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SBL Final > Pharm > Flashcards

Pharm Flashcards

1
Q

TQ

Which 2 drugs disrupt DNA & RNA integrity by inhibiting purine ring biosynthesis and nucleotide interconversion?

A

6-Mercaptopurine

6-Thioguanine

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2
Q

TQ

What is the mechanism of fludarabine (2-F-araA)?

A

Tumor cell kinases convert 2-F-araA to nucleotide triphosphates &raquo_space; inserted into DNA/RNA and disrupts synthesis

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3
Q

TQ
Name the drug.
Tumor cell kinases convert it to nucleotide analogs; inhibits DNA synthesis; also potent inhibitor of ribonucleotide reductase

A

Cladribine

2-Cl-deoxyadenosine

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4
Q

What are the 4 purine antimetabolites?

A

6-Mercaptopurine (6-MP)
6-thioguanine (6-TG)
Fludarabine (2-F-araA)
Cladribine (2-Cl-deoxyadenosine)

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5
Q

TQ

What is the therapeutic use of 6-MP?

A

Maintenance of remission in acute lymphocytic leukemia (ALL)

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6
Q

TQ

What is the therapeutic use of 6-TG?

A

Acute non-lymphocytic leukemia (with daunorubicin & cytarabine)

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7
Q

TQ

What are the 3 therapeutic uses of fludarabine (2-F-araA)?

A

Chronic lymphocytic leukemia (CLL) *
Hairy cell leukemia
Non-Hodgkin’s lymphoma (indolent-type)

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8
Q

TQ

What are the 3 therapeutic uses of cladribine?

A

Hairy cell leukemia *
Non-Hodgkin’s lymphoma
Chronic lymphocytic leukemia (CLL)

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9
Q

TQ

What are the 3 dose-limiting toxicities of 6-MP?

A
  • Myelosuppression
  • Dose adjustment with allopurinol or febuxostat (xanthine oxidase inhibitor) *
  • Hepatotoxicity&raquo_space; jaundice
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10
Q

What are the 2 dose-limiting toxicities of 6-TG?

A
  • Myelosuppression

- Hepatotoxicity with long term use

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11
Q

What are the 2 dose-limiting toxicities of fludarabine (2-F-araA)?

A
  • Myelosuppression
  • Opportunistic infections

IV only to avoid intestinal bacteria generating toxic fluoroadenine.

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12
Q

What are the 2 dose-limiting toxicities of cladribine?

A
  • Myelosuppression

- Drug fever

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13
Q

TQ
Explain the hepatic inactivation of 6-MP:
What 2 enzymes are at work?
What 2 inactive metabolites result?

A

6-MP goes into the liver….

  • TPMT (thiopurine methyltransferase) &raquo_space; Methyl-6-MP
  • XO (xanthine oxidase) &raquo_space; 6-Thiouric acid
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14
Q

TQ
What is the first bioactivation enzyme as 6-MP meets the liver?
What is the resultant metabolite?

A
  • Enzyme = HPRT

- Resultant metabolite = TIMP

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15
Q

TQ
TIMP is turned into what 2 active nucleotide metabolites that are anti-neoplastic?
What 2 enzymes are used?

A
  • 6-methyl-TIMP ribonucleotides (via TPMT)

- TXMP (via IMPDH)

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16
Q

TQ

Which 2 liver enzymes inactivate 6-MP?

A

TPMT and XO

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17
Q

TQ

Explain 6-MP toxicity due to drug interaction with gout meds.

A
  • Gout meds (allopurinol & febuxostat) inhibit xanthine oxidase &raquo_space; decreases uric acid
  • Allopurinol & febuxostat inhibit metabolism of xanthine drugs (6-MP, azathioprine, theophylline) used in cancer chem, immunosuppression & asthma &raquo_space; Risk of overexposure and requires dose adjustments
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18
Q

TQ
Explain how chemotherapy can sometimes cause abrupt death of vast #’s of tumor cells, e.g., especially in leukemia or lymphoma.
What syndrome is this called?

A

Chemicals released from dying cells can produce hyperuricemia, hyperkalemia, hyperphosphatemia (hypocalcemia).

Tumor lysis syndrome

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19
Q

TQ

Acute nephrotoxicity produced by excessive uric acid from tumor lysis syndrome is managed by co-administration of:

A

Allopurinol (a xanthine oxidase inhibitor)

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20
Q

TQ
What is the problem with simultaneous administration of allopurinol & 6-MP?
How do you combat this problem?

A

Simultaneous administration of allopurinol & 6-MP chemotherapy can result in excessive exposure to 6-MP because it is metabolized (inactivated) by xanthine oxidase.

To avoid this problem, the dose of 6-MP must be reduced.

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21
Q

What is pegloticase indicated for?

A

Hyperuricemia assoc with malignancy (tumor lysis syndrome)

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22
Q

TQ

What is unique about 6-TG in terms of drug interaction with XO inhibitors?

A

6-TG bypasses the XO inactivation step.

Therefore, it has no drug interaction with XO inhibitors (allopurinol or febuxostat).

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23
Q

TQ

6-TG is activated by what enzyme?

A

HPRT (makes 6-thio-GMP)

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24
Q

6-thio-GMP is activated by kinases and reductases to make:

A

6-thio-dGTP

6-thio-GTP

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25
Q

TQ

6-TG is inactivated by what enzyme?

A

TPMT

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26
Q

TQ

What is the risk and benefit assoc with the (H/H) genetic variant of TPMT (high TPMT activity)?

A

Risk: Relapse
Benefit: Lower toxicity

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27
Q

TQ

What is the risk and benefit assoc with the (L/L) genetic variant of TPMT (low TPMT activity)?

A

Risk: Myelosuppression and secondary malignancy
Benefit: Efficacy

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28
Q

TQ

Which metabolite inhibits de novo purine synthesis?

A

TIMP

the closest thing to inhibiting de novo purine synthesis

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29
Q

TQ

What is the mechanism of fludarabine and cladribine?

A

Fludarabine and cladribine enter tumor cells by active transport.
Converted to nucleotide mono-, di-, and tri-phosphates, and deoxynucleotide di- and tri-phosphates.
These active metabolites inhibit DNA polymerase and have damaging effects as they’re incorporated into DNA/RNA.

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30
Q

TQ

Anti-metabolites act against tumor cells that are in what phase of the cell cycle?

A

S-phase

DNA synthesis as chromosome duplicate

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31
Q

TQ

With adjuvant therapy you can expect to see _ log kill.

A

2 log kill

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32
Q

What is the diagnostic threshold in terms of cell count?

A

10^9 cells = detectable tumor

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33
Q

TQ

E.g., If detectable growth of a tumor levels off around age 52, would a cell cycle-specific agent be efficacious?

A

No…

If growth of the tumor is leveling off, an agent that acted on cells in S-phase would not help at all.

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34
Q 
Drug class that inhibits tubulin polymerization (blocks assembly of microtubules):
Name 3 drugs in the class.
A

Vinca alkaloids.

  • Vinblastine
  • Vincristine
  • Vinorelbine
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35
Q 
Drug class that enhances tubulin polymerization (stabilizes microtubules so they're excessively long and don't work):
Name 2 drugs in the class.
A

Taxanes.

  • Taxol (Paclitaxel)
  • Taxotere (Docetaxel)
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36
Q

TQ

What is the 3-drug therapeutic regimen for testicular cancer?

A

Vinblastine with bleomycin & cisplatin

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37
Q

Name 5 therapeutic uses for vincristine.

A 
ALL (pediatric)
Lymphoma
Neuroblastoma
Wilms' tumor
Ewing's sarcoma
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38
Q

Therapeutic use for vinorelbine.

A

Advanced NSCL cancer (alone or with cisplatin)

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39
Q

What is the 2-drug therapeutic regimen for ovarian cancer?

A

Paclitaxel with cisplatin

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40
Q

Therapeutic use for docetaxel:

A

Advanced breast, ovarian recurrence

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41
Q

Taxanes are effective against:

A

Solid tumors

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42
Q

Main dose limiting toxicity of vincristine:

A

Neurotoxicity, peripheral neuropathy

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43
Q

Vinca alkaloids have a generic dose limiting toxicity of:

A

Bone marrow suppression

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44
Q

Taxanes have a generic dose limiting toxicity of:

A

Neutropenia, peripheral neuropathy

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45
Q

TQ

What is the mechanism of vinca alkaloids?

A

-Bind to B-tubulin at the forming end of microtubules and inhibit polymerization (‘fraying’ end continues)

i.e., inhibit microtubule elongation
(rate of depolymerization > rate of polymerization)

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46
Q

TQ

What is the mechanism of taxanes?

A
  • Bind to B-tubulin at the forming end of microtubules (once taxanes reach the negative end, they inhibit ‘fraying’ disassembly)
    i. e., enhanced tubulin polymerization&raquo_space; excessively long microtubules that don’t work
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47
Q

TQ

Vinca alkaloids and taxanes are cell cycle-specific and act on cells in which phase?

A

M-phase

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48
Q

TQ

Peripheral neuropathy or neuritis are adverse effects of:

A

Vinca alkaloids

Taxanes

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49
Q

TQ
What is the name of an agent that works like taxanes, but does not produce MDR, and is used in breast cancer pts who have failed anthracycline antibiotic and taxane treatments?

A

Ixabepilone

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50
Q

TQ

Multi-drug resistance is established in tumor cells through the expression of an efflux pump called:

A

P-glycoprotein

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51
Q

TQ

Etoposide and teniposide are inhibitors of topoisomerase _, which cause what type of breaks in DNA?

A

Etoposide and teniposide:

  • Inhibit topoisomerase II
  • Double strand DNA breaks
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52
Q

TQ

Irinotecan and topotecan are inhibitors of topoisomerase _, which cause what type of breaks in DNA?

A

Irinotecan and topotecan:

  • Inhibit topoisomerase I
  • Single strand DNA breaks
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53
Q

TQ

2 therapeutic uses of etoposide:

A
  • Oat cell carcinoma of lung

- Testicular cancer (with cisplatin & bleomycin)

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54
Q

TQ

2 therapeutic uses for teniposide:

A
  • Glioma

- Neuroblastoma

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55
Q

TQ

Therapeutic use of irinotecan:

A

Metastatic colorectal cancer

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56
Q

TQ

Main toxicity of irinotecan:

A

Severe diarrhea

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57
Q

TQ
E.g., Someone fails prior therapy, tries new therapy, had to halt it because pt had severe diarrhea. When I looked at cell damage, what did I find?

A

Single strand DNA break.

How we arrived at answer:
Treated with irinotecan… Topoisomerase I inhibitor… Single strand DNA break.

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58
Q

Leukopenia is a dose limiting toxicity of which drug class?

A

Epipodophyllotoxins:

  • Etoposide
  • Teniposide
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59
Q

Mechanism of topoisomerase inhibitors:

A

Bind to DNA-enzyme complex and create a ‘persistently cleavable complex’

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60
Q

TQ

Topoisomerase I inhibitors (captothecins – irinotecan and topotecan) work primarily in what phase of the cell cycle?

A

S phase

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61
Q

TQ
Topoisomerase II inhibitors (epipodophyllotoxins – etoposide and teniposide) work primarily in what 2 phases of the cell cycle?

A

S phase

G2 phase

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62
Q

TQ

Which antibiotic works through Fe2+/3+ mediated free radical generation, leading to DNA strand breaks?

A

Bleomycin

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63
Q

TQ

Therapeutic use of bleomycin:

A

Testicular cancer

with vinblastine, cisplatin or etoposide

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64
Q

Doxorubicin and epirubicin are primarily used for:

A

Solid tumors.

-wide spectrum of use – breast, ovarian, lung, lymphoma, sarcoma, etc

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65
Q

TQ

Daunorubicin and idarubicin are primarily used for:

A

Hematologic cancers (e.g., leukemia)

  • Daunorubicin – leukemia (AML, ALL)
  • Idarubicin – leukemia (AML, ALL, CML blast crisis)
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66
Q

Mitoxantrone is used for several cancers, such as:

A

Breast, prostate, non-Hodgkin’s lymphoma

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67
Q

TQ

The main toxicity associated with bleomycin is:

A

Pulmonary fibrosis

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68
Q 
TQ
Anthracyclines (doxorubicin*, daunorubicin, epirubicin, idarubicin) have a dose limiting toxicity of:
A

Dilated cardiomyopathy *
Cardiotoxicity
CHF

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69
Q

What is the mechanism of anthracyclines?

A

Intercalate between DNA double helix and create distortions that disrupt DNA integrity and inhibit RNA synthesis & replication

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70
Q

TQ

How does doxorubicin cause superoxide oxidative DNA damage?

A
  • DOX combines with O2, which uses Cyp450 reductase to make superoxide from O2 and DOX Semi-quinone from DOX
  • Superoxide (H2O2) then causes strand breaks in DNA
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71
Q

TQ

Bleomycin causes damage to what 2 tissues?

A

Skin and lung

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72
Q

TQ
E.g., Pt presents with dyspnea and rales with dry cough and infiltrate while trying to treat his testicular cancer. What is the mechanism of the drug that he was prescribed?

A

Pulmonary fibrosis symptoms… Bleomycin… Fe2+/3+ mediated free radical generation&raquo_space; oxidative DNA damage (strand breaks)

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73
Q

TQ
E.g., Pt presents with murmur and enlarged ventricles upon imaging study. Use of what drug caused these symptoms over time?

A

Doxorubicin

or any anthracycline

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74
Q

TQ

Bleomycin and anthracyclines are most active in which cell cycle phase?

A

G2 phase (a little S phase too)

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75
Q

Therapeutic use of dacarbazine (triazene; DNA alkylation):

A

Metastatic melanoma

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76
Q

Therapeutic use of procarbazine (triazene; DNA alkylation):

A

Metastatic glioma

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77
Q

Therapeutic use of temozolomide (triazene; DNA alkylation):

A

Treatment-resistant glioma and astrocytoma

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78
Q

Therapeutic use of carmustine and lomustine (nitrosourea; DNA alkylation):

A

Brain tumors, lymphoma, melanoma

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79
Q

Therapeutic use of streptozocin (nitrosourea; selective at islet ß cells):

A

Insulinomas

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80
Q

Name 3 nitrogen mustards.

Which is the vesicant?

A
  • Cyclophosphamide
  • Ifosfamide
  • Mechlorethamine (vesicant)
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81
Q

Therapeutic use of melphalan:

A

Multiple myeloma

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82
Q

Therapeutic use of chlorambucil:

A

CLL

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83
Q

Therapeutic use of busulfan:

A

CML

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84
Q

TQ
What are the 3 monofunctional agents?
What is their method of cross-linkage (i.e., alkylation)?

A

Dacarbazine
Procarbazine
Temozolomide

Cross-linkage = O6-G-methylation (puts a CH3 on a G)

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85
Q

TQ

The G-G cross-linkage that skips 2 AAs describes what 3 drugs?

A
  • N-mustards (cyclophosphamide, ifosfamide, mechlorethamine)
  • Thiotepa
  • Busulfan
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86
Q

TQ
The G-G cross-linkage that skips 1 AA describes what drug?
What is unique about this cross-linkage?

A

Mitomycin

More difficult to repair

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87
Q 
TQ
The G-C cross linkage at the same AA position describes what class of drugs?
A

Chloroethyl-nitrosoureas (carmustine, lomustine, streptozocin)

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88
Q

DNA alkylation/cross-linking can occur readily because these agents are cell cycle (specific/NON-specific).

A

DNA alkylation/cross-linking can occur readily because these agents are cell cycle NON-specific !!!

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89
Q

Cell cycle non-specific drugs are dependent on:

A

Dose (NOT schedule/timing)

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90
Q

TQ

Which 2 repair enzymes confer insensitivity to DNA alkylating/cross-linking agents?

A

Guanine O6-alkyl transferase (OAT)

Methyl guanine methyl transferase (MGMT)

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91
Q

TQ

Resistance to DNA alkylating/cross-linking agents is achieved if cancer cells produce more:

A

Glutathione

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92
Q

-Instantaneous activation by water upon infusion &raquo_space;
Potent vesicant can cause blisters, necrosis if extravasation occurs
-MOPP: Hodgkin’s disease

Which drug is described?

A

Mechlorethamine

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93
Q

TQ
Mechanism of cyclophosphamide and ifosfamide:
What 2 metabolites result?
What major toxicity results?

A
  • Activation by liver Cyp450 enzymes.
  • Acrolein and phosphoramide mustard
  • Acrolein – urotoxicity (hemorrhagic cystitis) ***
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94
Q

TQ
Nitrosoureas (e.g., carmustine, lomustine) are used primarily for:
Why?

A

Brain cancers

-Lipophilic nature favors CNS distribution

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95
Q

TQ

What is the dose limiting toxicity of nitrosoureas (e.g., carmustine, lomustine)?

A

Myelosuppression

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96
Q

TQ

What is different between dacarbazine and temozolomide in terms of mechanism of action and therapeutic use?

A

Dacarbazine

  • I.V., Cyp450 activation
  • MTIC (activated metabolite)
  • Metastatic melanoma

Temozolomide (penetrates CNS)

  • P.O., spontaneous (H+)
  • MTIC (activated metabolite)
  • Refractory anaplastic astrocytoma and glioblastoma
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97
Q

TQ

The status of which enzyme in the tumor influences the efficacy of temozolomide?

A

MGMT

  • Low MGMT = susceptible
  • High MGMT = Refractory
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98
Q

TQ

Epigenetic ‘silencing’ of MGMT is a biomarker for the efficacy of which drug?

A

Tomozolomide

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99
Q
  • Platinum–Cl- complex
  • Stable in plasma and high Cl- milieu
  • Hydrolyses in cell to active agent
  • Complex elimination due to cell uptake

Which drug is described?

A

Cisplatin

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100
Q

What is the more stable analog of cisplatin?

A

carboplatin

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101
Q

TQ

Therapeutic use of cisplatin:

A
  • Testicular cancer (with bleomycin, vinblastine or etoposide)
  • Ovarian cancer
  • NSCL
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102
Q

TQ

3 dose limiting toxicities of cisplatin:

A
  • Renal failure (nephrotoxicity) ***
  • N/V
  • Ototoxicity – acoustic nerve damage
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103
Q

TQ

Therapeutic use of carboplatin:

A

Ovarian cancer

104
Q

Dose limiting toxicity of carboplatin:

A

Neutropenia

105
Q

TQ

Therapeutic use of oxaliplatin:

A

Colorectal cancer

FOLFOX regimen – Folinic acid, FU, Oxaliplatin

106
Q

2 dose limiting toxicities of oxaliplatin:

A
  • Neutropenia

- Cold-induced neuropathy

107
Q

How do cisplatin and related compounds enter cells?

A

Diffusion and Cu2+ transporter

108
Q

TQ
When is cisplatin nephrotoxicity seen?
How does it manifest?

A

After 10 days of cisplatin administration.

  • Decr GFR
  • Incr serum creatinine
  • Decr serum Mg2+ and K+
109
Q

2 Bcr-Abl tyrosine kinase inhibitors:

A

Imatinib

Dasatinib

110
Q

TQ
Imatinib is an effective treatment for:
What is the mechanism?

A

CML

Imatinib occupies the ATP cofactor binding site on Bcr-Abl, inhibiting transfer of phosphate to tyrosine on substrates.

111
Q

TQ

Imatinib-resistant CML is treated with:

A

Dasatinib

112
Q

TQ

Imatinib targets which 3 tyrosine kinases?

A

Bcr-Abl
c-kit
PDGFR (a RTK)

113
Q

TQ

2 therapeutic uses of imatinib:

A

CML

GIST

114
Q

TQ

Dasatinib targets which 2 tyrosine kinases?

A

Bcr-Abl

Src family

115
Q

TQ

2 therapeutic uses of dasatinib:

A

Imatinib-resistant CML

Ph+ ALL

116
Q

What would you give for imatinib-resistant GIST?

A

Sunitinib

117
Q

TQ

The overexpression of which ErbB family member is commonly assoc with breast cancer?

A

HER2 (ErbB2)

118
Q

TQ
Which RTK inhibitor acts on both EGFR and HER2?
Used in:

A

-Lapatinib – breast cancer

119
Q

TQ
Which 2 RTK inhibitors act only on EGFR?
Both used in:

A

Gefitinib
Erlotinib

Both used in NSCLC

120
Q

TQ
Which RTK inhibitor acts on c-kit, PDGFR, and VEGFR?
Used in:

A

Sunitinib – GIST and RCC*

121
Q

TQ
Which agent inhibits RAF kinase?
Used in:

A

so’RAF’enib – RCC* and HCC

122
Q

TQ
Vemurafenib specifically inhibits mutant:
What kind of cancer?

A

BRAF V600E

Metastatic malignant melanoma

123
Q

TQ

BCR-ABL is targeted by what 2 drugs?

A

Imatinib

Dasatinib

124
Q

TQ

EGFR is targeted by which 2 drugs and which 2 antibodies?

A

EGFR:
Drugs = Erlotinib & Gefitinib
Abs = Cetuximab & Panitumumab

125
Q

TQ

HER2 is targeted by which drug and which antibody?

A

HER2:
Drug = Lapatinib
Ab = Trastuzumab

126
Q

TQ

PDGFR and VEGFR are targeted by which 2 drugs?

A

Sunitinib

Sorafinib

127
Q

TQ

VEGF-ligand is targeted by which antibody?

A

Bevacizumab

128
Q

Therapeutic uses of cetuximab (targets EGFR):

A

Colorectal; head & neck

tumors with KRAS mutation are unresponsive

129
Q

Therapeutic use of panitumumab (targets EGFR):

A 
Colorectal cancer
(except KRAS mutations)
130
Q

TQ

Therapeutic use of trastuzumab (targets HER2):

A

HER2+ breast cancer

131
Q

TQ

Therapeutic use of bevacizumab (targets VEGF-ligand):

A

Renal cell carcinoma

132
Q

TQ

Why is mutational status of KRAS a determinant of response to antibodies that inhibit EGFR activation?

A

A mutation in RAS can bypass inhibition of EGFR tyrosine kinase, so Abs that inhibit EGFR activation would become null.

133
Q

TQ

Which 3 angiogenesis inhibitors (2 drugs, 1 Ab) are used to treat renal cell carcinoma (RCC)?

A
  • Sunitinib
  • Sorafenib
  • Bevacizumab
134
Q

TQ
Rituximab is approved for the treatment of:
Would P-glycoprotein have an effect on this drug?

A

CD20+ B-cell cancers:
B-cell lymphoma (Non-hodgkin lymphoma)
B-cell leukemia (chronic lymphocytic leukemia – CLL)

P-glycoprotein would not have an effect on Rituximab because the drug acts on the cell exterior.

135
Q

TQ
What does bortezomib (i.v.) target?
Used in:

A

Bortezomib:

  • Targets 26S proteasome
  • Multiple myeloma, mantle cell lymphoma
136
Q

TQ
What does vorinostat (p.o.) target?
Used in:

A

Vorinostat:

  • Histone deacetylase (HDAC) inhibitor
  • Cutaneous T-cell lymphoma
137
Q

TQ
What does anastrozole target?
Used in:

A

Anastrozole:

  • Aromatase inhibitor
  • Estrogen-dependent breast cancer (post-menopausal women)
138
Q

TQ
What does exemestane target?
Used in:

A

Exemestane:

  • Aromatase inactivator
  • Advanced breast cancer
139
Q

Toxicities from cancer chemotherapies:

  • N/V – ?
  • Myelosuppression – ?
  • Diarrhea – ?
  • Cystitis – ?
  • Neuropathy – ?
  • Pulmonary fibrosis – ?
  • Cardiotoxicity – ?
  • Renal failure – ?
A

Toxicities from cancer chemotherapies:

  • N/V – Dacarbazine
  • Myelosuppression – Dacarbazine
  • Diarrhea – Irinotecan
  • Cystitis – Cyclophosphamide (acrolein)
  • Neuropathy – Vinblastine
  • Pulmonary fibrosis – Bleomycin
  • Cardiotoxicity – Anthracyclines (doxorubicin) and Trastuzumab
  • Renal failure – Cisplatin
140
Q

TQ

What are the toxicities of the ABVD regimen (used for Hodgkin’s lymphoma)?

A

Adriamycin (doxorubicin) – cardiotoxicity
Bleomycin – pulmonary fibrosis
Vinblastine – peripheral neuropathy
Dacarbazine – N/V, myelosuppression

141
Q

TQ
ABVD Regimen
Activity: Anti-mitotic (M-phase active agent) that destabilizes microtubules; causes peripheral neuropathy.

A

Vinblastine

142
Q

TQ
ABVD Regimen
Activity: Anti-tumor antibiotic; causes pulmonary fibrosis.

A

Bleomycin

143
Q

TQ
ABVD Regimen
Activity: DNA damage as an intercalating agent; causes dilated cardiomyopathy.

A

Adriamycin (aka Doxorubicin*)

144
Q

TQ
ABVD Regimen
Activity: DNA damage as an alkylating agent; causes marrow suppression.

A

Dacarbazine

145
Q

TQ
What is the CHOP regimen for Non-Hodgkin’s lymphoma?
What are the toxicities of each drug?

A

Cyclophosphamide – hemorrhagic cystitis (due to acrolein)
Hydroxy-daunorubicin (Doxorubicin) – cardiotoxicity (dilated cardiomyopathy)
Oncovorin (Vincristine) – peripheral neuropathy
Prednisone – hyperglycemia, osteopenia

146
Q

What are the 2 molecular etiologies of chemotherapy-induced N/V?

A
  1. Direct activation of medullary CTZ – activates 5-HT3, D2, and substance P neurokinin (NK1) receptors.
  2. Cell damage of GI tract – Serotonin released from enterochromaffin cells activates 5-HT3 receptors and NK1 receptors on extrinsic intestinal vagal and spinal afferent nerves.
147
Q

TQ

What is unique about the 5-HT3 receptor?

A

The 5-HT3 receptor subtype is the only channel that’s NOT coupled to a G protein… 5-HT3 is instead coupled to a direct ion (Na+, 2K+) channel

148
Q

Name 4 anti-emetic 5-HT3 receptor antagonists and their HLs.

A

Ondansetron (i.v., oral) – 4h
Granisetron (i.v., oral, patch) – 10h
Dolasetron (oral only) – 8h
Palonosetron (i.v., oral) – 40h

149
Q

TQ

5-HT3 receptor antagonists are used for (acute/delayed) emesis assoc with CINV.

A

5-HT3 receptor antagonists are used for ACUTE emesis assoc with CINV.

150
Q

Main adverse effect of 5-HT3 receptor antagonists:

A

QTc prolongation

151
Q

TQ
Delayed emesis is most common after high-dose:
What anti-emetic would you give?

A 
Cisplatin
Give Aprepitant (NK1 receptor antagonist, competes with substance P)
152
Q

TQ

What is the 3-drug regimen for high emetic risk?

A

5-HT3 receptor antagonist (-setron)
Aprepitant
Dexamethasone

153
Q

TQ

What is the 2-drug regimen for moderate emetic risk?

A

5-HT3 receptor antagonist (-setron)

Dexamethasone

154
Q

What is given for low emetic risk?

A

Dexamethasone

155
Q

TQ

Anticipatory emesis should be treated with:

A

Benzodiazepines (e.g., lorazepam)

156
Q

TQ
When neutrophil count < 0.5 it is an oncology emergency.
What should be given?

A

G-CSF (filgrastim)

GM-CSF (sargramostim)

157
Q

TQ

Main adverse effect of G-CSF and GM-CSF:

A

Bone pain

158
Q

TQ

Oprelvekin (IL-11) increases platelets and is used for:

A

Prevention! …NOT for the treatment of thrombocytopenia.

159
Q

Explain leucovorin rescue.

A

Leucovorin bypasses the blocked DHFR enzyme and replenishes the folate pool of normal cells. It can moderate toxicity assoc with HDMTX.

160
Q

TQ

What is given with cyclophosphamide as prophylaxis for hemorrhagic cystitis?

A

MESNA (a sulfhydryl agent) – reacts with acrolein to diminish its toxic effect on the bladder

161
Q

TQ

When would you use the protectant agent Dexrasoxane?

A

Doxorubicin cardiotoxicity

162
Q

TQ

When would you use the protectant agent Amifostine?

A

Cisplatin nephrotoxicity

163
Q

Mechanism of amphotericin (drug class = polyene):

A

Binds ergosterol (unique to fungi); forms membrane pores that allow leakage of electrolytes.

-AmphoTERicin “TEARs” holes in the fungal membrane by forming pores.

164
Q

Amphotericin B toxicities at the onset of infusion:

A

Fever/chills (“shake and bake”)
Hypotension
Anemia
Nephrotoxicity (later onset)

165
Q

Amphotericin B causes direct damage to the distal tubule membrane, leading to wasting of which electrolytes?

Arteriole constriction results, so what happens to the GFR?

A

Na+
K+
Mg2+

Arteriole constriction&raquo_space; Decreased GFR

166
Q

TQ

Treatment for mucormycosis (zygomycosis):

A

Amphotericin B

167
Q

TQ

Treatment for cryptococcal meningitis:

A

Amphotericin B + 5-FC (flucytosine)

168
Q

TQ

Mechanism of flucytosine:

A

Inhibits DNA and RNA biosynthesis by conversion to 5-fluorouracil (5-FU) by cytosine deaminase.

169
Q

Resistance limits 5-FC clinical use.

2 ways resistance to 5-FC develops:

A
  • Intrinsic resistance – mutated cytosine permease

- Acquired resistance – mutated cytosine deaminase

170
Q

TQ

Treatment for invasive fungal infection (unresponsive to other therapy):

A

Amphotericin B

171
Q

What are the 3 echinocandin agents?

A

Caspofungin
Micafungin
Anidulafungin

172
Q

TQ

Mechanism of echinocandins (caspofungin, micafungin, anidulafungin):

A

Inhibits cell wall synthesis by inhibiting synthesis of ß-(1,3)-glucan synthase.

173
Q

How are echinocandins (e.g., caspofungin) metabolized?

A

Hepatic metabolism

174
Q

TQ

2 clinical uses of echinocandins (e.g., caspofungin):

A
  • Invasive aspergillosis

- Invasive Candida

175
Q

TQ

Mechanism of azoles (imidazoles & triazoles):

A

Inhibit fungal sterol (ergosterol) synthesis by inhibiting the CYP450 enzyme (lanosterol 14-a-demethylase) that converts lanosterol to ergosterol.

i.e., inhibit Lanosterol&raquo_space; Ergosterol biosynthetic pathway

176
Q

TQ

4 fungal resistance mechanisms to azoles:

A
  • Mutation of lanosterol-14a-demethylase
  • Overexpression of lanosterol-14a-demethylase
  • Energy-dependent efflux systems
  • Changes in sterol and/or phospholipid composition of fungal cell membrane (decreased permeability)
177
Q

How is fluconazole cleared?

A

Renally (75%)

178
Q

Which 3 triazoles can you give for Candida?

A

Fluconazole
Itraconazole
Voriconazole

179
Q

TQ

Which triazole is given for Aspergillus?

A

Voriconazole

180
Q

TQ

Which triazole is given for Cryptococcus neoformans?

A

Fluconazole

181
Q

TQ
Which triazole is front line / recommended for Blastomyces, Coccidioides, and Histoplasmosis (true pathogenic infections)?

A

Itraconazole

-Broad spectrum

182
Q

TQ

What is the toxicity assoc with ketoconazole?

A
  • Testosterone synthesis inhibition (gynecomastia)

- Liver dysfunction (inhibits CYP450)

183
Q

TQ

Which 2 triazoles are readily absorbed with excellent distribution including CSF?

A

Fluconazole

Voriconazole

184
Q
  • Like ketoconazole, it requires gastric acidity to dissolve.
  • Antacids, PPI, H2-antagonists
  • Poor CSF penetration

Which agent?

A

Itraconazole

185
Q

TQ

2 triazoles that are both strong inhibitors of hepatic CYP450 and enhance renal toxicity

A

Voriconazole

Itraconazole

186
Q

T/F: Avoid all triazoles in pregnancy.

A

TRUE

187
Q

T/F: All triazoles can damage liver.

A

TRUE

188
Q

T/F: Voriconazole disturbs vision.

A

TRUE

189
Q

TQ
2 fluconazole indications:
-Narrow spectrum

A
  • Candida albicans *

- Cryptococcus (with Ampho-B)

190
Q

TQ
What is the drug of choice for invasive aspergillosis?
-Also used for candidiasis resistant to fluconazole (e.g., C krusei, C glabrata)

A

Voriconazole

191
Q

Antifungal drugs targeting ergosterol:

3 polyenes:

A
  • Amphotericin B
  • Nystatin
  • Natamycin
192
Q

Antifungal drugs targeting ergosterol:

2 allylamines:

A
  • Terbinafine

- Naftitine

193
Q

TQ
Indicated for ophthalmological fungal conditions:
-Fungal keratitis, conjunctivitis, blepharitis

A

Natamycin

-Fungicidal

194
Q 
TQ
Indicated for mouth (oropharyngeal) and digestive tract fungal conditions:
-Esophageal, pharyngeal (i.e., thrush)
-"Topical" action in intestinal lumen
-Candida ONLY
A

Nystatin

195
Q

TQ

Mechanism of allylamines (terbinafine, naftifine):

A
  • Inhibits the fungal enzyme squalene-2,3-epoxidase &raquo_space;

- Inhibits lanosterol synthesis

196
Q

TQ
Clinical use of allylamines (e.g., terbinafine):
-Localized infection = topical application
-Often fungicidal

A 
Cutaneous dermatophytosis
(especially fungal infections of finger or toe nails)
-Tinea cruris ("jock" itch)
-Tinea corporis (ringworm)
-Tinea pedis (athlete's foot)
-Tinea unguium (nails)
197
Q

TQ

Indicated for widespread Tinea corporis (ringworm):

A

Terbinafine

oral route for systemic delivery

198
Q

TQ

Azole indicated for oropharyngeal candidiasis:

A

Clotrimazole (aka troche)

199
Q

TQ

An immunocompromised host with oropharyngeal candidiasis may also need add what azole?

A

Itraconazole

200
Q

TQ
Azole indicated for vulvovaginal candidiasis:
-Multi-day cream – (2)
-Once-a-day – (2)

A
  • Multi-day cream – Clotrimazole 1%, Miconazole 2%

- Once-a-day – Clotrimazole, Tiaconazole

201
Q

TQ

Indicated for candiduria:

A

Fluconazole

75% renal excretion

202
Q

TQ

Mechanism of griseofulvin:

A
  • Interferes with microtubule function (tubulin, microtubule proteins – MAP); disrupts mitosis *
  • Deposits in keratin-containing tissues (e.g., nails)
203
Q

TQ

Clinical use of griseofulvin (p.o.):

A
  • Oral treatment of superficial infections

- Inhibits growth of dermatophytes (tinea, ringworm) *

204
Q

TQ

Main contraindication of oral Terbinafine:

A

Pregnancy

205
Q

TQ

Adverse effect of griseofulvin:

A
  • CYP450 induction

- Avoid alcohol

206
Q

TQ

2 clinical uses of acyclovir, famciclovir (penciclovir), valacyclovir:

A

HSV and VZV

207
Q

TQ
Drug indicated for acyclovir-resistant HSV/VZV:

A

Foscarnet

208
Q

5 drugs for CMV infections:

A
  • Ganciclovir
  • Valganciclovir
  • Cidofovir
  • Foscarnet
  • Fomivirsen
209
Q

TQ

Mechanism of acyclovir (ACV) and penciclovir (PCV):

A

Monophosphorylated by HSV/VZV thymidine kinase *

  • Guanosine analog
  • Triphosphate formed by cellular kinases *
  • Preferentially inhibits viral DNA polymerase by chain termination *
210
Q

TQ

Mechanism of ganciclovir (GCV):

A

5’-monophosphate formed by a CMV viral kinase (UL97 kinase) *

  • Guanosine analog
  • Triphosphate formed by cellular kinases *
  • Preferentially inhibits viral DNA polymerase *
211
Q

TQ
What is the mechanism of resistance against ACV and PCV?

What is the mechanism of resistance against GCV?

A
  • Deficit (TK-) or mutation in thymidine kinase&raquo_space; resistance to ACV and PCV
  • Deficit (UL97-) or mutation in UL97 kinase&raquo_space; resistance to GCV

For TQ: Think about what you’d see in a petri dish with:

1) No drug + HSV&raquo_space; HSV-infected cells in dish
2) Acyclovir + HSV(wt)&raquo_space; Small amt of HSV-infected cells
3) Acyclovir + HSV(TK-)&raquo_space; HSV-infected cells (due to TK deficit)

212
Q

TQ
Acyclovir is most active against:
(Valacyclovir (pro-drug) has similar spectrum)

A

HSV-1 ≥ HSV-2

NOT CMV

213
Q

TQ

What is the toxicity of acyclovir?

A

Obstructive crystalline nephropathy&raquo_space; acute renal failure *
-Minimize by hydration

May also present with neurologic toxicity in pts with renal failure.

214
Q

TQ

Ganciclovir is most active against:

A

CMV

215
Q

TQ

2 clinical indications for ganciclovir:

A
  • CMV retinitis in immunocompromised pts

- prevention of CMV dz in transplant pts

216
Q

TQ

2 ganciclovir toxicities / complications:

A
  • Bone marrow suppression (leukopenia, neutropenia, thrombocytopenia)
  • Renal toxicity
217
Q

TQ

Which 3 antiviral nucleoside agents do NOT require phosphorylation by viral kinase?

A

Cidofovir
Vidarabine
Trifluridine

218
Q

TQ

Why is trifluridine unique among the 3 antiviral nucleoside agents which do NOT undergo viral-mediated phosphorylation?

A

In addition to trifluridine being tri-phosphorylated and inhibiting viral DNA pol (like cidofovir and vidarabine)…

Trifluridine also can be monophosphorylated to inhibit viral thymidylate synthetase ***

219
Q

TQ

Main clinical use of cidofovir:

A

CMV retinitis in HIV pts

ophthalmic CMV infections

220
Q

TQ

Cidofovir toxicity:

A

Nephrotoxicity

221
Q

TQ

What do you co-administer cidofovir with to decrease nephrotoxicity?

A

Probenecid

222
Q

TQ

What would you give for HSV or VZV keratitis and HSV keratoconjunctivitis in immunocompromised pts?

A

Vidarabine

223
Q

TQ

What is the drug of choice for HSV keratoconjunctivitis and recurrent epithelial keratitis?

A

Trifluridine

224
Q

TQ

Mechanism of foscarnet:

A

Viral DNA polymerase inhibitor that binds to the pyrophosphate-binding site of the enzyme.
(Does not require activation by viral kinase)

FOScarnet = pyroFOSphate analog

225
Q

TQ

2 clinical uses of foscarnet:

A
  • CMV retinitis (when ganciclovir fails)

- Acyclovir-resistant HSV & VZV

226
Q

TQ
Toxicity of foscarnet:
Major complication of foscarnet (due to Ca2+ chelation):

A
  • Nephrotoxicity

- Hypocalcemia

227
Q
  • An anti-sense oligonucleotide that disrupts CMV replication
  • Active against CMV resistant to ganciclovir & foscarnet
  • Administered intravitreally (CMV retinitis)
A

Fomiversen

228
Q
  • Approved by FDA to shorten healing time of cold sores

- Blocks virus entry into cells

A

Docosanol (aka Abreva)

229
Q

TQ

What is the one major contraindication when using IFN-a or PEG-IFN-a for treatment of chronic HBV infection?

A

IFN-a or PEG-IFN-a can be dangerous in decompensated cirrhosis!!!

Pts with:

  • Ascites
  • Encephalopathy
  • Variceal bleeding
  • Coagulopathy
  • Hepatocellular carcinoma
230
Q

TQ

Step-by-step action by IFN-a binding to IFN receptor:

A

1) IFN:receptor binding activates JAK1 & Tyk2 receptor-associated tyrosine kinases.
2) JAK1 & Tyk2 phosphorylate IFN receptor.
3) Phospho-IFN receptor recruits STATs.
4) JAK1 & Tyk2 phosphorylate STATs.
5) Phospho-STATs “undock” from IFN receptor, then dimerize.
6) Phospho-STATs relocalize to the nucleus
7) ISGF3:DNA complex upregulates transcription of Interferon Stimulated Genes (ISG).

231
Q

TQ

Explain the ISG pathway that ultimately leads to viral RNA degradation.

A 
ISG  >>
2'5'-OAS (+ATP)  >>
2'5'-AAA  >>
Activates ribonuclease L  >>
Degrades viral RNA!
232
Q

TQ

Explain the ISG pathway that ultimately leads to the inhibition of viral protein synthesis.

A

ISG &raquo_space;
PKR (+ATP) &raquo_space;
Phospho-eIF &raquo_space;
Inhibits viral protein synthesis!

233
Q

TQ

IFN-a (via IFN-gamma) favors cell-mediated immunity (Th1 / Th2) phenotype.

A

IFN-a favors Th1 phenotype

234
Q

TQ

How do you know that seroconversion is progressing when given PEG-IFN-a?

A

You know seroconversion is progression when there’s a hepatitis ‘flare’ …
-ALT increases

235
Q

4 adverse effects of IFN-a:

A
  • Flu-like syndrome after injection (fever/chills, myalgia, arthralgia) *
  • Fatigue and mental depression
  • Bone marrow toxicity (neutropenia) *
  • Neurotoxicity (behavioral changes)
236
Q

Which 2 NRTIs are approved for treatment of both HIV and HBV?

Which 2 NRTIs are nucleoTide monophosphates?

A

For HIV and HBV: Tenofovir (adenosine analog) and Lamivudine (cytosine analog)

nucleoTides: Tenofovir and Adefovir (adenosine analogs)

237
Q

What is unique about NRTIs in terms of pts with decompensated cirrhosis?

A

NRTIs can be given to pts with decompensated cirrhosis!

238
Q

TQ

2 resistance mechanisms of HBV to NRTIs:

A
  • Impaired purine/pyrimidine kinase activity

- Mutation of DNA polymerase

239
Q

How do we know that resistance by HBV involves impaired purine/pyrimidine kinase activity?

A

Because nucleoTide analogs (adefovir and tenofovir) are useful in pts resistant to nucleoSide analogs (lamivudine, entecavir and telbivudine).

240
Q

TQ

What is the mutant DNA pol / Reverse Transcriptase segment which confers resistance by HBV to lamivudine (LAM)?

A

YMDD becomes YVDD

241
Q

TQ
Breakthrough infection due to antiviral drug resistance…
For lamivudine or telbivudine resistance:

A

Add adefovir or switch to tenofovir.

242
Q

TQ
Breakthrough infection due to antiviral drug resistance…
For entecavir resistance:

A

Add tenofovir.

243
Q

TQ
Breakthrough infection due to antiviral drug resistance…
For adefovir resistance:

A

Add lamivudine, telbivudine or entecavir.

244
Q

TQ

First-line oral anti-HBV 2-drug regimen:

A

Tenofovir (TDF) and Entecavir (ETV)

245
Q

TQ

Second-line oral anti-HBV 2-drug regimen:

A

Lamivudine (LAM) and Telbivudine (TBV)

246
Q

Which NRTI for HBV has the best pregnancy profile?

A

Tenofovir (TDF) – Category B

247
Q

Which NRTI for HBV is the worst at eliminating HBV DNA (worst antiviral effect) after 1 year?
Which NRTI is the best?

A 
Worst = Adefovir (20%)
Best = Tenofovir (80%)
248
Q

Which NRTI for HBV has the most resistance (worst)?

Which NRTI has the least (best)?

A 
Worst = Lamivudine
Best = Tenofovir
249
Q

TQ
Long-term efficacy of lamivudine is limited by frequent emergence of drug-resistant HBV.
What is the mutation?

A

YMDD&raquo_space; YVDD mutant in catalytic domain of HBV polymerase

250
Q

TQ

What is the 3-drug regimen for HCV infection since 2011?

A

PEG-IFN + ribavirin + oral protease inhibitor (telaprevir or boceprevir)
(24-48 weeks)

251
Q

How do some HCV strains have partial resistance to IFN-a?

A

If HCV genome encodes proteins that negate interferon stimulated genes (ISGs – 2’5’-OAS, PKR, ADAR, MxA…).

252
Q

TQ

Mechanism of Ribavirin:

A
  • Ribavirin-monoP inhibits IMP dehydrogenase (inhibits synthesis of guanine nucleotides) *
  • Ribavirin-triP inhibits RNA-dependent RNA polymerase (inhibits RNA replication)
  • Ribavirin-triP also leads to lethal mutagenesis and ‘defective’ HCV
253
Q

TQ

2 Ribavirin toxicities/adverse effects:

A
  • Hemolytic anemia

- Severe teratogen

254
Q

Both telaprevir and boceprevir interfere with HCV replication by inhibiting what key viral enzyme?

A

NS3/4A serine protease

255
Q

TQ

What is the 3-drug regimen for HCV infection?

A
  • PEG-interferon
  • Ribavirin
  • Boceprevir or telaprevir

SBL Final (4 decks)

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