -> chromosomal mutations (in target genes or genes for drug
transport) or gaining genetic material from other bacteria (horizontal transmission)
o Mutations transferred to daughter cells = vertical transmission
o MRSA and VRSA -> resistance genes acquired
Acquisition of genetic material ->
o Conjugation = chromosomal/plasma DNA transferred directly between bacteria
o Transduction = DNA transferred by bacterial virus (bacteriophage)
o Transformation = naked DNA in environment taken up by bacteria
Resistance most often from transfer of plasmids (extrachromosomal strands of DNA with drug
resistance genes)
Reduced intracellular drug concentration:
o Resistance to penicillins and cephalosporins from β-lactamase (cleaves β-lactam ring
disabling drug active site) or cancer overexpression of deaminase enzyme inactivate
(antimetabolites)
o Prevent uptake of the drug -> alter porins (folate-transport system resistant to
methotrexate that require transport to inhibit DHFR)
o Drug efflux -> overproduction of membrane pumps (P-glycoprotein aka p170 or MDR1)
transport lipophilic and amphipathic molecules out
Target based mechanism:
o Alteration in drug target -> altered peptidoglycan lowers binding affinity of vancomycin
(mutant DHFR)
o Bypass metabolic requirement for target -> inhibition of thymidylate synthase bypassed
by exogenous thymidine (tamoxifen resistance)
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Insensitivity to Apoptosis:
o Molecular lesions from drugs can arrest cell-cycle, activate repair, or apoptosis
o P53 or Bcl2 mutations can fail apoptotic response
Overprescription of antibiotics, drug barriers (abscess or BBB), poor patient adherence,
international travel, and demographic shifts promote drug resistance
Methods of treatment
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Combination Chemotherapy ->
o Significantly decrease probability of resistance, standard in tuberculosis and HIV
o Targets multiple steps in cancer growth (max rate of killing)
o Lower doses of synergistically acting drugs can reduce adverse effects
o Can give each drug in maximum tolerated dose (increased killing)
Prophylactic chemotherapeutics ->
o Used in high-risk patients to prevent infections (travelers and malaria), in surgery to
prevent wound infection, before dental procedures in high risk endocarditis pts, if pt
immunocompromised
o Used in healthy person after exposure to certain pathogens (gonorrhea, syphilis,
meningitis, HIV)
Inhibitors of Folate Metabolism
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Folic acid = reactions essential for DNA and RNA, AA (glycine, methionine, and glutamic acid),
formyl-methionine initiatior tRNA biosynthesis
o Has pteridine ring system, para-aminobenzoic acid (PABA; absorbs UV rays) and AA
glutamate
Folate cycle: dihydrofolate -> tetrahydrofolate via DHFR -> donates carbon atom in reactions
Antimetabolites = inhibitors of folate metabolism, purine metabolism ribonucleotide reductase,
and nucleotid analogues
o Inhibitors of folate metabolism = inhibitors of dihydropteroate synthase and inhibitors
of DHFR
Bacteria must synthesize folic acid de novo
Resistance to sulfonamides -> from overproduction of endogenous PABA, mutation in PABA
binding site on dihydropteroate synthase, or decreased permeability of bacterial membrane