Exam Flashcards
While in microbes selective toxicity tends to apply to structural differences between prokaryotes and eukaryotes, in cancer we are killing our own cells. So, what options do we have to target cancer cells? How is this similar and different to antimicrobials?
Anti-cancer drugs still target many of the same steps as do antimicrobials with respect to the cell cycle. However, whereas antimicrobials like trimethoprim, sulfonilamide, and fluoroquinolones all target differences in structure, anti-cancer drugs exploit differences in rate.
Basically, we kill our own cells in the process but hope that the rate at which a tumor cell divides is much faster than that of our cells. That way the tumor dies before we die.
Would a male or a female be more likely to become sterile with chemotherapeutics? Why?
A male would because spermatogenesis is a process that occurs throughout life whereas oogenesis occurs embryonic life. So, inhibiting the synthesis of DNA would prevent this process.
What metric is used to gauge the selective toxicity of chemotherapeutics? How is it expressed? If the value of this was 1, would you prescribe the drug? Why or why not?
Chemotherapeutic Index
CI = toxicity to cancer cells/ toxicity to normal cells
No you would not prescribe the drug if CI = 1.
Since toxicity refers to the LD<strong>50</strong>, then,
CI = LD50 Cancer/ LD50 Normal
That means if the CI was equal to 1 that any given dose would kill an equal number of normal cells as it would cancer cells, it’s not a good drug.
Growth factors can bind to receptors and induce signal cascades to get the cell through what two major cell cycle transitions?
How could a mutation in a part of this system lead to uncontrolled division?
G0–>G1
G1–>S
If the receptor is mutated such that it is in a conformation that tells the cell that it is “on” all of the time, then no growth factor is needed to stimulate the cell cycle = no control.
Sometimes a single anti-cancer drug doesn’t do the job. What are 3 things that can be accomplished with a drug cocktail vs. a single drug?
1) It provides maximum tumor cell kill that is tolerated by the host!
2) It provides a broader range of coverage for pre-existing resistant cell-lines in heterogenous tumors.
3) It prevents the formation of new resistant cell lines that could create heterogenous tumors.
Differentiate primary resistance and acquired resistance. What are examples of cancers that show these characteristics? What mechanisms create these types of resistance?
Primary Resistance–this is the absence of a response to a drug or drugs the first time around and occurs in colon cancer and NON-small cell lung cancers.
Acquired Resistance–this is the development of resistance to drugs after exposure. And this occurs in many cancers.
The major difference is that in primary resistance there is basically a natural immunity to the drug. In Acquired resistance there is often either A) amplification of genes or B) overexpression of genes, and these genes encode the proteins that get rid of the drugs, hence the resistance.
What three drugs have been experimentally shown to reverse multi-drug resistance?
Calcium Channel Blockers: Vermapil, Quinidine, and Cyclosporin.
Multi-drug resistance can often be caused by the overexpression of transport proteins to get rid of the drug. We talked about two in class:
1) What are they?
2) What kinds of proteins are they? How are they different in terms of energy requirement?
3) What kinds of drugs to they get rid of?
1) Multi-Drug Resistance Protein (MRP) and P-Glycoprotein
2) Both are transmembrane transporter proteins with ATPase domains; however, P-Glycoprotein has 2 ATP binding sites whereas MRP only has 1.
—–Only one of P-glycoproteins ATPase’s is needed for drug expulsion, though.
3) MRP gets rid of anthracyclines and vinca alkaloids both of which are anti-cancer meds.
P-Glycoprotein, on the other hand, gets rid of BOTH anti-cancer and anti-microbial drugs.
What are the 3 goals of chemotherapy?
A generalized drug-resistance phenotype in a patient would indicate a mutation in what gene? Why?
1) Control of Spread– this is pretty self-explanatory
2) Possible cure–again pretty obvious
3) Palliative Tx–not so obvious, this is when the drug has already metastasized and cure is no longer an option. So goals 1 and 2 are not possible. But this can reduce the symptoms and improve quality of life
MDR1… This is the gene that encodes for P-Glycoprotein. The fact that it is a generalized drug resistance and not just anti-cancer indicates that P-Glycoprotein is the problem, not MRP.
If a patient started chemotherapy and had the following symptoms, what about the effect of the drug on the body would cause these?
A) Fatigue and Dizziness
B) Shaking Chills and a Runny nose
C) Weight loss
D) Hair loss
E) Severe bruising when bumping themself
What do all of these have in common?
A) The fatigue and dizziness would most likely be caused by the effect of the drug on bone marrow, in this case it is by a lack of myeloid stem cells resulting in low RBC or anemia.
B) The shaking and runny nose are also a result of the effect on bone marrow–this time on the lymphoid stem cells… Causes Leukopenia
C) Weight loss is caused by lack of growth of G.I. epithileum and decreased ability to absorb nutrients.
D) Hair loss–the regenerative (stem) cells of the hair shaft cannot divide.
E) Again an effect on the bone marrow, this is from thrombocytopenia–lack of platelets and clotting
ALL of these come from tissues in which cells are constantly replaced by rapidly dividing stem cells. Thus, since chemo targets rate, these cells are the most like cancer cells. That is why there is no real effect on muscle cells, for example.
In general, (not just for cancer), what two regions of the CNS do antiemetics act on?
1) The vestibular apparatus–prevent motion sickness
2) The Chemoreceptor Trigger Zone (CTZ)–prevent illness from poisons or drugs.
What two general classes to anti-emetics fall under? Which is the front-line choice?
Serotonin-Receptor (5HT3)-antagonists–front line
Dopamine-Receptor (DA2)-antagonists
Assuming that a person is NOT on anti-emetics and they just took a bunch of toxic drugs, describe the entire process of how the brain would cause the person to start barfing.
1) The drugs would be taken into the bloodstream from somewhere, i.e. stomach, intestine, etc.
2) The drugs then flow to the brain where they stimulate the Chemoreceptor Trigger Zone. There probably is no blood-brain barrier here if I had to guess.
3) If CTZ is sufficiently stimulated it will fire signals, using BOTH dopamine and serotonin (5HT) as its neurotransmitters, to the vomiting center located in the area postrema on the floor of the fourth ventricle.
4) Since the vomiting response is parasympathetic, if the stimulation at the vomiting center is strong enough it will fire action potentials down the vagus nerve to the stomach and GI causing emesis.
This is the bodies way of getting rid of nasty stuff.
Name 3 Serotonin-antagonist drugs, what receptor do they act on?
1) Dolasetron, Granestron, Ondansetron
5HT3
Name 3 anti-dopaminergic drugs, what receptor do these act on?
Prochlorperazine, Fluphenazine, Chlorpromazine
DA2
Are the following anti-dopaminergic drugs or anti-serotonergic drugs?
1) Prochlorperazine
2) Fluphenzine
3) Granisetron
4) Ondanestron
5) Chlorpromazine
6) Dolasetron
1) Anti-dop
2) Anti-dop
3) anti-ser
4) anti-er
5) anti-dop
6) anti-ser
1) What is meant by “chemotherapy” in antimicrobials?
2) What, specifically, is an antibiotic?
1) This is the use use of chemical agents against infectious organisms
2) An antibiotic is a chemical made by a microorganism that is used to kill other microorganisms.
What five (6) pieces of information do you need to select the most appropriate antimicrobial medication?
1) The identity of the organism and its sensitivity to the prospective drug.
2) The site of infection on the host.
3) The safety of the drug to the host.
4) Patient Factors i.e. allergy to drug
5) The Cost of the medication
In general, what is empiric therapy and when is it justified?
Empiric Therapy is basically when you treat an infection without knowledge of the identity of the causal organism. Normally, this is not ideal because of issues with resistance etc. but it is justified if there is evidence that demonstrates that early intervention will improve the outcome.
There are specific regimens of empiric therapy that Caldwell talked about.
What are they? What drugs are used in each? What do they have in common?
1) Single Broad Spectrum Therapy–imipenem/cilastatin
2) Combination Broad Spectrum Therapy–gentamicin and clindamycin
Both of these regimens are broad spectrum. Thus, they both treat gram negative, gram positve, and anaerobic bacteria.
There is a slide that says “Characteristics of Selective Toxicity”. Really, these are all independent of each other. So, what are three general but separate requirements for selective toxicity?
Which would also apply to selective toxicity in cancer?
EITHER
1) The target is unique to the pathogen, it is not present in the host at all.
OR
2) The target is structurally different from the host version.
OR
3) The target is more important for the pathogen than it is for the host.
—This would apply to cancer since cancerous cells tend to divide faster than normal cells. 1-2 would not because cancerous cells are still human cells.
A 22 year old medical student is sitting at a desk studying pharmacology and begins to experience tachycardia with respirations 20-25/min. At the ER the physician believes he is having an anxiety attack because he got “gooed” while studying. How is it possible for one to get “gooed” while studying?
NGU’D
Describe how cephalosporins and penicillins exhibit selective toxicity.
Aside from bacteria that are resistant these drugs, which bacteria in a population inoculated with these drugs would not be affected?
Cephalosporins and penicillins exhibit selective toxicity because they target the synthesis of cell walls. Since humans do not have cell walls, these have not effect on us.
The bacteria that are not dividing will not be killed. This is because the process of cell wall synthesis only occurs during replication.
Sulfamethoxazole is a combination of what two drugs?
Describe how this drug (drugs?) exhibits selective toxicity.
What does each component of the drug do?
Sulfamethoxazole is a combo of trimethoprim and a sulfonamide.
This drug exhibits selective toxicity because it targets a process that only occurs in bacteria–the synthesis of folate. Moreover, bacteria cannot take up folate like we can so this is lethal to them.
Folate Synthesis: TWO STEPS
A) the sulfonamide component inhibits the first reaction by mimicking the structure of para-aminobenzoic acid (PABA). This is the rxn of PABA–>TH2
B) Trimethoprim inhibits the second reaction of bacterial dihydrofoloate reductase TH2–TH4
Name 5 general ways to target microbes
1) Inhibit cell wall synthesis
2) Inhibit DNA replication
3) Inhibit protein synthesis
4) Inhibit an enzyme specific to the microbe4
5) Disrupt the membrane
Differentiate MIC and MBC.
MIC is the minimal inhibitory concentration. That is the minimal plasma concentration of the drug required to INHIBIT bacterial growth.
MBC is the minimal bactericidal concentration. Thats is the minimal plasma concentration of the drug required to KILL bacteria.
What sets the size limitations for drug action on intracellular receptors in gram negative bacteria?
What kind of mutation could occur so that a drug that previously entered the cell no longer does?
The size of the porins. Only small molecules are allowed in, large drugs are not.
If a mutation happens in the gene encoding for a particular porin that a drug uses, then that could confer resistance to the bacterium.
What are four general ways that a drug may fail to reach its receptor?
1) There could be efflux pumps for the drug
2) Active transport of the drug into the cell could be blocked. Many drugs are actively taken up into bacterial cells, if this is blocked the bacteria are resistant.
3) The drug may be metabolized by the body too greatly.
4) The drug may not be able to get into the cell due to size limitations, i.e. gram negative bacteria and porins.
What process does gentamicin act on? How does it reach its target?
Name 2 ways that the process of reaching its target could be interfered with and why.
Gentamicin acts on ribosomes so it halts protein synthesis. It reaches its target by being actively transported the cell via an electrochemical gradient.
1) If there is a mutation in the transporter, then it will not get in.
2) Under anaerobic conditions. This is because the active transporter uses the electrochemical gradient generated by oxidative phosphorylation. Recall bacterial Ox-Phos occurs on the membrane since they lack mitochondria, so it is easily coupled to the transporter.
So, if there is no oxygen to do Ox-Phos, there will be no gradient. If this was a regular ATPase, it wouldn’t matter since ATP is still being generated from fermentation.
Name 5 drug classes that are actively transported OUT of bacterial cells by efflux pumps.
What do each of these drugs do (general)?
1) Fluoroquinolones–inhibit DNA gyrase, stop replication.
2) Macrolides– 50S ribosome, protein synthesis
3) Beta lactams–knock out PBP, inhibit cell wall synthesis in REPLICATING CELLS
4) Tetracylcines– 30S ribosome, protein synthesis
5) Chloramphenicol–50S ribosome, protein synthesis
Describe a specific situation in which the failure to activate a prodrug leads to bacterial resistance.
What other drugs are always combined with this drug?
Mycobacterium tuberculosis metabolizes the drug isoniazid into an active form. A mutation in the enzyme that converts the prodrug to active will lead to resistance against isoniazid.
But… Isoniazid is always given with
Ethambutol
Rifampin
Pyrazinamide
Which antibiotics promote resistance? Of these, which are the worst offenders? Why?
What is the usual reason that bacteria will get resistance to aminoglycosides and penicillin?
ALL antibiotics promote resistance, every antibiotic that has ever been made has at least one documented case of resistance, even if just in vitro.
The worst are the broad-spectrum antibiotics because they are capable of killing off competing microbes.
A major reason for resistance to aminoglycosides and penicillins is the production of enzymes that destroy them.
How is superinfection defined?
Why does superinfection occur? What antibiotics are usually the cause of superinfection?
1) Superinfection is defined as the development of a secondary infection during treatment of the primary infection.
2) It is usually caused by administering broad spectrum antibiotics because they knock out the inhibitory effects of normal flora which leads to an infection with unusual bacteria.
For those of you ecology aficionados, this would be a good example of the competitive exclusion principle since the infectious organisms normally cannot compete for resources with our normal flora, but when normal flora are knocked out they can move in.
Or you can use Caldwell’s morbid example of a gazelle carcass in Africaand something about a rifle and shotgun.
In the first part of antimicrobial lecture, Caldwell said to name 5 items you need when selecting an antibiotic.
In the second lecture he asks for 3 principle ones which happen to be 3/5 from the last lecture.
So, I guess, what are the 5 things you need when selecting an antimicrobial and which 3 are most important?
1) The identity of the microbe and sensitivity to the drug you want to use.
2) The site of infection
3) The cost of the medication
4) The safety of the drug to the patient
5) Host factors like allergies etc.
Most important: Identity of microbe, sensitivity, and patient factors.
When are three general times that you would choose to use a second-line (alternative) antibiotic rather than the main one for any given infection.
Name 2 specific examples of contraindications for antibiotics in neonates and the deleterious effect of the drug when given.
1) If the patient is allergic this is an obvious no-no
2) If the site of infection cannot be reached… Best I can think of would be like meningitis and not being able to get through the BBB.
3) The patient is unusually susceptible to toxicity i.e. maybe in liver failure and low plasma proteins, or an ultrafast metabolizer.
A) Sulfonamides in newborns bind to plasma proteins and displace bilirubin from the plasma proteins. This causes the neurological disease– kernicterus
B) Tetracyclines in newborns can cause staining of the developing teeth.
What are 5 pretty solid reasons to use antibiotic combinations?
1) Initial treatment of EITHER a severe infection or a neutropenic host (or a severe infection in a neutropenic host, I guess).
2) Prevention of resistance–TB–isoniazid, ethambutol, rifampin, pyrazinamide
3) Preventing toxicity of one of the drugs
4) Used when drugs potentiate each other
5) Mixed infections–i.e. your intestines rip open and a bunch of stuff spills into the peritoneum.
Give an example of a situation in which it would be beneficial to treat with a drug cocktail in order to reduce the toxicity of one of the drugs. What is the toxic effect?
When treating fungal meningitis with amphotericin B, you run the risk of causing damage to the kidneys.
But if you combine amphotericin B and Flucytosine, the toxicity is reduced!
List the four types of ion channels that are present in cells of the CNS.
1) Voltage-Gated Ion channels
2) Ligand-Gated Ion channels (where ligand = neurotransmitter)
3) Membrane Delimited Metabotropic Ion Channel
4) Diffusible Second Messenger Metabotropic Ion Channel
Why does a person on cocaine:
A) Feel like the man
B) Have high cardiac output
How does chronic use of cocaine affect the bodies ability to manufacture certain catecholamines, why?
A) People feel like high because coke is blocking dopamine reuptake which means there is more in the synapse to stimulate the next cell (this prob is referring, specifically tot he mesolimbic pathway, don’t quote me).
B) Cocaine also blocks norepinephrine reuptake. Since sympathetic innervation to the heart uses norepi, that means more will stimulate nodal tissue (HR) and myocardial cells (stroke volume)– CO = HR x SV
By continuously stimulating post-synaptic dopaminergic cells, the pre-synaptic cell responds by producing less dopamine. Now to get as high as you did the first time you need more cocaine.
Name 3 drugs that cause mydriasis, what do you use these for? What receptor?
Name 2 drugs used to treat Glaucoma? Explain the rationale for using these.
Mydriasis = dilation of sphincter pupillae, used for fundic eye exam.
Use Scopalamine, Atropine, Hyoscyamine–these are antimuscarincs acting on M3 (M3 are located on smooth muscle)
Glaucoma– aqueous humor is produced by ciliary muscles. Using muscarinic agonists: physostigmine and pilocarbine basically move the ciliary muscle out of the way to expose the Canal of Schlemm which drains the aqeuous humor.
