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Drug Action IV > Mitosis Inhibitors (MC) - Block 4 > Flashcards

Mitosis Inhibitors (MC) - Block 4 Flashcards

1
Q

What are Nonionic surfactant formulations used to dissolve very lipophillic drugs? Why?

A

Cremohor EL/Kolliphor EL: molecules resemble nonionic block copolymers -> activate proteins of immune responses

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2
Q

What is the MOA of mitosis inhibitors?

A

Inhibits changes in microtubular structure -> mitotic arrest and apoptosis

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3
Q

What occurs during cell division?

A

Altenation of polymerization (tubular elongation) and depolymerization (tubular shortening)

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4
Q

What is the MOA of taxanes?

A

Bind to polymerized b-tubulin -> promoting polymerization preventing depolymerization
* Formation of asters due to extensive polymerization

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5
Q

What phase do taxanes work best?

A

M phase

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6
Q

What is the major mechanism of resistance towards taxanes?

A

PgP substrate

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7
Q

ADR of taxanes?

A

Myelosuppression

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8
Q

How do you reduce the hypersensitivity risk of paclitaxel?

A
  1. Administer in vehicle of 50% alcohol/50% Cremophor EL due to low water solubility
  2. Pretreat with antihistamines and corticosteroids due to surfactant formulation

Very heavily protein bound -> give abumin bound formulation

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9
Q

ADR and DDI of paclitaxel?

A

ADR: Category D teratogen
DDI: Metabolized by CYP2C8

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10
Q

How is docetaxel an improvement of pacitaxel?

A

Better water solubility -> can give in polysorbate 80 (less hypersensitivity than Cremophor) -> pretreat with corticosteroids

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11
Q

What is better about carbazitaxel?

A

Better water solubulity -> give in polysorbate 80
* Dimethoxy analog (metabolite) of docetaxel -> lowers affintiy for PgP (sustained retention in tumor cells and better BBB penetration)

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12
Q

ADR of carbazitaxel?

A

Diarrhea due to accumulation in enterocytes (doesn’t not get pumped out by Pgp)

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13
Q

What is the major issue with taxans? What drug class was developed to overcome those problems?

A

Water solubilty and Pgp efflux -> epothilones

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14
Q

Binding of epothilones?

A

Same as taxanes (polymerized b-tubulin to promote polymerization)

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15
Q

Looking at the structure what are the properties of this epothilone?

A

Ixabepilone is very lipophilic and still requires Cremophor EL for administration

Not as different from taxanes

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16
Q

What is the MOA of vinca alkaloids?

A

Inhibits polymerization (promoting depolymerization) binding at site on b-tubulin

Works in M phase

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17
Q

Describe the structure of vinca alkaloids?

A

Ionizable amines - given as water soluble salts

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18
Q

Metabolism of vinca alkaloids?

A

Undergoes O-deacylation to metabolites equal or more active than parent drugs

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19
Q

ADR of vinca alkaloids?

A

Severe vesicants (necrosis) -> cold exacerbates tissue destruction therefore you should apply heat instead

All category D teratogens

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20
Q

What vina is the least lipophilic but longest half life?

A

Vincristine (more prolonged tumor cell exposure)

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21
Q

What is the major dose-limiting ADR?

A

Peripheral neuropathy
Lacks myelosupprssion

DDI if mitomycin -> delayed pulmonary toxicity

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22
Q

Describe the structure of vinblastine?

A

Increased lipophilicity due to NCh3 replacing formyl group

23
Q

What is the dose-limiting ADR of vinblastine?

A

Leukopenia (does cause myelosuppression)

24
Q

What is the only venca that doesn’t cause myelosuppression?

A

Vincristine

25
Q

What is the major ADR of vinorelbine?

A

Granulocytopenia and monitor for respiratory distress

26
Q

What is the mechanism of topoisomerases?

A

II: cleaves dsDNA
I: cleaves ssDNA

27
Q

What is the mechanism of topoisomerase poisons?

A

Stimulates DNA cleavage but inhibits the DNA resealing activity -> irreversibly damaged DNA and no replication

28
Q

What type of poison is epipodophyllotoxins

A

TopIIa

29
Q

Where do epipodo target on the cell cycle

A

S and early G2 phase

30
Q

Metabolism of epipodos?

A

CYP3A4

31
Q

ADR of epipodos?

A

Mucositis, myelosuppression, Category D

32
Q

What are the problems with epipodo?

A

Very water insoluble -> need solubility ehancers (Kolliphor EL)
* Hypersensitivity rx (hypotension, thrombophlebitis) -> coadminister with epinephrine, antihistamines, and corticosteroids

33
Q

How can epipodo become carcinogenic?

A

Reactive orthoquinone can promote topoisomerase-mediated DNA cleavage -> can cause translocation -> therapy-induced acute myeloid leukemia in children

34
Q

What is the purpose for etoposide formulated with phosphate?

A

Phosphate ester analog -> water solubility (prodrug) and phosphate is removed in plasma

35
Q

DDI of etoposides?

A

Organoplatinum

36
Q

How does teniposide change the PK property compared to other epipodo?

A

More lipophilic and less soluble -> greater cellular uptake and more potent
* More protein binding -> longer half-life
* Likes to the precipitate

37
Q

What is the natural antagonists camptothecins mimic?

A

Camptothecin

38
Q

Looking at the structure what is the mechanism of this drug?

A

Flat ring system -> easy intercalation at site of cleavage (like DNA base)

39
Q

What is the source of instability of camptothecins?

A

Lactones easily open and cleave
* Hydrolyzed lactone (inactive) in equilibrium with intact lactone (active) -> bindign to pp leads to a shift towards more intact and active lactone

  • Lipophilic and acidic drugs increase bind to PP
40
Q

What type of poison is camptothecins?

A

TopI

  • Works in S phase
41
Q

ADR of camptothecins?

A

Myelosuppression

42
Q

What dids irinotecan more potency?

A
  1. More lipophilic and binds to PP
  2. Prodrug: basic side chain (amine) is removed making it more lipophilic
43
Q

What is the active form of iromptecan?

A

Needs phenol for activity

44
Q

Metabolism of irinotecan?

A

Glucoronidation by UGTs (genetic variations can lead to toxicity)

45
Q

ADRs of irinotecan?

A

Delayed diarrhea (dose-limiting) -> loperamide
Acute diarrhea: anticholigeric tx

46
Q

How does topotecan differ from irinotecan?

A
  • Not a prodrug -> basic chain remains intact (phenol)
  • Less serum protein binding -> more hydrolysis (opening) of lactone because charged amine stays (less activity)
47
Q

Why was topotecan developed if it hasless activity?

A

No toxicty with UGT polymorphisms

48
Q

What is the MOA of demethylators?

A

Inhibits DNA methylation on genes respnsible for defferentiation and growth -> selectively killing cells that stopped responding to cellular proliferation control processes

49
Q

Why are DNA demethylators given as prodrugs

A

Incorporated into DNA in place of cytidine or guanin -> irreversibly inhibit DNA methyltransferase

50
Q

ADR of DNA demthylators

A

Anemia, neutropenia, thrombocytopenia

51
Q

In order to have activity what does a DNA methyltransferase nhibitor need to have?

A

Undergo phosphorylation

52
Q

What makes nelarabine an unique DNA methyltransferase inhibitor? ADR of nelarabine?

A

Can be metabolized to guanine/xanthine/urate
* Give allopurinol (XOI) to hydrate and basify urine to reduce hyperuricemia

ADR: severe, irreversible neurologic sx

53
Q

Toxicity of azacitidine

A

Renal

54
Q

Types of DNA methyltransferase inhibitors?

A
  1. Azacitidine
  2. Decitabine
  3. Nelarabine

Drug Action IV (28 decks)

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