Heme-Onc

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  1. Anticoagulants
    drugs that decrease the formation of FIBRIN clots.

    • -Oral anticoagulants (Warfarin) --> decrease hepatic synthesis of II, VII, IX, X
    • -Heparin--> inhibits activity of activated clotting factors (esp. IIa, Xa)
    • -Endogenous anticoagulants (Protein C, S)--> proteolyze V, VIII
  2. Heparin
    • anticoagulant
    • -mix of large sulfated polysacch, water-soluble (Parenteral!)
    • -cofactor for Antithrombin III (ser-protease inhibitor)-->breakdown II,IX,X,XI, XII (intrinsic path!)
    • -works both in vivo, in vitro
    • -short half-life. Does NOT cross placenta (safe in pregnancy)
    • -monitor w/ PTT

    USE- immediate anticoagulation for Pulm embolism, stroke, acute coronary syndrome, MI, DVT, DIC, unstable angina, (safe in pregnancy)

    • SE- bleeding, Osteoporosis, Heparin-induced thrombocytopenia (type II)- anti-heparin-PF4 IgG
    • (actually thrombosis!)
    • Antidote for HIT- Protamine sulfate
    • Alternative- Argatroban, Lepirudin, Bivalirudin
  3. Enoxaparin
    • low molecular weight heparin
    • -bind, activate thrombin
  4. Antidote for Heparin-induced thrombocytopenia
    Protamine sulfate

    • - + charged molecule, bind and block Heparin
    • -fast onset
  5. Low molecular weight Heparins
    (ex) Enoxaparin

    • Advantages over unfractionated Heparin:
    • -longer half life, better bioavailability
    • -LESS heparin-induced thrombocytopenia
    • -better action against Thrombin (Xa)
    • -can be given SubQ
    • -no need to monitor

    • Disadvantages:
    • -Not easily reversible.
  6. Lepirudin, Bivalirudin, Argatroban
    • Thrombin-specific anticoagulant
    • -Hirudin
    • -directly inhibit Thrombin
    • -does NOT need antithrombin (like Heparin does)

    USE- alternative to Heparin for anticoagulating patients with HIT!

    Bivalirudin- use with Aspirin in unstable angina when doing PTCA.
  7. Warfarin (coumadin)
    • Long term Anticoaglant
    • -small, lipid soluble, vit-K derivative
    • -inhibit liver epoxide reductase--> prevent gamma carboxylation of vit-K dependent coag factors (II, VII, IX, X, Protein C, S)
    • -more effect on Extrinsic pathway (b/c VII shortest half life)
    • -works only in vivo
    • -long half life, PO
    • -HIGH protein binding, metabolized by Cyps
    • -CROSS placenta! teratogenic!
    • -monitor w/ PT/INR (intrinsic)

    USE- long-term anticoagulation (ambulatory) for thromboses, emboli, post-MI, heart valve, atrial arrhythmias

    SE- Bleeding, Hemorrhagic skin necrosis! (low protein C initially), Teratogenic, drug interactions (Cyp-inducers decrease efficacy, Cyp inhibitors increase toxicity), Cholestyramine (trap bile salt) decrease absorption!, Displaced by other drugs (ASA, sufonamides, phenytoins--> incr PT)

    Antidote or overdose- Vit K (takes time), FFP (immediate reversal)
  8. Warfarin induced hemorrhagic skin necrosis
    • Warfarin inhibits syn of II, VII, XI, X, Protein C, S
    • -VII, protein C have the shortest half lives.

    -Warfarin initially cause transient deficiency of Protein C b/c protein C has shorter half life than others, first one to decrease--> inactivate extrinsic pathway, Protein C but intrinsic coag path remain active for a few more days--> hypercoagulability--> vascular thrombosis, skin necrosis!

    • RX- start the patient on Heparin and very small dose of Warfarin initially.
  9. Drug interactions of Warfarin
    • Highly protein bound, but weakly bound, so can be displaced by other highly protein bound drugs:
    • -Phenytoin
    • -Sulfonamides
    • -ASA

    • Broken down by Cyps
    • Decrease efficacy w/ Cyp inducers:
    • -Phenobarbital
    • -Phenytoin
    • -Rifampin
    • -Carbamazapine

    • Increase toxicity with Cyp blockers:
    • -Cimetidine
    • -Amiodarone
    • -Metronidazole
    • -TMP-SMX
    • note: many A-fib patients on both Amiodarone + Warfarin!

    • Warfarin is PO, lipid soluble, so absorbed via Bile micellization like Fat soluble vitamins:
    • -Cholestyramine decrease GI absorption of Warfarin!
  10. Thrombolytics/ Fibrinolytics
    • Break thrombi by catalyzing formation of endogenous fibrinolytic plasmin (serine protease)!!
    • -enhance Plasminogen---> Plasmin--> degrade Thrombin, Fibrinogen, Fibrin.
    • -increase PT, PTT, no change in Plts!

    • Drugs:
    • -Alteplase- recombinant tPA
    • -Streptokinase (bacterial)
    • -Urokinase

    USE- IV, short-term emergency management of Coronary thrombosis in MI, DVT, Pulm embolism, Ischemic stroke (tPA)- but SCAN it first to rule out Hemorrhagic stroke!

    • -Effectiveness depends on TIMING for MI!
    • must give within 4 hrs! (when still reversible)
    • -ASA, beta-blockers, nitrates further decrease mortality
    • -Adenosine decrease infarct size

    SE- bleeding, intracerebral hemorrhage

    Antidote: treat toxicity w/ Aminocaproic acid, Tranexamic acids
  11. Streptokinase
    • Thrombolytic/ fibrinolytic
    • -derived from bacteria (beta-hemolytic streps)
    • -Act on both bound and free plasminogen (not clot specific)--> deplete circulating plasminogen and V, VIII.
    • -Bind plasminogen to activate it to plasmin
    • -increase PT, PTT, no change in plts

    USE- IV, short-term emergency management of Coronary thrombosis in MI, DVT, Pulm embolism, Ischemic stroke- but SCAN it first to rule out Hemorrhagic stroke!

    • SE- antigenic! (strep antibodies may decrease efficacy), bleeding, intracerebral hemorrhage
    • DO NOT use in patients with active bleeding, hx of intracranial bleeding, severe HTN

    Rx toxicity w: Aminocaproic acid, Tranexamic acid
  12. Alteplace
    • Thrombolytic/ Fibrinolytic
    • -recombinant tPA
    • -catalyze Plasminogen--> Plasmin
    • -increase PT, PTT, no change in Plts
    • -Clot specific! acting mainly on Fibrin-bound plasminogen
    • -natural activator, so NO allergy problems!
    • -expensive!

    USE- IV, short-term emergency management of Coronary thrombosis in MI, DVT, Pulm embolism, Ischemic stroke (tPA)- but SCAN it first to rule out Hemorrhagic stroke!

    • SE- bleeding, intracranial hemorrhage.
    • DO NOT use in patients with active bleeding, hx of intracranial bleeding, severe HTN

    Rx toxicity w: Aminocaproic acid, Tranexamic acid
  13. Platelet aggregation
    -Inhibitors and Activators
    • Platelet aggregation:
    • Increase by:
    • -ADP, 5-HT, TXA2, Thrombin, Alpha-2 agonists

    • Decrease by:
    • -PGI2, cAMP, ASA, Ticlopidine, Clopidogrel
    • gP IIb/IIIa blockers
  14. Aspirin (ASA)
    • Antiplatelet
    • -acetylate, irreversibly inhibit Cox-1 and Cox-2 (at high dose)--> prevent TXA2--> increase bleeding time
    • -NO effect of PT, PTT.

    • USE- low dose prevent MI, recurrence
    • -prophylaxis in atrial arrhythmias
    • -antipyretic, analgesic, anti-inflammatory, anti-platelet

    • SE- gastric ulcer (decr PGE2), Bleeding, Hyperventilation, Reye's syndrome, Tinnitis (CN VIII)
    • Salicylim (very high dose)- vertigo, tinnitis, hearing loss, stimulate respiratory drive--> hyperventilate--> resp alkalosis plus salicilate metabolic acidosis

    Samter's triad: Asthma, aspirin hypersensitivity (nasal, bronchospasm, flushing), nasal polyposis (b/c increase leukotriens!!)
  15. Clopidogrel (plavix), Ticlopidine
    • Antiplatelet
    • -irreversibly block ADP-receptor-->block platelet activation/ aggregation (decrease gP IIb/IIIa expression)

    • USE- acute coronary syndrome, coronary stenting!
    • -alternative to ASA in TIA, post-MI, unstable angina (decrease recurrence of thrombotic stroke)

    • SE- Hemorrhage,
    • Ticlopidine--> Neutropenia!! (fever, mouth ulcers, neutropenia, ITP (do CBC every 3 weeks initially)
  16. Abciximab
    (also Eptifibatide, Tirofiban)
    • Antiplatelet
    • -monoclonal antibody block gp IIb/IIIa (fibrinogen receptor) on activated platelets--> decrease plt aggregation

    USE- Acute coronary syndromes, PTCA, Post angioplasty (mainly hospital use)

    SE- bleeding, thrombocytopenia
  17. Desmopressin acetate
    • Synthetic vasopressin analog
    • -also release vWF and VIII from endothelium!

    • USE- Central Diabetes Insipidus
    • -Hemophila A, von-Willebrand disease
  18. Cancer therapy principles
    Log-kill therapy
    Growth fraction
    • Log kill-therapy
    • -cytotoxic actions of anticancer drugs follow 1st-order kinetics
    • -Kill fixed Percentage of tumor cells, NOT fixed number
    • -why used in combo

    • Growth fraction
    • -More effective against tumors w/ high growth fraction
    • -So normal cells with high growth fractions (bone marrow, GI mucosa) more sensitive to anticancer drugs
  19. M phase cancer drugs
    • -all screw up the microtubule
    • Vinblastin
    • Vincristine
    • Paclitaxel
  20. G0 phase cancer drugs / DMA damaging
    • Alkylating agents
    • -Cyclophosphamide
    • -Ifosfamide
    • -Nitrosoureas (Carmustine, Lomustine, Semustine, Streptozocin)
    • -Busulfan
    • -Cysplatin
    • Antitumor antibiotics
    • -Dactinomycin
    • -Daunorubicin
  21. S phase anticancer drugs
    • Antimetabolites
    • -Methotrexate
    • -5-Fluorouracil
    • -6-Mercaptopurine
    • -6-thioguanine
    • -Cytarabine

    -Etoposide (antitumor antibiotic)
  22. G2 phase anticancer drugs
    • antitumor antibiotics
    • -Etoposide
    • -Bleomycin
  23. Methotrexate
    • S-phase anticancer drug
    • -antimetabolite
    • -Folic acid analog
    • -block Dihydrofolate reductase--> decrs dTMP--> block DNA, protein synthesis

    • USE- Leukemia, Lymphoma, Choriosarcoma
    • Non-cancer- Abortion, ectopic pregnancy, Rheumatoid arthritis, Psoriasis

    • SE- Marrow suppression (reverse with Leucovorin- folinic acid), Macrovesicular fatty change in liver
    • -Mucositis, Teratogenic!
  24. Cladribine
    • Purine analog
    • -resistant to degradation by adenosine deaminase
    • -can reach high conc in cell

    USE- hairy cell leukemia
  25. Symptoms of marrow suppression from chemotherapy
    • fever
    • apthous ulcers
    • pancytopenia
  26. 5-Fluorouracil
    • S-phase anticancer drug
    • -antimetabolite
    • -Pyrimidine analog
    • -activated to 5F-dUMP-->complex w/ folic acid--> block Thymidylate synthase--> decr dTMP--> block DNA, protein synthesis

    • USE- Colon cancer, solid tumors
    • -topical for basal cell carcinoma
    • -synergy with Methotrexate!

    • SE- Marrow suppression (NOT rescued by Leucovorin!) rescue w/ Thymidine
    • -Photosensitivity
  27. 6-Mercaptopurine (6-MP)
    • S-phase anticancer drug
    • -antimetabolite
    • -Purine analog
    • -block de novo purine synthesis
    • -activated by HGPR transferase (Leish-Nayan)
    • -metabolized by Xanthine oxidase

    • USE- Leukemias, Lymphomas (NOT CLL or Hodgkins)
    • -immunosuppression

    • SE- Marrow suppression, GI, Liver
    • -increased toxicity with Allopurinol!
  28. 6-Thioguanine (6-TG)
    • S-phase anticancer drug
    • -antimetabolite
    • -Purine analog
    • -block de novo purine synthesis
    • -activated by HGPR transferase (Leish-Nayan)

    USE-ALL

    • SE- Marrow suppression, liver
    • but you CAN give with allopurinol (unlike 6-Mercaptopurine!)
  29. Cytarabine (ara-C)
    • S-phase anticancer drug
    • -antimetabolite
    • -Pyrimidine antagonist--> block DNA polymerase!

    USE- AML, ALL, high grade non-Hodgkin's lymphoma

    USE- Leukopenia, thrombocytopenia, megaloblastic anemia!
  30. Dactinomycin
    • Anticancer drug
    • -antitumor antibiotic
    • -intercalate into DNA!
    • USE-Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma
    • -for childhood tumors!

    SE- Marrow suppression
  31. Doxorubicin
    • Anticancer drug
    • -antitumor antibiotic
    • -gen free radicals, noncovalently intercalate into DNA--> break DNA--> block replication
    • -inhibit topoisomerase

    USE- Hodgkin's lymphoma, Myeloma, Sarcoma, solid tumor ( Breast, Ovary)

    • SE- Cardiotoxic! delayed CHF (Dexrazoxane- antidote!- Fe-chelating agent prevent FR form)
    • Marrow suppression, alopecia
    • -toxic to tissues with extravasation.
  32. Daunorubicin
    • Anticancer drug
    • -antitumor antibiotic
    • -gen free radicals, noncovalently intercalate into DNA--> break DNA
    • --> block replication
    • -inhibit topoisomerase

    USE- Hodgkin's lymphoma, Myeloma, Sarcoma, solid tumor ( Breast, Ovary)

    SE- Cardiotoxic! delayed CHF (Dexrazoxane- antidote!- Fe-chelating agent prevent FR form) Marrow suppression, alopecia-toxic to tissues with extravasation.
  33. Bleomycin
    • Anticancer drug
    • -G2 block!
    • -antitumor antibiotic
    • - complex w/ Fe, O2, free radical formation--> break DNA strands
    • -NO marrow suppression!

    USE- Testicular cancer, Hodgkins lymphoma

    • SE- Pulmonary fibrosis, Skin changes,
    • no marrow suppression!!
  34. Etoposide

    Teniposide
    • Anticancer drug
    • -S and G2 block!
    • -antitumor antibiotic
    • -block topoisomerase II--> increase DNA breakdown!

    • USE- small cell carcinoma of lung, prostate,
    • testicular carcinoma

    SE- Marrow suppression, GI, alopecia
  35. Podophyllin
    same as Etoposide, but used for genital warts!
  36. Cyclophosphamide
    • Anticancer drug
    • -alkylating agent!
    • -Covalently crosslink DNA at guanine N-7
    • -must be activated by liver--> Acrolein

    USE- Non-hodgkin's lymphoma, breast, ovarian carcinoma, Neuroblastoma

    • SE- Marrow suppression, Hemorrhagic cystitis!
    • (prevent w/ Mesna- thiol group bind toxic metabolite)

    -similar: Ifosfamide
  37. Nitrosoureas
    (four of them)
    Carmustine, Lomustine, Semustine, Streptozocin

    • Anticancer drug
    • -Alkylating agents
    • -must be activated--> cross BBB--> CNS!!

    USE-Brain tumors! (Glioblastoma multiform)

    SE- CNS toxicity (dizziness, ataxia)
  38. Busulfan
    • Anticancer drug
    • -Alkylate DNA

    • USE-CML
    • -also for ablating bone marrow before bone marrow transplantation

    SE- Pulmonary fibrosis, Hyperpigmentation
  39. Cisplatin
    carboplatin
    • Anticancer drug
    • -Alkylate DNA--> crosslink DNA
    • -NO marrow suppression!, but severe nausea, vomiting!

    USE- Testicular cancer, Bladder cancer, Lung cancer

    • SE- Nephrotoxicity (antidote= Amifostine), VIII nerve damage -deafness!
    • Severe Nausea, vomiting (give w/ Ondensetron)
    • NO marrow suppression!!
  40. Vincristine
    • Anticancer drug
    • -M-phase!
    • -block microtubules, block polymerization--> block mitotic spindle formation
    • -NO marrow suppression!

    USE- Hodgkin's lymphoma , Wim's tumor, Choriocarcinoma

    • SE- Neurotoxicity- areflexia, peripheral neuritis
    • NO marrow suppression!
  41. Vinblastin
    • Anticancer drug
    • -M-phase!
    • -block microtubules, block polymerization--> block mitotic spindle formation

    USE-Hodgkin's lymphoma, Kaposi sarcoma, testicular cancer

    SE-Marrow suppression, GI, Alopecia
  42. Paclitaxel
    • Anticancer drugs
    • -M-phase!
    • -block Microtubule depol (breakdown)! --> anaphase cannot occur!

    USE- Ovarian, breast cancer

    SE- Marrow suppression, hypersensitivity
  43. Colchicine
    • anti-gout drug
    • also block microtubules
  44. Hydroxyurea
    • Anticancer drug
    • -S-phase!
    • -block Ribonucleotide reductase--> block DNA synthesis

    USE- melanoma, CML, sickle cell disease--> increase HbF

    SE- Marrow suppression, GI upset
  45. Prednisone
    • USE- most commonly used glucocorticoid in cancer chemotherapy
    • -used in CLL, Hodgkins's lymphoma
    • -immunosuppressant used in autoimmune diseases

    • SE- Cushing-like syptoms, immunosuppression, cataracts, acne, osteoporosis, HTN, peptic ulcer, hyperglycemia, psychosis.
    • may rigger apoptosismay even work on nondividing cells
  46. Tamoxifen,
    Raloxifene
    • anticancer drug
    • -receptor antagonists in breast and agonist in bone
    • -block binding of Estrogen to Estrogen receptor + cells

    • USE- breast cancer
    • -also useful to prevent osteoporosis

    • SE- may increase risk of endometrial carcinoma via partial agonist effects (hot flashes)
    • NO increased risk with Raloxifene (b/c endometrial antagonist)
  47. Trastuzumab (Herceptin)
    • anticancer antibody
    • -monoclonal antibody against HER-2 (erb-B2)
    • -kill breast cancer cells that overexpress HER-2
    • (via antibody-dependent cytotoxicity?)

    USE- Metastatic breast cancer

    SE- cardiotoxicity
  48. Imatinib (Gleevac)
    • anticancer antibody
    • -philadelphia chromosome Bcr-abl Tyr-kinase inhibitor

    USE- CML, GI stromal tumors

    SE- fluid retention
  49. Rituximab
    • anticancer antibody
    • monoclonal antibody against CD-20 (on most B-cell neoplasms)

    USE- Non-hodgkin's lymphoma. Rheumatoid arthritis (w/ methotrexate)
  50. Anticancer drugs NOT marrow suppressing
    • Cisplatin
    • Bleomycin
    • Vincristine
  51. Nephrotoxic anticancer drugs
    • Cisplatin
    • Methotrexate
  52. Cardiotoxic anticancer drugs
    • Doxorubicin
    • Daunorubicin
  53. Neurotoxic anticancer drugs
    • Vincristine
    • Cisplatin
  54. Hepatotoxic anticancer drugs
    • 6-Mercaptopurine
    • Busulfan
    • Cyclophosphamide
  55. Pulmonary toxic anticancer drugs
    • Bleomycin
    • Busulfan
    • Procarbazine
  56. Immunosuppressive anticancer drugs
    • Cyclophosphamide
    • Methotrexate
  57. Ondansetron
    inhibit 5-HT3 receptors in GI, area postrema, SNT

    USE - nausea, vomiting after chemotherapy
  58. Amifostine
    Cytoprotective FR scavenger

    • USE-decrease nephrotoxicity assoc. w/ platinum containing and alkylating chemotherapy drugs
    • -decrease xerostomia
  59. Filgrastin
    • G-CSF
    • -increase granulocytes

    USE- marrow recovery
  60. Sargramostim
    • GM-CSF
    • increase granulocytes, macs

    USE- marrow recovery
  61. EPO
    USE- anemia esp assoc w/ renal failure
  62. Thrombopoeitin
    USE-thrombocytopenia

    note-
    can also use IL-11 increase platelet formation
  63. Aldesleukin
    • IL-2
    • increase lymphocyte differentiation, NK cells

    USE- renal cell cancer, metastatic melanoma

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