Msd Review: Antineoplastics/anticoags

Front 1

Antineoplastics:

Back 1

begin

Front 2

Nucleotide synth inhibitors:

Back 2

MTX, 5FU, 6MP, 6TG, Cytarabine

Front 3

DNA inhibition: 1. TOPO Ø 2. X-linking 3. Intercalators

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1. Etoposide, Doxorubicin 2. Cisplatin, alkylators 3. dactinomycin, doxorubicin, cyclophosphamide, Nitrosureas, Busulfan

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Cellular division inhibition: 1. block MT synthesis 2. block MT depolymerization

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1. Vinca alkaloids 2. Paclitaxel (Taxol)

Front 5

MTX: 1. MOA 2. Uses

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1. folate analog that inhibits DHF reductase, decreased dTMP hinder DNA/protein synthesis. S-phase specific. 2. leuk/lymphomas, breast cancer, termination of ectopic pregnancy, RA, psoriasis,

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MTX: Toxicities

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suppresses bone marrow REVERSIBLY, (give folinic acid LEUCOVORIN to 'rescue' myelosuppression. Stomatitis, hepatotoxic, CI: pregnancy

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5-FU 1. MOA 2. Uses

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1. Thymidine antimetabolite converted to dUMP which binds to folic acid and inhibits THYMIDYLATE SYNTHASE. Sphase 2. breast, ovarian, colon, HEENT cancers, basal cell carcinomas.

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5-FU toxicities:

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IRREVERSIBLE myelosuppression, photosensitivity, GI irritation.

Front 9

6-MP 1. MOA 2. Uses (mini people)

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activated by HGPRT and inhibits purine synthesis; Sphase specific. 2. acute leukemias, CML, non-Hodgkin

Front 10

6-MP Toxicities: (tall grownups)

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BMS, Hepatotoxic (coadmin with allopurinol increases toxicity). Azathioprine forms 6-MP

Front 11

6-TG 1. MOA 2. Uses 3. TOX

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same as 6MP. 2. uses: ALL 3. BMS, liver, CAN BE USED WITH ALLOPURINOL (unlike 6-MP)

Front 12

Cytarabine 1. MOA 2. Uses 3. Tox

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1. pyrimidine antimetabolite, Sphase, DNA pol inhibition. 2. Acute leukemias. 3. BMS, GI irritation, increase dose = neurotoxic

Front 13

Dactinomycin: 1. MOA 2. Uses 3. Toxicities

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1. intercalates DNA 2. Wilm's, Ewings, rhabdomyosarcoma, CHILDREN ACT OUT (Ped tumours) 3. MYELOSUPPRESION

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Doxorubicin (adriamycin) 1. MOA 2. Uses 3. Tox

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1. intercalator, creates DNA breaks, hinders replication/transcription. 2. Hodgkins (ABVD+), breast, endometrial, lung, ovarian, myeloma, sarcomas. 3. Cardiotoxic (dilation), BMS, GI distress

Front 15

How to tx doxorubicin toxicity??

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Dexrazoxane: inhibits free radical formation and may protect the heart in cardiomyopathy from doxorubicin.

Front 16

Bleomycin?? 1. MOA 2. Uses 3. Tox

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1. Generates free radicals, DNA strand scission, G2phase specific. 2. lymphomas, testicular skin CA 3. Pulm fibrosis, mucocutaneous reactions (blisters), HSN rcn

Front 17

Etoposide 1. MOA 2. Uses 3. Tox:

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1. Inhibits TOPO II, increase DNA degradation, Late S/early G2 phase reactant. 2. small cell carcinoma, prostate/testicular cancer. 3. BMS, GI irritation

Front 18

Cyclophosphamide 1. MOA 2. Uses 3. Tox

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1. alkylate DNA, attacks guanine N7, induces X-linking 2. nonHodgkin, ovarian/breast cancer/neuroblastoma, vasculitides. 3. BMS, hemorrhagic cystitis (mesna)

Front 19

Nitrosureas (lomustine, carmustine) 1. MOA 2. Uses 3. Tox

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1. Alkylates DNA, CROSSES BBB 2. Brain tumours 3. NEUROlogic

Front 20

Busulfan 1. MOA 2. Uses 3. Tox

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1. Alkylates DNA 2. CML 3. Pulm fibrosis, hyperpigmentation, adrenal insufficiency.

Front 21

Cisplatin, Carboplatin, Oxiplatin. 1. MOA 2. Uses 3. Tox

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1. alkylates DNA 2. testicular, bladdder, lung , ovarian 3. nephrotoxic, (add amifostine); deafness/tinnitis BMS (carbo>cis)

Front 22

Vinblastine: 1. MOA 2. Uses 3. Tox

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1. inhibit MT formation M-phase. 2. lymphoma, wilms, choriocarcinoma. 3. BMS

Front 23

Vincristine 1. MOA 2. Uses 3. Tox

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1. inhibit MT formation, M-phase 2. same uses as vinblastine (MOPP) 3. neurotoxic, GI distress

Front 24

Paclitaxel 1. MOA 2. Uses 3. Tox

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1. stabilizes MTs/NO DEPOLARIZES, M-phase 2. ovarian/breast carcinomas 3. BMS

Front 25

Hydroxyurea (HU) 1. MOA 2. Uses 3. Tox

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1. an antimetabolite that inhibits RIBONUCLEOTIDE REDUCTASE, reactivates HbF synthesis. 2. Sickle cell, PV, CML

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Prednisone: 1. MOA 2. Uses 3. Tox

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1. induces apoptosis of lymphoid cells, PLA2 blockage, IL2 suppression, COX2 block. 2. CLL, Hodgkin lympohma (MOPP), Autoimmune disease/suppression. 3. iatrogenic Cushing syndrome, GC excess (decrease Ca, K increased Na)

Front 27

Tamoxifen/Raloxifene: 1. MOA 2. Uses 3. Tox

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1. SERMs (selective estrogen receptor modulators). Prevents estrogen from binding estrogen receptor-positive breast CA cells leading to involution of estrogen-dependent tumours. 2. Breast Cancer. 3.hot flashes, increased risk of endometrial cancer. (RALOXIFENE IS RISK FREE OF EC)

Front 28

Trastuzumab (Herceptin) MOA, Uses, Tox

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monoclonal-Ab anti-HER2 (erb-B2); metastatic breat cancer, CARDIOTOXIC

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Imantinib (Gleevac) MOA, Uses, TOX

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small molecule anti-bcr/abl fusion; CML, GI stromal tumours; FLUID RETENTION

Front 30

Rituximab MOA, Uses, Tox

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mc-Ab against CD20, on most Bcell neoplasms; non-hodgkins lymphomas, RA (+ MTX)

Front 31

Vemurafenib MOA, Uses, Tox

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small molecule inhibitor of forms of B-Raf kinase with V600E mutation, Metastatic melanoma.

Front 32

Bevacizumab MOA USES

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mc-Ab against VEGF, inhibits angiogenesis; SOLID TUMOURS

Front 33

AntiCOAGs

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begin:

Front 34

Heparin (IV, SC) MOA

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activates ANTITHROMBIN III. INACTIVATES: Factors 2,7,9,10,11,12 (intrinsic). Slows PTT.

Front 35

heparin MOA/USES

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binds AT-III; complex inactivates THROMBIN/9a, 10a,12a. Acts in SECONDS, used ACUTELY (IV). Uses: acute MI, DVT, PE, Stroke, beginning therapy

Front 36

LMWHs (ardeparin, dalteparin, enoxaparin)

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inhibit Factor 10a, more nad thrombin less than heparin. USED IN LONGTERM use due to risk of heparin-Induced Thrombocytopenia (HIT).

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Protamine sulfate?

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reverses heparin and LMWH use

Front 38

Direct thrombin inhibitors: Lepirudin/argatroban, hirudin, bivalirudin

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bind directly to thrombin substrates/thrombin. (ATIII independent). Bind to soluble thrombin/clot-bound thrombin.

Front 39

Warfin (PO), Coumadin

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interferes with synthesis of vitamin K-dependent clotting factors (2, 7, 9, 10). Takes 2-5 days to work (chronic use). PT/INR used to monitor. Vit K reverses efx. CONTRAIND: Pregnancy. CYP450-Inducers DECREASE EFX, CYP450Ø incr. efx.

Front 40

Thrombolytics: (streptokinase, alteplase, urokinase) MOA, Uses

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convert plasminogen to plasmin to bust clots, uses: MI DVT PE ischemic stroke (tPA); CONTRAIND: active bleed, intracranial bleed (hemorrhagic stroke), recent surgery, severe HTN, OD: aminocaproic acid

Front 41

Protein S MOA

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activates protein C, this inactivates Factors 5a, 8a

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tPA MOA

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cleaves fibring mesh by activating plasminogen/plasmin

Front 43

GpIIb/IIIa inhibitors:

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reversible inhibitors. abciximab, eptifibatide, tirofiban.

Front 44

Bernard Soulier disease

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defective plug formation due to GPIb deficiency and platelets cannot bind to vWF

Front 45

Glanzmann thrombasthenia:

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defective plug formation from decreased GpIIb/IIIa which inhibits platelet-to-platelet aggregation (abcixumab MOA). Fibrinogen xlinking using these receptors. ADP induces these receptors to surface as well (so

Front 46

Clopidogrel/Ticlopidine

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BLOCK ADP receptor to inhibit aggregation

Front 47

Aspirin

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blocks Cox1/2 irreversibly, platelet aggregation inhibited through DECRE. PG synth (TXA2 stimulates platelet aggregation and vasoconstriction)

Front 48

von Willebrand disease (AD)

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defective platelet plug formation due to defect in quantity or quality of vWF which binds to exposed collagen in the SEC which facilitates platelet binding to wall via GpIb. vWF deficiency= increased bleeding time and PTT (vWF stabilizes Factor 8)

Front 49

Tests for Coag system: PT/PTT

Back 49

PT: extrinsic, 7, 10, 5, prothrombin, fibrinogen. PTT: intrinsic 12,11, 9, 8, 10, 5, prothrombin, fibrinogen

Front 50

DX diseases of Platelets: Bernard-Soulier/Glanzmann

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PTT, PT not affected, BLEEDING TIME INCREASED. Signs: gum bleeding, epistaxis, petechiae,

Front 51

ITP (idiopathic thrombocytopenic purpura)

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spleen makes Ab against platelet antigen (GPIIB/IIIA, GPIb/IX) Destoyed plates via splenic MØ, acute form: postviral/kids, selflimited. Chronic: adults, 1' or 2' (HIV, SLE). CS, Ig therapy, Splenectomy. Enlarged immature platelets, PT/PTT normal

Front 52

TTP (thrombotic thrombocytopenic purpura)

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pentad (Thrombocytopenic purpura, fever, renal failure, neuro changes, microangiopathic hemolytic anemia) usually in younger women, Smear= few plates, schistocytes. HUS looks similar (BUT DIARRHEA FOLLOWING E.COLI O157:H7 Infection)

Front 53

vWF disease:

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defective platelet plug due to defieint levels of vWF. AD. Increased BT, PTT (vWF stabilizes factor 8). Tx: Desmopressin??

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DIC:

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massive persistent activation of both coag/fibrinolytic system. Consumption deficiency. Etiology: amniotic fluid embolism, infection (gram neg, sepsis), malignancy, major traumas, head injury. DX: low plates, low fibrinogen, increased PTT/PT, INCR D DIMER, schistocytes

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Excessive thrombosis: causes:

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Protein C/S deficiency, Factor V Leiden deficiency, Prothrombin gene mutation, ATIII deficiency.

Front 56

Protein C/S deficient:

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lost ability to inactivate Factors 5/8, incr. DVT/PE, Cerebral V. thrombosis, Warfarin-induced skin necrosis

Front 57

Prothrombin gene mutation:

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3' untranslated region causes increased circulating thrombin and venous clots.

Front 58

ATIII deficiency

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potent inhibitor of clotting cascade and its deficiency leads to increased venous clots

Front 59

Factor V Leiden deficiency (AD)

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Mutation in factor 5 making it resistant to inactivation by Protein C. inherited disorder of blood clotting/hypercoagulability. PTT prolonged. DVT association and risk of clot in pregnancy.