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100 Cards in this Set

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  • Back
Anti-HIV Fusion Inhibitor
Enfuvirtide (T-20)
What is Enfuvirtide's mechanism of action?
binds gp41 of HIV envelope, blocking fusion of viral and host cell membranes
1. type of compound
2. administration
3. half-life
4. blocks infection of ____
1. Synthetic peptide (36 aa's)
2. Subcutaneous injection
3. 4 hours
4. new cells
Alternate name for Zidovudine
Azidothymidine (AZT)
NRTI Thymidine analog
Zidovudine (AZT)

Stavudine (d4T)
Zidovudine pharmacokinetics:
1. Distribution
2. Downside
1. Widely distributed, CNS 60% of serum level

2. rapidly metabolized and excreted
-half life = 1-3 hours
- urine, 75% as glucuronide
- Competitive inhibitor so need to maintain levels to have therapeutic effect
What is Zidovudine an analog of?
What is the clinical use of Zidovudine?
-Temporarily reduces morbidity and mortality from HIV
-used in 3 drug cocktail (HAART)
-reduces mother-to-newborn transmission

**inhibits infection of new cells
How is resistance to Zidovudine to attained?
mutations in RT
NRTI with these ADR's that are common and may be very severe:
1. Bone marrow depression
2. CNS = headaches, agitation, insomnia
How can toxicity to Zidovudine be enhanced?
by drugs which compete for glucuronidation = that is how the drug is cleared
What is the abbreviation of Didanosine?
dideoxyinosine (ddI)
How is Didanosine administered?
Oral, but acid labile
What is the mechanism of Didanosine?
RT inhibitor
- incorporated into viral DNA to cause chain termination
T or F: Didanosine may not be cross-resistant with AZT
True = viruses resistant to AZT may not be resistant to ddI
Anti-HIV that may cause:
1) Dose-dependent Pancreatitis

2) Peripheral neuropathy
What is the abbreviation for Stavudine?
d4T = analog of thymidine
Stavudine is similar to ddI (Didanosine), but is different in what way?
Higher bioavailability
NRTI that readily crosses the BBB
NRTI with these ADR's:
1. Peripheral neuropathy
2. Lactic acidosis
What is Zalcitabine?
Nucleoside RT Inhibitor

NRTI with these properties:
-actively transported into cells
-resistant to hepatic metabolism
-high bioavailability
-dose-dependent Peripheral neuropathy
-phenotypic resistance is rare
Zalcitabine (ddC)
Abacavir is an analog of?
NRTI that is a Guanosine analog and resistance to it requires 2-3 concomitant mutations (develops slowly)
What does resistance to Abacavir require?
2-3 concomitant mutations = develops slowly
NRTI with these ADR's:
1. Skin rash in 50%
2. Hypersensitivity in 5% (can be fatal)
1st generation oral Non-nucleoside RT Inhibitor
How do NNRTI's work?
Non-competitive (allosteric) inhibitors of Reverse Transcriptase
- binds near but not active site
What is the downfall of Nevirapine? What is done to prevent it?
RAPID emergence of resistance

Only approved for combination therapy with NRTI's
What is the exception to giving Nevirapine in combination therapy?
Single doses are given to mother and neonate
T or F: Nevirapine cannot be active against AZT-resistant HIV

False: it can be active against AZT-resistant HIV b/c they bind different sites on RT
Protease Inhibitor that has these ADR's:
1. Skin rash - 17%

2. Hepatotoxicity - 4%
Anti-HIV that is both a substrate for and inducer of CYP 3A4
What is the ending of all Protease Inhibitors?

*Never (navir) tease a pro (protease inhibitors)
Describe how HIV Protease Inhibitors work
-HIV proteins are translated as a polyprotein
- Must be cleaved to yield active individual proteins
-PI's inhibit the action of the Protease = prevent viral assembly and release of infectious particles
What type of protease is the HIV protease?
Aspartyl protease (aspartic acid is in active site)
What are the adverse effects of Protease Inhibitors
1. Altered body fat distribution
- girdle of fat around hips
- extensive deposits in face
-"buffalo hump"
2. Hyperlipidemia
3. Insulin resistance

**PUDGY Protease Inhibitors
1st HIV Protease Inhibitor on the market
Protease Inhibitor that is a good substrate for "first-pass" metabolism b/c it is a substrate for and inducer of CYP 3A4 = 95% metabolized before reaching systemic circulation
How does resistance to Saquinavir develop?
Via mutations in HIV Protease

*but SLOWLY!!!
What do you use HIV Protease Inhibitors in combination with?
HIV Protease Inhibitor with the highest CNS levels
HIV Protease Inhibitor that may cause:
-Nephrolithiasis = renal calculi
HIV Protease Inhibitor that currently has the highest levels in the CNS
Protease Inbititor metabolized by CYP 3A4 and CYP 2D6

*but not as an efficient substrate as other PI's for CYP's
Combination of HIV Protease Inhibitors where one blocks CYP 3A, allowing the other protection from 1st Pass metabolism
Lopinavir and Ritonavir (blocks CYP3A)
-ORAL HIV protease inhibitor, rapidly absorbed but extensively metabolized (CYP 3A4)
-Causes gastrointestinal effects: Nausea, vomiting, diarrhea, abdominal pain
What is Interfefon-alpha used to treat?
Hep B (management) and C (eradication with Ribavirin)
How is Interferon-alpha administered?
Subcutaneous or IM injection 3-7 times weekly
Describe the Pegylated form of INF-alpha?
provides a longer half-life (weekly administration vs. 3-7 / wk)
What is the most common side effect of IFN-alpha?
Flu-like syndrome
What is Lamivudine an analog of?
Antiviral with these 2 actions:

2. HBV DNA Polymerase Inhibitor
1. administration?
2. excretion?
1. oral

2. unchanged in urine
Lamivudine half-lives:
1. Serum?
2. Cellular triphosphate in HIV infected cells?
3. Cellular triphosphate in HBV-infected cells?
1. 2.5 hrs
2. 10-15 hrs
3. 17-19 hrs
Resistance to this antiviral is associated with Hepatitis flares and progression of Liver damage

*NRTI & HBV DNA Pol Inhibitor
Pegylated IFN-alpha plus ______ is standard of care for eradication of HCV
3 drugs used in Anti-Influenza chemotherapy
1. Rimantidine
2. Oseltamivir (Tamiflu)
3. Zanamavir (Relenza)
What is Rimantadine's mechanism of action?
blocks Influenza's uncoating by blocking M2 proton channel

***"A man to dine" takes off his COAT
When is Rimantadine supposed to be given?
in first 48 hours after contact
What are the adverse effects of Rimantadine?
GI intolerance

CNS effects

**"A man to dine" has UPSET STOMACH and SLURRED SPEECH
What is Rimantadine clinically used for?
INfluenza A
What are the 2 Influenza Neuraminidase Inhibitors?
Oseltamivir (Tamiflu)

Zanamivir (Relenza)

Describe the mechanism of action Influenza Neuraminidase Inhibitors
Prevent viral release from infected cells = prevents infection of additional cells

*causes viral clumping at surface
First oral agent effective against all common Influenza strains
Oseltamivir (Tamiflu)
-Pro-drug; activated in the gut and liver = can only give orally
-Well tolerated, some transient nausea and vomiting
-Anti-influenza drug
Oseltamivir (Tamiflu)
1. Administration?
2. Active against?
3. Excretion?
4. When effective?
5. Adverse effect
1. Oral inhalation
2. Influenza A and B
3. urine, unchanged
4. early in infection (>2 days)
5. Bronchospasm in asthmatics
List the 5 general characteristics of tumor cells
1. Excessive/inappropriate growth
2. diminished apoptosis
3. loss of differentiation
4. Invasive
5. Metastatic
What is Multi-modality therapy?
Chemotherapy + Surgery
# of tumor cells that is a fatal burden?
# of tumor cells that elicit unmistakable symptoms?
# of tumor cells correlating with the Subclinical range?
10^9 and below
Cure requires "total Kill":
-must kill all cells with __1__
- __2__ detection/eradication of tumor cells is very poor
1. Proliferative potential

2. Immune
Chemotherapy following surgery or radiation
Chemotherapy before surgery or radiation
Variable Success Rates in Cancer Treatment:
-About 50% of cancers can be cured using __1__ therapy
-About 17% can be cured by __2__ alone
-highly variable by __3__
1. Multi-modality

2. Chemotherapy

3. Tumor site/type
List the groups of Anti-cancer drugs that are Cell-cycle specific
1. Antimetabolites = nucleoside analogs = S phase
2. Topoisomerase inhibitors
3. Microtubule poisons
4. Bleomycin
What groups of anti-cancer drugs are effective during any stage of the cell cycle?

But what types of cells are they most effective against?
1. Alkylating agents
2. Antitumor antibiotics

Rapidly cycling cells
What is the target for selective toxicity with Anti-cancer agents?
Tumor cells have a high proliferative potential
List the groups of cells/body sites that also have high proliferative potential
1. Bone marrow
2. Epithelial cells
3. Immune system
4. Hair follicles
What do most effective anticancer drugs activate?
Apoptosis does not occur in the absence of functional _____

*tumors that have lost this will be far more resistant to the effects of cytotoxic anti-cancer drugs
What is the most prominent acute adverse effect of anti-tumor drugs?
Nausea and Vomiting
How can nausea and vomiting be treated when giving anti-tumor drugs?
Treat with Antiemetics
1. 5-HT3 antagonists = Ondansetron
2. Phenothiazines

*30% unaffected by antiemetics
What are the two "-penia's" that usually occur first as a delayed effect of Anti-tumor drugs? What do they put you at risk for?
1. Leukopenia (neutropenia) = risk of infection

2. Thrombocytopenia = risk of bleeding
How do you treat the Myelosuppression effects of anti-tumor drugs? (3)
1. Leukopenia with GM-CSF

2. Thrombocytopenia with Platelet transfusions

3. Anemia with Erythropoietin
Why are there GI effects with anti-tumor drugs?
b/c we have an epithelial cell population that has to be replenished every day
What is "Hand and Foot Syndrome" associated with some Anti-tumor drugs
Edema, pigmentation, and neural changes in the hands and feet
Describe Secondary Malignancy associated with Anti-cancer drugs
- many anti-cancer drugs act by modification of nuclear DNA, leading to altered structure and fxn
-therapy which helped cure the primary malignancy may cause a secondary malignancy years later
-usually a lag period of 10-20 years
When is Secondary Malignancy less of a concern?
In a person who is older

*a younger person has whole life to develop secondary malignancy
Since anti-cancer chemotherapy selects for resistance, what is the approach used?
Combination chemotherapy
Describe Primary Resistance of tumor cells
tumor cells are initially not sensitive to a given drug therapy

*can bypass this by IN VITRO sensitivity testing
Describe Secondary Resistance of tumor cells
tumors develop resistance during therapy
-changes in: permeability, amplification/alteration of targets, enhanced repair
What confers MULTI-DRUG RESISTANCE to Anti-cancer drugs?
Active export by P-glycoprotein (MDR-1) = pumps out drugs
List the 7 major classes of Antineoplastic Drugs
1. Alkylating agents
2. Antimetabolites
3. Plant Alkaloids
4. Antitumor Antibiotics
5. Hormones and Hormone Modulators
6. Antibodies
7. Signal Transduction inhibitors
Alkylating agents:
-__1__ bind to/modify biological molecules
-__2__ is the key target
-must be __3__--inherent, or generated by metabolism
-__4__, but replicating cells are more sensitive
1. Covalently
2. DNA
3. Reactive
4. Cell cycle non-specific
Why are Alkylating agents more effective when cells are replicating?
b/c it decreases the chances that the adduct will be repaired
The differences in clinical uses of Akylating agents primarily reflects the ______ differences of each drug
What is the mechanism of action of Alkylating agents?
Covalently bind to BASES in DNA
Explain the "bifunctionality" of Alkylating agents
they latch on to a DNA base with one arm and then latch on to another piece of DNA with another part = blocks ability to read through that strand