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Pharm Exam 3

STUDY
PLAY
Colonization is the presence of bacteria which are NOT causing disease.

Infection is The presence of bacteria which ARE causing disease, often found in normally sterile
location(s).
What is the difference between Colonization and Infection?
mouth and oropharynx (including sputum)
GI tract
skin
Sites that are normally NON-STERILE are what?
Mouth anaerobes (normal mouth flora)
Gut anaerobes (normal gut flora)
What bacteria would you normally find in the mouth and GI tract?
Staphylococcus
Streptococcus
What bacteria would you normally find on the skin?
Blood
CSF
Urine
What are the sites that are commonly STERILE in the body?
Staphylococcus and Streptococcus from skin goes into the blood...

Gut anaerobes from GI tract goes into blood after sex (tearing of anal wall, for example)...
What bacteria can be found in the blood?
Otitis media bugs (S. pneumoniae, H. influenzae)
because Ear Canal close to BBB...

Staph and Strep from skin, goes into blood, then to CSF...
What bacteria can be found in the CSF?
Gut bugs - Gram negatives
Staph and Strep
What bacteria can be found in the urine?
Contaminant

Mouth anaerobes cannot survive in the lungs, so the sample taken must have been contaminated.
You did a bronchial lavage culture. The report came back as "mouth anaerobes".

Is this colonization, infection, or contaminant?
Infection

Streptococcus pneumoniae typically not found in the mouth.
You did a bronchial lavage culture. The report came back as "Streptococcus pneumoniae".

Is this colonization, infection, or contaminant?
Susceptibility testing
Infection of hospitalized patients or infections requiring hospitalizations: What kind of test is first ordered?
A narrow spectrum antibiotic is used to treat the patients while adjustments are made to the medication accordingly.

Narrow spectrum used to prevent resistance and superinfection.
After getting results from susceptibility testing, what happens?
A test which uses antibiotic-impregnated wafers to test whether particular bacteria are susceptible to specific antibiotics.

A known quantity of bacteria are grown on agar plates in the presence of thin wafers containing relevant antibiotics. If the bacteria are susceptible to a particular antibiotic, an area of clearing surrounds the wafer where bacteria are not capable of growing (called a zone of inhibition).

Along with rate of antibiotic diffusion, it's used to estimate the bacteria's sensitivity to that particular antibiotic.
What is the Kirby-Bauer Test?
Correlates with smaller MIC
In general, how do larger zones in a Kirby-Bauer test correlate with MIC?
An agar diffusion method used to determine whether or not a specific strain of bacterium or fungus is susceptible to the action of a specific antibiotic.

This is most commonly used in the setting of medicine, where a doctor treating an infected patient seeks guidance on what concentration of antibiotic is suitable.

The Etest utilises a rectangular strip that has been impregnated with the drug to be studied. A lawn of bacteria is spread and grown on an agar plate, and the Etest strip is laid on top; the drug diffuses out into the agar, producing an exponential gradient of the drug to be tested. There is an exponential scale printed on the strip. After 24 hours of incubation, an elliptical zone of inhibition is produced and the point at which the ellipse meets the strip gives a reading for the minimum inhibitory concentration (MIC) of the drug.
What is the E Test?
Minimum inhibitory concentration (MIC)

The lowest concentration of the antibiotic that
results in inhibition of visible growth under
standard conditions.
What is MIC?
Minimum bactericidal concentration (MBC)

The lowest concentration of the antibiotic that kills
99.9% of the original inoculum in a given time.
What is MBC?
PREVENT infection
Antibiotic selected in prophylactic therapy is used to do what?
HIV/AIDS

Immunocompromised...
...Organ transplant
...Long-term steroid use

Recurrent UTIs
What disease states or conditions do we utilize
prophylactic therapies and WHY?
A SUSPECTED pathogen as you await for culture results

(BROAD SPECTRUM ANTIBIOTIC USED)
Antibiotic selected in Empiric therapy is used to treat what?
A KNOWN pathogen once culture and sensitivity results are known

(NARROW SPECTRUM ANTIBIOTIC USED)
Antibiotic selected in Specific therapy is used to treat what?
The highest concentration of antibiotics that can be safely attained in the blood using the recommended dosing regimen.
What is the Breakpoint MIC?
MIC of organism is LESS THAN breakpoint MIC

Yes.
How does the MIC of the infecting organism compare to the Breakpoint MIC if the organism is SENSITIVE to the antibiotic?

Can you use this Antibiotic?
MIC of organism EQUALS Breakpoint MIC

It's okay to use ONLY if there is no other option.
How does the MIC of the infecting organism compare to the Breakpoint MIC if the organism has INTERMEDIATE SENSITIVITY to the antibiotic?

Can you use this Antibiotic?
MIC of organism is GREATER THAN breakpoint MIC

Absolutely NOT.
How does the MIC of the infecting organism compare to the Breakpoint MIC if the organism is RESISTANT to the antibiotic?

Can you use this Antibiotic?
Dose can be toxic to the patient.

Dose may cause adverse effects in the patient.
What can happen if the drug dose is greater than the Breakpoint MIC?
Sensitive
Ampicillin
Organism MIC = 0.1
Breakpoint MIC = 8

Sensitive, Intermediate Sensitivity, or Resistant?
Sensitive

Not "I" because the fraction is TMP/SMX.

For TMP, it's 1 vs. 2.
For SMX, it's 19 vs. 38.

So, for both numerator and denominator, the Breakpoint MIC is higher, so Sensitive.
TMP/SMX
Organism MIC = 1/19
Breakpoint MIC = 2/38

Sensitive, Intermediate Sensitivity, or Resistant?
Intermediate
Ceftazidime
Organism MIC = 16
Breakpoint MIC = 16

Sensitive, Intermediate Sensitivity, or Resistant?
Resistant
Aztreonam
Organism MIC = 64
Breakpoint MIC = 16

Sensitive, Intermediate Sensitivity, or Resistant?
Must achieve MIC at site of infection.
Antibiotics that work via time-dependent killing must do what in order to be effective?
Peak levels determine adequacy of treatment

Trough levels predicts toxicity
When using antibiotics that work via concentration-dependent killing, peak and trough levels determine what?
Can lead to bacterial growth and/or resistance
What can happen if the drug level is less than the organism's MIC?
Can cause adverse effects
For certain antibiotics, what can happen if you give a patient another dose before the old dose is cleared from the body?
Absorption (bioavailability)
Distribution
What two factors determine the dose, route and frequency of administration of antibiotic?
The antibiotic must be able to reach the site of infection. If it can't reach the infection site, it won't be able to act.
In order for any antibiotic to work, what must first happen?
During the dosing interval, time-dependent drugs are effective because of the extensive amount of time the antibiotics bind to the microorganism while their their concentration exceeds the MIC for the microorganism.

Hence, these antibiotics are referred to as time-dependent antibiotics. For time-dependent drugs, the pharmacodynamic parameter can be simplified to the time that serum concentrations remain above the MIC during the dosing interval (t>MIC).
Describe the concept of time-dependent killing and time-dependent antibiotics.
Concentration-dependent drugs have high concentrations at the binding site which eradicates the microorganism.

For concentration-dependent agents, the pharmacodynamic parameter can be simplified as a peak/MIC ratio.
Describe the concept of concentration-dependent killing and concentration-dependent antibiotics.
Cell-wall active agents...
...Βeta-lactam antibiotics
...Vancomycin
What kind of antibiotics works via time-dependent killing?
Persistent suppression of bacterial growth after a brief exposure (1 or 2 hours) of bacteria to an antibiotic even in the absence of host defense mechanisms. Factors that affect the duration of the post antibiotic effect include duration of antibiotic exposure, bacterial species, culture medium and class of antibiotic.
What is the post-antibiotic effect?
the greater the antibiotic effect

- Aminoglycosides
- Fluoroquinolones
For antibiotics that work via concentration-dependent killing, the higher the achieved concentration vs. MIC (Peak/MIC > 10), the what?

This is true for what antibiotics?
The greater the antibiotic effect

-Fluoroquinolones
-Β-lactam antibiotics
-Vancomycin
For antibiotics that work via concentration-dependent killing, the greater the AUC/MIC (>125), the what?

This is true for what antibiotics?
-thromycin
Macrolide names end in what?
-floxacin
Fluoroquinolone names end in what?
-amicin/ -amycin

Exceptions:
Amikacin (aminoglycoside)
Vancomycin (not aminoglycoside)
Daptomycin (not aminoglycoside)
Clindamycin (not aminoglycoside)
Aminoglycoside names end in what?

What are the exceptions?
- CSF
- Lung
- Bone
- Heart
- Abscesses
What sites are the most difficult to get antibiotics to?
-Lack of antibiotic penetration
-pH inactivation of antibiotic (<6)
-Enzyme inactivation
Why is it difficult to get antibiotics to penetrate abscesses?
Above - Clindamycin

Below - Metronidazole
Which antibiotics treat abscesses above and below the diaphragm, respectively?
-Hypotension (decrease blood (and therefore drugs) to organs)
-Ileus (Changes amount and consistency of drug absorption)
-Colitis (Changes amount and consistency of drug absorption)
-Bowel ischemia (Changes amount and consistency of drug absorption)
-Change in gastric pH (Changes the rate at which a drug is absorbed)
Identify conditions that would impair the bioavailability of an intravenous or oral medication. Give a brief explanation as to why this is.
-Cirrhosis
-CHF
-Pregnancy

These are all conditions that increase the amount of fluid in a person. Drugs that require dosing based on volume distribution will need to have dosing adjusted.
Identify conditions that would increase the volume of distribution, requiring larger doses to be given. Give a brief explanation as to why this is.
...
Study the image.
Endocarditis
Meningitis

Bacteriocidal used when the condition is more severe or if there is greater risk of complications.
Which of the following medical conditions should you use a bacteriCIDAL agent? Check all that apply.
-Endocarditis
-Urinary tract infection
-Strep throat
-Meningitis
Amoxicillin
Ciprofloxacin
Most oral therapy.

NEVER in children.
Give an example of an antibiotic with a recommended dose that does not take into account pharmacokinetic principles (is the same for everyone).
For children, dosing are ALWAYS determined based on mg of drug per kg of body weight.
What is the dosing rule when it comes to children?
-Good oral bioavailability
-DOES NOT have narrow therapeutic window
-No adverse reactions associated with peaks and troughs
For drugs that have a recommended dose and does not take into account pharmacokinetic principles, what are the characteristics that allow dosing for almost every person to be the same?
Vancomycin
Aminoglycoside
Any agents with narrow therapeutic windows
Give an example of an antibiotic that requires pharmacokinetic principles to determine the dose.
-If they are based on volume and distribution
-If they require renal dosing adjustments
-The site of infection
-If there are toxic doses that necessitates the monitoring of troughs and peaks.
For drugs that require pharmacokinetic principles to determine the dose, what are the characteristics of this drug that causes dosing for almost every person be different?
N-acetylglucosamine

N-acteylmuramic acid
The building blocks of bacterial cell walls consist of what two amino sugars?
Beta-1,4-glycosidic linkages
In the bacterial cell wall, N-acetylglucosamine and N-acteylmuramic acid are connected via what bond?
Each N-acetylmuramic acid has 5-AA peptide attach to it. The 5-AA peptide of adjacent N-acetylmuramic acids bind one another (forming peptide bonds).

This reaction is catalyzed by TRANSPEPTIDASE.
Describe the peptide bonds formed between the building blocks of bacterial cell walls.

What enzyme catalyzes the formation of this bond?
Transglycosylase
What enzyme catalyzes the formation of the Beta-1,4-glycosidic linkages between N-acetylglucosamine and N-acteylmuramic acid?
Inhibits cell wall synthesis
What is the Mechanism of Action (MOA) of Penicillin?
Inhibits cell wall synthesis
What is the Mechanism of Action (MOA) of Cephalosporins?
Inhibits cell wall synthesis

Similar to Vancomycin.

Vancomycin: Inhibits the formation of peptidoglycan, so cross-linking of peptidoglycan cannot occur. It does this by mimicking the D-Ala-D-Ala dipeptide of peptidoglycan and getting incorporated into the cell wall. This leads to osmotic fragility and cell lysis.
What is the Mechanism of Action (MOA) of Bacitracin?
Injury to plasma membrane
What is the Mechanism of Action (MOA) of Polymixin B?
Inhibits cell wall synthesis

Inhibits the formation of peptidoglycan, so cross-linking of peptidoglycan cannot occur. It does this by mimicking the D-Ala-D-Ala dipeptide of peptidoglycan and getting incorporated into the cell wall. This leads to osmotic fragility and cell lysis.
What is the Mechanism of Action (MOA) of Vancomycin?
Inhibit protein synthesis

Binds to 50S subunit of bacterial ribosome. Prevents translocation - movement of ribosome along the mRNA.
What is the Mechanism of Action (MOA) of Macrolide?
Inhibit protein synthesis

Changes shape of 30S portion of bacterial ribosome by binding irreversibly to it. This causes code on mRNA to be read incorrectly.
What is the Mechanism of Action (MOA) of Aminoglycoside?
Inhibits synthesis of essential metabolites

Blocks synthesis of Dihydropteroate
What is the Mechanism of Action (MOA) of Sulfonamide?
Inhibits synthesis of essential metabolites

Blocks action of Dihydrofolate reductase, so Tetrahydrofolic acid not formed!
What is the Mechanism of Action (MOA) of Trimethoprim (TMP)?
Inhibit protein synthesis

Binds irreversibly to 30S ribosomal subunit and interferes with attachment of tRNA to mRNA complex.
What is the Mechanism of Action (MOA) of Tetracycline?
Inhibits DNA/RNA replication or transcription
What is the Mechanism of Action (MOA) of Quinolones?
Inhibit protein synthesis

Inhibits bacterial protein synthesis by binding to the
50S ribosomal subunit (NOT present in human cells) and blocking translocation reactions
What is the Mechanism of Action (MOA) of Clindamycin?
Inhibit protein synthesis

Inhibits protein synthesis by binding to a receptor on 23S ribosomal RNA (part of the 50S subunit)
What is the Mechanism of Action (MOA) of Linezolid?
Inhibit protein synthesis

Dalfopristin:
Blocks an early step in protein synthesis by forming a bond with a ribosome to prevent elongation of peptide chain.
What is the Mechanism of Action (MOA) of Dalfopristin?
Inhibit protein synthesis

Quinupristin:
Blocks a later step in protein synthesis by preventing
the extension of peptide chains.
What is the Mechanism of Action (MOA) of Quinopristin?
Inhibits cell wall synthesis
What is the Mechanism of Action (MOA) of Monobactams?
Inhibits RNA replication or transcription

Binds to the Beta subunit of bacterial DNA-dependent RNA polymerase. This inhibits RNA
synthesis.
What is the Mechanism of Action (MOA) of Rifampin?
Inhibits cell wall synthesis
What is the Mechanism of Action (MOA) of Carbapenems?
When 2 or more antibiotics, with different MOAs, working together to allow a dosage reduction and/or faster and enhanced drug effect on organism.
What is synergism?
When one antibiotic interferes with the effects of another antibiotic.
What is antibiotic antagonism?
The more sites targeted on a microorganism, the greater the likelihood that it will get eradicated.
Why do you want to use antibiotics with different MOAs to achieve synergy?
Beta lactams

Should not be used together because they will compete for the same binding sites. This will eventually lead to resistance.
Name antibiotics that cannot be used together or infused with one another.
b) Penicillin and aminoglycoside

a) Wrong. They have the same MOAs.
c) Wrong. Have different MOAs but act on different bacteria.
d) Wrong. Target different subunit of the ribosome, so spectrum of activity is not the same.
What antibiotic classes, when used together, would be synergistic in treating an infection?
a) Penicillin and cephalosporin
b) Penicillin and aminoglycoside
c) Rifampin and quinolone
d) Erythromycin and tetracycline
A) Synergism (left-most)
B) Antagonism (middle)
C) Neither (right-most) - The graph of the combined effects of E and F indicates that the combined effects is still just as good as F alone. E did not bring it down.
Exaggerated, inappropriate, or prolonged immune
responses that cause damage to otherwise normal tissue.
Drugs can cause an allergic reaction. What is allergy?
An adverse side effect that is NOT immune- mediated.

Continuation of therapy may or may not be effected

Examples:
- Upset stomach
- Light-headedness
- Dry mouth
- Cough
What is drug sensitivity?

Should you stop treatment if a patient has drug sensitivity?

Give examples of drug sensitivities.
All other Beta-lactams - Because they all have the Beta-lactam ring structure.
If the patient has a penicillin allergy, what other class(es) would the patient potentially have a reaction to? Explain your reasoning.
Inhibit Cell Wall Synthesis:

-Bind to Penicillin-Binding Proteins (PBPs) located
on the inner surface of the cell wall.
-Interferes with cross-linking of peptidoglycan
-Osmotic fragility and cell lysis
How do Beta Lactams work?
Inhibitors of cell wall synthesis.
Vancomycin, Bacitracin, and Daptomycin are all what?
Beta lactam ring.
What are we looking at here?
The beta-lactam ring.
What site on a beta-lactam bind penicillin binding protein and is also targeted by beta-lactamases?
Bactericidal
Beta lactams are bacteriocidal or bacteriostatic?
time-dependent
Are beta-lactams time-dependent killers or concentration-dependent killers?
If the active form is unchanged via excretion in the kidneys, then it can be used to treat UTIs.
Beta lactams are excreted unchanged via the kidneys. How can this be beneficial?
Beta-lactams

Infusion is NOT the same as using together at the same time.
What family of antibiotics should NOT be infused with any other antibiotic (even though they can be used simultaneously with some other antibiotic)?
The penicillin will inactivate the aminoglycoside.

So, you will need to infuse penicillin first, then aminoglycoside second.
What will happen if you infuse penicillins with aminoglycosides?
True
True or False?
ALL antibiotics can cause GI upset.
Sensitivity reaction
The GI upset caused by antibiotics is considered an allergic reaction of a sensitivity reaction?
Fever, urticaria, angioedema, arthralgia
What are the symptoms of Interstitial nephritis?
Hemolytic anemia
Coomb's Test is used to test for what?
-Interstitial nephritis
-Decreased platelet aggregation
-Hemolysis
-Leukopenia, neutropenia, thrombocytopenia
with prolonged therapy (> 2 weeks)
-Neurologic complaints (w/ penicillins and
carbapenems)
What are the adverse effects of Beta-lactams?
It will mutate and produce Beta-lactamase (resistance)
What will happen to an organism if you continually expose it to Beta-lactams?
-Staphylococci
-Haemophilus influenzae
-Bacteriodes fragilis
-Klebsiella species
Name 4 common bacteria that produce β-lactamases.
Beta-lactamase Enzymes
The leading cause of resistance to Beta-lactam antibiotics is what?
A Beta-Lactamase Inhibitor is added.
Most penicillins are inactivated by bacteria that produce Beta-lactamase unless what happens?
Clavulanic acid
Sulbactam
Tazobactam
What are the compounds typically added to beta-lactams to confer resistance to beta-lactamase?
-Anti-staph penicillins (Naficillin)
-ALL cephalosporins (but not all are active against
staph)
-Carbapenems
-Vancomycin
Which Beta-lactams are structurally resistant to Beta-lactamase?
That the resistance is not due to beta lactamase.
If one of the structurally resistant (to beta lactamase) beta lactams are reported as being resistant to a particular bacteria, you know what for certain?
mecA
What gene confers classical methicillin resistance to certain strains of bacteria?
Extended spectrum (3rd generation) cephalosporins and monobactams.
Extended-Spectrum Beta-Lactamases (ESBLs) are enzymes that cause resistance to what antibiotics?
Only the Carbapenem and 2nd generation cephalosporin will work.

The bacteria will have resistance to the monobactam (thanks to the ESBL enzyme).
A person is infected with a bacteria that is strengthened with ESBL enzymes. Your colleague decides to treat him with either a 2nd generation cephalosporin, monobactam, or a carbapenem, and asks you which one will work.

What would you tell him?
-Penicillins
-3rd generation cephalosporins
-aztreonam
If you detect ESBL in a patient, you should avoid using what antibiotics?
Ampicillin and Amoxicillin
What are the aminopenicillins?
Beta-Lactamase resistant penicillins
Nafcillin and Methicillin are both what?
-Na+ or K+ overload with IV formulations of penicillins

-Beta-lactamase inhibitors increase incidence of
diarrhea

-If patient has VIRAL infection or on ALLOPURINOL, increased incidence of rash (only for Amoxicillin and Ampicillin)
What are three adverse effects associated with penicillins?
Overgrowth of Candida pseudomembranous colitis, which is secondary to C. difficile infection.
Over exposure to antibiotics can cause something associated with C. difficile. What is it?
HT or CHF

Because patients may retain more fluid
secondary to increase in sodium leading to fluid
overload (exacerbating the condition).
What disease states do you need to monitor if a patient is going to receive IV Penicillin?
Ampicillin or Amoxicillin

A TOXIC REACTION can occur (NOT allergy to penicillin, but actually a TOXIC reaction to these two specific drugs).

Symptoms:
Macular or maculopapular erythematous, pruritic rash on face, neck, trunk, and extremities
Patients with mononucleosis (viral infection) may present with a strept throat infection. What should you NEVER give these patients?
Supportive care

No.
Joanne is a 15 year-old female diagnosed with mononucleosis. She has no known allergies. What treatment do you recommend?

Does Joanne need antibiotic therapy?
Yes, Penicillin.

Amoxicillin and Ampicillin.
Paula is a 15 year-old female diagnosed with mononucleosis and strep throat. She has no known allergies.

Does Paula need antibiotic therapy? If yes, what therapy?

What medication(s) can you NOT give Paula?
No.
Are upset stomach and/or nausea/vomiting symptoms of a true allergy to penicillin?
Range from mild rash to anaphylaxis.

Serum sickness, fever, urticaria, angioedema, and
arthralgia.
In about 3-10% of the population, allergy to penicillin is in the form of hypersensitivity reaction. What are the symptoms associated with it?
Any beta-lactam - though it is less with monobactams.
If a patient has true penicillin allergy, you should avoid giving him/her what?
Higher if given via IV
Would you expect higher or lower incidence of penicillin allergy-derived hypersensitivity reaction when the drug is administered via IV as opposed to other routes?
Cephalosporin's incorporate themselves into the
cell wall by binding to Penicillin Binding Protein (PBP).

During replication, daughter cells are unable to
"close" where the cell wall was in contact with the
cephalosporin leading to cell death.
What is the mechanism of action of Cephalosporins?
Same as those for penicillins and other beta-lactams.
What are the adverse effects of cephalosporins?
AVOID ALCOHOL!!!

Can cause disulfiram-like reaction secondary to MTT group blocking alcohol metabolism
What should you warn patients who are about to be placed on a Cefotetan treatment regimen?
Abdominal pain and nausea/vomiting, especially after fatty meals. This can lead to gallstone formation.
Ceftriaxone can cause biliary sludging. What symptoms are associated with this?
False. Not all of them.
True or False?
All cephalosporins have activity against Staphylococcus (MRSA) or gram positive infections.
ONLY GRAM-NEGATIVES!!!

Klebsiella, E. coli, Enterobacteriaceae (Salmonella
and Proteus), Pseudomonas (PSA)
What common bacteria produce ESBLs?
1st generation = more gram + activity

2nd generation = maintains some gram +, but gains
gram -

3rd generation = still has gram +, but increased gram -

4th generation = maintains gram - activity, but regains gram +

5th generation = "Advanced Generation" - advanced
gram + activity (MRSA, VISA, and VRSA), but little gram - activity
Describe each of the cephalosporin generation of antibiotics in terms of their effectiveness in treating gram-neg and gram-pos infections.
Cephalexin = PO

Cefazolin = IV
Between Cephalexin and Cefazolin, which one is PO and which one IV?
Gram(+) bacteria = Staph (MSSA, MSSE) and Strep
Also, active against most "E, P, K" (Gram(-))
Cephalexin and Cefazolin are active against what type of bacteria?
Enterococci
Cephalexin and Cefazolin are not active against what type of gram(+) bacteria?
Second - because they have poor CNS penetration
If you suspect meningitis or other CNS infection, what generation cephalosporin should you avoid? Why?
Sinusitis and otitis media
Cefuroxime (can be given via IV or PO) and Cefaclor (can be given via PO) are both 2nd generation antibiotics. They are good for treating what?
Abdominal infections or ischemic skin and soft tissue conditions.
Cefoxitin (given via IV) and Cefotetan (given via IV) are second generation cephalosporins. They are good for treating what?
-Third generation Cephalosporin.

-Best activity against penicillin resistant strains of bacteria.
-Streptococcus pneumoniae.
-Good gram(-) coverage

-Bad against Pseudomonas.
Ceftriaxone (given via IV) is what type of antibiotic? How is it administered?

It is best used for treating what? Not good against what strains?
Second generation cephalosporin. Given via IV.
What type of antibiotic is Cefotetan? How is it administered?
Yes.

Third generation = Good CNS penetration
Would you ever use a third generation cephalosporin to treat a CNS bacterial infection?
- Low molecular weight
- Non-ionized at physiological pH
- Highly lipid soluble (large Vd)
- Not extensively protein bound
- More ABX can cross if meninges are inflamed
- Not a p-glycoprotein substrate
What are the unique characteristics of those antibiotics that can penetrate the BBB (i.e. what allows the drug to penetrate the blood brain barrier)?
Only available in IV
Fourth generation cephalosporins can be administered via what route(s)?
Better action against gram (+) while retaining potency for gram (-)
How are 4th generation cephalosporins an improvement over the 3rd generation?
Effective =
- Skin/Soft tissue gram(+): MRSA, VISA, and VRSA
- Respiratory gram(-): M. catarrhalis and H. influenzae

Not Effective = Bacteria with ESBLs
5th generation cephalosporins are the "advanced generation" cephalosporins. They are active against what?

What are they NOT effective against?
First generation: Cefazolin
What generation Cephalosporin is typically given via IV to prevent pre- and post-operative incision site infection?
Carbapenems
What beta lactam group has the broadest spectrum of activity (compared to the other beta lactams)?
Pseudomonas (PSA) and Acinetobacter
What two family of antibiotics develops resistance quickly to Carbapenems?
Yes.

Yes.
Are carbapenems beta lactamase resistant?

Are they resistant against bacteria with ESBL?
...
Bacteria not covered by Carbapenems.

Don't memorize this unless you have time. FYI only!
NO!

Cross sensitivity w/ penicillin, so they may get allergic reaction.
Can you use Carbapenems in patients allergic to penicillins? Why or why not?
Leukopenia, neutropenia and thrombocytopenia.
Prolonged therapy (over 2 weeks) with carbapenems may cause what?
Those with renal insufficiency.
You need to adjust the dose periodically if you give carbapenems to what patient population?
Kidneys

renal dehydropeptidase
Imipenem can be hydrolyzed and inactivated where and by what enzyme in the body?
Those with high risk of seizure or those living with seizure disorders

Imipenem decreases the seizure threshold (easier to get seizures).
You should never prescribe Imipenem to members of what patient population? Why not?
Cilastatin

No
What is given with Imipenem that will inhibit
dehydropeptidase?

Does it have antimicrobial activity?
No
Do the other carbapenems (aside from Imipenems) need Cilastatin to be effective?
Great against = Gram(-)

Suck against = Gram(+) and Anaerobes
Monobactam (aztreonam) are great against gram(+) or gram(-)?

They suck against gram(+) or gram(-)?
Yes for both.
Are monobactams (aztreonam) effective against PSA? Enterobacter?
Yes. No reported cross-sensitivity reaction. Though, you should use it with caution.
Can you use monobactam (aztreonam) in patients who are allergic to penicillin?
-Ceftazadime
-Cefepime
What beta-lactam antibiotic would be the best choice to treat PSA infection?
-2nd generation cephalosporin:
cefoxitin and cefotetan

-Carbapenems:
meropenems or imipenem

The above antibiotics maintain their activity
against ESBL producing bacteria
SM is a 53-year-old female being seen for a recurrent UTI secondary to self-catheterization on a daily basis. She presents with fever and is diaphoretic. Her last infection was cultured and shown to be caused by ESBL of E. coli.

What antibiotics would you recommend? Explain why.
Why: Patient at greatest risk for wound infection caused by staph or strep after surgery. Need to prevent infection.

How: Administered 1 hour prior to surgery and for the first 24 hours post-surgery
Why and how do we use cell wall biosynthesis inhibitors pre-operatively?
D-Ala-D-Ala

Cross-linking the peptidoglycan subunits.
What dipeptide can be found at the terminus of peptidoglycan?

It is responsible for what?
Gram(+) bacteria (especially MRSA)

NO Gram (-) activity
Vancomycin is used specifically to treat what?

It is not effective against what type of bacteria?
Bacteriocidal, except for Enterococcus (bacteriostatic)
If Vancomycin bacteriocidal or bacteriostatic?
CSF - Cannot cross the BBB because of its large size.
Once administered, Vancomycin is widely distributed in the body, except where? Why?
Yes. It is excreted unchanged in the urine.
Would you ever need to dose adjust Vancomycin based on kidney function?
To treat infections by resistant bacterial strains, serious infections, and patients with penicillin allergies.

Also, it is used to treat:
-Endocarditis
-Osteomyelitis
-S. pneumonia
Vancomycin is reserved to treat what conditions?
Bacteria that are localized in the GI tract:
C. difficile or S. aureus enterocolitis (because the drug is not absorbed systemically from the GI tract - max action will be in GI tract)
Oral administration of Vancomycin is reserved for treating infections by what bacteria? Why?
Kidneys - nephrotoxic
Vancomycin is toxic to what organ at high doses?
Rare = Chills, fever, rash

Common = Red neck syndrome (NOT ALLERGY)
Skin gets flushed in neck region
Hypotension
Concurrent tachycardia
What are the rare adverse effects of Vancomycin?

What is the common adverse effect seen when you give the drug too fast via IV?
Increase length of infusion (1g over 60 minutes or
longer) or pre-treat with an antihistamine
How might you lessen the effects of Red Neck Syndrome in patients undergoing treatment with Vancomycin?
The bacteria modifies the D-Ala-D-Ala of Vancomycin into D-Ala-D-Lactate, so Vancomycin cannot bind to cell wall.

This leads to loss of antibacterial activity.
What is the mechanism behind Vancomycin resistance in VISA and VRSA?
Topical application for treatment of gram(+) infections
Bacitracin is reserved for treatment of what?
Bacitracin = Effective against Gram(+)

Neomycin/Polymyxin B = Helps with Gram (-)
Why is Bacitracin given as a solution with Neomycin or Polymyxin B mixed in?
Binds to cell membrane via calcium-dependent
insertion of its lipid tail. This results in depolarization of cell membrane with continuous potassium efflux and rapid cell death.
What is the MOA of Daptomycin?
Vancomycin-resistant (VRSA, VISA) infections.
Daptomycin is typically used to treat what?
Myopathy

Must monitor creatine phosphokinase levels
What are the adverse effects of Daptomycin?

So, what must we do when treating a patient with Daptomycin?
Pulmonary surfactant antagonizes daptomycin
making it ineffective in treating pulmonary infections.
Why is Daptomycin not used to treat pneumonia?
Inhibiting the 70S bacterial ribosome in one way or another.
Antibiotics that inhibit protein synthesis are actually doing what?
Bacteriostatic
Tetracyclines are bacteriocidal or bacteriostatic?
Dairy products and antacids - should wait about 2 hours after ingestion to take meds.

The drug chelates with divalent metal ions (calcium, magnesium, iron, aluminum). This interferes with absorption and antibiotic activity.
You should warn patients taking tetracyclines about consuming what?
Pregnant patients

Tetracycline crosses the placenta and is excreted in breast milk. Chelation with calcium will damage growing bones and teeth of fetus.
You should NEVER give tetracyclines to what patient population? Why not?
No. The drug can passively and actively cross the cell wall and plasma membrane.
Do you need to prescribe a cell wall inhibitor drug with tetracycline?
Best: Doxycycline and minocycline

Worst: Tigecycline (Because of this, it's only available in IV.)
Oral bioavailability varies from one tetracycline to the next. Which one(s) are the best to give orally and which one(s) are the worst?
Bile and Kidneys

Yes.
Most of the tetracyclines are excreted via what?
So, would you need to dose adjust?
Doxycycline and Tigecycline
What two tetracyclines are excreted via the feces and do not require dose adjustment?
No. It is no longer recommended for gonorrhea.
Would you treat a patient with gonorrhea with Tetracycline?
BROAD:
- Gram +
- Gram -
- Anaerobes
- Rickettsiae
- Chlamydia (but NOT gonorrhea)
- Mycoplasmas
- Some Protozoa
Tetracyclines are a broad or narrow-spectrum antibiotic?
Change antibiotic structure, so it can't bind its target.
Describe tetracycline resistance caused by enzymatic inactivation.
Impaired influx or increased efflux by an active transport protein pump.

This explains gram(-) resistance to older tetracyclines and gram(+) (i.e., Staph) resistance to current tetracyclines.
Aside from enzymatic inactivation, what is another cause of tetracycline resistance dealing with influx and efflux?

This explains what?
Ribosome protection by proteins that interfere with tetracycline binding site (on the ribosome itself).

So, the gram(+) bacterial ribosome is protected from all tetracyclines, except Tigecycline.
Lastly, aside from enzymatic inactivation and influx/efflux issues associated with active transport protein pump, tetracycline resistance can be caused by what?
1) It can withstand resistance from all causes
2) VERY broad spectrum of activity - MRSA, VISA, VRSA, Acinetobacter, enterococci, enterobacteriaceae, other atypical strains
3) Great tissue and intracellular tissue penetration - large volume of distribution (Vd) - Used for skin and soft tissue infection and intra-abdominal infection.
What are the advantages of using Tigecycline?
1) Nausea, Vomiting, Diarrhea (so give with food)
2) Candidiasis; enterocolitis
3) Kidney toxicity
4) Teeth discoloration
5) Bone deformity or growth inhibition
6) Photosensitization
7) Vestibular reactions
8) Liver toxicity
What are the adverse effects of Tetracyclines?
Causes renal tubular acidosis leading to nitrogen
retention (also seen when combined with diuretics)
Describe the kidney toxicity associated with certain tetracyclines (that have renal clearance).
1) Interferes with the initiation complex of peptide
formation
2) Induce misreading of mRNA, leading to the incorporation of the wrong amino acid into the peptide, which leads to nonfunctional or toxic protein.
3) Causes a breakup of polymers into nonfunctional
monomers
What are the 3 ways in which aminoglycosides inhibit protein synthesis once they irreversibly bind to 30S subunit?
Bacteriocidal
Are aminoglycosides bacteriocidal or bacteriostatic?
concentration-dependent
Aminoglycosides are antibiotics that function via concentration-dependent or time-dependent killing?
-Target peak concentration for antibiotic effect
- Re-dose when target trough is achieved (to prevent toxicity)
-Dose according to patient's weight and renally dose-adjust.
What must you do while giving aminoglycosides to a patient?
Yes. PAE persists even with unmeasurable concentration of aminoglycosides.
Would you expect post-antibiotic effects (PAE) in patients that you treat with aminoglycosides?
-Best for gram(-) enteric bacteria
-Can not treat gram(+) bacteria by itself
Aminoglycosides are effective against gram(-) or gram(+) bacteria?
Beta-lactams or Vancomycin
What antibiotics are aminoglycosides typically used with?
At high concentrations, aminoglycosides may precipitate, leading to loss of antimicrobial activity.
Why should you not infuse aminoglycosides with other antimicrobials?
Bacteria mutate and produce a transferase enzyme that inactivates the drug, impairing the entry of aminoglycosides into the cell.

Also, a mutation may lead to the receptor protein on the 30S ribosomal subunit to be deleted or altered.
What causes resistance to aminoglycosides?
- Auditory damage (tinnitus, high frequency hearing
loss)
- Vestibular damage (vertigo, ataxia, loss of balance)
Describe the Ototoxicity associated with aminoglycoside use.
- Increased serum creatinine
- Early indication = Increased serum [aminoglycoside] or lack of clearance
Describe the Renal toxicity associated with aminoglycoside use.
Target a trough < 2 mcg/mL (traditional dosing)
What is the traditional dosing rule to prevent aminoglycoside toxicity?
Inhibits bacterial protein synthesis by binding to the
50S ribosomal subunit (NOT present in human cells) and blocking translocation reactions.
What is the MOA of Chloramphenicol?
Bacteriostatic, but bacteriocidal at higher concentration.
Macrolides are bacteriostatic or bacteriocidal?
Good distribution to most tissues.

BUT NOT effective in treating CNS infections.
Describe the tissue penetration of macrolides. What is the extent to which it can penetrate?
Erythro = Clarithro > Azithro
As macrolides, how effective are erythromycin, clarithromycin, and azithromycin in treating gram(+) Pneumococci infections?
Erythro = Clarithro > Azithro
As macrolides, how effective are erythromycin, clarithromycin, and azithromycin in treating gram(+) Streptococci infections?
Azithro > Clarithro >> Erythro
As macrolides, how effective are erythromycin, clarithromycin, and azithromycin in treating gram(+) Mycoplasma infections?
Azithro >> Clarithro = Erythro
As macrolides, how effective are erythromycin, clarithromycin, and azithromycin in treating gram(+) Chlamydia infections?
Azithro = Clarithro >> Erythro
As macrolides, how effective are erythromycin, clarithromycin, and azithromycin in treating gram(-) Neisseria infections?
Azithro = Clarithro >> Erythro
As macrolides, how effective are erythromycin, clarithromycin, and azithromycin in treating gram(-) Hamophilus influenzae infections?
Azithro = Clarithro >> Erythro
As macrolides, how effective are erythromycin, clarithromycin, and azithromycin in treating gram(-) Bordetella infections?
Azithro = Clarithro >> Erythro
As macrolides, how effective are erythromycin, clarithromycin, and azithromycin in treating gram(-) Bartonella infections?
-Reduced permeability of cell membrane or active efflux
-Production of esterases that hydrolyze macrolides
-Modification of ribosomal binding site by chromosomal mutation or enzymatic inactivation via constitutively expressed methylase
What are the three ways in which a bacteria can become resistant to macrolides?
True.
True or False?
If a bacteria is resistant to 1 macrolide, NONE of the remaining macrolides will be effective in getting rid of it.
-Nausea/Vomiting and Abdominal pain (after stimulation of gut motility)
-Cholestatic hepatitis (fever, jaundice) hypersensitivity reaction
-Prolonged QTc interval
-Drug-drug interactions (DDI)
-Skin rash
What are the adverse effects of using macrolides?
Erythromycin
The adverse effects of macrolides is most common with the use of which one?
True.
True or False?
If you get a skin rash from one of the macrolides, you will probably get rashes from using any one of the remaining macrolides.
YES!!!

It's a toxic reaction (red rash with purple pin pattern extending from the trunk to the extremities).
Do you need to stop medication if a patient develops a macrolide skin rash?
Clarithromycin
What is the only macrolide that needs renal dose adjusting?
Without meals.

It has to be taken one hour before or two hours after meals.
Would you advise patients to take Azithromycin with or without meals?
Slow release - effective up to 7 hours after last dose.
Describe the tissue penetration characteristic of Azithromycin.
C. difficile-associated diarrhea
The new macrolide, Fidaxomicin, is approved for treating what?
Bacteriostatic
Clindamycin is bacteriostatic or bacteriocidal?
-Good penetration into abscesses
-Not effective in treating CNS infections
Describe the tissue penetration characteristic of Clindamycin.
• Gram + anaerobes
• Staphylococci
• Pneumococci
• Gram - anaerobes
• Moderate activity against Bacteroides
What type of bacterial infections can be effectively treated with Clindamycin?
Resistant to:
-Enterococci (Group D Strep)
-Gram(-) aerobic organisms
What bacteria strains are resistant to Clindamycin?
-Skin rash
-Nausea
-Diarrhea -Pseudomembrane colitis secondary to C. difficile overgrowth
What are the adverse effects of Clindamycin?
Quinupristin
Dalfopristin
What are the Streptogramins introduced in class?
Synergistic
Would combination of Quinupristin and Dalfopristin be synergistic or antagonistic?
-Vancomycin-resistant E. faecium infections.
-MRSA/E infections
-Infections by resistant strains of Streptococci
Streptogramins have been used to treat what kind of infections?
No.

E. Faecalis has an intrinsic resistance to streptogramins.
Can you use the streptgramins to treat E. faecalis infection?
Hepatic and biliary elimination
What is the predominant route of elimination of streptogramin from the body?
-Pain at infusion site
-Arthralgia-myalgia syndrome
What are the adverse effects of streptogramin treatment?
Inhibits CYP-450 3A4
Streptogramins have drug-drug interactions (inhibition) with what?
Bacteriostatic, but is bactericidal against streptococci.
Oxazolidinones-Linezolid are bacteriostatic or bacteriocidal?
Trick Question:
It has NO cross resistance with other antibiotics.
Oxazolidinones-Linezolid have cross resistance with what other antibiotics?
23S binding site mutation
Resistance to Oxazolidinones-Linezolid is due to what?
ONLY Gram(+)
Linezolid is only effective against what type of bacteria?
-Vancomycin-resistant E. faecium
-Nosocomial pneumonia
-Skin infections
Linezolid is reserved only for what infections?
SSRIs and MAOIs - Can cause Serotonin Syndrome
What "significant" drug-drug interactions occur with Linezolid that could cause severe adverse events or toxicity?
• Thrombocytopenia
• Neutropenia
• Serotonin syndrome
What are the adverse effects of Linezolid?
topoisomerases
Fluoroquinolones inhibit what bacterial enzymes?
Gram(-) = DNA gyrase (topoisomerase II)

Gram(+) = Topoisomerase IV
What is the primary fluoroquinolone target in gram(-) bacteria? How about gram(+)?
Concentration-dependent bactericidal activity
Do Fluoroquinolones work via time or concentration-dependent killing?

Is it bacteriocidal or bacteriostatic?
Good.
Fluoroquinolones have good or poor oral bioavailability?
Antacids

It can lead to chelation.
You should warn patients taking Fluoroquinolones not to take them with what? Why?
It needs to be renally dose adjusted (with one exception).
When giving patients Fluoroquinolones, what must you keep in mind about dosing?
Moxifloxacin
What is the only Fluoroquinolone that is not renally cleared?
Those with hepatic failure
Moxifloxacin is contraindicated in what patient population?
-Altered target sites - Chromosomal mutations in DNA gyrase and topoisomerase IV

-Altered cell wall permeability - Decreased porin expression

-Active efflux pump - Transfers drug out of cell
What are the three mechanisms of Fluoroquinolone Resistance?
No.
Fluoroquinolone cross-resistance occurs within the same class.

So, the Levofloxacin won't be sensitive for long.
You test out ciprofloxacin and levofloxacin on a patient with bacterial infection. If the bacteria is resistant to Ciprofloxacin, but sensitive to Levofloxacin, would you used Levofloxacin on the patient?
Group 1: (Norfloxacin)

Group 2 (Ciprofloxacin and Levofloxacin)

Group 3 (Moxifloxacin)
Fluoroquinolones have how many subgroups? What are the members of each subgroup?
Group 3 is inferior to Group 1 and 2 in fighting off Gram(-).

Group 3 is superior to Group 1 and Group 2 in fighting off Gram(+).
How does Group 3 Fluoroquinolones compare to Group 1 and 2 in terms of spectrum of activity?
Moxifloxacin is not concentrated or excreted in
the urine and would not treat the UTI. Use
ciprofloxacin.
Patient has symptoms of a UTI. You decide to prescribe moxifloxacin. Why does the pharmacist contact you?
• Photosensitivity
• QT prolongation
• Tendonitis or tendon rupture
• May damage growth of cartilage (avoid in children and during pregnancy)
What are the adverse effects of Fluoroquinolones?
Patients with uncorrected hypokalemia or receiving Class IA or Class III anti-arrhythmic agents

Because Fluoroquinolones cause QT prolongation.
You should use caution in using Fluoroquinolones to treat what patient population? Why?
- Nitro group is chemically reduced in anaerobic
bacteria and sensitive protozoans
- Reaction disrupts DNA and inhibits nucleic acid
synthesis
What is the MOA of Metronidazole?
Intestinal and extraintestinal tissue infections, including CNS.

Drug of Choice for C. difficile.
Metronidazole can penetrate many tissues and is effective in treating what?

Can it penetrate the CNS?
• Nausea
• Headache
• Dry mouth
• Metallic taste
• Pancreatitis
• CNS toxicity (rare)
• May be Teratogenic
• Disulfiram reaction
• Seizures and Peripheral Neuropathy
What are the adverse effects of using Metronidazole?
With alcohol:
Severe vomiting, tachycardia, shortness of breath
What is a Disulfiram reaction?
2 days
How long after dosing do patients taking Metronidazole need to wait in order to drink alcohol?
Point mutations in the gene that codes for the Beta subunit
Resistance to Metronidazole results from what?
Bactericidal
Metronidazole is bacteriostatic or bacteriocidal?
• Gram(+) cocci
• Gram(-) cocci
• Enteric bacteria
• Mycobacteria
• Chlamydia
Rifampin is effective against what types of bacteria?
None.
Would you expect Rifampin to have cross resistance to other antimicrobials? If yes, which one?
• Orange bodily fluids (tears, urine, sweat) -
Harmless but stains (including contact lenses)
• Rash
• Thrombocytopenia
• Nephritis
• Cholestatic jaundice
• Proteinuria
• Induces MOST CYP450 isoforms
What are the adverse effects of Rifampin?
Purines that will eventually be integrated as DNA.

PABA - p-aminobenzoic acid
Both Sulfonamides and Trimethoprim ultimately block the synthesis of what?

Normally, the purines are synthesized from what original, parent compound?
No. Only non-mammals.
Do humans produce PABA?
TMP + Sulfonamide
What is Bactrim?
Sulfonamide
What drug is the structural analog of PABA and inhibits folate production?
Bacteriocidal
Are antifolate drugs (e.g., Sulfonamides, TMP) bactericidal or bacteriostatic?
CNS = Yes
Placenta = Yes
Antifolate drugs are widely distributed into body fluids and tissues once administered.
Is it capable of penetrating the CNS?
How about the placenta?
Good.
Antifolate drugs have good or poor oral bioavailability?
Fluid overload
What can occur as a result of IV administration of antifolate drugs?
Yes.
Most or some of the drug is excreted via urine.
Would you need to renally dose adjust antifolate drugs?
What does this tell you?
TMP component
In TMP/Sulfa (Bactrim), dosing is dependent on the TMP or the Sulfa component of the drug?
-Best against gram(+)

-Effective against most gram(-)

-Atypical organisms
(EXCEPT mycoplasma)
Antifolates are active against what type of bacteria?
PSA and Neisseria
What two bacteria strains are resistant to antifolates?
-Intrinsic resistance:
Mammalian cells and some bacteria lack the enzymes required for folate synthesis from PABA

-Acquired resistance:
Overproduction of PABA
Production of a folic acid-synthesizing enzyme
with low affinity for sulfonamides
Impaired permeability to the sulfonamide
Bacterial resistance to antifolate medications is due to what?
• Increased adverse effects in patients with AIDs

• Avoid in patients with G6PD deficiency
• Avoid in pregnant or nursing patients
On what patient populations must you take caution in using antifolate drugs?

You must avoid using the drug completely in what patient populations?
• Rash
• Fever
• Thrombocytopenia
• Megaloblastic anemia
• Jaundice and kernicterus in infants
• Disulfiram reaction
What are the adverse effects of antifolate drugs?
Mammalian cells can utilize exogenous folate and
do not synthesize folate using the same mechanism as bacteria.
Why do sulfonamides not affect mammalian
cells?
Interferes with metabolism and inhibits protein
and cell wall synthesis
What is the MOA of Nitrofurantoin?
Bacteriostatic AND bactericidal
Is Nitrofurantoin bacteriocidal or bacteriostatic?
- Systemic infections or upper UTIs
-Because it is rapidly excreted in the urine via glomerular filtration and tubular secretion
Nitrofurantoin is NOT to be used for what? Why?
Both Gram + and Gram -
Nitrofurantoin is effective against gram(+) or gram(-) bacteria?
PSA and other proteus strains of bacteria due to resistance
Nitrofurantoin is not effective against what?
Those with severe renal insufficiency
Nitrofurantoin should NOT be given to what patient population?
-Nausea and vomiting
-Neuropathies and hemolytic anemia in G6PD deficiency
What are the adverse effects of Nitrofurantoin?
-Fourth
-Mortality rate ≈ 35%
Fungal infection is the (blank - rank) leading cause of fatal infections and continues to rise.
What is the mortality rate from fungal infections?
...
Study this if you have time.
• Mechanical ventilation
• Use of antibiotics
• Critically ill

Switched to: Caspofungin

Monitored:
- Pts clinical picture
- Monitor Liver Function Tests (LFTs)
- Cultures
EW, is a 54 F. She underwent renal mass resection on 08/12/08 and was discharged home. She was readmitted 08/16/08. CT scan revealed cecal perforation. She underwent resection of the right colon with a primary anastomosis and closure of the abdomen. Pt was admitted to SICU post-op.

-Mechanical Ventilation
-Post-op ABX: ampicillin, gentamicin, metronidazole, and fluconazole for surgical prophylaxis
-Febrile since admission

Labs:
WBC: 11.3 (incr)
SCr: 0.5 (stable)
BUN: 8
CrCl: 74.9 mL/min
Chest x-ray: extensive, bilateral infiltrates

Her risks of developing fungal infection is most attributable to what?

What should the antifungal be switched to?

What should be monitored?
• Intrinsic Resistance: Have never been susceptible to medication, due to gene mutation or having no structure for drug to bind to...naturally does not have activity

• Acquired Resistance: Resistance after exposure to medication by causing upregulation of efflux pumps or cross resistance between organism.
What is the difference between acquired and intrinsic resistance?
Patient has clinical progression of disease
- Febrile
- (+) cultures
- Previous failure on antimicrobials
When should you initiate therapy for fungal infections?
Earlier generation = Fungistatic

Later generation = Fungicidal
Are azoles fungistatic or fungicidal?
Interferes with fungal Cyp450 activity and decreases ergosterol synthesis.
What is the MOA of azoles?
Most Candida spp. (C. albicans, C. parapsilosis)
What organism is susceptible to Fluconazole?
Intermediate susceptibility: C. glabrata
What organism has intermediate susceptibility to Fluconazole?
Resistant: C. krusei, Aspergillus (Intrinsic resistance)
What organism is resistant to Fluconazole?
Great penetration into body fluids (blood, urine, CSF, peritoneal fluid, sputum)
Describe the extent to which Fluconazole can penetrate patients' tissues.
• Rash
• Drug-drug interactions
• Hepatotoxicity- monitor LFTs (monitor once tx exceeds 2 weeks)
• Monitor renal function (for dosing adjustment, not toxicity)
• Hypokalemia- risk of arrhythmias
What are the adverse effects of Fluconazole?
Candida, Aspergillus, Cryptococcus
Itraconazole is active against what species of fungi?
It penetrates through adipose tissue, mucus membranes - leaving little concentration in CSF and urine.
Itraconazole is highly lipophilic. What does this mean?
No.
Do you need to make renal dose adjustments for Itraconzaole?
Cyp-3A4
Itraconazole is extensively metabolized by what enzyme?
The oral solution of Itraconazole
You should be sure to inform patients taking oral capsule form of Itraconazole not to use it interchangebly with what?
No. Poor oral bioavailability.
Would it be okay to administer Itraconzaole via oral solution for patients with systemic infection?
• Take oral capsule with food
• Take oral solution on empty stomach
Patient 1 is taking Itraconazole oral capsule and Patient 2 is taking Itraconazole oral solution. In terms of taking it on an empty stomach or with food, what would you tell Patient 1 and Patient 2?
Rare:
Serious cardiovascular adverse events, including death, ventricular tachycardia, and torsades due to drug-drug interactions.

Hepatoxicity
What are the adverse effects of Itraconazole?
Patients with left ventricular dysfunction or history of CHF.
Itraconazole should not be used/used with caution in what patient population?
-Fluconazole- resistant Candida (deep tissue infection and Candidemia in non-neutropenic patients)
-Invasive Aspergillus
Voriconazole has an extended spectrum of activity. It is effective against what?
Absolutely. Voriconazole requires dose adjustments in patients with renal and hepatic dysfunction.
Would you need to make dose adjustments for Voriconazole?
-Teratogenic
-Reversible Ocular changes in 15-20% of pts.
-Hepatotoxicity in about 14% of pts.
-Cholestasis- monitor bilirubin and alk phos
-Infusion related reactions
-Rash in about 10% of pts.
What are the adverse effects of Voriconazole?
In patients with arrhythmias
You should use Voriconazole with caution in what patient populations?
Posaconazole
Which azole has the broadest spectrum of activity?
Prophylaxis after bone marrow transplant with a
diagnosis of graft vs. host disease or febrile
neutropenia.

Oropharyngeal candidiasis nonresponsive
to fluconazole or itraconazole

Salvage therapy for refractory invasive infections
Posaconazole is used to treat what?
No adjustment needed for renal impairment because not removed by hemodialysis

No adjustment needed for hepatic impairment because not metabolized by the CYP system. Primarily glucoronidation.
Would you need to make renal dose adjustments for posaconazole? How about hepatic dose adjustment?
Should be administered with a full meal or
liquid nutritional supplement
Do patients need to take Posaconazole with food or without food?
-Teratogenic
-Reversible Ocular changes
-Hepatotoxicity - must monitor LFTs
-Cholestasis - must monitor bilirubin and alk phos
-Possible QT prolongation
What are the adverse effects of Posaconazole?
Fungicidal

But, against Aspergillus, it's Fungistatic.
Echinocandins are fungicidal or fungistatic?
-Concentration dependent inhibition of 1,3-beta-D-glucan synthase

-Reduces the formation of the essential polysaccharide composing 30-60% of candida cell walls

-Leading to osmotic instability and cell lysis
What is the MOA of Echinocandins?
Azoles
Which one is more hepatotoxic, Azoles or Echinocandins?
Aspergillus and refractory or resistant Candida
Caspofungin is use to treat infections with what fungi?
- Intra-abdominal cavity
- Abscesses
- Peritoneum
- Pleural space

BUT, has POOR penetration into URINE.
Caspofungin can penetrate what tissues/fluids?
-No adjustment for renal impairment because it's not dialyzable

-Moderate hepatic impairment requires decrease
in dose. No data on what to do with severe hepatic impairment.

-Concurrent RIFAMPIN therapy requires higher
dosing.
What do you have to remember about dosing of Caspofungin?
Adverse effects are Infusion-related reactions:
• Nausea/ vomiting
• Elevated AST/ALT and alk phos- monitor LFTs
• Hypokalemia - monitor electrolytes
• Pulmonary edema
What are the adverse effects of Caspofungin?
Binds to ergosterol altering cell membrane
permeability, causing leakage of cell components.
What is the MOA of Amphotericin B?
Aspergillus
Blastomyces
Candida
Cryptococcus
Histoplasma
Zygomycetes
Amphotericin B is effective against what fungi?
Refractory or resistant fungal infections
Amphotericin B is typically used to treat what?
-Pre-medicate using NSAID or acetaminophen with
diphenhydramine or hydrocortisone
-Infuse for over 4-6 hours
-Administer Bolus NS before and after Amp B infusion to prevent hypotension.
-The total duration of therapy should be between 4-12 weeks
-If rigors occurs, treat with meperidine IVP.
What is the protocol for using the current formulation of Amphotericin B?
- Inhaled
- Intraoccular
- Subconjunctival application
- Intracavitary
- Bladder irrigations
What are the many forms of Amphotericin B, aside from the conventional IV?
- Hypotension
- Fever/chills after infusion
- Anemia
- Anaphylaxis
- Respiratory distress
- Renal toxicity
What are the adverse effects of IV Amphotericin B?
- Pre-medicate using NSAID or acetaminophen with
diphenhydramine or hydrocortisone
- Lipid Dosing: Infuse over 2 hours
- Conventional dosing: Infuse over 4-6 hours
- The total duration of therapy should be between 4-12 weeks
- NS boluses NOTNEEDED with lipid formula
- If rigors occurs, treat with meperidine IVP.
What is the protocol for using the lipid formulation of Amphotericin B?
- Peripheral edema
- Tachycardia/hypotension
- Chills/fever post infusion
- Electrolyte imbalances
- Arrhythmias
What are the adverse effects of the Lipid formulation of Amphotericin B?
Renal impairment due to drug possible, so if suspected, decrease dose to 50% or administer every other day (conventional)

Dialysis: poorly dialyzed, no supplement
What dosing adjustments need to be made for Amphotericin B?
Greater than 1 mg/kg/day
Risk of renal toxicity is greater when doses exceed what?
Conventional
Which one is more toxic, the lipid or the conventional formulation?
• Renal function
• Ins/outs (fluid intake and urine output)
• Electrolytes (potassium and magnesium)
• Liver function
• Temperature
• DDI with nephrotoxic agents
When treating a patient with Amphotericin B, what do you have to monitor (in all)?
Fluconazole remains the drug of choice for most candida infections.

Refractory candida: voriconazole or echinocandin.

Reserve Amp B for severe infections, refractory to all other antifungals.
What is generally accepted practice for the use of Fluconazole, Voriconazole, Echinocandin, and Amphotericin B?
...
Study image if you have time...
...
Study image if you have time.
• Prevent viral entry into host cell
• Prevent replication
• Inhibit viral uncoating
• Inhibit viral processing
What is the goal of antiretroviral therapy?
HSV-1: Mouth, face, skin, esophagus, or brain

HSV-2: Genitals, rectum, skin, hands, or meninges
HSV-1 infects what body parts?

HSV-2 infects what body parts?
No. Once infected, ALWAYS infected.
Can you clear an HSV infection (cure)?
- Painful sores or blisters
- Flu-like symptoms
- Psychological distress
What are the general symptoms of Herpes Simplex viral infection?
- HSV encephalitis
- Fatal infection in newborns
What are complications of Herpes Simplex viral infection?
• Primary infection:
-Initiate therapy at the first clinical sign of infection

• Recurrent infection:
- Episodic suppressive therapy (At the onset of symptoms but no more than 24 hours after the appearance of lesions)
- Chronic suppressive therapy
What are the steps taken in treating primary and recurrent HSV infections?
Suppressive therapy reduces frequency and
severity of recurrence but does NOT prevent viral
shedding, so there is risk of disease transmission.
What are the uses and drawbacks of using suppressive therapy to treat HSV infections?
• Fever and itchy rash:
- Blister-like
- Face, scalp, trunk
What are symptoms of Varicella-Zoster infection?
• Highly contagious
- Coughing and sneezing
- Direct contact
What is the mechanism of transmission of Varicella-Zoster virus?
Most common in those who HAD VZV infections (those who had chickenpox before).

Think shingles.
Prevalence of VZV infection is highest in what population?
-Risk of getting shingles increases with age.
-It is caused by VZV that remains dormant.
-The virus gets reactivated, travels along nerves causing a localized rash (along the dermatome).

(Remember that the virus stores itself in the ganglia).
Describe the etiology of shingles.
- Postherpetic neuralgia
- Scarring
- Bacterial infection
- Ocular abnormalities
What are complications associated with Varicella-Zoster infection?
Acyclovir (Trade name = Zovirax) - PO, IV, topical

Famciclovir (Trade name = Famvir) - PO

Valacyclovir (Trade name = Valtrex) - PO
What drugs are used in Anti-Herpes Therapy?

Administered in what form?
- Drug taken up by ALL host cells
- Phosphorylated to monophosphate by a virus-encoded
thymidine kinase (only infected host cells affected - selective toxicity).
- Converted to triphosphate by host cell enzymes
- Leads to competitive inhibition of viral DNA polymerase
What is the MOA of Acyclovir?
-Absence or partial production of viral thymidine kinase
-Altered thymidine kinase specificity
-Altered viral DNA polymerase
What is the mechanism of Acyclovir resistance?
HSV-1 > HSV-2 > VZV > Cytomegalovirus
Rank the effectiveness of Acyclovir in treating infections caused by the following:
HSV-2
CMV
HSV-1
VZV
- Poor oral bioavailability

- Decrease with increased doses

- Topical application will decrease effectiveness
Acyclovir has good or poor oral bioavailability?

Bioavailability increases or decreases if you increase dose?

How effective is the topical administration?
Yes. It's excreted in the urine unchanged.
You somehow find VZV in a patient's urinary tract. Can you use Acyclovir to treat it?
• Nausea, diarrhea
• Rash
• Headache
• Renal insufficiency and neurotoxicity with IV
formulation
What are the adverse effects of Acyclovir?
Acyclovir

Converted rapidly and completely via enzymatic
hydrolysis
Valacyclovir is a prodrug of what antiviral drug?

How is it converted?
Better

Same adverse effects.
How does oral bioavailability of Valacyclovir compare to that of Acyclovir?

How do the adverse effects of Valacyclovir compare to that of Acyclovir?
- As effective as acyclovir for HSV
- More effective in treating VZV
What are the clinical uses of Valacyclovir?
...
Study symptoms of Flu.
-Vaccination: Everyone 6 months or older.

-Antiviral therapy: Indicated for those at high risk of serious complications
Flu vaccination and Antiviral therapy are for whom?
Amantadine
Rimantadine

Because of RESISTANCE!!!
What medication is not used for Anti-Influenza? Why?
• Oseltamivir
• Zanamivir
What medication IS used for Anti-Influenza?
Inhibitor of Influenza A and B neuraminidases, causing a conformational change within the enzyme's active site.
What is the MOA of Oseltamivir and Zanamivir (same)?
-Mutations to hemagglutinin or neuraminidase
-Those variants have reduced infectivity and virulence.
What causes resistance to Oseltamivir and Zanamivir (same)?
GI upset
What is the adverse effect of Oseltamivir?
-Prophylaxis in those who cannot receive vaccine
-Early treatment leads to decrease symptoms by 1-2 days (1-3 days for Zanamivir).
What are the clinical uses of Oseltamivir and Zanamivir?
Esterases - in GI tract and liver
Oseltamivir is activated and metabolized by what enzymes?
Renal - cleared by the kidneys.
Oseltamivir is eliminated predominantly via what route?
Poor.

They are available as oral INHALANTS!
Zanamivir has good or poor oral bioavailability?
- Wheezing
- Broncospasm
What are the adverse effects of Zanamivir?
Respiratory Syncytial Virus (RSV)
What is the most common cause of bronchiolitis and
pneumonia in children under 1 year of age?
Premature infants

Compromised immune systems (both children and adults)
Who are at increased risk for RSV?
Inhibits both RNA and DNA viruses secondary to
alterations of cellular nucleotide pools and inhibits
viral mRNA synthesis
What is the MOA of Ribavirin?
- Transient wheezing and rash (aerosolized)
- Increased bilirubin, anemia, and rigors (systemic)
- Teratogenic

TRICK QUESTION:
No reported resistance.
What are the adverse effects of Ribavirin?

Reported resistance in what population?
- Immune cells in the body attacking the liver
(autoimmune hepatitis)
- Infections from viruses, bacteria, or parasites
- Liver damage from alcohol, poisonous mushrooms
- Medications
What are the possible causes of Hepatitis?
Abdominal pain, dark urine, fatigue, jaundice, N/V,
weight loss, low-grade fever
What are symptoms associated with Hepatitis?
• Ribavirin

• Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
- Lamivudine
- Adefovir
- Entecavir
- Telbivudine
- Tenofivir

• Interferon
What are the possible drug treatments for Hepatitis?
Naturally occurring proteins produced by host
cells in response to viral infections.
What is Interferon Alfa?
Proteins produced by recombinant DNA technology. They stimulate the body's immune system to fight off virus.
What is Interferon Alfa-2b?
• Induction of gene transcription
• Inhibits cellular growth
• Alters the state of cellular differentiation
• Interferes with oncogene expression
• Alters cell surface antigen expression
• Increases phagocytic activity of macrophages
• Augments cytotoxicity of lymphocytes
What are the benefits of using Interferon Alfa-2b?
- Hepatitis B
- Hepatitis C
Interferon Alfa-2b is used to treat what viral infections?
Renal dose adjustment in those with renal insufficiency.
Interferon Alfa-2b requires what kind of dose adjustment?
Decrease therapy if patient develops severe pulmonary symptoms, autoimmune disorders, worsening hepatic function, psychiatric symptoms, ischemia, or infectious disorders
What is the black box warning for Interferon Alfa-2b?
...
Memorize this if you have time.
Enzymes involved in replication do not have proofreading capabilities!
Why is it that HIV mutations are common?
Reverse transcriptase

Allows HIV RNA to be transcribed from a single strand to a DNA double-helix that can be
incorporated in the CD4+ host cell's DNA
What enzyme is required for HIV replication?
This enzyme allows what?
Some cells may be non-replicating but are carriers
of infectious virus and can begin replicating at any
time.
Explain why there is no true latency period in HIV replication.
Prevent HIV from entering healthy CD4+ cells

-Block proteins on the surface of HIV or on the
CD4+ cell by binding to glycoprotein-41

-These proteins are required for the virus to gain entry into the cell
What is the MOA of Fusion Inhibitors in treating HIV infection?
Subcutaneous (SC) injections - twice daily.
What is the route of administration of Fusion Inhibitors?
Does NOT affect the metabolism of other antivirals requiring the CYP system
- No reported Drug-drug Interaction
Describe the drug-drug interaction(s) of Fusion Inhibitors.
NO dose adjustments needed for renal or mild to moderate hepatic dysfunction.
Would you expect to dose adjust Fusion Inhibitors for renal or hepatic insufficiency?
Amino acid substitutions resulting in loss of activity.

Give in combination with other antivirals to decrease resistance.
Fusion Inhibitor resistance is due to what?
-Incorporates into the DNA of the virus
-Gets converted into a triphosphate
-The replication process is inhibited - DNA chain is terminated
-No new virus can be created.
What is the mechanism of action of Nucleoside Reverse Transcriptase Inhibitors (NRTIs)?
Zidovudine

Lamivudine
What are two Nucleoside Reverse Transcriptase
(NRTIs) that you should know?
It is well absorbed if taken orally, but food can slow down the absorption.
Explain how well Zidovudine is absorbed if administered orally.
Renally excreted
What is the predominant route of elimination of Zidovudine?
• Anemia
• Granulocytopenia/ bone marrow suppression
• Myopathy
• *Neuropathy
• *Pancreatitis
• *Steatosis
• *lipoatrophy
• Lactic acidosis (with or without hepatomegaly)
What are the adverse effects of NRTIs?
1) Impaired incorporation into viral DNA

2) Removed from viral DNA (Thymidine analog mutation removes NRTI from DNA. This leads to conformational change to reverse transcriptase. This causes a break in DNA chain and the DNA is unable to continue elongation.)
What are two mechanisms of NRTI resistance?
False, except for M184V mutation. Here, resistance results from a single mutation.
True or False?
A single mutation leads to NRTI resistance.
Stops HIV production within the host cell. Binds directly onto the reverse transcriptase, preventing the conversion of RNA to DNA.
What is the MOA of Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)?
- Nevirapine
- Efavirenz
What are two examples of NNRTIs?
False.

MUCH variability amongst individual NNRTIs
True or False?
All NNRTIs have the same pharmacokinetics.
Well absorbed - NOT altered by food.
Describe how well NNRTIs are absorbed if taken orally. Also, what if it's taken with food?
Does NOT require intracellular phosphorylation to be active
How are NNRTIs different from NRTIs?
No. Crosses placenta and concentrated in breast milk
Are NNRTIs safe for pregnant or lactating women?
By CYP enzymes
NNRTIs are metabolized by what enzymes?
No activity - no effect.
What effect do NNRTIs have on host cell DNA polymerase?
It is highly susceptible to resistance - Single mutation affecting binding site.

There is cross resistance between NNRTIs.
Why must you not use NNRTIs as part of monotherapy?
Prevent HIV from being assembled and released from the infected CD4+ cell
What is the MOA of Protease Inhibitors (PIs)?
- Indinavir sulfate
- Ritonavir
- Nelfinavir
Name a few examples of Protease Inhibitors (PIs).
P-glycoprotein efflux pump substrate
What limits the concentration of PIs in the brain?
Hepatic clearance
What is the major route of elimination of PIs?
CYP 3A4 substrates
What is typically given with low dose Ritonavir?
False.
True or False?
If a bacteria is resistant to 1 Protease Inhibitor, it is resistant to ALL protease inhibitors.
The more mutations the bacteria have.

The likelihood of long-term response
What will increase likelihood of cross-resistance between different Protease Inhibitors?

Secondary resistance decreases what?
False. Multiple mutations in the enzymatic active site needed for high-level resistance.
True or False?
A single mutation (at the active site) can cause resistance to Protease Inhibitors.
False. Secondary mutations occur distant from the active site.
True or False?
Primary and secondary mutations that will lead to protease inhibitor resistance occur at the active site.
Prevents the transport and attachment of
proviral DNA to host-cell chromosomes, inhibiting transcription of viral proteins and the assembly of virus particles.
What is the MOA of Integrase Inhibitors (IIs)?
Raltegravir
Give an example of an Integrase Inhibitors (II).
- Rapid oral absorption
- Not affected by food
- Antacids decrease absorption
What are things to consider about oral administration of Integrase Inhibitors (II)?
P-glycoprotein (MINIMAL CNS PENETRATION!!!)
Integrase Inhibitors act as substrates for what molecule?
Mutations to viral integrase gene
What causes Integrase Inhibitor resistance?
- Selectively binds to a chemokine coreceptor (CCR5) that is partly responsible for the binding and then fusion of HIV to CD4 cells

- The interaction between CRA and coreceptor
blocks HIV interaction and inhibits fusion
What is the MOA of Chemokine Receptor Antagonists
(CRAs)?
Maraviroc
Give an example of a Chemokine Receptor Antagonists
(CRAs).
CYP3A4
Chemokine Receptor Antagonists (CRAs) are metabolized via what enzyme?
When it is given with other inhibitors or inducers
When MUST Chemokine Receptor Antagonists (CRAs) be dose adjusted?
P-glycoprotein (MINIMAL CNS PENETRATION!!!)
Chemokine Receptor Antagonists (CRAs) are a substrate for what molecule?
Tyrosine kinase inhibitors
Ex: Imatinib, Dasatinib
Drugs that suppress oncogenes are what? Give examples.
By activating the p53 suppressor gene in colon and head/neck cancers.
How do Monoclonal Antibody drugs work?
-Immortality (Treat by inducing apoptosis)

-Angiogenesis (Treat by disrupting angiogenesis)

-Escape detection (Treat by inducing immune response)
What are the three features of cancerous cells that can be targeted by different drugs?
Bortezomib
Name a drug that promotes apoptosis and is the first‐in‐class proteosome inhibitor (used to treat multiple myeloma).
Thalidomide and Lenolamide
Name two drugs that can disrupt angiogenesis in multiple myeloma.
Cytokines - not drugs.
Interferons and Interleukin‐2
Name two drugs that help induce immune response in renal cell carcinoma and melanoma.
Daily aspirin (for > 3 years)
A growing body of evidence suggests that taking what and for how long prevents colon cancer, especially in patients with colonic polyps?
A partial estrogen agonist/antagonist used in the prevention of invasive and noninvasive breast cancer in women with high‐risk features (i.e., women with the ductal carcinoma in‐situ pre‐malignant lesion).
What is Tamoxifen and how is it used?
Inhibitors of Microtubule Function
What class of anticancer drugs is specifically used during the Mitosis phase of the cell cycle?
Glucocorticoids
What class of anticancer drugs is specifically used during the G1 phase of the cell cycle?
Antimetabolites and Folate Pathway Inhibitors
What class of anticancer drugs is specifically used during the S phase of the cell cycle?
Topoisomerase Inhibitors
What class of anticancer drugs is specifically used during the S-G2 phase of the cell cycle?
Antitumor Antibiotics
What class of anticancer drugs is specifically used during the G2 phase of the cell cycle?
Alkylating agents
Platinum Complexes
What class of anticancer drugs is used non-specifically to inhibit phases of the cell cycle?
Cell cycle specific phase drugs exhibit a survival curve plateau (curve on the right) after an initial exponential drop seen in the low dose/concentration region.

With these agents, it is all about timing and synchronization!
Less
Slow-growing tumors (e.g., colon cancer) respond more or less to chemotherapy (and radiation) than rapidly-growing tumors (e.g., small cell lung cancer, testicular cancer, acute lymphoblastic leukemia)?
Slow-growing tumors
What kind of tumors are relatively resistant to cell cycle phase-specific drugs?
Rapidly proliferating cells
Which one is subject to more toxicity by chemotherapy - whether cell cycle phase-specific or non-specific): Normal/healthy, rapidly proliferating cells or slow-proliferating cells?
Bone marrow stem cells
Gastrointestinal mucosal cells
Hair follicles
Ovaries/testes (gonadal cells)
What are the rapidly-growing normal cells in the body?
(Effect on bone marrow):
Neutropenia/infections
Thrombocytopenia/bleeding
Anemia/fatigue

(Effect on GI):
Diarrhea/emesis/mucositis

(Effect on hair follicles):
Alopecia

(Effect on gonads):
Azoospermia
Amenorrhea/sterility
What are the side effects of Chemotherapy?
...
Study this image if you have time.
A mathematic model that predicts that tumor cells mutate to a resistant phenotype at a rate dependent on their intrinsic genetic instability.

The probability that a cancer would contain drug-resistant clones depends on the mutation rate and the size of the tumor. According to this hypothesis, even the smallest detectable cancers would contain at least one drug-resistant clone; therefore, the best chance of cure would be to use all effective chemotherapy drugs and introduce chemotherapy
early before resistance develops.
What is the The Goldie‐Coldman model?
Cross‐resistance without prior drug exposure.
P‐glycoprotein efflux pump confers what?
R‐CHOP
Rituximab
Cyclophosphamide
Doxorubicin
Vincristine
Prednisone
In Combination chemotherapy, the standard‐of‐care for most non‐Hodgkin lymphomas is what?
Monoclonal antibody targeted therapy.

"Vitamin R"
Rituximab is what kind of anticancer drug?

It is also called what?
Anthracycline that is cell cycle specific for the S-phase.
Doxorubicin is what kind of anticancer drug and how is it used?
Vinca alkaloid that is cell cycle specific for the M-phase.
Vincristine is what kind of anticancer drug and how is it used?
As IV bolus dose:
Incorporation into cellular RNA.
More myelosuppression.

As IV continuous infusion dose:
Incorporation into cellular DNA.
More skin toxicity
How is 5‐fluorouracil (5‐FU) given via IV?
What are the effects of each type of application?
5‐FU continuous infusion was superior
In advanced colorectal cancer, which was more effective in terms of response rate and survival: 5‐FU continuous infusion or 5‐FU bolus infusion?
Give cyclophosphamide at normal dose:
No cardiac or bladder toxicity

Give cyclophosphamide at high‐dose:
Cardiac toxicity, hemorrhagic cystitis

Give cyclophosphamide at normal but fractionated dose:
More efficacy in a subtype of non‐Hodgkin lymphoma (mantle cell lymphoma)
What are the effects of administering cyclophosphamide at normal, high, and normal/fractionated doses?
c) hemorrhagic cystitis
By virtue of their ability to damage DNA, alkylating agents can
themselves provoke mutations that can cause malignancy. In the clinical setting, this is often seen when cyclophosphamide is given (in combination chemotherapy) for the adjuvant treatment of breast cancer where ________ can occur.
a) encephalopathy
b) hand‐and‐foot syndrome
c) hemorrhagic cystitis
d) myelodysplastic syndrome
e) nephrotoxicity
d) oncogenes
The candidate drug XA‐0123 is being considered as an anti‐tumor compound . As such, pre‐clinical evaluation should demonstrate its ability to inhibit:
a) angiogenesis
b) apoptosis
c) immune system
d) oncogenes
e) tumor suppressor genes
3) activity against high‐growth fraction tumors
As an anti‐metabolite with S phase‐specific inhibitory
activity, methotrexate should demonstrate:
1) full dose‐dependent cytotoxicity
2) activity against slow‐growing tumors
3) activity against high‐growth fraction tumors
4) toxicity in muscle tissue
FIND OUT ANSWER!!!!
Cellular principles in chemotherapy often dictate the sequence of chemotherapy. To illustrate this, methotrexate treatment has to be given prior to the drug asparaginase in the treatment of acute lymphoblastic leukemia. Why?
FIND OUT ANSWER!!!!
Cellular principles in chemotherapy provide insight into the
side effects of cytotoxic drugs. A case in point, the antimetabolite cytarabine, commonly used in the treatment of
acute myelogenous leukemia, displays the following:

100‐200 mg/m2/day x 5‐7 days leads to No cerebellar or ocular toxicities.

1‐3 g/m2/day x 1‐3 days leads to Cerebellar and ocular (chemical conjunctivitis) toxicities.

Why?
S-phase
Antimetabolites, such as Methotrexate, specifically acts on what phase of the cell cycle?
Asparaginase
Name a G1-dependent drug.
Mitosis (M-Phase)
Vinca alkaloids and Podophyllotoxins are drugs that are specific to what phase of the cell cycle?
Alkylating agents represent a broad class of chemotherapeutic drugs, which are activated to reactive intermediates capable of forming
adducts with cellular macromolecules, the major target being DNA.
What are alkylating agents?
1) The mustards
2) Nitrosoureas
3) Triazenes
4) Platinum complexes
5) miscellaneous
Name the five classes of alkylating agents.
The lone pair of electrons on the nitrogen atom is delocalized. In other words, the benzene ring (part of structure) acts as an electron sink to reduce the nucleophilicity of the nitrogen atom.

A less reactive product allows for oral administration.
The high reactivity of mechlorethamine (alkylating agent) can be reduced considerably by attaching the "warhead" (image) to an aromatic ring.

How does this process work and why would we want a less reactive molecule?
Pro-drugs
Cyclophosphamide and Ifosfamide are both what?
Dose and schedule of administration.

Bladder side effects accompany high‐doses or continuous daily administration of these drugs. They are not seen in intermittent administration (most common in clinicaly setting).
The bladder side effects (hemorrhagic cystitis) caused by Cyclophosphamide and Ifosfamide are dependent on what?
Reacts with uroepithelial cellular NUCLEOPHILES.

This can be prevented by adequate hydration of the patient and by administration of sodium 2‐mercaptoethane sulfonate (Mesna).
The Acrolein by‐product of Cyclophosphamide and Ifosfamide reaction reacts with what?

This can be prevented with what?
Adding to the alpha, beta‐unsaturated aldehyde, preventing the Acrolein reaction with cellular nucleophiles.
The sulfhydryl group in Mesna is capable of inactivating Acrolein by doing what?
Ifosfamide

Metabolite= chloroacetaldehyde

Antidote = Methylene Blue
Between Cyclophosphamide and Ifosfamide, which one has central nervous system neurotoxicity?

This neurotoxicity is believed to be caused by what metabolite?

What is the antidote?
A new alkylating agent used for the treatment of
chronic lymphoblastic leukemia. It is a "cross" between an alkylating agent and an antimetabolite.

Its cytotoxicity is due in large part to the
alkylating moiety.
What is Bendamustine?

It's cytotoxicity is due to which of its components?
1) They liberate organic isocyanates, which react with lysine residues leading to the inactivation of some proteins, particularly DNA repair enzymes.

2) Carmustine (aka BCNU) and lomustine (aka CCNU) are highly lipophilic.
Although the Nitroureas (Lomustine, Carmustine and Streptozocin) are like all alkylating agents in that they form DNA adducts and interstrand DNA cross links, they are unique in what two ways?
The CNS - e.g., brain tumors

Can cross BBB.
Lipophilic anticancer drugs can be used to target what?
Methylation of DNA at the O6 and N7 positions of guanine in their shared active metabolite MTIC.
The cytotoxicity of the triazenes (Dacarbazine and Temozolamide) is due primarily to what?
Temozolamide
Between dacarbazine and temozolamide, which one is highly lipophilic?
Dacarbazine
In the "ABVD" standard of care regimen for Hodgkin's lymphoma, the "D" is what?
Cisplatin, Carboplatin and Oxaliplatin
What drugs make up the platinum complexes?
N7 of guanine is highly reactive.

Cross‐links form between adjacent guanines on different DNA strands and between guanine and adenine on the same strand.

The formation of inter strand cross‐links is a slower process than intra-strand cross-links.

End-product = DNA adducts

This results in replication and transcription inhibition, which leads to strand breaks and
miscoding.
What inter‐ and intra‐strand cross‐links occur when DNA is exposed to a platinum complex alkylating agent?

What is the end product of this reaction?
False. They are structurally unrelated.
True or False?
Alkylating agents that belong to the group, Procarbazine, are almost all identical in structure.
Monoamine Oxidase Inhibitor activity
Procarbazine has what kind of inhibitor activity?
3) monoamine oxidase inhibitor (i.e., anti‐depressants)
JJ is a 45‐year‐old male patient who is recently diagnosed with stage IV Hodgkin lymphoma. The patient is ineligible for ABVD standard treatment disease given a history of lung fibrosis (precluding the use of the "B" (bleomycin). Procarbazine‐based MOPP is initiated. Within 4 weeks of the first cycle, patient develops a hypertensive crisis with
attendant fatal hemorrhagic stroke. The fatal outcome observed here was most likely due to an interaction between procarbazine and a:

1) non‐selective B‐antagonist (i.e., anti‐hypertensive)
2) hypoxanthine oxidase inhibitor (i.e., anti‐hyperuricemics)
3) monoamine oxidase inhibitor (i.e., anti‐depressants)
4) selective B2‐agonist (i.e., bronchodilator)
b) high lipophilicity
A 25 year‐old patient is diagnosed with glioblastoma multiforme (an aggressive brain tumor). When designing an appropriate chemotherapeutic regimen for this patient, what pharmacokinetic characteristic should you look for in your selected chemotherapy (‐ies)?

a) high bioavailability
b) high lipophilicity
c) high molecular weight
d) long half‐life
e) low protein binding
c) mesna
The urinalysis from a patient receiving high‐dose cyclophosphamide reveals: 3+ blood and 25 red blood cells/high power field. Given the patient's hematuria, cyclophosphamide‐induced hemorrhagic cystitis is
suspected. To treat this condition, you should initiate:

a) amifostine
b) dexrazoxane
c) mesna
d) methylene blue
e) normal saline
d) methylene blue
DD is 55‐year‐old female patient with advanced stage sarcoma. She is in the chemotherapy infusion area receiving her first dose of ifosfamide. Ten minutes into the infusion, she starts losing consciousness. Her vital signs are stable. Suspecting ifosfamideinduced
encephalopathy, you should administer:

a) amifostine
b) dexrazoxane
c) mesna
d) methylene blue
e) normal saline
Structural analogs of naturally occurring metabolites. They interfere with the normal synthesis of nucleic acids by falsely substituting for biosynthetic precursors or other intermediates in metabolic pathways, ultimately becoming incorporated into the DNA and/or RNA.
What are Anti-metabolites?
The better the cellular penetration, especially in "sanctuary" tissue sites such as the brain and testes.
The higher the methotrexate dose, the better the what?
Folinic acid, folic acid
What is the Antidote to Methotrexate?
A high growth fraction.
Since Anti-metabolites are S-phase cell cycle specific, they are most effective against tumors that have what?
A new antifolate which inhibits enzymes in the purine and pyrimidine cycles (aka multitarget antifolate). It exhibits preferential cellular uptake and retention (vs. methotrexate).

It is used in conditions for which methotrexate is largely ineffective.
What is Pemetrexed?
GI tract: Both cause diarrhea/mucositis

Bone marrow: Both cause myelosuppression
Pemetrexed and Methotrexate are both toxic to normal/healthy cell that are rapidly-proliferating. What are their effects on the GI tract and Bone marrow?
Vitamin B12 and folic acid must be given at least 2 weeks before starting premetrexed treatment and continued as long as the patient is on the drug.
Due to its toxicity, what is the standard of care when it comes to using Pemetrexed?
Fluorouracil (5-FU), Capecitabine, Gemcitabine, Cytarabine, and Raltitrexed
What are the pyrimidine antagonist drugs?
Intracellular activation
Before they can be utilized, pyrimidine antagonist drugs need what?
Based on the observation that tumors use pyrimidine bases more efficiently than normal tissues

Pyrimidine antagonists act as a decoy or fraudulent pyrimidine base which inhibits important enzymes in the pyrimidine cycle (e.g., thymidylate synthase).
What is the MOA of pyrimidine antagonists?
GI tract - From esophagus all the way to the rectum.
Pyrimidine antagonists are typically used where in the body?
A thymidylate synthase inhibitor used for advanced colorectal cancer.
Raltitrexed is used as what?
-Cytarabine (aka ARA-C) is incorporated into the cell where it undergoes phosphorylation to the nucleotide triphosphate (ara-CTP).

The intracellular metabolite, ara-CTP, competes with deoxycytidine for DNA polymerase; thereby inhibiting DNA synthesis.
What is the MOA of Cytarabine?
Acute leukemias (AML and ALL)
Cytarabine is the backbone cytotoxic agent for what cancers?
The dosage given.
Side effects from Cytarabine use are dependent on what?
1) "masked termination"
The triphosphate analogue of Gemcitabine (aka, dFdC-TP) replaces the nucleoside cytidine. After incorporation of Gemcitabine nucleotide on the end of the elongating DNA strand, one more deoxynucleotide is added and thereafter, the DNA polymerases are unable to proceed. This action apparently locks the drug into DNA as the proofreading enzymes are unable to remove gemcitabine from this position.

2) Gemcitabine-disphosphate inhibits the enzyme ribonucleotide reductase, this decreases DNA synthesis by limiting the formation of deoxyribonucleotide.
What is the MOAs of Gemcitabine?
Think of Gemcitabine as a "broad spectrum" Cytarabine. It is effective against solid tumors (e.g., breast, bladder, pancreatic cancers) - where Cytarabine isn't.
How is Gemcitabine different from Cytarabine in its use?
Purine Antagonists
6-Mercaptopurine (6-MP), 6-thioguanine (6-TG), Fludarabine, Cladribine, Clofarabine, Nelarabine, and Pentostatin are all what?
Azathioprine
What is the prodrug for 6-Mercaptopurine (6-MP)?
6-MP (decoy for hypoxanthine) and 6-TG (decoy for guanine)
6-Mercaptopurine (6-MP) and 6-thioguanine (6-TG) are decoys for what purines?
6-thioguanine (6-TG)

6-Mercaptopurine is more myelosuppressive.
Which one is more potent and causes more GI toxicity: 6-Mercaptopurine (6-MP) or 6-thioguanine (6-TG)?
An analogue of the purine nucleoside adenosine. Pentostatin blocks conversion of adenosine to inosine by the enzyme adenosine deaminase. This results in cellular accumulation of adenosine, which appears to be selectively toxic to certain types of T-lymphocytes (IMMUNOSUPPRESSIVE).
What is Pentostatin? What is its MOA?
They are all precursors of the fraudulent nucleoside Ara-A, which ultimately inhibits DNA polymerase and ribonucleotide reductase enzymes

They all have MYELOSUPPRESSION as a cardinal SIDE EFFECT.
Aside from being purine antagonists, Fludarabine, Cladribine, Clofarabine and Nelarabine all have what in common?
They are mostly used in leukemias.
Fludarabine, Cladribine, Clofarabine and Nelarabine are all mostly used in what cancers?
An analog of urea that inhibits ribonucleotide reductase, so [DNA] decreases.

It has been used in the control of elevated leukocyte count in chronic myelogenous leukemia and the treatment of patients with myeloproliferative disorders (polycythemia vera and thrombocythemia).
What is Hydroxyurea?
What is its MOA?
It is used for what?
Stimulates the production of hemoglobin F (not as an anti-metabolite!)
Hydroxyurea confers what benefit in sickle-cell disease?
...
For reference.
...
For reference.
4) 2000 mg a week?

"Higher anti-metabolites doses allow for better penetration into difficult-to-treat sites."
Which methotrexate dosing regimen would you anticipate to be the most effective for the treatment of central nervous system (CNS) lymphoma?

1) 25 mg a week
2) 100 mg a week
3) 500 mg a week
4) 2000 mg a week
FIND OUT ANSWER!!!
In the treatment of colon cancer, the combination of 5-FU and
leucovorin (aka, folinic acid, reduced folate, citrovorum factor) is considered a cornerstone doublet for the control of this disease.
What is the pharmacological basis for this combination?
(Hint: It is not the same pharmacological basis governing the use of leucovorin (folinic acid) with methotrexate.)
b) T-cell lymphocyte suppression
In addition to the treatment of cancer, some anti-metabolites (
methotrexate, 6-MP, pentostatin) are used in conditions such as rheumatoid arthritis and crohn's disease. This is due to their:

a)non specific cell cycle cytotoxicity
b)T-cell lymphocyte suppression
c)P-glycoprotein inhibition
d)oncogene suppression
e)angiogenesis disruption
Allopurinol blocks Xanthine Oxidase (XO).

So, 6-MP cannot be broken down to 6-thiouric acid. This means that we will have more 6-MP (more Myelosuppression).

Anwer: d)myelosuppression
An ALL male patient is being considered for 6-MP consolidation treatment. His past medical history is significant for gout for which he is taking oral allopurinol 300 mg daily. Which of the following side effects is most likely to become exaggerated in this individual?

a)alopecia
b)azoospermia
c)diarrhea
d)myelosuppression
e)nephrotoxicity
a) cyanocobalamin

Patient was non-compliance with Vitamin B12 and Folic Acid. Answer closest to this is Cyanocobalamin.
JJ is a male patient with advanced stage non small cell lung cancer currently undergoing 2nd line pemetrexed chemotherapy for his relapsed disease. Shortly after the second cycle, he is admitted for severe mucositis, diarrhea and myelosuppression. He is neutropenic with an absolute neutrophil count of 200 cells/mm3. His blood culture is
positive for pseudomonas aeruginosa. Twenty four hours from
admission, patient dies from septic shock. The most likely cause of his demise is non-compliance with:

a) cyanocobalamin
b) mesna
c) methylene blue
d) pyridoxine
e) tyramine
They intercalate between base pairs in the DNA helix. This effect interferes with DNA chain elongation, and ultimately nucleic acid synthesis.

They inhibit topoisomerase II activity (G2 phase‐dependent). Topoisomerase II forms transient breaks in 2 strands, allowing strand passage to facilitate condensation/decondensation of supercoiled DNA.

They form free radicals.
What is the MOA of Anthracyclines?
doxorubicin, idarubicin, daunorubicin, epirubicin
What are the Anthracyclines?
Cardiac toxicity, presumably due to the formation of highly reactive oxygen‐derived free radical species.
Anthracyclines are known for their cumulative toxicity to what organ? This is because of what?
They are liposome‐encapsulated.
To mitigate their cardiotoxicity, certain anthracyclines are available for use (doxorubicin and daunorubicin). What sets these guys apart from the other anthracyclines?
They cause Hand‐and‐Foot Syndrome
Liposome-encapsulated anthracyclines (doxorubicin and daunorubicin) have what side effects?
Breast Cancer
Doxorubicin (along with the taxane docetaxol) is considered one of the most effective single agent against what cancer?
DNA intercalation, and inhibition of topoisomerase II
What is the MOA of Anthracenediones (Mitoxantrone)?
It does not form oxygen‐derived free radical species
How is Anthracenediones (Mitoxantrone) different from Anthracyclines?
Anthracenediones (Mitoxantrone)
What is the standard of care agent (+ corticosteroid) in prostate cancer?
The drug binds to guanosine‐cytosine‐rich portions of DNA and by partial intercalation of its "many" rings. A group of five nitrogen atoms arranged in a square‐pyramidal conformation binds divalent
metals including iron, the active ligand. Molecular oxygen, bound by the iron, can produce highly reactive free radicals. The free radicals produce DNA single‐strand breaks, a cell‐cycle‐phase specific cytotoxicity for G2 phase.
What is the MOA of Bleomycin?
Hydrolase

In the lungs and skin
What enzyme detoxifies Bleomycin? Where can this enzyme be found naturally?
Tumor Antibiotics
Anthracyclines, Anthracenediones (Mitoxantrone), and Bleomycin are all what?
Etoposide, Teniposide
What are the two Podophyllotoxins?
It is a Topoisomerase II poison. This leads to halting of cell progression out of the S/G2 phase interphase
How is Etoposide similar to Anthracylcines?
Gastrointestinal toxicities and myelosuppression
What are the are the most common side effects Podophyllotoxins?
Topotecan, Irinotecan
What are the Camptothecins?
They inhibit Topoisomerase I, a nuclear enzyme which relaxes torsionally strained (super coiled) DNA.
What is the MOA of Campotothecins?
Colorectal cancer
Irinotecan is ordinarily used to treat what?
Ovarian cancer and Small cell lung cancer
Topotecan is a common second‐line agent in what cancer?
- Early‐onset acute diarrhea (due to a cholinergic syndrome)
- Delayed‐onset diarrhea (unknown mechanism)
Irinotecan has unique GI side effects. What are they?
Irinotecan
Drug inhibitors and inducers of either CYP 450 3A4 or UGT can impact the disposition of what drug?
Vincristine, Vinorelbine and Vinblastine
What are the Vinca Alkaloids?
They block mitotic cell division by bonding to tubulin molecules and inhibiting their polymerisation to microtubules.
What are the MOA of Vinca Alkaloids?
Neurotoxicity

peripheral neuropathy
autonomic neuropathy
cranial nerve neuropathy
encephalopathy
What organ toxicity is associated with Vinca Alkaloids?

Neurotoxic effects may be divided into what four groups?
Vinorelbine
Out of all the Vinca alkaloids, which one causes the least neurotoxicity (the "trade‐off" being more myelosuppression)?
Paclitaxel, Docetaxel, Nanoparticle Albumin‐bound Paclitaxel
What are the taxanes?
Podophyllotoxins and Camptothecins
What are the topoisomerase inhibitors?
Vinca Alkaloids, Taxanes, and Epothilones (Ixabepilone)
What are the Antimicrotubule agents?
The taxanes are mitotic spindle poisons.

Unlike vinca alkaloids that inhibit mitotic spindle formation, taxanes stabilize microtubules against
depolymerization.
How are taxanes different from vinca alkaloids?
True.
True or False?
Taxanes are neurotoxic.
True.
True or False?
Epothilones (Ixabepilone) cause myelosuppression AND neurotoxicity.
Decreased affinity for efflux transporters, such as P‐glycoprotein.
Epothilones are less prone to resistance, thanks to what?
L‐Asparaginase
What is the backbone of Acute Lymphoblastic Leukemia (ALL) induction treatment?
Tumor (e.g., ALL) cells are dependent on Asparagine, a non‐essential amino acid in humans.

The hydrolysis of exogenous L‐Asparagine in the bloodstream by L-Asparaginase deprives the tumor of a required amino acid.
What is MOA of L-Asparaginase?
hyperglycemia/pancreatitis
thrombosis/bleeding
allergic reactions
What are the unique side effects of L-Asparaginase?
2) echocardiography

It's cardiotoxic.
Which safety monitoring test would you order at the conclusion of adjuvant doxorubicin‐based treatment in a young female with localized stage breast cancer?

1) chest X‐Ray
2) echocardiography
3) mini mental status examination
4) urinalysis
1) The cardiotoxicity may not be attributed only to free radical formation.

2) Mitoxantrone may be metabolized into a derivative molecule that causes cardiotoxicity.
Mitoxantrone does not form oxygen‐derived free radical species that are toxic to cardiomyocytes. Clinically, cardiotoxicity (especially congestive heart failure) has been well-documented with high cumulative mitoxantrone doses. How do you reconcile this discrepancy between the pharmacology of the drug and the clinical "real life" side effect of cardiotoxicity?
c) lung
Owing to the low levels of hydrolase (proteinase enzyme) in certain body tissues, patients are at risk of _________ toxicity when bleomycin is given, especially if they are older than 40 years of age and receive a lifetime bleomycin dose more than 400 units.

a) brain
b) liver
c) lung
d) ocular
e) renal
b) ipratropium

Ipratropium is derivative of Atropine
Irinotecan's (CPT‐11) most common side effect is diarrhea with early acute and delayed‐onset patterns. The pathophysiological mechanism of the acute diarrhea has been identified as a cholinergic excess. In clinical practice, acute early onset diarrhea should be treated with:
a) epinephrine
b) ipratropium
c) physostigmine
d) propranolol
e) neostigimine
a) anthracyclines‐based ???
JJ is a 55 year old female patient who is recently diagnosed with metastatic breast cancer in the viscera and bones. She is about to start chemotherapy chemotherapy. Her past medical history is significant for diabetes (x 10 years), diabetes‐associated peripheral neuropathy and idiopathic
pulmonary fibrosis. Taken into account the patient's co‐morbidities, her chemotherapy regimen should be:

a) anthracyclines‐based
b) bleomycin‐based
c) epothilones‐based
d) taxanes‐based
e) vinca alkaloids‐based
The "‐nibs" (imatinib, dasatinib and nilotinib)
What are the Tyrosine Kinase Inhibitors (TKIs)?
It inhibits the proliferation of bcr‐abl fusion protein (encoded by Philadelphia (Ph+) chromosome (aka: t(9, 22) translocation), which is responsible for the unregulated activity of the tyrosine kinase, abl. Specifically, it binds to ATP binding pocket of select tyrosine kinases (bcr‐abl, c‐kit, etc.)
What is the MOA of Imatinib?
Both Dasatinib and Nilotinib are treatment options for Imatinib‐refractory chronic myelogenous (or myeloid) leukemia (CML) patients. They are able to circumvent bcr‐abl resistance.
What is the advantage of using Dasatinib and nilotinib for treatment of CML as opposed to Imatinib?
Imatinib has about a 70% complete cytogenetic remissions (0% Ph+ in the bone marrow); however, it is not a cure.
How effective is Imatinib in treating chronic-phase chronic myelogenous leukemia (CML)?
Inhibit Src kinase.

Dasatinib is able to do it.
In order for a Tyrpsine Kinase Inhibitor to overcome Imatinib resistance, it must do what?

Between Dasatinib and Nilotinib, which one is able to do it?
Dasatinib.

Dasatinib has two types of kinase inhibitors - ABL and Src. Nilotinib only has ABL.

The more kinases that are inhibited, the more kinases‐dependent tumors.
one can treat
Between Dasatinib and Nilotinib, which one has a greater range of neoplastic conditions that it can treat?
Their indiscriminate inhibition of kinases used by healthy cells.

-Edema: Not Nilotinib (Dasa = Pleural and Heart; Imatinib = Peripheral)
-QT prolongation: All of them
-GI irritation: Not Nilotinib
-Myelosuppression: All of them
-Rash: All of them
Side effects caused by Tyrosine Kinase inhibitors are due to what?

What adverse effects does this lead to?
Azacitidine and Decitabine
What are the Hypomethylating agents?
Hypomethylating agents are inhibitors that must be incorporated into DNA through a reduced metabolite before methyltransferase is inhibited.

The resulting DNA strand after one cycle of replication is only hemimethylated. It takes two cycles of replication before the DNA may be entirely
demethylated, and even then, some remethylation occurs. So, that is why it takes several doses and cycles (3‐4 cycles; each cycle=28 days) before a clinical response is seen.
What are the MOA of Hypomethylating agents?

Explain why it takes some time for appropriate clinical response to be achieved.
Vorinostat and Romidepsin
What are the Histone Deacetylase Inhibitors (HDACi)?
Acetylation causes histones to unwind. Deacetylase keeps the histones wound up.

Histone Deacetylase Inhibitors (HDACi) cause histones to be acetylated, so less structure becomes more loose. This frees it up for transcription and downstream cell growth arrest, differentiation, and apoptosis.
What is the proposed MOA of HDACIs?
Bortezomib
What is the proteosome inhibitor that we talked about in class?
In euks, the ubiquitin proteasome pathway (UPP) is responsible for the breakdown of cellular proteins. Impeding this degradation leads to accumulation of several important regulatory proteins, including the inhibitor of nuclear factor kappa beta (NF‐κB).

These drugs arrest the growth of tumor cells, induce apoptosis, inhibit angiogenesis, and increase the sensitivity of tumor cells to chemotherapy or radiation therapy.
What are the effects of Proteosome Inhibitors?
myeloma
relapsed mantle cell lymphoma
Bortezomib is indicated in the treatment of what?
Because 72 hours between administration is sufficient for recovery of proteasome function in normal tissues.
Why is Bortezomib given every 72 hours?
Thrombocytopenia because of decreased thrombopoiesis.
What is the side effect of using proteosome inhibitors?
Mammalian Target of Rapamycin (mTOR)
Inhibitors:

The inhibitors bind to an intracellular protein, FKBP‐12, resulting in an inhibitory complex formation and
inhibition of mTOR kinase activity downstream of the PI3K/AKT. Inhibition of mTOR reduces cell
proliferation, angiogenesis, and glucose uptake.
What is the mechanism of action of mTOR Inhibitors?
Temsirolimus and Everolimus
What are the mTOR Inhibitors?
Indicated for untreated and relapsed renal cell carcinoma.

mTOR Inhibitors also have cytotoxic/cytostatic effects because of their action on the G1‐phase of the cell cycle.
mTOR Inhibitors are indicated for what cancers?

Explain how mTOR Inhibitors are a "cross" between targeted and cytotoxic treatments.
All‐trans Retinoic Acid (ATRA) and Arsenic Trioxide
What are the two types of Biologic Response Modifiers that we talked about in class?
ATRA stimulates tumor regression by way of altering tumor‐cell interaction or inducing body immune response, rather than direct bone marrow toxicity.

It binds to its native receptor RAR‐alpha to release the co‐repressor complex and allows for normal maturation and differentiation of aberrant leukemic cells.
What is the MOA of All‐trans Retinoic Acid (ATRA)?
Alteration of cellular physiology, not direct cytotoxic effect.
Toxicity of All‐trans Retinoic Acid (ATRA) is due to what?
ATRA/Arsenic trioxide
When ATRA/anthracycline‐based therapy fails (might be because the patient cannot tolerate anthracyline), what is used instead?
1) Activation of complement cascade.
2) Tagging the cells for phagocytosis and cell-mediated cytotoxicity
3) Tagging cells for attack by MAC and NK cells.
What are three pathways in which Rituximab-opsonized B-cells are subjected to attack and killing?
a) dasatinib
A chronic phase chronic myelogenous leukemia (CP‐CML) patient on an unknown TKI presents with dyspnea, hypotension and pulsus paradoxus. His chest X‐ray reveals severe pericardial effusion. Cardiac tamponade is suspected. The likely culprit TKI causing this "off target" side effect is:

a) dasatinib
b) gefitinib
c) imatinib
d) lapatinib
e) nilotinib
d) 3 months
JJ is an intermediate‐risk myelodysplastic syndrome (MDS) male patient with profound anemia (hemoglobin= 9 g/dl) and attendant fatigue. He was started on subcutaneous azacytidine 5 times a week. Two weeks after treatment initiation, the patient mutters about this drug saying it
does not work . As an astute clinician with solid foundation in
pharmacology, you tell the patient that it will take the drug a minimum of ______ to work.
a) 3 weeks
b) 1 month
c) 2 months
d) 3 months
3) cells in G1‐phase
Myelosuppression is frequently seen with the mTOR inhibitors
temsirolimus and everolimus. This is likely due to their inhibition of:

1) DNA methyltransferase
2) histone deacetylase
3) cells in G1‐phase
4) Src tyrosine kinase
5) ubiquitin proteasome pathway
c) ATRA + Arsenic trioxide
A 20 year-old male patient is diagnosed with acute promyelocytic leukemia (APL). His pre‐chemotherapy work‐up notes an cardiac ejection fraction of 35% on 2‐D echocardiography and other findings suggestive of a history of dilated cardiomyopathy. Given his co‐morbidity, the patient's
chemotherapy should be:

a) Daunarubicin + ATRA
b) Daunarubicin + Arsenic trioxide
c) ATRA + Arsenic trioxide
d) Idarubicin + ATRA
e) Idarubicin + Arsenic trioxide
1) complement mediated cytotoxicity?
Rituximab's efficacy and side effects (e.g., infusion‐related reaction) are best explained by which pharmacological mechanism?

1) complement mediated cytotoxicity
2) DNA polymerase inhibition
3) IgE‐mediated histamine release
4) non cell cycle specific cytotoxicity
5) topoisomerase II inhibition
75%
About what percent of all breast cancers are estrogen receptor positive ER+ (they grow in response to the hormone estrogen)?
65%
About what percent of ER+ breast cancers are also progesterone receptor positive PR+ (they grow in response to progesterone)?
60% likelihood
How likely are breast cancer tumors that are ER+/PR+ to respond to hormonal therapy?
Only 5% to 10% likelihood
How likely are breast cancer tumors that are ER-/PR- to respond to hormonal therapy?
True.

It converts to Endoxifen.
True or False?
Tamoxifen is a pro-drug.
It is a partial estrogen agonist (bone, uterus) and estrogen antagonist (breast) categorized as a Selective Estrogen Receptor Modulator (SERM). It is used to prevent breast cancer in high‐risk patients and to treat patients with advanced or localized stage disease.
Explain how Tamoxifen is used as an estrogen agonist and antagonist.
It converts the adrenal androgen (androstenedione) to estrogen in the peripheral tissues, which is the primary source of estrogen synthesis in postmenopausal women.
What is the role of aromatase in the body?
Only patients with nonfunctioning ovaries (postmenopausal) because AIs may not overcome ovarian aromatase activity.
Aromatase Inhibitors are only effective in what patient population?
Tamoxifen
Aromatase Inhibitor (if Tamoxifen fails)
In ER+/PR+ post‐menopausal women with advanced stage breast cancer, what two drugs are typically used as first line defense?
AIs:
1) Don't cause endometrial hyperplasia.
2) Are associated with arthralgia/musculoskeletal
pain.
Side effects of Tamoxifen and Aromatase Inhibitor are similar, but there are differences as well. What are the differences?
They don't have estrogenic agonist activity. They are also not as bone or lipid "friendly"!
Why is it that AIs don't cause endometrial hyperplasia?
Cause prostate gland involution and, clinically, prolong disease‐free interval/survival.
Prostate cancer is an androgen‐dependent malignancy. What would you expect to happen if you completely block androgen production?
Testes: Testosterone

Adrenal glands: Androsteinedione and Dehydroepiandrosterone.
Androgens are synthesized as what in men?
Hypothalamus secrete GnRH. This causes anterior pituitary to secrete LH. This causes testes to release testosterone.

Hypothalamus secrete corticotropin-releasing
hormone (CRH). This causes anterior pituitary to secrete adrenocorticotropic hormone (ACTH). This causes the adrenal glands to release androsteinedione and dehydroepiandrosterone.
Describe the events that lead to the stimulation of the testes and adrenal gland to produce their respective androgens.
leuprolide, goserelin, triptorelin
What are the Gonadotropins agonists?
Following an initial LH/FSH surge, protracted exposure will cause LH/FSH receptors to down regulate. When this occurs, testosterone (and estrogen) are not released. The same mechanism underlies their use in breast cancer.
In Androgen Deprivation Therapy (treatment of Prostate Cancer), giving patients GnRH agonists inhibits pituitary stimulation of the testes. How?
"tumor flare" phenomenon
Treatment with GnRH agonists in Androgen Deprivation Therapy can lead to an initial LH/FSH surge. This can lead to what phenomenon?
Anti‐androgens (AKA, Androgen receptor antagonists).

They inhibit the binding of dihydrotestosterone (DHT) and testosterone to their androgen receptor (AR).
If tumor flare is a concern with GnRH antagonists, what is used instead?

What is their MOA?
Complete androgen blockade
GnRH agonist + anti‐androgen = ?
It's a granulocyte colony stimulating factor.

It causes dose‐dependent stimulation of the proliferation and the differentiation of neutrophils by way of binding to its cell surface receptor.

Clinically, they are used to prevent chemotherapy‐induced neutropenia.
Filgastrim is a G‐CSF. What does this mean?
It's a granulocyte macrophage colony stimulating factor.

It causes dose‐dependent stimulation of the proliferation and the differentiation of macrophages by way of binding to its cell surface receptor.
Sargramostim is a GM‐CSF. What does this mean?
Result: A "neutrophil‐dependent pharmacokinetics" - Serum
clearance is directly related to the neutrophils present.
Pegfilgrastim, through the addition of polyethylene glycol, becomes a larger molecule than filgrastim and is unable to be cleared renally. What is the resultant effect?
Formerly AMD 1300, a drug investigated in HIV treatment. During HIV trials, a dose-dependent
side effect "leukocytosis" led to the exploration of the drug in stem cell mobilization in preparation for autologous bone marrow transplant.

Target = CXCR-4
What is Plerixafor?
The retention of hematopoietic stem cells (CD34+) in the bone marrow due to the interaction between SDF-1 and CXCR-4.
What is "homing"?
A pro‐drug that is dephospharylated by alkaline phosphatases in tissues to a pharmacologically active free thiol metabolite that scavenges free
radicals caused by radiation or reduce toxic effects of chemotherapy (e.g., the alkylating agent cisplatin).
What is Amifostine?
To lower the rate of moderate to severe xerostomia (i.e., dry mouth) in head and neck cancer
patients receiving post‐operative radiation

To prevent cisplatin‐induced nephrotoxicity
What are the uses of Amifostine?
An analog of the chelator ETDA, dexrazoxane is hydrolyzed to a heavy metal chelator capable of intracellular iron binding, thereby hampering the formation of free radicals.

But, in the process of countering chemotherapy toxicity, they may also counter its anti‐tumor activity.
What is Dexrazoxane and what is its MOA?
A keratinocyte growth factor (KGF), shown to decrease the duration and incidence of severe oral mucositis in patients with hematological malignancies receiving bone marrow transplantation.
What is Palifermin?
Found on epithelial cells in many tissues including the tongue, buccal mucosa, salivary gland, esophagus, stomach, intestine, lung, liver, pancreas, kidney, bladder, mammary gland and eye lens as well as on tumor cells of different histology. Not found on lymphoma and lymphoblastic leukemia cell lines.
Where are KGF receptors found and where are they NOT found?
Down‐regulation of proinflammatory cytokines and increases anti-inflammatory cytokines (e.g., IL‐13). It protects the epithelium against reactive oxygen molecules by modifying the expression of detoxifying transcription factors and enzymes.
What is the MOA of Palifermin?
Thickening of oral mucosa and tongue.
What are unique side effects of Palifermin?
Hot flashes
Which of the following clinical syndromes are due to either the antiestrogenic or estrogenic properties of tamoxifen?

Hot flashes
Endometrial hyperplasia
Arterial or venous thrombosis
The rare risk of liver carcinogenesis
Prevention of osteopororis
Decrease in LDL‐cholesterol
The treatment of breast cancer
3) Paroxetine's cytochrome P450 2D6 induction?
JJ is a 55‐year‐old female patient who was recently started on tamoxifen for advanced stage breast cancer. The patient demonstrates complete response at 6 months follow‐up; however, she complains of bothersome hot flashes. She is initiated on the SSRI paroxetine given its established efficacy to reduce tamoxifen‐induced hot flashes. Within 4 months, the patient's breast cancer relapses. The likely cause of this patient's tumor recurrence is:

1) Tamoxifen's breast cancer resistance
2) Paroxetine's cytochrome P450 2D6 inhibition
3) Paroxetine's cytochrome P450 2D6 induction
4) Tamoxifen's estrogenic stimulation
AIs won't do anything for her because she's not post-menopausal.

SERMs is currently being used to treat breast cancer in pre-menopausal women.
A 31 year‐old female patient is diagnosed with localized right breast cancer. Following successful removal of the malignant tissue and subsequent 4 cycles of chemotherapy, she is slated to receive hormonal treatment for 5 years (i.e., adjuvant treatment). Her menses are normal at this time. Is she a candidate for SERMs (e.g., tamoxifen) or AIs (e.g, letrozole) treatment?
c) LH antagonism
A patient with metastatic prostate cancer to the lumbar vertebrae is likely to experience a disease flare (i.e. back pain) when GnRH agonist therapy (without anti-androgens) is introduced. The good news is that two new compounds (abarelix, degarelix) will not have this problem. The likely mechanism of action of those products is:

a) AR activation
b) AI inhibition
c) LH antagonism
d) LH release
NEED ANSWER!!!
Each time a chemoprotectant (e.g., dexrazoxane) is developed, one has to be wary of it adversely affecting the anti‐tumor efficacy of the chemotherapy agent against which it is protecting. This is not the case with amifostine because:

1) cardiomycocytes are deficient in oxyradical‐detoxifying enzymes
2) normal cells are deficient in alkaline phosphatase
3) normal cells are deficient in hydrolase
4) tumor cells are deficient in alkaline phosphatase
5) tumor cells are deficient in hydrolase
NEED ANSWER!!!
KGF receptors are present on epithelial cells in many tissues including the tongue, buccal mucosa, salivary gland, esophagus, stomach, intestine, lung, liver, pancreas, kidney, bladder, mammary gland and eye lens. Clinically, when patients receive the KGF receptor activator, palifermin, a biochemical rise in _______ is invariably seen.

1) amylase
2) atrial natriuretic peptide
3) creatinine kinase
4) hemoglobin
5) troponin