Hematology/Oncology Pharmacology

Question 1

Hematology/Oncology Pharmacology

Heparin

Answer 1

MOA: Lowers the activity of thrombin and factor Xa. Short half-life.

Use: Immediate anticoagulation for PE, acute coronary syndrome, MI, DVT. Used during pregnancy (does not cross placenta). Follow PTT. LMWH (enoxaparin, dalteparin) and fondaparinux act more on factor Xa, have better availability, and 2-4x longer half-life; can be administered subcutaneously and without lab monitoring.

Adverse Effects: Bleeding, thrombocytopenia (HIT), osteoporosis, drug-drug interactions.

Rapid reversal: Protamine sulfate (⊕ molecule that binds ⊖ heparin)

Question 2

Hematology/Oncology Pharmacology

Bivalirudin

Answer 2

MOA: Direct thrombin inhibitor. Directly inhibits activity of free and clot-associated thrombin.

Use: Venous thromboembolism, atrial fibrillation. Can be used in HIT. Does not require lab monitoring.

Adverse Effects: Bleeding; no specific reversal agent. Can attempt to use activated prothrombin complex concentrates and/or fibrinolytics.

Question 3

Hematology/Oncology Pharmacology

Warfarin

Answer 3

MOA: Interferes with γ-carboxylation of vitamin K-dependent clotting factors II, VII, IX, and X, and proteins C and S. Metabolism affected by polymorphism in the gene for vitamin K epoxide reductase complex. In laboratory assay, has effect on extrinsic pathway and ↑ PT. Long half-life.

Use: Chronic anticoagulation. Not used in pregnant women. Follow PT/INR.

Adverse Effects: Bleeding, teratogenic, skin/tissue necrosis, drug-drug interactions. Proteins C and S have shorter half-lives than clotting factors II, VII, IX, and X, resulting in early transient hypercoagulability with warfarin use. Skin/tissue necrosis within first few days of large doses believed to be due to small vessel microthromboses.

Question 4

Hematology/Oncology Pharmacology

Apixaban, rivaroxaban

Answer 4

MOA: Direct factor Xa inhibitors. Bind to and directly inhibit factor Xa.

Use: Treatment and prophylaxis for DVT and PE (rivaroxaban); stroke prophylaxis in patients with atrial fibrillation.

Adverse Effects: Bleeding (no reversal agent available)

Question 5

Hematology/Oncology Pharmacology

Alteplase (tPA), reteplase (rPA), streptokinase, tenecteplase (TNK-tPA)

Answer 5

MOA: Thrombolytics. Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. ↑ PT, ↑ PTT, no change in platelet count.

Use: Early MI, early ischemic stroke, direct thrombolysis of severe PE.

Adverse Effects: Bleeding. Contraindicated in patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension.

Toxicity treatment: Aminocaproic acid. Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies.

Question 6

Hematology/Oncology Pharmacology

Clopidogrel, prasugrel, ticagrelor (reversible), ticlopidine

Answer 6

MOA: ADP receptor inhibitors. Inhibit platelet aggregation by irreversibly blocking ADP receptors. Prevent expression of glycoproteins IIb/IIIa on platelet surface.

Use: Acute coronary syndrome; coronary stenting. ↓ incidence or recurrence of thrombotic stroke.

Adverse Effects: Neutropenia (ticlopidine). TPP may be seen.

Question 7

Hematology/Oncology Pharmacology

Cilostazol, dipyridamole

Answer 7

MOA: Phosphodiesterase III inhibitor; ↑ cAMP in platelets → inhibition of platelet aggregation; vasodilators.

Use: Intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with aspirin), angina prophylaxis.

Adverse Effects: Nausea, headache, facial flushing, hypotension, abdominal pain.

Question 8

Hematology/Oncology Pharmacology

Abciximab, eptifibatide, tirofiban

Answer 8

MOA: Bind to glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. Abciximab is made from monoclonal antibody Fab fragments.

Use: Unstable angina, percutaneous transluminal coronary angioplasty.

Adverse Effects: Bleeding, thrombocytopenia

Question 9

Hematology/Oncology Pharmacology

Azathioprine, 6-mercaptopurine

Answer 9

MOA: Purine (thiol) analogs → ↓ de novo purine synthesis. Activated by HGPRT. Azathioprine is metabolized into 6-MP. S-phase specific.

Use: Preventing organ rejection, rheumatoid arthritis, IBD, SLE; used to wean patients off steroids in chronic disease and to treat steroid-refractory chronic disease.

Adverse Effects: Myelosuppression, GI, liver. Azathioprine and 6-MP are metabolized by xanthine oxidase; thus both have ↑ toxicity with allopurinol or febuxostat.

Question 10

Hematology/Oncology Pharmacology

Cladribine

Answer 10

MOA: Purine analog → multiple mechanisms (eg. inhibition of DNA polymerase, DNA strand breaks) S-phase specific.

Use: Hairy cell leukemia

Adverse Effects: Myelosuppression, nephrotoxicity, neurotoxicity.

Question 11

Hematology/Oncology Pharmacology

Cytarabine (arabinofuranosyl cytidine)

Answer 11

MOA: Pyrimidine analog → inhibition of DNA polymerase. S-phase specific.

Use: Leukemias (AML), lymphomas.

Adverse Effects: Myelosuppression with megaloblastic anemia. Cytrabine causes pancytopenia.

Question 12

Hematology/Oncology Pharmacology

5-fluorouracil

Answer 12

MOA: Pyrimidine analog bioactivated to 5-FdUMP, which covalently complexes folic acid → inhibits thymidylate synthase → ↓ dTMP → ↓ DNA synthesis. S-phase specific.

Use: Colon cancer, pancreatic cancer, basal cell carcinoma (topical). Effects enhanced with the addition of leucovorin.

Adverse Effects: Myelosuppression - worsened with the addition of leucovorin (folinic aicid)

Question 13

Hematology/Oncology Pharmacology

Methotrexate

Answer 13

MOA: Folic acid analog that competitively inhibits dihydrofolate reductase → ↓ dTMP → ↓ DNA synthesis. S-phase specific.

Use: Cancers (ALL, lymphomas, choriocarcinoma, sarcomas). Non-neoplastic: ectopic pregnancy, medical abortion (with misoprostol), rheumatoid arthritis, psoriasis, IBD, vasculitis.

Adverse Effects: Myelosuppression, which is reversible with leucovorin “rescue”. Hepatotoxicity, mucositis, pulmonary fibrosis.

Question 14

Hematology/Oncology Pharmacology

Bleomycin

Answer 14

MOA: Induces free radical formation → breaks in DNA strands

Use: Testicular cancer, Hodgkin lymphoma.

Adverse Effects: Pulmonary fibrosis, skin hyperpigmentation. Minimal myelosuppression.

Question 15

Hematology/Oncology Pharmacology

Dactinomycin (actinomycin D)

Answer 15

MOA: Intercalates in DNA

Use: Wilms tumor, Ewing sarcoma, rhabdomyosarcoma. Used for childhood tumors.

Adverse Effects: Myelosuppression.

Question 16

Hematology/Oncology Pharmacology

Doxorubicin, daunorubicin

Answer 16

MOA: Generate free radicals. Intercalate in DNA → breaks in DNA → ↓ replication.

Use: Solid tumors, leukemias, lymphomas.

Adverse Effects: Cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia. Dexrazoxane (iron chleating angent) used to prevent cardiotoxicity.

Question 17

Hematology/Oncology Pharmacology

Busulfan

Answer 17

MOA: Cross-links DNA

Use: CML, also used to ablate patient’s bone marrow before bone marrow transplantation.

Adverse Effects: Severe myelosuppression (in almost all cases), pulmonary fibrosis, hyperpigmentation.

Question 18

Hematology/Oncology Pharmacology

Cyclophosphamide, ifosfoamide

Answer 18

MOA: Cross-link DNA at guanine N-7. Require bioactivation by liver.

Use: Solid tumors, leukemia, lymphomas.

Adverse Effects: Myelosuppression; hemorrhagic cystitis, prevented with mesna (thiol group of mesna binds toxic metabolites) or N-acetylcysteine

Question 19

Hematology/Oncology Pharmacology

Nitrosureas (carmustine, lomustine, semustine, streptozocin)

Answer 19

MOA: Require bioactivation. Cross blood-brain-barrier → CNS. Cross-link DNA.

Use: Brain tumors (including glioblastoma multiforme)

Adverse Effects: CNS toxicity (convulsions, dizziness, ataxia).

Question 20

Hematology/Oncology Pharmacology

Paclitaxel, other taxols

Answer 20

MOA: Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur).

Use: Ovarian and breast carcinomas

Adverse Effects: Myelosuppression, neuropathy, hypersensitivity.

Question 21

Hematology/Oncology Pharmacology

Vincristine, vinblastine

Answer 21

MOA: Vinca alkaloids that bind β-tubulin and inhibit its polymerization into microtubles → prevent mitotic spindle formation (M-phase arrest)

Use: Solid tumors, leukemias, Hodgkin (vinblastine) and non-Hodgkin (vincristine) lymphomas.

Adverse Effects:
Vincristine: neurotoxicity (areflexia, peripheral neuritis), constipation (including paralytic ileus)

Question 22

Hematology/Oncology Pharmacology

Cisplatin, carboplatin

Answer 22

MOA: Cross-link DNA

Use: Testicular, bladder, ovary, and lung carcinomas

Adverse Effects: Nephrotoxicity, peripheral neuropathy, ototoxicity. Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride (saline) diuresis)

Question 23

Hematology/Oncology Pharmacology

Etoposide, teniposide

Answer 23

MOA: Inhibits topoisomerase II → ↑ DNA degradation

Use: Solid tumors (particularly testicular and small cell lung cancer), leukemias, lymphomas

Adverse Effects: Myelosuppression, alopecia

Question 24

Hematology/Oncology Pharmacology

Irinotecan, topotecan

Answer 24

MOA: Inhibits topoisomerase I and prevent DNA unwinding and replication

Use: Colon cancer (irinotecan); ovarian and small cell lung cancers (topotecan)

Adverse Effects: Severe myelosuppression, diarrhea

Question 25

Hematology/Oncology Pharmacology

Hydroxyurea

Answer 25

MOA: Inhibits ribonucleotide reductase → ↓ DNA synthesis (S-phase specific)

Use: Melanoma, CML, sickle cel disease (↑ HbF)

Adverse Effects: Severe myelosuppression

Question 26

Hematology/Oncology Pharmacology

Prednisone, prednisolone

Answer 26

MOA: Various, bind intracytoplasmic steroid receptor; alter gene transcription

Use: Most commonly used glucocorticoids in cancer chemotherapy. Used in CLL, non-Hodgkin lymphoma. Also used as immunosuppressants.

Adverse Effects: Cushing-like symptoms, weight gain, central obesity, muscle breakdown, cataracts, acne, osteoporosis, hypertension, peptic ulcers, hyperglycemia, psychosis.

Question 27

Hematology/Oncology Pharmacology

Bevacizumab

Answer 27

MOA: Monoclonal antibody against VEGF. Inhibits angiogenesis

Use: Solid tumors (colorectal cancer, renal cell carcinoma)

Adverse Effects: Hemorrhage, blood clots, and impaired wound healing

Question 28

Hematology/Oncology Pharmacology

Erlotinib

Answer 28

MOA: EGFR tyrosine kinase inhibitor

Use: Non-small cell lung cancer

Adverse Effects: Rash

Question 29

Hematology/Oncology Pharmacology

Cetuximab

Answer 29

MOA: Monoclonal antibody against EGFR

Use: Stage IV colorectal cancer (wild-type KRAS), head and neck cancer

Adverse Effects: Rash, ↑ LFTs, diarrhea

Question 30

Hematology/Oncology Pharmacology

Imatinib

Answer 30

MOA: Tyrosine kinase inhibitor of BCR-ABL (Philadelphia chromosome fusion gene in CML) and c-kit (common in GI stromal tumors)

Use: CML, GI stromal tumors

Adverse Effects: Fluid retention

Question 31

Hematology/Oncology Pharmacology

Rituximab

Answer 31

MOA: Monoclonal antibody against CD20, which is found on most B cell neoplasms

Use: Non-Hodgkin lymphoma, CLL, ITP, rheumatoid arthritis

Adverse Effects: ↑ risk of progressive multifocal leukoencephalopathy

Question 32

Hematology/Oncology Pharmacology

Tamoxifen, raloxifene

Answer 32

MOA: Selective estrogen receptor modulator (SERMs) - receptor antagonists in breast and agonists in bone. Block the binding of estrogen to ER ⊕ cells

Use: Breast cancer treatment (tamoxifen) and prevention. Prevention of osteoporosis (raloxifene)

Adverse Effects:
Tamoxifen: partial agonist in endometrium, which ↑ risk of endometrial cancer; “hot flashes.”
Raloxifene: no ↑ risk in endometrial carcinoma (estrogen receptor antagonist in endometrial tissue)
Both: ↑ risk of thromboembolic events

Question 33

Hematology/Oncology Pharmacology

Trastuzumab (Herceptin)

Answer 33

MOA: Monoclonal Ab against HER-2 (c-erbB2), a tyrosine kinase receptor. Helps kill cancer cells that overexpress HER-2, through inhibition of HER2–initiated cellular signaling and antibody-dependent cytotoxicity.

Use: HER-2 ⊕ bresat cancer and gastric cancer

Adverse Effects: Cardiotoxicity

Question 34

Hematology/Oncology Pharmacology

Vemurafenib

Answer 34

MOA: Small molecular inhibitor of BRAF oncogene ⊕ melanoma. For V600E-mutated BRAF inhibition.

Use: Metastatic melanoma