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heme/onc > Oncology Pharm > Flashcards

Oncology Pharm Flashcards

1
Q

Log Kill Hypothesis

A

Cytotoxic drugs= first order kinetics

  • Given dose, constant fraction of cells killed (not fixed number)
  • Toxicity to normal tissues= major dose-limiting factor
  • Need multiple cycles of chemo to eradicate tumor (ex: only killing 20% of cancer with each dose)
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2
Q

Gompertzian Kinetics

A

Increased doubling time as tumor burden increases

  • Takes longer time for tumor to enlarge as it gets larger
  • Subclinical–> diagnosis–> symptoms–> death
  • Increases in cellularity occur over longer periods of time
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3
Q

Adjuvant therapy

A

Used after surgery or radiation therapy

- Eradicate residual tumor

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4
Q

Neoadjuvant therapy

A

Used before surgery/radiation

- Shrink tumor to make surgical removal easier

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5
Q

Alkylating agents

A

MOA: Alkylate DNA (N7 of guanine)

  • DNA cross-linked, strand breaks, inhibits replication, transcription
  • No cell cycle specificity

Includes:

  • Nitrogen mustards
  • Nitrosoureas
  • Platinum Analogues
  • Others
Toxicity:
Dose limiting: 
- myelosuppression (febrile neutropenia)
- Mucositis
- Nausea and vomiting
- Alopecia
- Infertility
- Secondary leukemias
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6
Q

Nitrogen mustards

A

Includes: bendamustine, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine (first anticancer drug- mustard gas–> lymphopenia), melphalan

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7
Q

Cyclophosamide

A

Broad spectrum nitrogen mustard

Prodrug. Activated by liver to active and toxic metabolites

IV and PO

Adverse effects:
- Hemorrhagic cystitis: production of acrolein causes irritation to bladder wall.
Treatment for AEs:
- Adequate hydration, Mesna with high doses

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8
Q

Ifosfamide

A

Analog of cyclophosphamide.

Also requires hepatic activation to same active metabolites
- Less potent, requires 4 x dose for efficacy

Adverse effects:

  • Increased production of acrolein accumulates in bladder and causes hemorrhagic cystitis
  • Administer with Mesna (IV/PO), hydration important.
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9
Q

Melphalan

A

Nitrogen mustard

Oral and IV

High dose used for Bone marrow transplant

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10
Q

Bendamustine

A

Nitrogen mustard: combination alkylating agent and purine analog

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11
Q

Nitrosoureas

A

Nitrogen mustard

  • Lipophilic, good CNS penetration
  • Delayed myelosuppression, 4 week nadir

AEs:
Severe N/V, pulmonary toxicity, hepatotoxicity

Carmustine implant: Gliadel Wafer

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12
Q

Dacarbazine

A

Other alkylating agent with CNS penetration

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13
Q

Temozalmide

A

Alkylating agnet

Oral, converts to Dacarbazine

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14
Q

Platinum Analogs

A

Binds to and causes double-stranded DNA breaks

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15
Q

Cisplatin

A

Platinum analogs

AEs: Nephrotoxic, ototoxic, N/V
- Avoid with hydration, antiemetics

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16
Q

Carboplatin

A

Platinum analog

AE:

  • Myelosuppression
  • less N/V, neuropathy, nephrotoxicity than cisplatin

Dosed NOT by weight

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17
Q

Oxaliplatin

A

Platinum analog

AE: acute: cold induced neuropathy, cumulative peripheral neuropathy,

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18
Q

Topoisomerase inhibitors

A

MOA:
Topoisomerases (I and II) are nuclear enzymes that unravel DNA for repair and replication

Specifically they participate in DNA replication and repair by:

  • cleaving and resealing the phosphodiester bonds that comprise the backbone of DNA (Topo II)
  • unwinding DNA (Topo I)

Inhibiting topoisomerases can induce DNA damage such as unrepairable strand breaks leading to cell apoptosis

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19
Q

Anthracycline

A

Topoisomerase II inhibitor

MOA:

  • High affinity binding to DNA
  • Intercalates between base pairs, inhibits the activity of enzymes involved in DNA replication (topoisomerase II)
  • Anthracyclines form free radical compounds that damage biological macromolecules

AEs:

  • Specifically can cause CHF when cumulative dose reached
  • As dose approached, must monitor ejection fractions
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20
Q

Camptothecins:

A

Topoisomerase I inhibitor

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21
Q

Topotecan

A

Topoisomerase I inhibitor:

AE: dose-limiting marrow suppression

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22
Q

Irinotecan

A

Topoisomerase I inhibitor

AE:

  • Diarrhea is a dose limiting side effect
    1. Early form
  • Cholinergic syndrome treated with IV atropine
    2. Late form
  • Direct GI toxicity. Loperamide 4 mg x 1, 2 mg q2hr.
  • May cause serious dehydration
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23
Q

Bleomycin

A

Glycopeptide antibiotic

MOA: Bleomycin produces single and double strand breaks in DNA through the production of highly reactive free radicals

Toxicity:

  • Pulmonary fibrosis (avoid cumulative dose >400 units, current radiation/oxygen).
  • Hyperpigmentation, rash, fever, allergic rxn.
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24
Q

Vinca Alkaloids

A

Vinblastine, vincristine, vinorelbine

MOA:
Inhibit microtubule function in M phase
- inhibit the formation of tubulin, which prevents polymerization into microtubules
- CAN’T FORM

Toxicity:
- All vesicants

Vincristine:

  • neurotoxicity, constipation
  • Max dose 2 mg/week

Vinblastine/vinorelbine:

  • Myelosuppression
  • Less neurotoxicity
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25
Q

Docetaxel, Paclitaxel

A

Taxanes

MOA:
Inhibit microtubule function in M phase
- bind to beta tubulin and stabilize the alpha and beta tubulin heterodimers, preventing the breakdown of microtubules
- CAN’T BREAK DOWN

AEs:
Require premedication with steroids due to solubilizing agents

Paclitaxel: Neuropathy, Albumin-bound paclitaxel (Abraxane), no solubilizer

Docetaxel: Fluid retention syndrome: dex 8 mg PO BID x 3 days

Cabazitaxel: Crosses BBB, not affected by P-glycoprotein

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26
Q

Ixabepilone

A

Epothilones

MOA:
Inhibit microtubule function in M phase
- bind to beta tubulin and stabilize the alpha and beta tubulin heterodimers, preventing the breakdown of microtubules

AEs:
Require premedication with steroids due to solubilizing agents
Ixabepilone: Distinct tubulin binding site, not effected by Pgp

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27
Q

Antimetabolites

A

MOA:

  1. Mimic nucleotide cousins
  2. S-phase specific
  3. One or combination:
    - inhibiting enzymes involved in nucleotide synthesis
    - inhibiting enzymes involved in DNA replication
    - replacing naturally occurring nucleotides in DNA that is actively being replicated. This serves to disrupt the natural structure of DNA, causing apoptosis.
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28
Q

Methotrexate

A

MOA: inhibitors dihydrofolate reductase
- decreases reduced folates, inhibits thymidylate synthase

ROA: IM, IV, IT< PO

PK: cleared renally, can accumulate in 3rd spaces
- Avoid in CHF, liver failure, renal failure causing ascites

AEs:
Mucositis, pneumonitis, renal failure, increased LFT’s

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29
Q

Purine analogs

A

Thioguanine (6-TG) and mercaptopurine (6-MP)
- Oral agents
- Metabolized by xanthine oxidase
AEs: Cause liver toxicity, mucositis

Fludarabine, cladrabine, pentostatin
AEs: Immunosuppression (lymphopenia)

Nelarabine
AEs: Neurotoxicity is dose-limiting

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30
Q

Cytarabine (Ara-C)

Gemcitabine

A

Pyramidine analog
MOA: Analogue of cytidine

AEs:

  1. Flu-like syndrome, rash
  2. High dose: (HiDAC)
    - Marrow suppression
    - Cerebellar toxicity (ataxia)
    - Conjunctivitis: steroid eye drops

Gemcitabine= same MOA

31
Q

Fluorouracil

A

Pyramidine analog
Converted to 5-FdUMP causing inhibition of thymidylate synthase, thymidine depletion, apoptosis

Toxicity: dose, frequency-dependent

  • Intermittent bolus: myelosuppression
  • Continuous: Hand-foot syndrome (rashes)
  • Administration of leucovorin potentiates effects.
32
Q

Capecitabine

A

Pyramidine analog
Oral agent converted to fluorouracil
- Activated by tumor cells

AEs:
- Hand-foot syndrome, GI

33
Q

5-Azacitidine

Decitabine

A 
DNA hypomethylators
MOA: 
1. Inhibits DNA methyltransferase
2. Hypomethylates DNA
3. Activates "silenced" tumor suppressor genes
- Inhibits angiogenesis, metastasis
- Allows apoptosis
34
Q

Monoclonal antibodies: types

A
  1. Disrupt signal transduction:
    - Bevacizumab: neutralize ligand
    - Cetuximab, panitumumab: inhibit extracellular receptors
  2. Direct cytotoxicity:
    - Rituximab, alemtuzumab
    - Completment-dependent, antibody-dependent, induction of apoptosis:
  3. Delivery of cytotoxic agents:
    - Tositumomab, Irbitumomab: Radioactive moieties
    - Brentuximab, Vedotin: antineoplastic
35
Q

Monoclonal antibodies: nomenclature

A

First part= specific to drug

Second part= target

  • Li(m)= immune system
  • tu(m)= miscellaneous tumor
  • ci(r)= circulatory

Third part= source

  • a= rat
  • e= hamster
  • i= primate
  • o= mouse
  • u= human
  • xi= chimeric
  • zu= humanized

Last part= mab

36
Q

Rituximab

A

MOA: anti-CD20 antibody (found on all B lymphocytes)

Uses: CD20 seen in > 90% of B-cell NHL and leukemias

AEs:

  • Infusion reactions (human better tolerated)
  • Tumor lysis syndrome
  • Respiratory, renal failure

*Ofatumumab= binds to different epitope on CD20

37
Q

Alemtuzumab

A

MOA:
- Anti CD52 antibody; CD52 is expressed on most normal and malignant B and T lymphocytes, NK cells, monocytes, and macrophages

Uses:
- Refractory CLL, T-cell leukemia

AEs:

  • Infusion reactions, anaphylaxis
  • Profound, prolonged immunosuppression, HSV and PCP prophylaxis recommended
38
Q

Ibritumomab

A

MOA: Radioactive immunoconjugate with anti-CD20 antibody attached to radioactive moeity

Uses:
- Relapsed and/or refractory CD20-positive, follicular NHL

AEs:
- Avoid in patients with > 25% involvement of the bone marrow by lymphoma and/or impaired bone marrow reserve.

39
Q

Tositumomab

A

MOA: Radioactive immunoconjugate with anti-CD20 antibody attached to radioactive moeity

Uses:
- Relapsed and/or refractory CD20-positive, follicular NHL

AEs:
- Avoid in patients with > 25% involvement of the bone marrow by lymphoma and/or impaired bone marrow reserve.

40
Q

Brentuximab

A

MOA:

  • Anti-CD30 antibody attached to monomethyl auristatin E (MMAE)
  • MMAE is a mitotic spindle poison

Uses:
- Hodgkin, anaplastic large cell lymphoma

AEs:
- Infusion reactions, myelosuppression, peripheral neuropathy

41
Q

Denileukin Diftitox

A

MOA:
Anti CD25 antibody (IL2 receptor) attached to diphtheria toxin

Uses:
Persistent or recurrent cutaneous T-cell lymphoma

AEs:
Infusion reactions, vascular leak, flu-like syndrome, hepatotoxicity

42
Q

Trastuzumab/Pertuzumab

A 
MOA:
MOA:
Anti HER2/neu receptor antibody
HER2 overexpressed on 25 – 30% of breast cancers
Binding results in apoptosis and ADCC

Uses:
Breast cancers

AEs:

  • Infusion related reactions, anaphylaxis
  • Cardiotoxicity (CHF), especially when used with cyclophosphamide or an anthracycline
  • Renal insufficiency, Stevens-Johnson syndrome
43
Q

Cetuximab/Panitumab

A

MOA:
Anti-EGFR antibody

Uses:

  • EGFR over expressed in many solid tumors
  • Binding results in inhibition of proliferation, growth, metastasis, and angiogenesis
  • Enhanced response to chemotherapy and radiation

AEs:

  • Infusion related reactions, anaphylaxis
  • Skin toxicity, may be severe
44
Q

Bevacizumab

A

MOA:
Anti VEGF antibody

Uses:
Inhibits formation of new blood vessels in primary and metastatic tumors

AEs:

  • Infusion reactions, anaphylaxis
  • GI perforations and impaired wound healing
  • Bleeding, arterial thrombosis, hypertension, CHF
  • Tracheoesophageal fistulas
45
Q

Ipilimumab

A

MOA:
Binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)
Blockade of CTLA-4 augments T-cell activation and proliferation

AEs:
can result in severe and fatal immune-mediated adverse reactions due to T-cell activation.

46
Q

Tyrosine Kinase Inhibitors

A

TKI: Two types: receptor based and cellular
- Dependent on activity/function of receptor (some are constitutively active, others are activated by other factors)

MOA:
These enzymes are involved in cellular signaling pathways and regulate key cell functions such as proliferation, differentiation, anti-apoptotic signaling
- Inhibitors occupy ATP binding site and prevent phosphorlyation of substrates

PK: All are CYP3A4 substrates

47
Q

Erlotinib

A

Receptor-based TKI

MOA:
- Inhibit epidermal growth factor receptor (EGFR) TK

Uses: NSCLC (non-small cell lung cancer)

AEs:
Diarrhea, skin rash (correlates with efficacy)
Life-threatening interstitial pneumonitis

48
Q

Imatinib

A

Intracellular TKI
MOA:
Inhibits BCR-ABL TK created by Ph chromosome translocation (9;22), PDGF, cKIT

Uses:
CML therapy

Nilotinib more potent than imatinib
Dasatinib also inhibits SRC kinase

AEs:
myelosuppression

49
Q

Sutinib

A

Receptor based TKI including PDGF, VEGF

Uses:
Renal Cell Cancer

AEs:
GI, skin discoloration , fatigue, hypertension, bleeding, CHF

50
Q

Sorafinib

A

Receptor based TKI including PDGF, VEGF

Used in RCC, Hepatocellular Cancer

Toxicities: GI, rash, hypertension, bleeding, hand-foot syndrome

51
Q

Lapatinib

A

Receptor based TKI of EGFR and Her-2

Used Her2+ breast cancer

Toxicities: diarrhea, decreased LVEF, QT prolongation

52
Q

Rapamycin

A

mTOR inhibitor

Mechanism:
Binds to FK Binding Protein
FKBP-drug complex inhibits mTOR kinase activity
Decreased production of Hypoxia Inducible Factor, VEGF, PDGF, TGF

53
Q

Temsirolimus

A

mTOR inhibitor

Mechanism:
Binds to FK Binding Protein
FKBP-drug complex inhibits mTOR kinase activity
Decreased production of Hypoxia Inducible Factor, VEGF, PDGF, TGF

AEs:
Hyperglycemia
Increased triglycerides/cholesterol
Rash, asthenia, mucositis 
Pulmonary syndrome (hypoxia, noninfectious infiltrates)
54
Q

Differentiating agents

A

Clinical use:

  • Acute promyelocytic leukemia is characterized by the t(15;17) translocation
  • Produces PML-RAR receptor protein
  • PML-RAR suppresses DNA transcription at normal retinoic acid levels
  • Accumulation of promyelocytes (cell stopped in one stage of maturation

MOA:
Differentiating agents release block, allow cells to mature

55
Q

All-trans-retinoic-acid (ATRA)

A

MOA:
ATRA provides high levels of retinoic acid
Induces differentiation and maturation of acute promyelocytic cells to normal myelocyte cells .

AEs:

  • Differentiation syndrome.
  • Fever, leukocytosis, dyspnea, weight gain, diffuse pulmonary infiltrates, and pleural and/or pericardial effusions.
  • Observed with WBC > 10,000/mm3.
  • Usually observed during the first month of therapy but may follow the initial drug dose.
  • Drug causes increased maturation of neutrophils–> AEs related to increased circulating neutrophils
56
Q

Arsenic trioxide

A

MOA:
Induces differentiation of APL cells by degrading the chimeric PML/RAR-α protein, resulting in release of the maturation block.

AEs:
Differentiation syndrome, QT prolongation
- Keep Mg and K within normal ranges

57
Q

Thalidomide
lenalidomide
pomalidomide

A

Immunomodulatory agents

MOA:
Induce apoptosis, enhance T cell and NK cell cytotoxicity, inhibit angiogenesis

Used for multiple myeloma

AEs:
Thalidomide: sedation, constipation, rash, neuropathy
Lenalidamide: marrow suppression, thromboembolism
Restricted distribution system, teratogen.

58
Q

Bortezomib

A

Proteosome Inhibitor

MOA:
Inhibits proteosome function. Prevents degradation of pro-apoptotic proteins
- Proteosome= “garbage disposer of cell”–> ubiquinate and degrade proteins
- IkB inhibits NFkB
- IkB normally broken down by proteosomes–> NFkB active–> cell proliferation
- Proteosome inhibition–> increased IkB–> decreased NFkB activity
- Accumulation of malformed proteins–> cell can’t handle trash–> dies

Uses:
Highly active in multiple myeloma

AEs:
Toxicities include neuropathy and thrombocytopenia.

59
Q

Ruxolitinib

A

JAK inhibitor

- Myelofibrosis

60
Q

Vemurafenib

A

BRAF inhibitor

- Melanoma with BRAF V600E mutation

61
Q

Crizotinib

A

ALK inhibitor

- ALK positive NSC lung cancer

62
Q

Vismodegib:

A

Hedgehog inhibitor

  • Basal cell skin cancer
  • Embryotoxic and teratogenic
63
Q

Dasatinib

A

Intracellular TKI
MOA:
Inhibits BCR-ABL TK created by Ph chromosome translocation (9;22), PDGF, cKIT

Uses:
CML therapy

Nilotinib more potent than imatinib
Dasatinib also inhibits SRC kinase

AEs:
myelosuppression

64
Q

Nilotinib

A

Intracellular TKI
MOA:
Inhibits BCR-ABL TK created by Ph chromosome translocation (9;22), PDGF, cKIT

Uses:
CML therapy

Nilotinib more potent than imatinib
Dasatinib also inhibits SRC kinase

AEs:
myelosuppression

65
Q

Gefitinib

A

Receptor-based TKI

MOA:
- Inhibit epidermal growth factor receptor (EGFR) TK

Uses: NSCLC (non-small cell lung cancer)

AEs:
Diarrhea, skin rash (correlates with efficacy)
Life-threatening interstitial pneumonitis

66
Q

Ondansetron (Zofran®)
Granisetron (Kytril®)
Dolasetron (Anzemet®)
Palonosetron (Aloxi®)

A

Serotonin (5HT3) Antagonists
-setron drugs:
—Longest acting

MOA:
Inhibition of 5HT3 receptors on vagal afferent neurons in GI and in CTZ
** USED IN PREVENTION ONLY**

Efficacy improved when used with a steroid (20%)
Well tolerated, minimal side effects
Transient, non-significant ECG changes

67
Q

Aprepitant, Fosaprepitant

A

Neurokinin-1 (NK-1) Receptor Antagonists
-prepitant drugs:

MOA:
selective, high affinity antagonist of human substance P at neurokinin 1 (NK1) receptors –> interferes with the substance P pathway

Drug Interactions with CYP450 system-reduce dose of dexamethasone

68
Q

Corticosteroids for nausea

A

Dexamethasone, Methylprednisolone

MOA:?decrease 5HT3 release in gut/brain stem, ?antagonism of 5HT3 receptors, ?activate glucocorticoid receptors in brain

Generally well tolerated–elevated BS, insomnia, GI sxs, edema, weight gain, agitation

Used as single agent(low)/combined with aprepitant/5HT3 antagonists (moderate-high)

69
Q

Prochlorperazine(Compazine®)

Promethazine(Phenergan®)

A

Dopamine (D2) receptor antagonists: Phenothiazines

MOA: antagonize D2 receptors in CTZ
** USE IF ALREADY SICK**

Potent Antipsychotic agents
ADR: sedation, akathisia, dystonia

70
Q

Metoclopramide

A

Dopamine (D2) receptor antagonist: Benzamide analog

MOA: stimulates gut motility; blocks intestinal 5HT2 receptors

Crosses Blood Brain Barrier = EPR’s (high doses)
- Prevention with diphenhydramine/lorazepam
Age-dependent reaction (younger 30%>elderly 2%)
Common: trismus, akathisia, dystonia

71
Q

Haloperidol (Haldol®)

Droperidol (Inapsine®)

A

Dopamine (D2) Receptor antagonists: Butyrophenones

MOA: antagonize D2 receptors in CTZ

*As effective as Phenothiazines with less incidence of EPRs/hypotension in delayed emesis

AEs:
Sedation and anticholinergic effects
Droperidol: cases of QT prolongation/TdP

72
Q

Lorazepam

A

Benzodiazepine

MOA: no antiemetic properties; antegrade amnesia used for prevention

Place in therapy for anticipatory N/V

73
Q

Dronabinol

Nabilone

A

Cannabinoids for N/V:

MOA: agonism of cannabinoid(CB1) receptors in the CNS and gut; indirectly inhibit other neurotransmitters released in emesis process

Tolerance develops to adverse effects
Effective for moderate-high emetogenic regimens
Utilized in Refractory patients

heme/onc (6 decks)

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