PHARMACOLOGY

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PHARMACOLOGY

• Cancer drugs

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OBJECTIVES

• Identify the classes of drugs used to treat
  cancer.
• Identify the uses and varying actions of these
  drugs.
• Identify how these drugs are absorbed,
  distributed, metabolized, and excreted.
• Identify drug interactions and adverse reactions
  of these drugs.

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DRUGS AND CANCER

• The following are classifications of
  antineoplastic (chemotherapeutic) drugs
• Alkylating drugs
• Antimetabolite drugs
• Antibiotic antineoplastic drugs
• Hormonal antineoplastic drugs
• Natural antineoplastic drugs
• Unclassifiable antineoplastic drugs

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ALKYLATING DRUGS

• Effective against various malignant neoplasms.
• Produce their effects by deactivating DNA.
• Six classes nitrogen mustards, alkyl sulfonates,
  nitrosoureas, triazenes, ethylenimines, and
  alkylating-like drugs.

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NITROGEN MUSTARDS

• Largest group of alkylating drugs that include
  chlorambucil, cyclophosphamide, estramustine,
  ifosfamide, mechlorethamine hydrochloride (the
  first introduced and the most rapid-acting),
  melphalan, and uracil mustard.

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NITROGEN MUSTARDS

• Pharmacokinetics
• Vary widely metabolized in the liver excreted
  by the kidneys mechlorethamine is metabolized
  almost immediately.
• Pharmacodynamics
• Form covalent bonds with DNA molecules in a
  chemical reaction called alkylation resulting in
  cell death.

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NITROGEN MUSTARDS

• Pharmacotherapeutics
• Because they produce leukopenia, they are
  effective against malignant neoplasms such as
  Hodgkins disease, leukemia, malignant lymphoma,
  multiple myeloma, melanoma, and cancers of the
  breast, ovaries, uterus, lung, brain, testes,
  bladder, prostate, and stomach.

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NITROGEN MUSTARDS

• Drug interactions
• Interact with a wide variety of other drugs.
• Adverse reactions
• Fatigue

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ALKYL SULFONATES

• Busulfan is commonly used to treat chronic
  myelogenous leukemia and less commonly to treat
  polycythemia vera.
• Pharmacokinetics
• Absorbed rapidly and well from the GI tract
  little known about distribution metabolized
  extensively in the liver excreted in the urine.

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ALKYL SULFONATES

• Pharmacodynamics
• Forms covalent bonds with DNA molecules in
  alkylation.
• Pharmacotherapeutics
• Primarily affects granulocytes and platelets
  resulting in being the drug of choice for chronic
  myelogenous leukemia.

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ALKYL SULFONATES

• Drug interactions
• Increased risk of bleeding when taken with
  anticoagulants or aspirin.
• Adverse reactions
• Bone marrow suppression

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NITROSOUREAS

• Include carmustine, lomustine, and streptozocin.
• Pharmacokinetics
• When administered topically to treat mycosis
  fungoides, is 5-28 systemically absorbed when
  administered orally, is absorbed adequately but
  incompletely streptozocin is administered IV and
  is not absorbed.

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NITROSOUREAS

• Distribute to fatty tissues and CSF metabolized
  extensively in the liver excreted in the urine.
• Pharmacodynamics
• Interfere with amino acids, purines, and DNA
  halting their reproduction.

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NITROSOUREAS

• Pharmacotherapeutics
• Easily cross the blood-brain barrier, therefore
  are used to treat brain tumors and meningeal
  leukemias.
• Drug interactions
• Each has its own interactions.
• Adverse reactions
• Severe nausea and vomiting.

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TRIAZENES

• Dacarbazine functions as an alkylating drug after
  it has been activated by the liver.
• Pharmacokinetics
• After IV Injection is distributed throughout the
  body metabolized in the liver excreted by the
  kidneys (half is excreted unchanged and half is
  excreted as one of the metabolites).

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TRIAZENES

• Pharmacodynamics
• First must be metabolized by the liver and then
  seems to inhibit RNA and protein synthesis.
• Pharmacotherapeutics
• Used primarily to treat patients with malignant
  melanoma and Hodgkins disease.

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TRIAZENES

• Drug interactions
• No significant interactions.
• Adverse reactions
• Leukopenia

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ETHYLENIMINES

• Thiotepa is a multifunctional alkylating drug.
• Pharmacokinetics
• After IV administration, is 100 bioavailable
  crosses the blood-brain barrier and is
  metabolized extensively by the liver excreted in
  the urine.

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ETHYLENIMINES

• Pharmacodynamics
• Interferes with DNA replication and RNA
  transcription.
• Pharmacotherapeutics
• Primarily used to treat bladder cancer and may
  also be useful in other cancers.

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ETHYLENIMINES

• Drug interactions
• Use with anticoagulants and aspirin may increase
  the risk of bleeding.
• Adverse reactions
• Blood-related including leukopenia,
  thrombocytopenia, and pancytopenia.

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ALKYLATING-LIKE DRUGS

• Carboplatin and cisplatin are heavy metal
  complexes that contain platinum and resemble
  bifunctional alkylating drugs.
• Pharmacokinetics
• Distribution and metabolism of carboplatin arent
  clear eliminated by the kidneys
• When cisplatin is administered interpleurally or
  intraperitoneally, may be systemically absorbed.

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ALKYLATING-LIKE DRUGS

• Pharmacodynamics
• Cell non-specific and inhibit DNA synthesis by
  cross-linking strands of DNA and inhibiting DNA
  synthesis.
• Pharmacotherapeutics
• Carboplatin is used to treat ovarian and lung
  cancer.
• Cisplatin is used to treat bladder, ovarian, and
  metastatic testicular cancers.

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ALKYLATING-LIKE DRUGS

• Drug interactions
• When administered with an aminoglycoside, the
  risk of toxicity to the kidney increases.
• Adverse reactions
• Bone marrow depression

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ANTIMETABOLITE DRUGS

• Resemble natural metabolites and become involved
  in their process of nucleic acid and protein
  synthesis.
• Are cell cycle-specific and primarily affect
  cells that actively synthesize DNA (S
  phase-specific).

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ANTIMETABOLITE DRUGS

• Classified according to the metabolite affected
• folic acid analogues
• pyrimidine analogues
• purine analogues

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FOLIC ACID ANALOGUES

• Methotrexate is the most commonly used.
• Pharmacokinetics
• Absorbed well and distributed throughout the
  body metabolized partially excreted primarily
  unchanged in the urine.
• Pharmacodynamics
• Reversibly inhibits the action of the enzyme
  dihydrofolate reductase blocking normal
  biochemical reactions.

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FOLIC ACID ANALOGUES

• Pharmacotherapeutics
• Useful in treating acute lymphoblastic leukemia,
  choriocarcinoma, osteogenic sarcoma, malignant
  lymphomas, and carcinomas of the head, neck,
  bladder, testis, and breast.
• Also prescribed for psoriasis and rheumatoid
  arthritis.

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FOLIC ACID ANALOGUES

• Drug interactions
• Interact with several drugs.
• Salicylates and NSAIDS increase toxicity.
• Concurrent use of alcohol increases the risk of
  liver toxicity.
• Adverse reactions
• Bone marrow suppression

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PYRIMIDINE ANALOGUES

• A diverse group of drugs that inhibit production
  of pyrimidine nucleotides necessary for DNA
  synthesis.
• Includes
• Cytarabine
• Floxuridine
• Flourouracil
• Gemcitabine

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PYRIMIDINE ANALOGUES

• Pharmacokinetics
• Because of poor oral absorption, are given by
  other routes for the most part are distributed
  well throughout the body including the CSF
  metabolized extensively in the liver excreted in
  the urine.

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PYRIMIDINE ANALOGUES

• Pharmacodynamics
• Kill cancer cells by interfering with the natural
  function of pyrimidine nucleotides.
• Pharmacotherapeutics
• Used to treat many tumors as well as acute
  leukemias, GI tract adenocarcinomas, carcinomas
  of the breast and ovaries, and malignant
  lymphomas.

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PYRIMIDINE ANALOGUES

• Drug interactions
• No significant interactions.
• Adverse reactions
• fatigue and lack of energy
• inflammation of the mouth, esophagus, and throat,
  bone marrow suppression, nausea, and anorexia.

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PURINE ANALOGUES

• Incorporated into DNA and RNA interfering with
  nucleic acid synthesis and replication.
• Include
• Fludarabine phosphate
• Cladribine
• Mercaptopurine
• Thioguanine

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PURINE ANALOGUES

• Pharmacokinetics
• Not clearly defined largely metabolized in the
  liver excreted in the urine.
• Pharmacodynamics
• First must undergo conversion to the nucleotide
  level to be active and the resulting nucleotides
  are then incorporated into DNA (similar to
  pyrimidine analogues).

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PURINE ANALOGUES

• Pharmacotherapeutics
• Used to treat acute and chronic leukemias and
  lymphomas.
• Drug interactions
• No significant interactions.
• Adverse reactions
• Bone marrow suppression, nausea, vomiting,
  anorexia, diarrhea, stomatitis.

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ANTIBIOTIC NEOPLASTICS

• Are antimicrobial products that produce
  tumoricidal effects by binding with DNA and
  inhibiting processes of normal and malignant
  cells.
• Include bleomycin sulfate, dactinomycin,
  daunorubicin, doxorubicin hydrochloride,
  idarubicin hydrochloride, mitomycin, mitoxantrone
  hydrochloride, pentostatin, and plicamycin.

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ANTIBIOTIC NEOPLASTICS

• Pharmacokinetics
• Because usually administered IV, no absorption
  occurs distribution, metabolism, and elimination
  vary.
• Pharmacodynamics
• Intercalate or insert themselves between adjacent
  base pairs of a DNA molecule physically
  separating them.

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ANTIBIOTIC NEOPLASTICS

• Pharmacotherapeutics
• Act against many cancers.
• Drug interactions
• Interact with many other drugs.
• Adverse reactions
• bone marrow suppression.

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HORMONAL ANTINEOPLASTIC DRUGS

• Prescribed to alter the growth of malignant
  neoplasms or to manage or treat their
  physiological effects.
• Effective against hormone-dependent tumors.
• Include antiestrogens, androgens, antiandrogens,
  progestins, and gonadotropin-releasing hormone
  analogues.

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ANTIESTROGENS

• Tamoxifen citrate is the drug of choice for
  advanced breast cancer involving
  estrogen-receptor-positive tumors in
  postmenopausal women.
• Also used as an adjunct treatment for breast CA
  and to reduce its incidence in high risk women.

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ANTIESTROGENS

• Pharmacokinetics
• After oral administration is absorbed well
  extensively metabolized in the liver excreted in
  the feces.
• Pharmacodynamics
• Binds to the estrogen receptors and inhibits
  estrogen-mediated tumor growth.

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ANTIESTROGENS

• Pharmacotherapeutics
• Used in the palliative treatment of metastatic
  breast cancer that is estrogen-receptor-positive.
• Drug interactions
• Few interactions reported.
• Adverse reactions
• Relatively nontoxic.

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ANTIESTROGENS

• Drug interactions
• Antacids may affect absorption when taken in
  enteric-coated form.
• Adverse reactions
• Hot flashes, fluid retention, N, V, D.

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ANDROGENS

• Are synthetic forms of testosterone
  (fluoxymesterone, testolactone, testosterone
  enanthate and testosterone propionate).
• Pharmacokinetics
• Oral agents are absorbed well parenteral agents
  are absorbed slowly distributed well
  metabolized extensively in the liver excreted in
  the urine.

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ANDROGENS

• Pharmacodynamics
• Inhibit estrogen synthesis or competitively bind
  at estrogen receptors preventing estrogen from
  affecting estrogen-sensitive tumors.
• Pharmacotherapeutics
• Used for the palliative treatment of advanced
  breast cancer.

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ANDROGENS

• Drug interactions
• May alter dose requirements of insulin, oral
  antidiabetic drugs, or oral anticoagulants.
• Adverse reactions
• Nausea and vomiting.

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ANTIANDROGENS

• Used as adjunct therapy with gonadotropin-releasin
  g hormone analogues in treating advanced prostate
  cancer.
• Includes
• Flutamide
• Nilutamide
• Bicalutamide

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ANTIANDROGENS

• Pharmacokinetics
• Absorbed rapidly and completely metabolized
  rapidly and extensively excreted primarily in
  the urine.
• Pharmacodynamics
• Inhibit androgen uptake or prevent androgen
  binding in cell nuclei in target tissues.

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ANTIANDROGENS

• Pharmacotherapeutics
• Used along with gonadotropin-releasing hormone
  analogue to treat metastatic prostate cancer.
• Drug interactions
• No significant interactions.
• Adverse reactions
• Hot flashes and impotence.

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PROGESTINS

• Hormones used to treat various forms of cancer
  including
• Hydroprogesterone caproate
• Medroxyprogesterone acetate
• Megastrol acetate

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PROGESTINS

• Pharmacokinetics
• Absorbed well orally and slowly parenterally
  distributed well throughout the body metabolized
  in the liver excreted as metabolites in the
  urine.
• Pharmacodynamics
• Possibly bind to a specific receptor to act on
  hormonally sensitive cells (cytostatic).

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PROGESTINS

• Pharmacotherapeutics
• Used for the palliative treatment of advanced
  endometrial, breast, and renal cancers.
• Megestrol is used most often.
• Drug interactions None with megastrol.
• Adverse reactions Mild fluid retention.

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GONADOTROPIN-RELEASING HORMONE ANALOGUES

• Used for the treatment of advanced prostate
  cancer.
• Include
• Goserelin acetate
• Leuprolide acetate

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GONADOTROPIN-RELEASING HORMONE ANALOGUES

• Pharmacokinetics
• Goserelin is absorbed slowly the first 8 days and
  then quickly thereafter leuprolide is absorbed
  well subcutaneously distribution, metabolism,
  and excretion not known.
• Pharmacodynamics
• Act on the pituitary gland increasing luteinizing
  hormone secretion stimulating testosterone
  production.

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GONADOTROPIN-RELEASING HORMONE ANALOGUES

• Eventually the reverse occurs inhibiting the
  testicular release of testosterone which, in
  turn, inhibits tumor growth.
• Pharmacotherapeutics
• Used for the palliative treatment of metastatic
  prostate cancer.
• Drug interactions None.
• Adverse reactions Hot flashes impotence.

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NATURAL ANTINEOPLASTIC DRUGS

• Include vinca alkaloids and podophyllotoxins.
• Vinca alkaloids are nitrogenous bases derived
  from the periwinkle plant and include
  vinblastine, vincristine, and vinorelbine.
• Are cell-cycle specific and are effective during
  the phase of mitosis and cell division.

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NATURAL ANTINEOPLASTIC DRUGS

• Used to treat many types of cancer.
• Podophyllotoxins are also cell cycle-specific and
  include etoposide and teniposide.
• Used to treat testicular cancer, small-cell lung
  cancer, and acute lymphoblastic leukemia.
• Most common adverse reaction is hair loss.

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UNCLASSIFIABLE ANTINEOPLASTIC DRUGS

• Include asparaginase, procarbazine, hydroxyurea,
  interferon, aldesleukin, altretamine, paclitaxel,
  and docetaxel.
• Asparaginase deprives cancer cells of asparagine
  causing cell death.
• Used to induce remission in acute lymphocytic
  leukemia.

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UNCLASSIFIABLE ANTINEOPLASTIC DRUGS

• Procarbazine is used to treat Hodgkins disease
  (MOPP regimen) and primary and metastatic brain
  tumors.
• Because it has MAO inhibiting properties,
  tyramine-rich foods should be avoided.
• Hydroxyurea is used to treat chronic myelogenous
  leukemia, head and neck cancers, and solid tumors.

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UNCLASSIFIABLE ANTINEOPLASTIC DRUGS

• Interferons inhibit viral replication, suppress
  cell proliferation, enhance macrophage activity,
  and increase cytotoxicity of lymphocytes for
  target cells.
• Used to treat hairy cell leukemia, AIDS-related
  Kaposis sarcoma, and condylomata acuminata.

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UNCLASSIFIABLE ANTINEOPLASTIC DRUGS

• Aldesleukin is a human recombinant interleukin-2
  derivative which is used to treat metastatic
  renal cell carcinoma.
• Altretamine is a synthetic cytotoxic
  antineoplastic drug that is used as palliative
  treatment of ovarian cancer.

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UNCLASSIFIABLE ANTINEOPLASTIC DRUGS

• Taxines are used to treat metastatic ovarian and
  breast carcinoma after chemotherapy has failed.