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    This document summarizes key information about several alkylating agents, platinum-based compounds, and antimetabolites used as chemotherapeutics including their mechanisms of action, administration and metabolism, common uses, and adverse effects. Cyclophosphamide and ifosfamide are alkylating agents that cross-link DNA, especially with guanine, and require metabolic activation. Cisplatin and carboplatin are platinum-based compounds that covalently bind DNA bases, with cisplatin highly protein-bound and eliminated renally. Methotrexate is an antimetabolite that inhibits dihydrofolate reductase and depletes folates, impacting DNA/RNA synthesis, while 5

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    most of the chemotherapeutic drug are tried to cover in this PDF file

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    This document summarizes key information about several alkylating agents, platinum-based compounds, and antimetabolites used as chemotherapeutics including their mechanisms of action, administration and metabolism, common uses, and adverse effects. Cyclophosphamide and ifosfamide are alkylating agents that cross-link DNA, especially with guanine, and require metabolic activation. Cisplatin and carboplatin are platinum-based compounds that covalently bind DNA bases, with cisplatin highly protein-bound and eliminated renally. Methotrexate is an antimetabolite that inhibits dihydrofolate reductase and depletes folates, impacting DNA/RNA synthesis, while 5

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    Attribution Non-Commercial (BY-NC)
    Download as PDF, TXT or read online from Scribd
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    280 views6 pages

    Pharm Chemo Drugs Sauld

    Uploaded by

    neal
    This document summarizes key information about several alkylating agents, platinum-based compounds, and antimetabolites used as chemotherapeutics including their mechanisms of action, administration and metabolism, common uses, and adverse effects. Cyclophosphamide and ifosfamide are alkylating agents that cross-link DNA, especially with guanine, and require metabolic activation. Cisplatin and carboplatin are platinum-based compounds that covalently bind DNA bases, with cisplatin highly protein-bound and eliminated renally. Methotrexate is an antimetabolite that inhibits dihydrofolate reductase and depletes folates, impacting DNA/RNA synthesis, while 5

    Copyright:

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    of 6

    DRUG MECHANISM ADME USES A/E MISC

    ALKYLATING not cell-cycle phase


    AGENTS specific
    Cyclophosphamide - cross-linking of DNA via. - oral broad general activity - MYELOSUPPRESSION - resistance via.
    (Cytoxan) covalent bond of alkyl group to - pro-drug, must 1st be solid tumors - mucosal damage to GI tract glutathione conjugation,
    DNA template (esp. rxn w/ 7- metabolized by CYP450 into - HEMORRHAGIC enhanced DNA repair
    nitrogen of guanine) reactive cytotoxic metabolites CYSTITIS (via. acrolein mechanisms or increased
    i.e. acrolein metabolite) – keep pts well metabolism to inactive
    hydrated, administer Mesna metabolites
    - cardiotoxicity – monitor pts - acquired resistance does
    w/ ECGs not imply cross resistance
    - SIADH - ↓serum Na+ and
    CNS toxicity, can get seizures
    Ifosfamide - cross-linking of DNA (esp. rxn - oral testis, sarcomas - MYELOSUPPRESSION
    w/ 7-nitrogen of guanine) - activated by hydroxylation in solid tumors - mucosal damage to GI tract
    liver (slower than - hemorrhagic cystitis (via.
    cyclophosphamide) to chloracetaldehyde metabolite)
    dechlorinated metabolite and – keep pts well hydrated,
    chloracetaldehyde (toxic administer Mesna
    metabolite) - CNS toxicity w/ intrathecal
    administration, encephalopathy
    PLATINUM BASED
    CMPDS
    Cisplatin - covalently binds DNA bases - nonenyzmatic inactivation lung, testis, ovarian, - NEPHROTOXICITYw/ Mg - resistance via. enhanced
    and disrupts DNA function via. intracellularly and in the bladder wasting, hypokalemia – DNA repair
    crosslinking w/ platination bloodstream by sulfhydryl monitor electrolytes and
    groups maintain high urine flow
    - highly covalently bound to - N/V – prophylactic anti-
    proteins emetics
    - >90% renal elimination of - PERIPHERAL
    bound drug (adjust dose w/ NEUROPATHY, “stocking
    renal insufficiency) and glove” parasthesia, usually
    reversible
    - OTOTOXICITY, permanent
    - mild myelosuppression
    - rare hypersensitivity rxn
    Carboplatin - covalently binds DNA bases ovarian, lung, bladder - MYELOSUPPRESSION - not cross resistant with
    and disrupts DNA function via. (esp. WBCs) cisplatin
    crosslinking - less N/V
    - less nephrotoxicity,
    neurotoxicity, ototoxicity
    ANTIMETABOLITES
    Methotrexate (MTX) Folic Acid Analog - oral, intrathecal, IV, IM bladder, lymphoma, brain - myelosuppression - rescue BM and mucositis
    - inhibits dihydrofolate reductase - requires active transport into tumors, osteosarcoma, - mucositis, GI epithelial w/ Leucovorin
    (DHFR) Æ depletes reduced cell childhood ALL denudation - do not administer to pts
    folates - metabolized to - nephrotoxicity (prevent w/ w/ poor renal fcn; monitor
    - inhibits DNA and RNA polyglutamates in normal and hydration) creatinine clearance
    synthesis malignant tissues - pneumonitis - resistance via. increased
    - mainly active during S-phase – - doesn’t cross BBB (can - neurotoxicity (if intrathecal DHFR prodxn or
    give as 4 or 24 hour continuous administer intrathecally) or high doses) deccreased affinity for
    infusion - binds plasma prots but is - hepatotoxicity MTX or decreased cellular
    displace by aspirin and other - teratogenic uptake
    drugs
    - eliminated intact in urine; - inhibits cell-mediated
    urine alkalinization promotes immune rxns – used at low
    excretion (limited solubility in doses for rheumatoid
    acidic environment) arthritis, Crohn’s dz
    5-Fluorouracil (5-FU) Pyrimidine Analog of dUMP - IV (topical for skin Ca) - slow growing solid tumors - MYELOSUPPRESSION (if - cytotoxicity increased by
    - inhibits thymidylate synthetase - prodrug that must be bolus) Leucovorin in tx of colon
    Æ depletion of thymidine converted to nucleotide form breast, all GI (esp. colon), - MUCOSITIS (w/ continuous cancer; also increases
    - phase specific to G1 and S (F-dUMP) by liver bladder, breast, head & infusion) & hand-foot toxicity
    - inhibits DNA if given as - crosses BBB neck premalignant lesions syndrome of erythematous - resistance via. decrease
    continuous infusion - metabolized in liver (topical) desquamation in drug activation or use of
    - inhibits RNA if given as a bolus - excreted in lungs and urine - cardiac toxicity alternate pathways
    - hepatic toxicity
    - diarrhea, stomatitis
    Cytarabine Pyrimidine Analog of - IV or intrathecal acute leukemias - MYELOSUPPRESSION - resistance via. decrease
    dCTP/dCDP - must be phosphorylated to tri- - alopecia in drug activation, increase
    - inhibits nucleoside diphosphate P active form in the tumor - N/V in drug inactivation, use of
    reductase, DNA polymerase - rapidly inactivated by hepatic - neurotoxic (high doses) alternate pathways
    - S phase specific cytidine deaminase in the
    plasma therefore administered
    as a continuous IV infusion
    Gemcitibine Pyrimidine Analog - musb be phosphorylated to bladder, pancreas, lung - mild myelosuppression
    - inhibits ribonucleotide mono-P - mild flu-like sxs
    reductase Æ DNA strand - rashes
    termination
    - sensitizes cells to radiation
    therapy
    NATURAL
    PRODUCTS
    Vinblastine - binds tubulin and prevents - IV Hodgkin’s and non- - MYELOSUPPRESSION - no cross resistance b/w
    microtubule assembly Æ arrest in - metabolized in liver Hodgkin’s lymphoma, vinca alkaloids
    metaphase - excreted in bile breast - resistance via. MDR drug
    - w/ bleomycin for efflux pump
    testicular tumors
    Vincristine - binds tubulin and prevents - IV ALL, Hodgkin’s and non- - PERIPHERAL - minimal
    microtubule assembly Æ arrest in - metabolized in liver Hodgkin’s lymphoma NEUROPATHY myelosuppression
    metaphase - excreted in bile - SIADH - resistance via. MDR drug
    - longest half life of vincas Æ efflux pump
    lowest max tolerated dose
    - IV, never intrathecal b/c fatal
    Vinorelbine - binds tubulin and prevents - metabolized in liver - MYELOSUPPRESSION - newer and less toxic
    microtubule assembly Æ arrest in - excreted in bile - mild neuropathy
    metaphase
    Paclitaxol (Taxol) - binds tubulin and prevents - limited water solubility ovary, breast, bladder, - MYELOSUPPRESSION, - resistance via. mutations
    microtubule depolymerization Æ therefore formulated with prostate esp. neutropenia and in alpha or beta subunits of
    no mitosis ethanol thrombocytopenia tubulin
    - hepatic metabolism and - alopecia - anaphylactic rxn avoided
    biliary excretion - N/V by prophylaxis w/
    - sensory neuropathy antihistamine (i.e.
    - PERIPHERAL diphenhydramine/Benadryl
    NEUROPATHY + steroid/hydrocortisone
    - ANAPHYLAXIS
    - myalgias
    -cardiac toxicity
    Docitaxel (Taxotere) - binds tubulin and prevents - hepatic metabolism and breast, prostate - myelosuppression, esp. - resistance via. mutations
    microtubule depolymerization Æ biliary excretion neutropenia and in alpha or beta subunits of
    no mitosis thrombocytopenia tubulin
    - alopecia - anaphylactic rxn avoided
    - N/V by prophylaxis w/
    - sensory neuropathy antihistamine (i.e.
    - less neurotoxicity diphenhydramine/Benadryl
    - capillary leak syndrome Æ + steroid/hydrocortisone
    pleural effusion and periph
    edema
    Etoposide - inhibits topoisomerase II Æ - IV or parenteral lung, testis, lymphomas - MYELOSUPPRESSION - resistance via. MDR drug
    DNA strand breakage - N/V efflux pump
    - arrests cells in S and early G2 - alopecia
    - mucositis
    - 2ndary leukemias
    Irinotecan - targets topoisomerase I and -prodrug must be converted to colon - DELAYED ONSET
    causes double stranded DNA active metabolite DIARRHEA
    breaks - myelosuppression
    - N/V
    - alopecia, low fevers
    Doxorubicin Anthracycline antibiotic - IV broad general activity (no - CARDIAC TOXICITY – - reduce cardiac toxicity w/
    (Adriamycin) - inhibits RNA synthesis - elimination via. liver, bile, colon, lung) chronic congestive dexrazoxane or with an
    - binds dsDNA and intercalates aglycone formation and others cardiomyopathy via. iron chelator
    b/w GC pairs generation of free radicals in - can sensitize nml tissue
    - inhibits function of myocardial cells to radiation
    topoisomerase II Æ DNA - myelosuppression - increased risk of cardiac
    damage - MUCOSITIS (esp. if fx for pts w/ HTN,
    - free radical formation via. lipid continuous infustion) preexisting heart dz
    peroxidation - alopecia - resistance via. MDR drug
    - interacts w/ cell membrane - skin necrosis if extravasation efflux pump
    - urine discoloration
    Bleomycin Antibiotic - IV, IM, SQ -squamos cell carcinomas - PULMONARY FIBROSIS - v. minimal
    - nicks DNA and inhibits DNA - renal elimination of the head, neck, skin, - rare hypersensitivity rxn myelosuppresion
    ligase Æ DNA fragmentation esophagus and GU tract;
    - free radical formation Hodgkin’s and non-
    - most active during G2 and M Hodgkin’s lymphoma
    phases - w/ vinblastine or
    etoposide for testicular
    tumors
    Imatinib (Gleevec) tyrosine kinase inhibitor - oral CML - cyp450 inhibitor Æ drug
    - inhibits BCR-ABL of CML interactions
    Rituximab chimeric monoclonal Ab non-Hodgkin’s lymphoma - limited toxicity
    - binds CD20 antigen on B - pot’l for infusion related rxns
    lymphocytes Æ lysis of tumor - toxic epidermal necrolysis
    cells
    Trastuzumab Monoclonal Ab breast - pot’l for infustion related rxns
    (Herceptin) - binds HER2 receptor expressed - cardiotoxicity
    by some breast cancer celss
    BIOLOGICALS
    Tamoxifen - blocks estrogen-stimulated - oral breast - hot flashes - transient bone
    progesterone receptor synthesis, - hepatic metabolism - increased risk of endometrial pain/hypercalcemia
    52K protein synthesis, DNA carcinoma indicates that mets will
    polymerase activity, tritiated - venous thrombosis improve
    thymidine incorporation - intraretinal opacities (rare) - slows normal loss of
    - blocks cells in mid-G1 - thrombocytopenia (rare) bone density
    - binds estrogen receptor and - anovulation - lowers LDL
    promotes tight assn to nucleus - reduces incidence of 2nd
    - stimulates TGFbeta prodxn primary breast cancers
    Leuprolide GnRH antagonist prostate - hot flashes - prophylaxis for 1-2 wks
    - reduction of GnRH/LHRH - loss of libido w/ non-steroidal
    receptors in pituitary Æ fall in - impotence antiandrogen to block
    testosterone and DHT initial flair resonse w/ FSH
    and LH surges
    Flutamide non-steroidal antiandrogen prostate - hepatic toxicity – monitor pts
    - blocks cytoplasmic receptors for elevations in
    for dihydrotestosterone aminotransferase
    G-CSF - activates neutrophils, - produced by activated - prophylaxis for - recombinant form
    chemotactic for phagocytes monocytes, macrophages, chemotherapy associated available
    activated neutrophils, neutropenia
    fibroblasts and endothelial cells - treatment induced
    cytopenias
    Erythropoietin - hematopoietic growth factor anemia assoc w/ renal dz,
    stimulates RBC formation anemia assoc w/ chemo
    MISC
    Leucovorin folinic acid - usually administered 24-48 - MTX rescue of normal
    - bypasses inhibited enzyme hrs after MTX to prevent tissues
    DHFR by supplying reduced rescue of tumor cells - w/ 5-FU in tx of colon
    folates - competes with MTX for cell cancer
    - increases stability of FdUMP entry
    complex to increase activity of 5-
    FU
    Mesna sulfhydral groups bind acrolein - only combines with prevention of bladder
    (Cyclophosphamide metabolite) metabolites in renal tubules toxicity of alkylating agent
    or chloracetaldehyde (ifosfamide
    metabolite)
    Dexrazoxane - free radical scavenger - to prevent cardiac toxicity
    of doxorubicin

    NOT ON TEST
    Prednisone - synthetic anti-inflammatory - ALL, Hodgkin’s and non-
    corticosteroid w/ Hodgkin’s lymphoma
    lymphocytopenic action
    - binds intracellular steroid
    receptor and activates
    transcription of certain genes;
    exact mechanism unknown

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