Midterm #3 Flashcards
Penicillin Drugs
- penicillin (G and V)
- amoxycillin
Beta Lactam Drugs
- Cephalosporin
- Carbapenems
Cell Wall Attacking Drugs
- Vancomycin
- Bacitracin
3 classes of drugs that attack cell wall
- penicillin
- beta lactam drugs
- other cell well inhibitors (not penicillin based)
Penicillin
Mechanism - enters the cell, binds to PBP to inhibit it’s role in strengthening the peptidoglycan layer. Cell lysis.
- penicillin G breaks down in acid
- amoxycillin has a longer half life, has an effect o gram -‘ve bacteria, and has higher bioavailability. Better version of penicillin.
What effects the activity of penicillin?
porins - improve effect
beta lactamase - inhibit effect
Beta lactamase inhibitor
clavulanate
mechanism - occupies beta lactamase
Cephalosporins
structure next to the beta lactamase ring is slightly different than penicillin. Makes it more resistant to beta lactamase.
Carbapenems
- S in penicillin is changed to C in carbapenems - makes it beta lactamase resistant.
Vancomycin
inhibits growth/elongation of peptidoglycan strands. Unable to make a rigid structure without long strands. Lysis.
Bacitracin
works inside the cell (not at the location of the cell wal)) to inhibit cell wall formation
Classes of Drugs that inhibit protein synthesis (effect ribosomal subunits)
- Chloramphenicol
- Erythromycin
- Aminoglycosides
- Tetracyclines
Chloramphenical
binds to the 50S sunubit. Inhibits formation of peptide bonds between individual amino acids
- side effects - bone marrow disturbance, gray baby syndrome, serious drug interactions.
Erythromycin
changes the 30S subunit, causing the mRNA code to be read incorrectly (wrong amino acid)
- unstable in acid
- a macrolide
- used if a penicillin resistance develops.
Macrolide Drugs
Erythromycin < Clarithromycin < Azithromycin
Clarithromycin
same effect as erythromycin but can be given orally
Azithromycin
some effect on gram -‘ve
more potent
greater tissue penetration.
- better drug
Aminoglycosides
bind 50S subunit - prevents ribosomal movement along mRNA.
- streptomycin, gentamicin
- hexose ring linked to an amino sugar by a glycosidic linkage.
- effective against gram -‘ve
- given via IV
- side effects - ototoxic, nephrotoxic.
Aminoglycoside Mechanism (3)
- mRNA binds 30S, but 50S doesn’t join.
- miscoding in the polypeptide chain - causes the tRNA to hold the wrong amino acid
- blocks translocation
Tetracyclines
interfere with the acceptor site
- absorption effected by milk and antacids
- accumulates in bones and teeth.
- shouldn’t be given to pregnant woman or children.
Drugs that inhibit DNA Synthesis
sulfonamides
trimethoprim
Folic acid pathway
PABA -(DHPS)-> folate -(DHFR)-> THF -> Purines for DNA
Sulfonamide
Target and inhibit DHPS
Trimethoprims
Target and inhibit bacterial DHFR (because DHFR is in human cells too)
Other DHFR inhibitors
protozoa - pyrimathamine
cancer - methotrexate
DNA Replication inhibiting Drugs
Fluoroquinolones = fluorinated quinolones = ciprofloxacin
Activity of Fluoroquinolones
inhibit DNA gyrase/bacterial topoisomerase activity. DNA can’t be uncoiled so it can’t be replicated.
Problem with fluoroquinolones?
widespread resistance
Cell Membrane inhibiting Drugs
Polymyxins
Polymyxins
- detergent-like properties.
- destroy phospholipid membrane by binding to PE in the membrane and cause disruption to the structure.
Problem with polymyxins?
also has the same effect on human cells.
- can only be given topically. Never systemically
Common Combination Therapies
- chloramphenicol + aminoglycosides
- beta-lactam drugs + beta lactam inhibitors
- 2 beta lactam drugs that inhibit different PBPs
- sulfonamides and trimethoprims
Advantages of Combination Therapy
- wider spectrum
- can give lower doses
- synergism
Disadvantages of Combination Therapy
- antagonism
- adverse effects
- increased likelihood of resistance
Bacterial Resistance
- decreased entry
- efflux pump
- bypass pathway
- altered target proteins
- enzymes to degrade the drug
Examples of Bacterial Resistance
Sulfonamide resistance
Trimethoprim resistance
Sulfonamide Resistance
- decrease membrane permeability
- increased PABA
- change DHPS so it nolonger binds to sulfonamide
Trimethoprim Resistance
- decrease membrane permeability
- increase DHFR
- change DHFR so it not longer binds to trimethoprim.
Drugs for Fungi
- ketoconazole - oral
- fluconazole - oral
- amphotericin B - IV
Fluconazole
inhibits fungal cytochrome P450 -> enzyme involved in making ergosterone
Amphotericin B
amphoteric - one end is hydrophilic and the other is hydrophobic. Therefore it happily spans the membrane.
makes pores by binding to ergosterol.
- sometimes binds to cholesterol in humans - super dangerous - nephrotoxicity.
Causes of Cancer
Genetics
- oncogenes
- tumor suppressor genes
Environment - most important
Cancer Pathophysiology
1) Initiation - 1 cell gets mutated
2) Promotion - proliferation
3) Progression - malignant.
3 ways we treat cancer
1) surgery
2) radiation
3) chemotherapy
Traditional Cancer Treatments
Alkylating & Platinum Agents - target the DNA molecule itself.
Antimetabolites - target DNA synthesis
Antobiotics and Topoisomerase inhibitors - target transcription
Vinca Alkaloids & Taxanes - target the mitotic spindle.
Alkylating & Platinum Agents
alkylating - cyclophosphamide
platinum - cisplatin
mechanism - both bind the DNA strand, are detected as damage and cause DNA molecule death.
Cl is removed and 2 (incorrect) DNA base pairs covalently bind - destroyed.
Negative side effects - can also bind to other similar structures like lipids ad proteins - problematic for other bodily cells.
Antimetabolites
Purine antagonists - mercaptopurine
Pyrimidine antagonists - fluorouracil
Folic Acid antagonists - methotrexate
cell cycle specific - S phase drugs.
Mercaptopurine
- looks like adenine.
- inserts itself where adenine would bind in DNA and RNA.
- DNA enzymes recognize that DNA is wrong and destroy it.
Fluorouracil
- looks like U/T
- binds to thymidylate synthase, preventing thymidine form being made.
- can’t make any new DNA
Methotrexate
- inhibits cancer cell specific DHFR
- unable to make new nucleotides.
Antibiotic & Topoisomerase Inhibitors
Topoisomerase I inhibitors - topotecan
Topoisomerase II inhibitors - doxorubicin
Antibiotics - anthracycline
Topotecan
binds topoisomerase I, produces a fixed complex, inhibits DNA unwinding.
- leads to cell death
Doxorubicin
Binds topoisomerase II, prevents religation of DNA
- leads to cell death
Anthracycline
wedges itself between DNA, stabilized topoisomerase II complex, preventing religation.
- produces free radical
- unique cardiotoxicity
Vinca Alkaloids & Taxanes
Vinca Alkaloid - vincristine
Taxane - docetaxel
Vincristine
blocks assembly of microtubules in mitotic spindle.
Docataxel
blocks disassembly of microtubules in mitotic spindle.
Adverse effects of Traditional Antineoplastics?
- non-specific
- small therapeutic window
- immuno-suppressant
Combination Drugs
- must be effective by themselves
- should have similar recovery intervals/rates
- pick drugs with different aide effects so not to be additive.
Combination Therapy Example
CAV for lung cancer
C - cyclophosphamide
A - adriamycin (brand name for doxorubicin
V - vincristine
Targeted Anticancer Drugs - 5 targets
1) Cellular Markers
2) New Blood Vessel Growth - angiogenesis
3) Growth and Proliferation
4) Survival Proteins
5) Hormone Sensitive Cancer
Cellular Markers
CD-20 is a common cancer cell marker
also found on mature B cells
- monoclonal antibody - flags for immune system.
- conjugated radiation - kills cells with radiation that antibody binds to.
- conjugated cytotoxicity - kills cells through antimicrotubule action (eg. vincristine)
Tositumomab
radiation conjugated, monoclonal antibody targeted to CD-20.
Sipuleucel-T
anti-cancer vaccine.
virus expressing CD-20, activates immune system to respond to cells presenting CD-20
Bevacizumab
monoclonal antibody against VEGF.
- similar to VEGF, binds the VEGFR to inhibit binding and downstream signaling.
- inhibit angiogenosis
Sorafenib & Gefitinib
Small molecule TK inhibitor. Binds intracellular part of the tyrosine kinase to inhibit autophosphorylation and activation
- specific to receptor tyrosine kinases like HER-2
- inhibit angiogenesis
Trastuzumab
blocks EGF receptors.
- EGF - epidermal growht factors stimulates growth and proliferation of cancer cells.
- can be conjugated (cytotoxic) or unconjugated (just antagonistic)
- inhibits growth and proliferation
Imatinib
Bcl-2 is a survival protein that allows cells to ignore the apoptosis signal.
Bcl-Abl is a cytoplasmic TK involved in Bcl-2 upregulation.
Imatinib binds to Bcl-Abl, so the normal ligand can not bind/activate it. (anagonist)
- inhibits survival proteins
Hormone Sensitive Cancer Drugs
- Leuprolide
- Letrozole
- Tamoxifen
Leuprolide
looks like GnRH, involved in the production of testesterone and estrogen.
- effective against both breast cancer and prostate cancer
Letrozole
inhibits aromatase involved in estrogen conversion
- specific to breast cancer
Tamoxifen
estrogen receptor antagonist
- specific to breast cancer
1st line therapy
Old + New Eg. R-CHOP R - rituximab C - cyclophosphamide H - hydroxydaunorubicin (doxorubicin) O - oncovin (vincrisitne) P - prendisone adjuvant (reduce side effects)
