PHRM 203 Allison Beale Overview • Neoplasms – Introduction • Chemotherapy often – Causes associated with: – Types – Secondary malignancies – Seizures (~13% of patients) • Antineoplastic agents – Nausea & vomiting – Introduction – Examples A Beale PHRM 203 - Antineoplastic Agents 2 Neoplasms Introduction TERMS – Anaplasia • 2nd leading cause of • Loss of cellular death in US after CV organization • All cancers start with a – Autonomy cell or cells that is • Ignore growth regulations genetically different from the surrounding – Metastasis cells; all cell types can • Spread into other tissues become cancerous – Angiogenesis • Create their own blood supply A Beale PHRM 203 - Antineoplastic Agents 3 Neoplasms Causes • Genetic predisposition – Li-Fraumeni Syndrome – Familial Adenomatous Polyposis • Viral infection (e.g., herpes, HPV, EBV, HBV) • Nematode infection (e.g., Spirocerca lupi) • Constant irritation or inflammation • Stress • Chemicals (mutagens, carcinogens, e.g., Cisplatin) • Radiation (uv, ionizing) A Beale PHRM 203 - Antineoplastic Agents 4 Neoplasms • Solid Types – Carcinomas • Tumors of epithelium – Adenomas versus adenocarcinomas – Melanoma versus malignant melanoma (melanocarcinoma) – Sarcomas • Tumors of mesenchymal origin Osteoblasts in – Fibroma versus fibrosarcoma osteomas – Lymphoma versus lymphosarcoma produce LOTS of PG-E; pain – Osteoma versus osteosarcoma controlled with • Hematological malignancies ASPIRIN! – Leukemia (general term for cancer of white blood cells) A Beale PHRM 203 - Antineoplastic Agents 5 Carcinomas by WHO’s ICD-O* Code * International Classification of Diseases for Oncology • Epithelial NOS • Cystic, mucinous or • Squamous cell serous • Basal cell (skin) • Ductal, lobular or medullary • Transitional cell – Papillomas • Acinar (pancreas, breast, salivary glands) • Adenomas (glandular) • Complex epithelial • Adnexal (uterine) • Paragangliomas or • Mucoepidermoid glomus • Specialized gonadal • Nevi or melanoma A Beale PHRM 203 - Antineoplastic Agents 6 Carcinomas- many possibilities in one organ • Lung carcinomas Lung cancer is notorious for paraneoplastic syndrome – Adeno- • Glandular tissue origin, usually Goblet cells in the lung • Common, 30-40% of all lung carcinomas – Squamous cell Paraneoplastic syndromes: Effects caused by hormones • Usually hilar origin, 20-30% (e.g., ADH, ACTH) secreted – Small cell by tumors • Smoking related, may secrete ADH (patient becomes hyponatremic) – Syndrome of inappropriate ADH secretion (SIADH) – Large cell undifferentiated Paraneoplastic syndromes • Aggressive, difficult to recognize, 10-15% may take endocrine (SIADH, – Sinonasal undifferentiated Cushing’s), neurological, hematological or other forms A Beale PHRM 203 - Antineoplastic Agents 7 Sarcomas connective tissue tumors • Soft tissue • Bone – Muscle – Chondro- • Rhabdomyo- – Osteo- • Leiomyo- – Fat – Parosteal osteo- • Lipo- • Metaphysal – Nerves – Periosteal osteo- • Malignant peripheral • Anywhere else on surface nerve sheath tumor – Periosteal chondroma – Blood vessels • Cartilagenous tumor • Angio- – Small cell osteo- – Fibrous tissue • Fibro- – Ewing’s • Myxofibro- A Beale PHRM 203 - Antineoplastic Agents 8 All of these are diseases with too many of the affected cells Hematological • Acute lymphoid leukemia • Meningeal leukemia (ALL) • Hodgkin’s lymphoma – Lymphocytes – Reed-Sternberg cells • Acute myeloid leukemia (altered B-cells) (AML) • Non-Hodgkin’s – Granulocytes – T-cell types – Acute promyelocytic • Mycosis fungoides (skin) leukemia (APL) – B-cell types • Chronic forms of above: • Burkitt’s lymphoma – CLL – EBV = cause • Diffuse large B-cell – CML lymphoma – CPL • Myelomas A Beale PHRM 203 - Antineoplastic Agents 9 Antineoplastic drugs Overview Focus on Tumor Lysis • Mechanisms vary Syndrome – Alter cell survival • Break-down products from – Alter immune response dead cells • Classes – Hyperkalemia (cardiotoxic) – Hyperphosphatemia* – Alkylating agents – Hyperuricemia* – Antimetabolites – Hypocalcemia (tetany) – Natural products – Acute renal failure (ARF) – Hormones and • Allopurinol or Rasburicase ↓ hormone modulators hyperuricemia * These conditions may cause ARF – Miscellaneous agents A Beale PHRM 203 - Antineoplastic Agents 10 Effectiveness of cancer chemotherapy by disease 1. Curative • ALL, Hodgkin’s, diffuse histiocytic lymphoma, Burkitt’s lymphoma,Testicular cancer, choriocarcinoma (placental) 2. Probably curative • AML, small cell, breast, osteogenic sarcoma 3. Major therapeutic benefit • Head & neck, cervical, metastatic breast, ovarian, soft tissue sarcomas, nodular lymphomas, chronic leukemias, insulinomas 4. Limited effectiveness • Lung, GI, prostate, melanoma A Beale PHRM 203 - Antineoplastic Agents 11 Mechanisms of Resistance Adapted from pages 493-4, Brenner, Pharmacology 2nd ed. • Innate: ABC Transporters – P-glycoprotein efflux pumps • Anthracyclines, taxanes and vinca alkaloids – Multidrug resistance protein pumps • Organic Anion Transporter (OAT) subfamily • Glutathione conjugated drugs are pumped out • Anthracyclines, methotrexate and vinca alkaloids Innate means the tumor has resistance BEFORE therapy A Beale PHRM 203 - Antineoplastic Agents 12 Mechanisms of Resistance Adapted from pages 493-4, Brenner • Acquired Acquired resistance – Gene mutations are changes that are • Topoisomerase a RESULT of – Etoposide therapy • Dihydrofolate reductase – Methotrexate • Tubulin or microtubule proteins – Vinca alkaloids and taxanes – Altered gene expression • Dihydrofolate reductase over-expression – Methotrexate • Antiapoptotic protein induction A Beale PHRM 203 - Antineoplastic Agents 13 General Toxicity of Neoplastic Agents Adapted from page 494, Brenner • Inhibition of cell replication Irritant antineoplastics trigger 5-HT release from – Bone marrow, GI, Hair follicles enterochromaffin cells in the – Worst GIT leading to hypermotility of • Nitrosoureas (carmustine) the GIT (vomiting, diarrhea, nausea) – Intermediate • Methotrexate, fluorouracil, cyclophosphamide Some 5-HT is – Least absorbed into • Bleomycin, cisplastin, vincristine blood where platelets absorb it. • Chemoreceptor trigger zone in medulla Excess 5-HT – Nausea, vomiting triggers 5-HT3 receptors in CTZ. • Worst: cisplatin and carmustine A Beale PHRM 203 - Antineoplastic Agents 14 Hematopoietic Agents Colony stimulating factors WBC growth factors RBC growth factors Hormones that trigger stem Erythropoietin is a hormone cell differentiation into WBCs produced by endothelial cells in in bone marrow. Important to the liver and kidney replace neutrophils • Epoetin alfa (Procrit) ! (granulocytes & Macrophages, – rDNA erythropoietin too). • Darbepoetin alfa (Aranesp) ! • Pegfilgrastim (Neulasta) ! • Synthetic erythropoietin • Filgrastim (Neupogen) ! • Sargramostim (Leukine) ! SC, IV A Beale PHRM 203 - Antineoplastic Agents 15 Antiemetic Therapy Adapted from “Protocol for the use of antiemetics to prevent chemotherapy-induced nausea and vomiting” VHA Pharmacy Benefits Management Strategic Healthcare Group and Medical Advisory panel Antiemetic Class Receptor Site of Action Aprepitant ! Substance P antagonist GI Prochlorperazine ! Phenothiazine DA GI & CNS Haloperidol, droperidol! Butyrophenone DA GI & CNS Metoclopramide ! Benzamide DA, 5-HT GI & CNS Diphenhydramine ! Antihistamine Histamine CNS Scopolamine ! Anticholinergic ACh CNS Dronabinol ! C-III Cannabinoid CB1, CB2 CNS Ondansetron ! Serotonin antagonist 5-HT GI & CNS Dexamethasone ! Corticosteroid UNK GI A Beale PHRM 203 - Antineoplastic Agents 16 Antineoplastic drugs Alkylating Agents - nitrogen mustards Drug Indication Chlorambucil Lymphomas and leukemias including Hodgkin’s d; (Leukeran) ! under consideration to treat rheumatoid arthritis; Off label - amyloidosis, polycythemia vera, autoimmune hemolytic anemia, etc. PO In cocktails to treat lymphoma, myelomas, Cyclophosphamide leukemias etc. (Also used to treat autoimmune (Cytoxan) ! conditions: MS, rheumatoid arthritis, Lupus…). PO Table adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch, Lippincott, Williams & Wilkins, 2008 A Beale PHRM 203 - Antineoplastic Agents 17 Nitrogen Mustard ADRs Drug ADRs Seizures, nausea, vomiting, myelosuppression, liver Common to the failure, pulmonary fibrosis, Steven’s-Johnson, class Secondary malignancies (carcinogens, mutagens & teratogens) Chlorambucil Azoospermia Cardiotoxicity, hemorrhagic cystitis, SIADH, Cyclophosphamide alopecia, anaphylaxis A Beale PHRM 203 - Antineoplastic Agents 18 Antineoplastic drugs Alkylating Agents - nitrosoureas Drug Indication Note: therapeutic levels may be toxic! Brain tumors, Hodgkin’s d. and non-Hodgkin’s lymphoma, malignant melanoma, multiple myeloma. Available as an Carmustine implant for glioblastoma. (BCNU or BiCNU) ! IV infusion after reconstitution Carmustine ADRs include: Brain edema, kidney &/or liver failure, bone marrow suppression, pulmonary fibrosis, intense pain at injection site and secondary malignancies. It will stain skin BROWN. A Beale PHRM 203 - Antineoplastic Agents 19 Antineoplastic drugs Alkylating Agents • Mechanism of action of nitrogen mustards and nitrosoureas – Alkylate (cross-links) DNA (& RNA) which blocks the formation of the DNA-RNA complex in transcription A Beale PHRM 203 - Antineoplastic Agents 20 Antineoplastic drugs Alkylating Agents - Platinum Drug Indication Combo therapy for metastatic testicular or ovarian tumors, advanced bladder cancers, small cell carcinoma of lung, etc. Cisplatin (Platinol) ! IV infusion " ¨ Inadvertent overdose a problem Cisplatin ADRs include: Seizures,