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PHARMACOLOGY - Pulmonary > Topoisomerase and Spindle Inhibitors > Flashcards

Topoisomerase and Spindle Inhibitors Flashcards

1
Q

What are the Vinca Alkaloids?

  • MOA
  • Resistance
A

Vincrinstine and Vinblastine

MOA:
- Blocks Tubulin (alpha-beta) polymerization

  • METAPHASE arrest => APOPTOSIS

Resitance:

  • P-pg (aka MRP (multidrug reistance pump), BCRP)
  • Mutations in BETA-tubulin
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2
Q

How are the Vinca Alkaloids administered?- Elimination?

  • Toxicity?
  • NAME THEM
A

Administration:
- IV

Elimination:
- Hepatic

Toxicity:

  • NEUROTOXICITY
  • coma if intrathecal
  • Leukopenia with vinblastin, NOT vincristine- Extravasational necrosis (Hair loss, cellulitis too with ex.v.)

names:VINCRISTINE and VINBLASTINE

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3
Q

Besides the vinca alkaloids, what other drugs cause microtubule defects?

  • Name drugs in each of these classes.
  • method of administration.
A

Taxanes:

  • Paclitaxel [taxol]
  • Docataxel [taxotere]

Vinca Alkaloids:

  • Vincristine
  • Vinblastine

**IV administration for both classes

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4
Q

Taxanes:

  • NAME THEM.
  • MOA.
  • Administration.
  • Resistance.
A

Paclitaxel [taxol] and Docataxel [taxotere]

MOA:
- Binds to BETA-tubulin and prevents (antagonizes) microtubule DISassembly

Administration:

  • IV
  • less soluble so may be given with Cremaphor (with Paclitaxel) or Polysorbate (with Docetaxel)* (this can change pharacokinetics)

Resistance:

  • Mutation of Beta-Tubulin
  • Efflux (p-gp)
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5
Q

What toxicities are common to both types of microtubule inhibiting drugs?

  • Name the class of drug and drugs.
  • Elimination?
  • DIFFERENCES?
A

Both:

  • Peripheral Neurpathy
  • Blood Dyscrasias

Vinca Alkaloids (vincristine, vinblastine)

  • Vinblastine - Leukopenia
  • Vincristine - (no unique qualities?)

Taxols (Paclitaxel, Docataxel)
- Paclitaxel - Hypersensitivity Infusion Reactions

  • Docataxel - more severe, short lived, Neutropenia ***All microtubule inhibitors are eliminated hepatically
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6
Q

Are the Microtubule inhibitors cell cycle specific?

  • why or why not?
  • NAME THEM.
A

Yes, ALL Target M phase of the cell cycle Vinca Alkaloids:
- Vincristine and Vinblastin

Taxols:
- Paclitaxel and Docetaxel

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7
Q

Where on microtubules do the vinca alkaloids and Taxols bind?

  • Differences in effect.
  • NAME THEM.
A

Vinca Alkaloids
- Vincristine, Vinblastine:

  • bind at the + end- prevents addition of alpha-tubulin

EFFECT:
- no microtubule formation

Taxanes
- Paclitaxel, Docetaxel:

  • Binds at a site to stabilize tubulin subunits

EFFECT: - nucleus FULL of microtubules

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8
Q

Peripheral Neuropathy is produced most reliably by what 5 cancer drugs belonging to what 3 classes?
- Mechanism of this side effect.

A

Vinca Alkaloids and Taxols:
Distal Neuron Affected- Microtubules needed to transport nutrients along axon(drugs: Vincristine, Vinblastin, Paclitaxel, Docetaxel)

Platinum Alkylating agent:
CISPLATIN - messes up the nucleus

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9
Q

Which of all the microtubule drugs is most associated with glove and stocking syndrome?

A

Paclitaxel

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10
Q

What Drugs work by inhibiting Topoisomerase I?

A

Camptothecins - Irinotecan and its metabolite SN-38

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11
Q

Camptothecins:

  • NAME THEM
  • MOA
  • Administration
A

Irinotecan [camptosar] Topotecan [hycamtin]

MOA:
- Binds to Topoisomerase I causing Single and Double strand breaks

  • ONLY DOUBLE strand breaks are truly effective BUT this only happend when DNA fork encounters the complex of Camptothecin/Topoisomerase I complex

Administration: - IV (irotecan has a greater 1/2 life)

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12
Q

Are the Camptothecins cell cycle specific?
- if so what phase are they specific for?

A

Yes, they they are only affective during S phase because they require the replication fork encountering the Topo-1/drug complex S-phase specific

Names:

  • Irotecan
  • Topotecan
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13
Q

Which of the camptothecins has a unique toxicity and why is this?
- what patients is this particularly problematic in?

A

Irinotecan metabolized by phase II glucuronidation

Patients:
- Gilbert Syndrome patients that have SNPs in the UDP-glucuronosyltransferase (UGT) 1 A1 gene

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14
Q

Toxicities of the camptothecins?

  • differences among drugs in the class.
  • dose limitations.
A

BOTH:

  • Elevated Hepatic Enzymes
  • myelosuppression

Topotecan:
- Nuetropenia

Irinotecan:
- DOSE LIMITING DIARRHEA

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15
Q

Etoposides

  • Name Them.
  • MOA
  • Resistance
  • Administration
A

Etoposide and VP-16 [toposar]

MOA:
- Forms complex with Topo-II causing 2x DNA breaks

Resistance: - Efflux, downregulation of Topo II

Administration:

  • Oral
  • Renally Excreted
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16
Q

Are etoposides cell cycle phase specific?

A

NO, only the Topo-I inhibitors are

17
Q

Anthracyclines

  • NAME THEM.
  • MOAs
  • Resistance
A

Daunorubicin [cerubidine], Doxorubicin [adriamycin], Idarubicin [idamycin]

MOAs:
- Intercalation with DNA (affects transcription and replication)

  • Complexes with TOPO-II- Forms Free Radicals

Resistance:

  • Efflux
  • Glutathione Peroxidase (soak up free rads)
  • Topo Mutation
18
Q

Toxicities of the Anthracyclines

  • Name them.
  • Agents to protect against them?
A

Daunorubicin [cerubidine], Doxorubicin [adriamycin], Idarubicin [idamycin]

Toxicity:

  • Extravasational Necrosis (causing alopecia, GI issue, etc)
  • TACHYCARDIA, ARRRHYTHMIAS, TROPONIN T RELEASE
  • Congestive Heart Failure

Dexrazoxane: - Inhibits Free Radicalformation

Liposomal Formulations are also believed to be less toxic

19
Q

Bleomycin [blenoxan]

  • MOA
  • Administration
  • Resistance
  • Elimination
A

Bleomycin [blenoxane]

MOA:

  • Intercalating Agent that generates Free Rads
  • Binds DNA, causes single and double strand Breaks, and inhibits DNA synthesis

Resistance:

  • Inactivation by Thiols and Thiol-rich proteins
  • Decreased drug uptake, increased DNA repair

Elimination:
- Tissue Enzymes and Renal Clearance

Administration:
- Must be given parenterally (IV or IM)

20
Q

What is the Toxicity of Bleomycin?
- Dose limiting?

A

Toxicity:

  • Pulmonary Disfunction (fibrosis, pneumontitis)
  • slow developing and DOSE-LIMITING - DRY COUGH!!
  • HYPERSENSITIVITY reactions are common (fever, chills, anaphylaxis) - Blister Formation, Hyperkeratosis, Blister Formation (note: myelosuppression is not really an issue here)
21
Q

Pegaspargase [oncaspar]

  • MOA
  • Resistance
  • Toxicity
A

MOA:
- Degrades Asparagine “starving” protein synthesis (pegylated to increase duration in body)

Resistance:
- Asparagine Synthetase Upregulation

Toxicity:
- PANCREATITIS => Issues regulating blood sugar levels- Immune System suppression

22
Q

Lenalidomide [revlimid]

  • MOA
  • Toxicity
A

MOA:
- Unknown, but it inhibits tumor cell proliferation, inhibits tumor cell adhesion to stroma, inhibits angiogenesis, Enhances NK cell activity

Toxicity:

  • PERIPHERAL SENSORY NEUROPATHY
  • Blood Dyscrasias
  • Atrial Embolism
23
Q

Retinoids

  • drug name
  • MOA
A

Tretinoin [retin-A]

MOA:
In acute promyelocytic leukemia (APML), (15:17) translocation causes fusion protein PML-RARalpha to form which binds co-repressors over RXR-RARalpha

  • Physiologic levels of retinoic acid can’t overcome this so we give them ALL-TRANS RETANOIC ACID (ATRA) = the drug
24
Q

What kinds of cancers are retinoids used to treat?
- drug name

A

Treats Acute Promyelocytic Leukemia (APML)

Tretinoin [retin-A]

25
Q

T or F: cancer drugs are often given in combinations, and no two drugs in a regimen should act through the same mechanism

A

TRUE

PHARMACOLOGY - Pulmonary (30 decks)

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