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29 terms

Pharm - Hematology/Oncology

First Aid 2012 pg 395-402 Drug vs. mechanism/clinical use/toxicity, when applicable
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Heparin
Mech: Cofactor for activation of antithrombin; decreases thrombin (IIa) and decreases Xa. Short half life. Parenteral.
Use: Immediate anticoagulation for pulmonary embolism, stroke, actue coronary syndrome, MI, DVT. Used during prgnancy (does NOT cross placenta). Follow PTT.
Tox: Bleeding, thrombocytopenia (HIT), osteoporosis, drug-drug interactions. For rapid reversal (antidote), use protamine sulfate (positively charged molecule that binds negativel charged heparin).
***LMWH (Enoxaparin) act more on Xa, have better bioavailability, and 2-4x longer half life. Administered subcutaneously.
Lepirudin, bivalirudin, argatroban
Mech: Hiruding derivatives; directly inhibit thrombin. Bind to soluble AND clot-bound thrombin.
Use: Alternative to heparin for anticoagulating patients with HIT.
Tox: bleeding
Warfarin (Coumadin)
Mech: Interferes with normal synthesis and gamma-carboxylation of vitK dependent clotting factors II, VII, IX, X and proteins C and S. Metabolized by P450 pathway. In lab assay, has effect on extrinsic pathway and increased PT. Long half life.
Use: Chronic anticoagulation (post STEMI, venous thromboembolism prophylaxis). Not used in pregnant women (bc warfarin, unlike heparin, can cross the placenta). Follow PT, INR values.
Tox: Bleeding, teratogenic, skin/tissue necrosis, drug-drug interactions.
Thrombolytics (Streptokinase, Urokinase, tPA (alteplase), APSAC (anistreplase))
Mech: Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. Increased PT, PTT; no changei n platelet count.
Use: Early MI, early ischemic stroke
Tox: Bleeding. Contraindicated in patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses (eg. vWD), or severe HTN. Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis (prevents conversion of plasminogen to plasmin).
Aspirin (ASA)
Mech: Acetylates and irreverisbly inhibits COX1 and COX2 to prevent conversion of arachidonic acid to TXA2. Increases bleeding time. No effect on PT, PTT
Use: Antipyretic, analgesic, anti-inflammatory, antiplatelet drug. Give to patients who are high risk for stroke, MI.
Tox: Gastric ulceration, bleeding, hyperventilation (resp alkalosis, and then anion gap metabolic acidosis), Reye's syndrome, tinnitus (CN VIII).
Clopidogrel, Ticlopidine
Mech: Inhibit platelet aggregation by irreversibly blocking ADP receptors., Inhibit fibrinogen binding by preventing GP IIb/IIIa expression.
Use: Acute coronary syndrome; coronary stenting. Decrease incidence or recurrence of thrombotic stroke.
Tox: Neutropenia (w/ ticlopidine)
Cilostazol, Dipyridamole
Mech: Phosphoesterase III inhibitor; Increase cAMP in platelets thus inhibiting platelet aggregation.
Use: Intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (when combined with aspirin), angina prophylaxis.
Tox: Nausea, headache, facial flushing, hypotension, abdominal pain
Abciximab, Eptifibatide
Mech: Monoclonal Ab that binds to GP IIb/IIIa receptor on activated platelets, preventing aggregation.
Use: Acute coronary syndromes, percutaneous transluminal coronary angioplasty
Tox: Bleeding, thrombocytopenia
Methotrexate
Mech: Folic acid analogue that inhibits dihydrofolate reductase --> decreased dTMP --> decreased DNA and decreased protein synthesis.
Use: Cancers: Leukemias, lymphomas, choriocarcinoma, sarcomas; Non-neoplastic: Abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis
Tox: Myelosuppression, which is reversible with leucovorin (folinic acid) rescue. Macrovesicular fatty change in liver. Mucositis. Teratogenic.
5-fluorouracil
Mech: Pyrimidine analogue bioactivated to 5F-dUMP, which covalently complexes folic acid. This complex inhibits thymidylate synthase --> decreased dTMP --> decreased DNA and decreased protein synthesis.
Use: Colon cancer and other solid tumors, basal cell carcinoma (topical). Synergy with methotrexate
Tox: Myelosuppression, which is NOT reversible with leucovorin. Overdose: "rescue" with thymidine. Photosensitivity.
6-mercaptopurine
Mech: Purine (thiol) analogue --> decreases de novo purine synthesis. Activated by HGPRTase.
Use: Leukemias, lympphomas (not CLL or Hodgkin's).
Tox: Bone marrow, GI, liver. Metabolized by xanthine oxidase; thus, increased toxicity with allopurinol.
6-thioguanine
Mech: Purine (thiol) analogue --> decreases de novo purine synthesis. Activated by HGPRTase.
Use: Acute lymphoid leukemia (ALL)
Tox: Bone marrow suppression, liver. Can be given with allopurinol (unlike 6-MP)
Cytarabine (ara-C)
Mech: Pyrimidine analogue --> inhibition of DNA polymerase
Use: AML, ALL, high-grade non-Hodgkin's lymphoma.
Tox: Leukopenia, thrombocytopenia, megaloblastic anemia (=pancytopenia)
Dactinomycin (Actinomycin D)
Mech: Intercalates in DNA
Use: Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma. Used for childhood tumors.
Tox: Myelosuppression.
Doxorubicin (Adriamycin), Daunorubicin
Mech: Generate free radicals. Noncovalently intercalate in DNA --> breaks in DNA --> decrease replication.
Use: Hodgkin's lymphomas; also for myelomas, sarcomas, and solid tumors (breast, ovary, lung)
Tox: Cardiotoxicity (dilated cardiomyopathy), myelosuppression, and alopecia. Toxic to tissues with extravasation. Dexrazoxane (iron chelating agent) used to prevent cardiotoxicity.
Bleomycin
Mech: Induces free radical formation, which causes breaks in DNA strands. G2 phase specific.
Use: Testicular cancer, Hodgkin's lymphoma.
Tox: Pulmonary fibrosis, skin changes. Minimal myelosuppression.
Etoposide, Teniposide
Mech: Inhibits topoisomerase II --> increased DNA degradation. DNA supercoiling. Late S, early G2 phase specific.
Use: Small cell carcinoma of the lung and prostate, testicular carcinoma.
Tox: Myelosuppression, GI irritation, alopecia
Cyclophosphamide, Ifosfamide
Mech: Covalently X-link (interstrand) DNA at guanine N7. Require bioactivation by liver
Use: Non-Hodgkin's lymphoma, breast and ovarian carcinomas. Also immunosuppressants.
Tox: Myelosuppression; hemorrhagic cystitis, partially prevented with Mesna (thiol group of mesna binds toxic metabolite)
Nitrosureas (Carmustine, Lomustine, Semustine, Streptozocin)
Mech: Require bioactivation. Cross BBB --> CNS
Use: Brain tumors (including glioblastoma multiforme)
Tox: CNS toxicity (dizziness, ataxia)
Busulfan
Mech: Alkylates DNA.
Use: CML. Also used to ablate patient's BM before BM transplantation.
Tox: Pulmonary fibrosis, hyperpigmentation
Vincristine, Vinblastine
Mech: Alkaloids that bind to tubulin in M-phase and block polymerization of microtubules so that mitotic spindle cannot form.
Use: Hodgkin's lymphoma, Wilms' tumor, choriocarcinoma, ALL
Tox: Vincristine: neurotoxicity (areflexia, peripheral neuritis), paralytic ileus. Vinblastine: BM suppression.
Paclitaxel
Mech: Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase does not occur).
Use: Ovarian and breast carcinomas
Tox: Myelosuppression and hypersensitivity
Cisplatin, Carboplatin
Mech: Cross-link DNA, making non-functional DNA complexes.
Use: Testicular, bladder, ovary, and lung carcinomas.
Tox: Nephrotoxicity and acoustic nerve damage. Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride diuresis.
Hydroxyurea
Mech: Inhibits ribonucleotide reductase, which is necessary for converting rNTs into dNTs. Decreases DNA synthesis.
Use: Melanoma, CML, sickle cell disease (increases HbF)
Tox: BM suppression, GI upset
Prednisone
Mech: May trigger apoptosis. May even work on non-dividing cells.
Use: Most commonly used glucocorticoid in cancer chemotherapy. Used in CLL, Hodgkin's lymphomas (part of MOPP regimen). Also an immunosuppressant used in autoimmuned diseases.
Tox: Cushing-like symptoms; immunosuppression, cataracts, acne, osteoporosis, HTN, peptic ulcers, hyperglycemia, psychosis
Tamoxifen, Raloxifene (SERMs)
Mech: Estrogen receptor antagonists in breast and agonists in bone. Block the binding of estrogen to estrogen receptor positive cells.
Use: Breats cancer. Also useful to prevent osteoporosis.
Tox: Tamoxifen: may increase risk of endometrial carcinoma via partial agonist effects; "hot flashes." Raloxifene: no increase in endometrial carcinoma because it is an endometrial antagonist.
Trastuzumab (Herceptin)
Mech: Monoclonal Ab against HER2 (erb-B2), a tyrosine kinase. Helps kill breast cancer cells that overexpress HER2, possibly through antibody-dependent cytotoxicity.
Use: Metastatic breast cancer.
Tox: Cardiotoxicity
Imatinib (Gleevac)
Mech: Philadelphia chromosome bcr-abl tyrosine kinase inhibitor. t9:22 translocation
Use: CML, GI stromal tumors
Tox: Fluid retention
Rituximab
Mech: Monoclonal Ab against CD20, which is found on most B cell neoplasms
Use: Non-Hodgkin's lymphoma, rheumatoid arthritis (w/ methotrexate)