What is the mechanism by which heparin anticoagulates?
It catalyzes the activation of antithrombin III and reduces levels of thrombin and factor Xa
How can you rapidly reverse the anticoagulation induced by heparin administration?
Give protamine sulfate, a positively charged molecule that binds negatively charged heparin
Compare enoxaparin and heparin.
Enoxaparin is more specific for factor Xa, has higher bioavailability, and 2-4 times longer half-life
What difference between heparin and enoxaparin should be considered when there is a concern of excessive anticoagulation?
Enoxaparin is not easily reversible, whereas heparin can be reversed by the administration of protamine sulfate; heparin also has a shorter half-life
What are the benefits of enoxaparin that allow it to be used in the outpatient setting, as opposed to heparin?
Enoxaparin can be administered subcutaneously, has a longer half-life, and does not need monitoring
Name four toxicities of heparin.
Bleeding, thrombocytopenia, osteoporosis, and drug-drug interactions
During pregnancy, is heparin or warfarin the preferred method of anticoagulation?
Heparin; unlike warfarin, which is a teratogen, heparin does not cross the placenta and thus can be used during pregnancy
What laboratory test can be used to determine if the heparin dose is in the therapeutic range?
The partial thromboplastin time, because heparin activates antithrombin III, which is involved in the intrinsic coagulation pathway
A 70-year-old woman is given prophylactic heparin while hospitalized for pneumonia. Five days later she develops deep vein thromboses and has a low platelet count. What disease is the likely cause of her sudden thrombocytopenic, hypercoagulable state?
Heparin-induced thrombocytopenia; this is an antibody-mediated process that destroys some platelets and overactivates those that remain
Name five clinical uses for heparin.
Immediate anticoagulation for pulmonary embolism, stroke, acute coronary syndrome, myocardial infarction, deep vein thrombosis
What is the mechanism of action of lepirudin or bivalirudin?
These are hirudin derivatives (an anticoagulant produced by leeches) that directly inhibit thrombin
A patient who was started on heparin therapy develops heparin-induced thrombocytopenia; what change should be made to his treatment regimen?
Discontinue the heparin and continue anticoagulation using lepirudin or bivalirudin (direct thrombin inhibitors)
What is the mechanism by which warfarin anticoagulates?
It interferes with normal synthesis and the gamma-carboxylation of the vitamin K-dependent clotting factors II, VII, IX, and X and proteins C and S
What laboratory test is used to determine if a patient taking warfarin is in the therapeutic range?
The prothrombin time will be increased because warfarin affects the EXtrinsic pathway (factor VII) (remember: the EX-PresidenT went to WAR(farin))
What is the therapy of choice for patients who require chronic anticoagulation: heparin or warfarin?
Warfarin; this is preferred to heparin because it can be administered orally
Name four toxicities of warfarin.
Bleeding, teratogenic effects (contraindicated in pregnancy), drug-drug interactions, and skin/tissue necrosis
How is warfarin metabolized?
By the cytochrome P450 pathway in the liver
What is the difference in administration between heparin and warfarin?
Heparin is administered parenterally (intravenously or subcutaneously) whereas warfarin is given orally
What is the difference in the onset of action between heparin and warfarin?
Heparin acts within seconds, whereas warfarin has a slow onset dependent on the half-lives of the normal clotting factors
Describe the treatment of acute warfarin overdose.
Intravenous vitamin K and fresh frozen plasma
Name four drugs that can be used to lyse an existing thrombus.
Thrombolytics include streptokinase, urokinase, tissue plasminogen activator (alteplase), and anisoylated plasminogen streptokinase activator complex (anistreplase)
Which terminal pathway in the coagulation cascade is enhanced by the administration of thrombolytics?
Degradation of fibrin and fibrinogen to fibrin-split-products and deactivation of thrombin
What treatment option can potentially reverse the pathology of an early myocardial infarction or ischemic stroke?
Prompt administration of thrombolytics
What major complication can be seen from the administration of thrombolytics?
Bleeding
Name five contraindications for thrombolytics that are related to increased risk of bleeding.
Patients with active bleeding, a history of intracranial bleeding, recent surgery, known bleeding disorders, or severe hypertension
What is the pharmacologic treatment for thrombolytic toxicity?
Aminocaproic acid, an inhibitor of fibrinolysis; this medication can also be given to hemophiliacs for dental procedures
What is the primary enzymatic reaction that thrombolytics affect?
They either directly or indirectly aid the conversion of plasminogen to plasmin, which initiates fibrinolysis
How do thrombolytics affect the prothrombin time, partial thromboplastin time, and platelet count?
There is an increase in both the prothrombin time and partial thromboplastin time due to deactivation of thrombin, and no effect on the platelet count
How does abciximab downregulate platelet aggregation?
Abciximab is a monoclonal antibody that binds to the glycoprotein receptor IIb/IIIa on activated platelets, thereby preventing aggregation
What is the mechanism of action of aspirin as an anticoagulant?
Aspirin acetylates and irreversibly inhibits cyclooxygenase-1 and cyclooxygenase-2 to prevent the conversion of arachidonic acid to thromboxane A2
What is the effect of aspirin on bleeding time, prothrombin time, and partial thromboplastin time?
Aspirin increases bleeding time but has no effect on prothrombin time or partial thromboplastin time (it only affects platelets)
Name five common toxicities of aspirin.
Gastric ulceration, bleeding, hyperventilation, Reye’s syndrome, and tinnitus (cranial nerve VIII)
Name four clinical effects of aspirin administration.
Antipyretic, analgesic, antiinflammatory, and antiplatelet
What is the mechanism of action of clopidogrel and ticlopidine?
They inhibit platelet aggregation by irreversibly blocking adenosine diphosphate receptors; without adenosine diphosphate activation there is no glycoprotein IIb/IIIa expressed to bind fibrinogen
Name a potentially life-threatening toxicity of the antiplatelet drug ticlopidine.
Neutropenia
What are three common clinical uses of clopidogrel and ticlopidine?
Acute coronary syndrome, during coronary stenting, and reducing the incidence or recurrence of thrombotic stroke
Name a monoclonal antibody that binds the glycoprotein IIb/IIIa receptor on activated platelets and that prevents aggregation.
Abciximab
What are clinical uses of abciximab?
Coronary artery disease: acute coronary syndromes or during percutaneous transluminal coronary angioplasty
Name the two most common toxicities of abciximab.
Bleeding and thrombocytopenia
What occurs during stage G1 of the cell cycle?
The synthesis of components that are needed for DNA synthesis
What occurs during stage S of the cell cycle?
DNA synthesis
What occurs during stage G2 of the cell cycle?
The synthesis of components that are needed for mitosis
What occurs during stage M of the cell cycle?
Mitosis
During which stage of the cell cycle do vinca alkaloids and taxols work?
M
During which stage of the cell cycle do antimetabolite drugs work?
S
During which stages of the cell cycle does etoposide work?
S and G2
During which stage of the cell cycle does bleomycin work?
G2
Name three antineoplastic drugs that function by interfering with nucleotide synthesis.
Methotrexate, fluorouracil, and 6-mercaptopurine
What reaction is inhibited by the administration of either methotrexate or fluorouracil?
The synthesis of thymidine, a pyrimidine
What reaction is inhibited by the administration of 6-mercaptopurine?
The synthesis of purines
Name five antineoplastic drugs that function by damaging DNA.
Alkylating agents, cisplatin, dactinomycin, doxorubicin, etoposide
How do alkylating agents and cisplatin exert an antineoplastic effect?
These agents introduce cross-links in the DNA structure
Which antineoplastic drugs interfere with DNA by intercalating into the double helix?
Doxorubicin, dactinomycin
How does etoposide exert its antineoplastic effect?
Etoposide inhibits topoisomerase II, which is needed to relieve DNA supercoils
Name two antineoplastic drugs that function by interfering with cellular division.
Vinca alkaloids, paclitaxel
How do vinca alkaloids exert their antineoplastic effect?
They inhibit microtubule formation, which results in an inability of the cell to perform mitosis
How does paclitaxel exert its antineoplastic effect?
Paclitaxel inhibits microtubule disassembly, which interrupts the dynamic process required for cell division
What drug, used as an antineoplastic agent, is a folic acid analog that works by inhibiting dihydrofolate reductase?
Methotrexate; inhibiting dihydrofolate reductase results in less deoxythymidine monophosphate, which is needed for DNA and protein synthesis
Name four cancers that methotrexate can be used to treat.
Leukemias, lymphomas, choriocarcinomas, and sarcomas (all have many dividing tumor cells)
Name three nonneoplastic conditions in which methotrexate can be used.
Abortion in ectopic pregnancy (blocks cell proliferation), rheumatoid arthritis, and psoriasis (decreased immune proliferation and response)
What agent can be administered to reverse the bone marrow suppression seen with methotrexate use?
Leucovorin (folinic acid) can be used to rescue the bone marrow by competing with methotrexate for binding sites; however, it does not reverse the effects of fluorouracil
Other than myelosuppression, what are three toxicities of treatment with methotrexate?
Patients can develop a painful mucositis and microvesicular fatty changes in the liver, and it is a teratogen (remember: used for abortion in ectopic pregnancy)
How does fluorouracil, a pyrimidine, interact with folic acid?
Fluorouracil is converted to 5F-dUMP, which covalently binds folic acid rendering it ineffective (noncompetitive inhibition)
What enzyme is inhibited by the 5F-dUMP/folic acid complex?
This complex inhibits thymidylate synthase, which is needed to form deoxythymidine monophosphate for DNA and protein synthesis
Often given in conjunction with methotrexate, fluorouracil is administered in the treatment of which tumors?
Colon cancer and solid tumors (it is a part of the FOLFOX regimen); it is applied topically for basal cell carcinoma
A patient is given an excessive dose of fluorouracil; what can be administered to the patient to reduce toxicity?
Thymidine (remember: folinic acid will not reverse fluorouracil)
What precaution should patients on fluorouracil take, especially in the summer?
Sun protection; fluorouracil can cause photosensitivity
What is the mechanism by which 6-mercaptopurine and 6-thioguanine exert an antineoplastic effect?
These are purine analogs, which inhibit de novo purine synthesis; they are activated by hypoxanthine-guanine phosphoribosyltransferase
6-mercaptopurine is used in the treatment of what types of cancers?
Leukemias and lymphomas (although not used in chronic lymphocytic leukemia or Hodgkin’s lymphoma)
Which disease is treated using 6-thioguanine?
Acute lymphoblastic leukemia
You are treating a patient with leukemia and are considering using either 6-mercaptopurine or 6-thioguanine. Which should be used if you are also going to treat with allopurinol to prevent tumor lysis syndrome?
6-thioguanine; 6-mercaptopurine is metabolized by xanthine oxidase, the enzyme blocked by allopurinol and may thus reach toxic levels if given together
What adverse effects are seen in patients treated using 6-mercaptopurine or 6-thioguanine?
Bone marrow suppression and liver disease; patients on 6-mercaptopurine also often have gastrointestinal complaints
How does cytarabine exert its antineoplastic effect?
It is a pyrimidine antagonist, which inhibits DNA polymerase (needed in S phase)
What neoplasms are commonly treated using cytarabine?
Cytarabine is used to treat leukemias and lymphomas (acute myelogenous leukemia, acute lymphoblastic leukemia, and high-grade non-Hodgkin’s lymphoma)
What are three adverse effects seen in the use of cytarabine?
Leukopenia, thrombocytopenia, and megaloblastic anemia
Name three antineoplastic drugs that function by intercalating into DNA strands.
Dactinomycin (actinomycin D), daunorubicin, and doxorubicin work by intercalating in DNA strands, causing structural and functional distortions
What are three neoplasms in which dactinomycin is commonly used?
Ewing sarcoma, Wilms’ tumor, and rhabdomyosarcoma (think of childhood tumors: ACTinomycin D because children ACT out)
Which of the antitumor antibiotics has the least myelosuppression as an adverse effect?
Bleomycin; myelosuppression is a common adverse effect of all other antitumor antibiotics
What common mechanism is seen in the antineoplastic drugs bleomycin, daunorubicin, and doxorubicin?
These drugs generate free radicals, which can cause DNA strand breaks and halt cell replication
Which malignancies are commonly treated with doxorubicin or daunorubicin?
Hodgkin’s lymphoma (the A in the ABVD regimen), myeloma, sarcoma, and solid tumors like breast, lung, or ovarian cancer
A patient presents late in the course of chemotherapy treatments with new symptoms of heart failure; what antineoplastic drug was likely a part of his regimen?
Doxorubicin and daunorubicin are notorious for dose-dependent cardiotoxicity; patients may also develop alopecia or other tissue toxicity
Name two neoplasms commonly treated with bleomycin.
Testicular cancer and Hodgkin;s lymphoma (the B in the ABVD regimen)
After several rounds of chemotherapy, a patient complains of severe dyspnea and your exam fails to find symptoms of heart failure; what antitumor antibiotic is likely a part of his chemotherapy regimen?
Bleomycin, an antineoplastic agent that has the well-documented adverse effect of pulmonary fibrosis; you may also see skin changes as an adverse effect
When does etoposide interfere with the cell cycle?
Between G2 and S phase; etoposide inhibits topoisomerase II, which is needed to uncoil DNA strands and synthesize a sister chromatid
Name three neoplasms commonly treated using etoposide.
Small-cell carcinoma of the lung, small-cell carcinoma of the prostate, and testicular cancer
Which chemotherapeutic drugs are most likely to cause alopecia as an adverse effect?
Doxorubicin, daunorubicin, and etoposide
Which alkylating agent requires activation by the liver (and thus might not be effective in a patient with liver failure)?
Cyclophosphamide or ifosfamide; these cause DNA crosslinks at the 7 position of guanine
Which alkylating agents are effective at penetrating the blood-brain barrier to access the central nervous system?
Nitrosoureas, including carmustine, lomustine, semustine, and streptozotocin
Cyclophosphamide and ifosfamide are commonly used to treat which conditions?
These are used in breast cancer, ovarian cancer, and non-Hodgkin’s lymphoma; they are also used at lower doses as immunosuppressants
A patient who has been receiving chemotherapy for breast cancer presents with dark urine and is found to have many red blood cells in urine; this could have been avoided using what medication?
Mesna; this patient has hemorrhagic cystitis from cyclophosphamide use
Which alkylating agents are used especially in treating central nervous system neoplasms?
Nitrosoureas; since they penetrate the blood-brain barrier they are used to treat brain tumors like glioblastoma multiforme, but also have central nervous system toxicities like dizziness and ataxia
Which alkylating agent would you choose in a patient about to undergo hematopoietic stem cell transplantation?
Busulfan, which will ablate the host bone marrow before transplantation; it is also used in the treatment of chronic myelogenous leukemia
What toxicity is common to both busulfan and bleomycin?
Pulmonary fibrosis; both busulfan and bleomycin can result in lung disease
Which antineoplastic drugs bind to tubulin during the M phase, inhibiting the formation of microtubules?
Vincristine or vinblastine; microtubules are the vines of your cells, and without them the mitotic spindle cannot form
Name three neoplasms commonly treated using a vinca alkaloid (vincristine or vinblastine).
Hodgkin’s lymphoma (the MOPP regimen contains vincristine), Wilms’ tumor, and choriocarcinoma
What toxicities are associated with vincristine treatment?
Neurotoxicity, including areflexia and peripheral neuritis, as well as paralytic ileus
What toxicity is associated with vinblastine treatment?
Bone marrow suppression (remember: vinBLASTine BLASTs Bone marrow)
What antineoplastic drug functions by hyperstabilizing the mitotic spindle so that tumor cells are unable to complete anaphase?
PacliTAXel or other TAXols (remember: it is TAXing to stay polymerized [the microtubule stays polymerized])
Which neoplasms are commonly treated using taxols?
Breast and ovarian carcinomas
What are the clinical uses of cisplatin and carboplatin?
Testicular, bladder, ovary, and lung carcinomas
Name two major toxicities of cisplatin and carboplatin.
Nephrotoxicity and acoustic nerve damage
Which drug inhibits ribonucleotide reductase, acting during the S phase to decrease DNA synthesis?
Hydroxyurea
What are the three clinical uses for hydroxyurea?
Melanoma, chronic myelogenous leukemia, and sickle cell disease (hydroxyurea increases concentration of hemoglobin F)
What is the most commonly used glucocorticoid in cancer chemotherapy?
Prednisone
Which cancers have prednisone as part of their treatment regimen?
Chronic lymphocytic leukemia, Hodgkin’s lymphoma (MOPP regimen)
How is prednisone thought to exert an antineoplastic effect?
Prednisone is thought to induce apoptosis, and may even affect nondividing cells
Name two selective estrogen receptor modulators that are used to treat breast cancer.
Tamoxifen and raloxifene
What is the primary mechanism of action of tamoxifen and raloxifene?
They are selective estrogen receptor modulators that block binding of estrogen to estrogen-receptor-positive cells
A postmenopausal woman who recently started on a selective estrogen receptor modulator for breast cancer complains of vaginal spotting; what condition should you be concerned about?
Endometrial carcinoma; because of its partial agonist effects, tamoxifen increases the risk of endometrial carcinoma; raloxifene does not increase the risk of endometrial carcinoma
Why is raloxifene not associated with an increased risk of endometrial carcinoma?
Raloxifene acts as an antagonist at the level of the endometrium; tamoxifen acts as an agonist (increasing endometrial cancer risk)
The presence of what tumor marker would prompt you to use tamoxifen in the treatment of breast cancer?
Selective estrogen receptor modulators, like tamoxifen, act on the estrogen receptor, so the tumor should be estrogen receptor positive
What treatment option is available in a patient who has metastatic breast cancer that is HER-2/erb-B2 positive?
Trastuzumab, a monoclonal antibody against HER-2
What is the proposed mechanism of action of trastuzumab?
Helps kills breast cancer cells that overexpress HER-2, possibly through antibody-dependent cytotoxicity
What organ should be monitored closely for adverse effects in a patient taking trastuzumab?
The heart; an adverse effect of trastuzumab therapy is cardiotoxicity
What is the mechanism of action of imatinib?
This molecule binds to and inhibits the tyrosine kinase formed by the bcr-abl translocation found in chronic myelogenous leukemia
What are the clinical uses for imatinib?
Chronic myelogenous leukemia and gastrointestinal stromal tumors (both express the bcr-abl tyrosine kinase)
