RANG AND RANG & DALE'S Pharmacology Flashcards Flash Cards
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34.01 Methotrexate Anticancer drugs Diagram of the main targets for anticancer drug therapy Pyrimidine synthesis Purine synthesis Ribonucleotides Deoxyribonucleotides DNA RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Antimetabolite anticancer drug Actions Interferes with purine synthesis and the synthesis of thymidylate and thus with DNA synthesis. Methotrexate MOA Competitively inhibits dihydrofolate reductase (DHFR). Abs/Distrb/Elim Given orally, i.v., i.m., or intrathecally; taken up into cells by the folate transport system. Clinical use Acute lymphoblastic leukemia in children; choriocarcinoma; tumours of head, neck breast & lung. Adverse effects Myelosupression, GIT disturbances, mucositis and sometimes pneumonitis. Methotrexate DHFR DHFR FH4 Folic acid FH2 dTMP FH4 + 1-carbon unit Thymidylate synthetase dUMP FH2 = dihydrofolate FH4 = tetrahydrofolate dTMP = thymidylate dUMP = uridylate Special points High-dose regimens should be followed by ‘rescue’ with folinic acid – a form of tetrahydrofolate – to minimise toxic effects on the bone marrow and GIT mucosa. R&D 6e Ch 51, pp. 726-727; :D&H 2e p.105 34.02 Fluorouracil Anticancer drugs Diagram of the main targets for anticancer drug therapy Pyrimidine synthesis Purine synthesis Ribonucleotides Methotrexate inhibits purine synthesis and dTMP synthesis Deoxyribonucleotides DNA RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Fluorouracil Antimetabolite anticancer drug Actions Interferes with the synthesis of dTMP and thus with DNA synthesis. Methotrexate MOA Gives rise to a fraudulent nucleotide and Inhibits thymidylate synthetase. Abs/Distrb/Elim Given i.v. Clinical use Cancers of GIT (gastric, colorectal ), pancreas, breast; malignant skin conditions. DHFR DHFR FH4 Folic acid FH2 dTMP FH4 + 1-carbon unit Thymidylate synthetase dUMP FH2 = dihydrofolate Adverse effects Not common: myelosuppression, GIT disturbances, mucositis. Given long term: desquamation of feet & hands. FH4 = tetrahydrofolate dTMP = thymidylate dUMP = uridylate Fluorouracil Special points High-dose regimens should be followed by ‘rescue’ with folinic acid – a form of tetrahydrofolate – to minimise toxic effects on the bone marrow and GIT mucosa. R&D 6e Ch 51, pp. 726-727; :D&H 2e p.105 34.03 Mercaptopurine Anticancer drugs Diagram of the main targets for anticancer drug therapy Pyrimidine synthesis Purine synthesis Ribonucleotides Methotrexate inhibits purine synthesis and dTMP synthesis Fluorouracil inhibits dTMP synthesis Deoxyribonucleotides DNA RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Antimetabolite anticancer drug Mercaptopurine Actions & MOA Purine analogue that inhibits purine synthesis and gives rise to a fraudulent nucleotide. Abs/Distrb/Elim Given orally. Clinical use Acute leukemias and chronic myeloid leukemia. Adverse effects Myelosuppression, hepatotoxicity, immunosuppression. Rare: pancreatitis, GIT ulceration. Special points Note that azathioprine, an immunosuppressant agent, is metabolised to mercaptopurine. Similar drug Pentostatin, also a purine analogue, inhibits adenosine deaminase – important in generation of inosine, an early stage of ribonucleic acid synthesis. R&D 6e Ch 51, pp. 726-727; :D&H 2e p.104 34.04 Cytarabine Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Ribonucleotides Fluorouracil inhibits dTMP synthesis Deoxyribonucleotides DNA RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Antimetabolite anticancer drug Cytarabine Actions & MOA Pyrimidine analogue that is converted in the cell to the trisphosphate which inhibits DNA polymerase. Abs/Distrb/Elim Given i.v., subcut. or intrathecally. Clinical use Acute myeloblastic leukemia. Adverse effects Marked myelosuppression. GIT disturbances; cerebellar ataxia. Special points Careful haematological monitoring necessary. R&D 6e Ch 51, p. 726; :D&H 2e pp.104-105 34.05 Bleomycin Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Ribonucleotides Fluorouracil inhibits dTMP synthesis Deoxyribonucleotides Cytarabine inhibits DNA synthesis DNA RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Cytotoxic antibiotic anticancer drug Bleomycin Actions & MOA Causes DNA fragmentation. Abs/Distrb/Elim Given i.v. or i.m. Clinical use Squamous cell cancer, metastatic germ cell cancer. Non-Hodgkin’s lymphoma. Adverse effects Dose-related pulmonary fibrosis; skin toxicity (pigmentation, subcutaneous sclerotic plaques); mucositis; transient hypersensitivity reactions. Minimal myelosuppression. R&D 6e Ch 51, p. 728; :D&H 2e pp.104-105 34.06 Cisplatin Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Ribonucleotides Fluorouracil inhibits dTMP synthesis Deoxyribonucleotides Cytarabine inhibits DNA synthesis Bleomycin damages DNA DNA RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Cytotoxic anticancer drug Cisplatin Actions & MOA Forms a reactive complex that causes intrastrand cross-linking and denaturation of the DNA. Abs/Distrb/Elim Given by i.v. infusion. Can be given to outpatients. Clinical use Cancers of testes, ovaries, cervix, bladder, lung and head & neck. Adverse effects Nephrotoxicity, ototoxicity, severe nausea & vomiting, myelosuppression, peripheral neuropathy, hypomagnesaemia. Drug with Carboplatin: more myelosuppressive but other adverse effects less marked so better tolerated; similar action preferred for ovarian cancer. R&D 6e Ch 51, p. 725; :D&H 2e pp.104-105 34.07 Cyclophosphamide Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Ribonucleotides Fluorouracil inhibits dTMP synthesis Deoxyribonucleotides Bleomycin damages DNA Cytarabine inhibits DNA synthesis Cisplatin crosslinks DNA strands DNA RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Alkylating anticancer drug Cyclophosphamide Actions & MOA Cross-links DNA by forming covalent bonds with guanine residues on each strand, interfering with cell division and triggering apoptosis. Abs/Distrb/Elim Given orally or i.v. Metabolised in the liver to phosphoramide mustard (the active moiety) and acrolein. Clinical use Chronic lymphocytic leukemia, soft tissue sarcoma, osteogenic sarcoma, ovarian & breast cancers. Adverse effects Nausea & vomiting; myelosuppression; acrolein-mediated haemorrhagic cystitis; alopecia. Gametogenesis can be affected. Prolonged use can result in acute non-lymphocytic leukemia. R&D 6e Ch 51, p. 724; :D&H 2e pp.104-105 34.08 Doxorubicin Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Ribonucleotides Fluorouracil inhibits dTMP synthesis Deoxyribonucleotides Bleomycin damages DNA Cytarabine inhibits DNA synthesis Cisplatin crosslinks DNA strands DNA Cyclophosphamide intercalates & cross-links RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Cytotoxic anticancer drug Doxorubicin Actions & MOA Inhibits DNA and RNA synthesis through an effect on topoisomerase II. Abs/Distrb/Elim Given by infusion (extravasation can cause tissue damage); by bladder instillation for bladder cancers. Clinical use Acute leukemias; Hodgkin & non-Hodgkin lymphomas; tumours of breast, ovary, bladder, bronchi. Adverse effects Dose-related cardiac damage; nausea & vomiting; myelosuppression; hair loss. R&D 6e Ch 51, p. 727-728; :D&H 2e pp.104-105 34.09 Irinotecan Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Fluorouracil inhibits dTMP synthesis Ribonucleotides Bleomycin damages DNA Deoxyribonucleotides Cisplatin crosslinks DNA strands Cyclophosphamide intercalates & cross-links Cytarabine inhibits DNA synthesis DNA Doxorubicin intercalates & inhibits topoisomerase II RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Cytotoxic anticancer drug (plant derived) Irinotecan Actions & MOA Binds to and inhibits topoisomerase I, thus interfering with cell proliferation. Abs/Distrb/Elim Given by i.v. infusion Clinical use Metastatic tumours of colon and rectum (in combination with other agents). Adverse effects GIT disturbances, interstitial pulmonary disease. R&D 6e Ch 51, p. 729; D&H 2e pp.104-105 34.10 Dactinomycin Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Fluorouracil inhibits dTMP synthesis Ribonucleotides Bleomycin damages DNA Cisplatin crosslinks DNA strands Deoxyribonucleotides Cyclophosphamide intercalates & cross-links Cytarabine inhibits DNA synthesis Doxorubicin intercalates & inhibits topoisomerase II DNA Irinotecan inhibits topoisomerase I RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Anticancer antibiotic Dactinomycin Actions & MOA Intercalates in the DNA and inhibits RNA polymerase and topoisomerase II. Abs/Distrb/Elim Given by i.v. injection. Clinical use Paediatric cancers. Adverse effects Nausea & vomiting; myelosuppression; hair loss. R&D 6e Ch 51, p. 728; D&H 2e pp.104-105 34.11 Vincristine Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Fluorouracil inhibits dTMP synthesis Ribonucleotides Bleomycin damages DNA Cisplatin crosslinks DNA strands Deoxyribonucleotides Cyclophosphamide intercalates & cross-links Cytarabine inhibits DNA synthesis Doxorubicin intercalates & inhibits topoisomerase II DNA Dactinomycin inhibits topoisomerase II and RNA polymerase Irinotecan inhibits topoisomerase I RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Anticancer vinca alkaloid Vincristine Actions & MOA Binds to tubulin, preventing spindle formation in dividing cells stopping them in mitosis. Abs/Distrb/Elim Given by i.v. injection. Clinical use Leukemias, lymphomas, breast and lung cancers. Adverse effects Nausea & vomiting; hair loss; neurotoxicity (peripheral & autonomic); negligible myelosuppression. R&D 6e Ch 51, p. 728-729; D&H 2e pp.104-105 34.12 Paclitaxel Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Fluorouracil inhibits dTMP synthesis Ribonucleotides Bleomycin damages DNA Cisplatin crosslinks DNA strands Deoxyribonucleotides Cyclophosphamide intercalates & cross-links Cytarabine inhibits DNA synthesis Doxorubicin intercalates & inhibits topoisomerase II DNA Dactinomycin inhibits topoisomerase II and RNA polymerase Irinotecan inhibits topoisomerase I RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Vincristine inhibits microtubule function Anticancer yew tree derivative Paclitaxel Actions & MOA Binds to tubulin, keeping microtubules polymerised (‘frozen’), preventing spindle formation in dividing cells and stopping them in mitosis. Abs/Distrb/Elim Given by i.v. infusion. Clinical use Cancers of ovary and breast, non-small-cell lung cancer. Adverse effects Hypersensitivity reactions, myelosuppression, peripheral neuropathy, bradycardia, muscle & joint pain, hair loss. GIT disturbance: moderate. R&D 6e Ch 51, p. 728-729; D&H 2e pp.104-105 34.13 Imatinib Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Fluorouracil inhibits dTMP synthesis Ribonucleotides Bleomycin damages DNA Cisplatin crosslinks DNA strands Deoxyribonucleotides Cyclophosphamide intercalates & cross-links Cytarabine inhibits DNA synthesis Doxorubicin intercalates & inhibits topoisomerase II DNA Dactinomycin inhibits topoisomerase II and RNA polymerase Irinotecan inhibits topoisomerase I RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Vincristine, paclitaxel inhibit microtubule function Anticancer protein kinase inhibitor Imatinib Actions & MOA Inhibits protein kinases important in chronic myeloid leukemia and other malignancies. Abs/Distrb/Elim Given orally, well absorbed. Clinical use Chronic myeloid leukemia, acute lymphoblastic leukemia, GIT stromal tumours, chronic eosinophilic leukemia, myeloproliferative diseases. Adverse effects GIT disturbances, abdominal pain, oedema, haemorrhage, cough, dyspnoea, paraesthesia, arthralgia, conjunctivitis, photosensitivity, headache, dizziness, sweating, rash. R&D 6e Ch 51, p. 730-731; D&H 2e pp.104-105 34.14 Trastuzumab Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Fluorouracil inhibits dTMP synthesis Ribonucleotides Bleomycin damages DNA Cisplatin crosslinks DNA strands Deoxyribonucleotides Cyclophosphamide intercalates & cross-links Cytarabine inhibits DNA synthesis Doxorubicin intercalates & inhibits topoisomerase II DNA Dactinomycin inhibits topoisomerase II and RNA polymerase Irinotecan inhibits topoisomerase I RNA (transfer, messenger, ribosomal) Proteins Imatinib protein kinase inhibitor Enzymes Receptors Microtubules Vincristine, paclitaxel inhibit microtubule function Monoclonal antibody anticancer agent Trastuzumab Actions & MOA Binds to and inhibits the epidermal growth factor receptor (a tyrosine kinase receptor), preventing its activation and inhibiting cell proliferation. Abs/Distrb/Elim Given by i.v. infusion. Clinical use Breast cancers. Adverse effects GIT disturbances, abdominal pain, hypersensitivity reactions, cardiac toxicity, paraesthesia, headache, dizziness, anxiety, depression, oedema, arthralgia, bruising, bone pain, leg cramps, rash, alopecia. R&D 6e Ch 51, p. 730-731; D&H 2e pp.104-105 34.15 Tamoxifen Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Fluorouracil inhibits dTMP synthesis Ribonucleotides Bleomycin damages DNA Cisplatin crosslinks DNA strands Deoxyribonucleotides Cyclophosphamide intercalates & cross-links Cytarabine inhibits DNA synthesis Doxorubicin intercalates & inhibits topoisomerase II DNA Dactinomycin inhibits topoisomerase II and RNA polymerase Irinotecan inhibits topoisomerase I RNA (transfer, messenger, ribosomal) Proteins Imatinib protein kinase inhibitor Enzymes Receptors Microtubules Trastuzumab antibody v EGRF 2 (epidermal growth factor receptor 2) Vincristine, paclitaxel inhibit microtubule function Oestrogen receptor agonist Tamoxifen Actions & MOA Competes with endogenous oestrogen for the oestrogen receptor, preventing cell activation and proliferation. Abs/Distrb/Elim Given orally. Clinical use Breast cancer. Adverse effects Hot flushes, GIT disturbances, headache, menstrual irregularities. R&D 6e Ch 51, p. 729-730; D&H 2e pp.104-105 34.16 Crisantaspase Anticancer drugs Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Fluorouracil inhibits dTMP synthesis Ribonucleotides Bleomycin damages DNA Cisplatin crosslinks DNA strands Deoxyribonucleotides Cyclophosphamide intercalates & cross-links Cytarabine inhibits DNA synthesis Doxorubicin intercalates & inhibits topoisomerase II DNA Dactinomycin inhibits topoisomerase II and RNA polymerase Irinotecan inhibits topoisomerase I RNA (transfer, messenger, ribosomal) Proteins Imatinib protein kinase inhibitor Enzymes Receptors Microtubules Trastuzumab antibody v EGRF 2 (epidermal growth factor receptor 2) Tamoxifen, an antioestrogen Vincristine, paclitaxel inhibit microtubule function A preparation of the enzyme asparaginase used as an anticancer agent Crisantaspase Actions & MOA Breaks down asparagine and is active in tumours (e.g. acute lymphoblastic leukemia) that have lost the ability to synthesise asparagine and require an external source. Abs/Distrb/Elim Given i.v., i.m. or subcut. Clinical use Acute lymphoblastic leukemia. Adverse effects Nausea & vomiting, CNS depression, liver disorder, anaphylactic reactions, risk of hyperglycaemia. R&D 6e Ch 51, p. 730; D&H 2e pp.104-105 34.17 Anticancer drugs What are the main adverse effects of anticancer drugs? Diagram of the main targets for anticancer drug therapy Pentostatin, mercaptopurine inhibit purine & ribonucleotide synthesis Methotrexate inhibits purine synthesis and dTMP synthesis Pyrimidine synthesis Purine synthesis Fluorouracil inhibits dTMP synthesis Ribonucleotides Bleomycin damages DNA Cisplatin crosslinks DNA strands Deoxyribonucleotides Cyclophosphamide intercalates & cross-links Cytarabine inhibits DNA synthesis Crisantaspase deaminates asparagine, inhibits protein synthesis Imatinib protein kinase inhibitor Doxorubicin intercalates & inhibits topoisomerase II DNA Dactinomycin inhibits topoisomerase II and RNA polymerase Irinotecan inhibits topoisomerase I RNA (transfer, messenger, ribosomal) Proteins Enzymes Receptors Microtubules Trastuzumab antibody v EGRF 2 (epidermal growth factor receptor 2) Tamoxifen, an antioestrogen Vincristine, paclitaxel inhibit microtubule function The main adverse effects of anticancer drugs Most anticancer drugs are cytotoxic (they damage or kill cells) and they are antiproliferative (they stop cells from dividing – both cancer cells and rapidly dividing normal cells). Thus they can: • depress the bone marrow • impair healing • interfere with normal growth (in children) • cause sterility • result in hair loss • be teratogenic Most also cause nausea and vomiting. Different cytotoxic drugs manifest the above adverse effects to different degrees. Examples are the drugs that affect DNA & RNA synthesis and actions (see figure on the face of this card) Newer, non-proliferative agents target the underlying pathogenic mechanisms such as changes in: • the relevant growth factors and/or their receptors • cell cycle control mechanisms • apoptotic pathways • telomerase expression • tumour-related angiogenesis These agents are less likely to have the above cytotoxic actions but have their own adverse effects. Examples are the drugs that don’t affect DNA & RNA synthesis (see the face of this card) R&D 6e Ch 51, pp. 718-722; D&H 2e pp.104-105
