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6-mercaptopurine (6-MP):
- Blocks de novo purine synthesis. Activated by HGPRTase.
- Leukemia, lymphoma (not CLL or HL)
- BM, GI, liver. Metabolized by xanthine oxidase, thus inc. toxicity with allopurinol
Cytarabine (ara-C):
- Inhibits DNA polymerase
- AML
- Leukopenia, thrombocytopenia, megaloblastic anemia
Cyclophosphamide, ifosfamide:
- Alkylating agents; covalently crosslink DNA at guanine N7
- NHL, breast and ovarian CA, immunosuppressants
- Myelosuppression, HEMORRHAGIC CYSTITIS which can be partially prevented wtih mesna
Nitrosoureas (carmustine, lomustine, semustine, streptozocin):
- Alkylate DNA. Require bioactivation. Cross B-B barrier --> CNS
- Brain tumors including glioblastoma multiforme
- CNS toxicity (dizzy, ataxia)
Cisplatin, carboplatin:
- Act like alkylating agents
- Testicular, bladder, ovary, lung CA
- NEPHROtoxicity, acoustic nerve damage
Busulfan:
- Alkylates DNA
- CML
- Pulmonary fibrosis, hyperpigmentation
Doxorubicin (Adriamycin), daunorubcin:
- Generate free radicals and noncovalently intercalate in DNA --> break strand --> no replication
- HL, myeloma, sarcoma, solid tumor (breast/ovary/lung)
- CARDIOtoxicity, myelosuppression, marked alopecia. Toxic extravasation.
Dactinomycin (actinomycin D):
- Intercalate with DNA
- Wilm's, Ewing's, rhabodmyosarcoma
- Myelosuppression
Bleomycin:
- Induce free radicals, break DNA strands
- Testicular, lymphoma (HL)
- Pulmonary fibrosis, skin changes, minimal myelosuppresion
Etoposide:
- G2 phase specific agent that inhibits topoisomerase II and inc. DNA degradation
- Small cell CA of lung and prostate, testicular CA
- Myelosuppression, GI irritation, alopecia
Prednisone:
- May trigger apoptosis. May work on nondividing cells.
- CLL, HL, immunosuppressant used in autoimmune diseases
- Cushing's syndrome, immunosuppression, cataracts, acne, osteoprosis, HTN, peptic ulcers, hyperglycemia, psychosis
Tamoxifen, raloxifene:
- SERMs that block binding of estrogen to ER+ cells
- Breast cancer, prevent osteoporosis
- Tamoxifen inc. risk of endometrial CA, hot flashes
Trastuzumab (Herceptin):
- Monoclonal Ab against HER-2 (erb-B2) kill breast cancer cells overexpressing HER-2
- Metastatic breast cancer
- Cardiotoxicity
Imatinib (Gleevec):
- Ab against Philadelphia chromosome BCR-ABL tyrosine kinase
- CML, GI stromal tumors
- Fluid retention
Vincristine, vinblastine:
- M phase specific alkaloids bind tubulin and block microtubule polymerization
- Lymphoma, Wilm's, choriocarcinoma
- Bone marrow suppression, neurotoxicity (areflexia, peripheral neuritis), paralytic ileus
Paclitaxel, other taxols:
- M phase specific agent hyperstabilize microtubules
- Ovarian and breast CA
- Myelosuppression and hypersensitivity
Heparin:
- activates Antithrombin III, dec. thrombin & Xa
- Immediate anticoagulation for PE, DVT, stroke, angina, MI (safe during pregnancy)
- Bleeding, thrombocytopenia, drug interactions
What do you give for acute overdose of Heparin?
Protamine sulfate
Enoxaparin:
Low MW heparin, acts more on Xa, better bioavailability, long half-life, given subQ without PTT monitoring
Warfarin (coumadin):
- Inhibits gamma carboxylation of VitK dependent clotting factors II, VII, IX, X, protein C & S (extrinsinc pathway)
- Chronic anticoagulation (TERATOGENIC!!)
- Bleeding, teratogen, drug interactions
What do you give for acute overdose of Warfarin?
VitK injection and fresh frozen plasma
Thrombolytics (streptokinase, urokinase, tPA, APSAC):
- Help conversion of plasminogen to plasmin
- Early MI, early ischemic stroke
- Bleeding! Contraindicated in active bleeding, Hx of intracranial bleed, recent surgery, known bleeding disorder, severe HTN
How do you Tx thrombolytic toxicity?
Aminocaproic acid
Aspirin (ASA):
- Acetylates & irreversibly inhibits COX1 & 2 to prevent conversion of arachidonic acid to PGs
- Antipyretic, analgesic, anti-inflammatory, anti-platelet
- GI ulcer, bleeding, hyperventilation, Reyes syndrome, tinnitus
Clopidogrel, ticlopidine:
- Irreversibly block ADP receptors to inhibit PL aggregation; prevent expression of GPIIb/IIIa to inhibit fibrinogen binding
- Acute coronary syndrome, coronary stent, dec. incidence or recurrence of thrombotic stroke
- Neutropenia (ticlopidine)
Abciximab:
- Antibody against GPIIb/IIIa on activated PL to prevent aggregation
- Acute coronary syndrome, percutaneous transluminal coronary angioplasty
- Bleeding, thrombocytopenia
Methotrexate (MTX):
- S phase specific antimetabolite, Inhibits enzyme dihydrofolate reductase to prevent thymidine synthesis
- Leukemia, lymphoma, choriocarcinoma, sarcoma, ectopic pregnancy, abortion, RA, psoriasis
- Myelosuppression (reverse wtih leucovorin), macrovesicular fatty liver
5-fluorouracil (5-FU):
- S phase specific antimetabolite, Inhibits enzyme thymidylate synthase to prevent thymidine synthesis
- Colon cancer, solid tumors, basal cell CA
- Myelosuppression (NOT reversible with leucovorin)