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Flashcards in Heme-Onc Drugs Deck (118):
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Heparin mechanism

cofactor for the activation of antithrombin leading to decreased thrombin and factor Xa

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Use of Heparin

immediate anticoagulation for PE, acute coronary syndrome, MI, DVT **Follow PTT

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Heparin can be used during pregnancy bc...

it does not cross the placenta. Warfarin cannot be used in pregnancy.

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Toxicity of Heparin

-bleeding -HIT -osteoporosis

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For rapid reversal of Heparin, use...

protamine sulfate (which is a positively charged molecule that binds negatively charged heparin).

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Low-molecular weight heparins (2)

1. Enoxaparin 2. Dalteparin

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Low-molecular weight heparins act more on...

factor Xa, have better bioavailablity and 2-4x longer half life.

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Heparin Induced Thrombocytopenia (HIT)

-development of IgG antibodies agaisnt heparin bound to platelet factor 4 (PF4) -Ab-heparin-PF4 complex activates platelets leading to thrombosis and thrombocytopenia

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Argatroban, Bivalirudin MOA

Inhibit thrombin directly

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Argatroban and Bivalirudin are used...

instead of heparin for anticoagulating pts with HIT.

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Warfarin MOA

-interferes with normal synthesis and gamma-carboxylation of vitamin-K dependent clotting factors II, VII, IX and X and proteins C and S

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Warfarin is metabolized by...

the CYP450s.

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In lab assays, Warfarin has an effect on the...

extrinsic pathways and increases PT.

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Use of Warfarin

-chronic anticoagulation (after STEMI, venous thromboembolism prophylaxis, stroke prevention) **Follow PT/INR values.

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Toxicity of Warfarin

-bleeding -teratogenic -skin/tissue necrosis

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For reversal of warfarin overdose

-give vitamin K -if rapid reversal is necessary, give FFP

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Apixaban and Rivaroxaban MOA

bind and directly inhibit activity of factor Xa

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Use of Apixaban and Rivaroxaban

-treatment and prophylaxis of DVT and PE (rivaroxaban) -stroke prophylaxis

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Thrombolytics (3)

1. Alteplase (tPA) 2. Reteplase (rPA) 3. Tenecteplase (TNK-tPA)

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MOA of thrombolytics (tPA, etc)

directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots -increases PT and PTT

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Use of thrombolytics

-MI -ischemic stroke -directy thrombolysis of severe PE

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Thrombolytics are contraindicated in...

pts with active bleeding, hx of intracranial bleed, recent surgery, known bleeding diathesis or HTN.

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Treat thrombolytic toxicity with...

aminocaproic acid (inhibitor of fibrinolysis).

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Aspirin MOA

irreversibly inhibits COX1 and COX2 by covalent acetylation; platelets cannot synthesize new enzyme so the effects last until new platelets are produced

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Aspirin effects

-increased bleeding time -decreased TXA2 and prostaglandins -no effect on PT or PTT

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Use of Aspirin

-antipyretic -analgesic -anti-inflammatory -antiplatelet (decreased aggregation)

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Toxicity of aspirin

-gastric ulceration -tinnitus -reye syndrome in children with viral infxn

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Chronic use of aspirin can lead to...

acute renal failure, interstitial nephritis and upper GI bleeding.

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Overdose of aspirin causes....

respiratory alkalosis initially which is then superimposed by metabolic acidosis.

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ADP receptor inhibitors (4)

1. Clopidogrel 2. Ticlopidine 3. Prasugrel 4. Ticagrelor

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MOA of ADP recpetor inhibitors

inhibit platelet aggregation by irreversibly blocking ADP receptors; inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa binding

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Use of ADP receptor inhibitors

-acute coronary syndrome -coronary stenting (decreased risk of thrombotic stroke)

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Toxicity of ADP receptor inhibitors

-Neutropenia (Ticlopidine) -may see TTP/HUS

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Cilostazol and Dipyridamole MOA

phosphodiesterase III inhibitors leading to increased cAMP in platelets, thus inhibiting platelet aggregation vasodilators

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Use of Cilostazol and Dipyridamole

-intermittent claduication -coronary vasodilation -prevention of stroke/TIA/angina

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GP IIb/IIIa inhibitors (3)

Abciximab Eptifibatide Tirofiban

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GpIIb/IIIa inhibitor MOA

bind to the glycoprotein receptor IIb/IIIa on activated platelets, inhibiting aggregation

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Abciximab is made from...

monoclonal antibody Fab fragments.

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Use of GP IIb/IIIa inhibitors

-unstable angina -percutaneous transluminal coronary angioplasty

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Antimetabolites (6)

1. Metotrexate 2. 5-Fluorouracil 3. Cytarabine 4. Azathioprine 5. 6-Mercaptopurine 6. 6-Thioguanine *all are S-phase specific

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Methotrexate MOA

folic acid analog that inhibits dihydrofolate reductase leading to decreased dTMP, DNA and protein synthesis.

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Cancer uses of methotrexate

-leukemias/lymphomas -choriocarcinoma -sarcomas

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Non-neoplastic uses of methotrexate

-abortion/ectopic pregnancy -RA -psoriasis -IBD

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Toxicity of Methotrexate

-Myelosuppression -Macrovesicular fatty change in liver -mucositis -teratogenic

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Myelosuppression from methotrexate is reversible with...

leucovorin.

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5-FU MOA

pyrimidine analog bioactivated to 5F-dUMP which covalently complexes folic acid; this complex inhibits thymidylate synthase leading to decreased dTMP, DNA and protein synthesis

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Clinical uses of 5-FU

-colon cancer -pancreatic cancer -basal cell carcinoma

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Toxicity of 5-FU

-myelosuppression (not reversible w/ leucovorin; use uridine) -photosensitivity

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Cytarabine MOA

-pyrimidine analog leading to inhibition of DNA polymerase

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Clinical use of Cytarabine

-leukemias -lymphomas

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Cytarabine toxicity

Pancytopenia (thrombocytopenia, leukopenia, megaloblastic anemia)

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Azathioprine, 6-MP and 6-TG MOA

purine analogs that decrease de novo synthesis of purines; activated by HGPRT

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Clinical uses of azathioprine, 6-MP and 6-TG

-preventing organ rejection -RA -SLE (azathioprine) -Leukemia/IBD (6-MP, 6-TG)

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Toxicity of Azathioprine, 6-MP and 6-TG

-bone marrow, GI and liver

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Azathioprine and 6-MP are metabolized by...

xanthine oxidase and thus both have increased toxicity with allopurinol.

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Antitumor antibiotics (3)

1. Dactinomycin 2. Doxorubicin, Daunorubicin 3. Bleomycin

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Dactinomycin MOA

intercalates in DNA

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Use of Dactinomycin

-Wilms tumor -Ewing sarcoma -Rhabdomyosarcoma

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Toxicity of Dactinomycin

myelosuppression

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Doxorubicin, Daunorubicin MOA

generate free radicals; intercalate DNA decreasing replication

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Clinical use of Doxorubicin

solid tumors lymphomas/leukemias

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Toxciity of Doxorubicin

-Cardiotoxicity (DCM) -myelosuppression -alopecia

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When giving Doxorubicin, cardiotoxicity can be prevented with...

Dexrazoxane.

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Bleomycin MOA

induces free radical formation which causes breaks in DNA

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Uses of Bleomycin

-testicular cancer -Hodgkin lymphoma

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Toxicity of Bleomycin

-pulmonary fibrosis -skin changes -mucositis

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Alkylating Agents

1. Cyclophosphamide, Ifosfamide 2. Nitrosoureas (Carmustine, Lomustine, Semustine, Streptozocin) 3. Busulfan

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Cyclophosphamide and Ifosfamide MOA

covalently X-link (interstrand) DNA at guanine N-7; requires activation by liver

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Clinical uses of cyclophosphamide/Ifosfamide

-solid tumors -leukemia/lymphomas -some brain tumors

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Toxicity of Cyclophosphamide/Ifosfamide

-myelosuppression -hemorrhagic cystitis

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Hemorrhagic cystitis from cyclophosphamide and Ifosfamide can be partiall prevented with...

mensa which binds toxic metabolites.

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Nitrosureas (carmustine, lomustine, semustine, streptozocin) MOA

cross BBB and cross-links DNA; requires activation

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Use of Nitrosurease (carmustine, lomustine, semustine, streptozocin)

brain tumors (including glioblastoma multiforme)

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Toxicity of Nitrosureas

CNS toxicity

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Busulfan MOA

cross-links DNA

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Clinical use of Busulfan

CML -and to ablate pts bone marrow before BMT

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Toxicity of Busulfan

-severe myelosuppression -pulmonary fibrosis -hyperpigmentation

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Microtubule Inhibitors

1. Vincristine/Vinblastine 2. Paclitaxel (-taxols)

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MOA of Vincristine/Vinblastine

vinca alkaloids that bind beta-tubulin and inhibits its polymerization into microtubules, thereby preventing mitotic spindle formation (m-phase arrest)

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Clinical use of Vincristine/Vinblastine

-solid tumors -leukemias/lymphomas

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Toxicity of Vincristine/Vinblastine

-myelosuppression (vinblastine) -neuotoxicty, pralytic ileus (vincristine)

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Paclitaxel MOA

hyperstabilizes polymerized microtubules in M-phase so that mitotic spindle cannot break down preventing anaphase

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Use of Paclitaxel

-ovarian cancer -breast cancer

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Toxicity of Paclitaxel

-myelosuppression -alopecia -hypersensitivity

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Cisplatin and Carboplatin MOA

cross-link DNA

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Cisplatin and Carboplatin Use

testicular, bladder, ovary and lung carcinomas

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Cisplatin and Carboplatin toxicity

-nephrotoxicity -acoustic nerve damage

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Nephrotoxicity from cisplatin and carboplatin can be prevented with...

amifostine and chloride diuresis.

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Etoposide and Teniposide MOA

inhibits topoisomerase II leading to increased DNA degradation

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Clinical use of Etoposide and Teniposide

-solid tumors (esp. testicular, small cell lung) -leukemias/lymphomas

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Toxicity of Etoposide/Teniposide

-myelosuppression -GI irritation -alopecia

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Irinotecan and Topotecan MOA

inhibit topoisomerase I and prevent DNA unwinding and replication

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Use of Irinotecan and Topotecan

-colon cancer (irinotecan) -ovarian and small cell lung (topotecan)

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Toxicity of Irinotecan and Topotecan

-severe myelosuppression -diarrhea

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Hydroxyurea MOA

inhibits ribonucleotide reductase leading to decreased DNA synthesis

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Use of Hydroxyurea

-melanoma -CML -sickle cell

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Toxicity of Hydroxyurea

-myelosuppression -GI upset

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MOA of Prednisone and Prednisolone

may trigger apoptosis

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Use of Prednisone and Prednisolone

-most commonly used glucocorticoids in cancer chemo -used in CLL, non-Hodgkins -also as immunosuppressants

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Toxicity of Prenisone and Prednisolone

-Cushing-like symptoms

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Tamoxifen and Raloxifene MOA

selective estrogen reuptake modulators (SERMs) - receptor antagonists in breast and agonists in bone

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Use of tamoxifen and raloxifene

-breast cancer treatment (tamoxifen) -osteoporosis prevention (raloxifene)

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Tamoxifen toxicity

partial agonist in endometrium which increases risk of endometrial cancer

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Trastuzumab MOA

monoclonal Ab against HER-2, a tyrosine kinase receptor; helps kill breast cancer cells through inhibition of HER2 cellular signaling and Ab-dependent cytotoxicity

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Use of Trastuzumab

HER2 + breast and gastric cancer

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Toxicity of Trastuzumab

Cardiotoxicity

108

Imatinib MOA

tyrosine kinase inhibitor of bcr-abl and c-Kit

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Imatinib Use

-CML (bcr-abl) -GI stromal tumors (c-Kit)

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Imatinib toxicity

fluid retention

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Rituximab MOA

monoclonal antibody agaisnt CD20 which is found on most B-cell neoplasms

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Use of Rituximab

-Non-hodgkins -RA -ITP

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Toxicity of Rituximab

-incrneased risk of progressive multifocal leukoencephalopathy

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Vemurafenib MOA

inhibitor of forms of B-Raf kinase with V600E mutation

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Use of Vemurafenib

metastatic melanoma

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Bevacizumab MOA

monoclonal Ab against VEGF; inhibits angiogenesis

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Use of Bevacizumab

solid tumors (colorectal, RCC)

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Toxicity of Bevacizumab

-hemorrhage -impaired wound healing