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First Aid 2012 pg 395-402 Drug vs. mechanism/clinical use/toxicity, when applicable

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)

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