Hematology and Oncology - Pharmacology

Question 1

Heparin

• Mechanism
• Clinical use
• Toxicity
• Low-molecular-weight heparins
• Heparin-induced thrombocytopenia (HIT)

Answer 1

• Mechanism
  
  • Cofactor for the activation of antithrombin, decrease thrombin, and decrease factor Xa.
  • Short half-life.
• Clinical use
  
  • Immediate anticoagulation for PE, acute coronary syndrome, MI, DVT.
  • Used during pregnancy (does not cross placenta).
  • Follow PTT.
• Toxicity
  
  • Bleeding, thrombocytopenia (HIT), osteoporosis, drug-drug interactions.
  • For rapid reversal (antidote), use protamine sulfate (positively charged molecule that binds negatively charged heparin).
• Low-molecular-weight heparins (e.g., enoxaparin, dalteparin)
  
  • Act more on factor Xa
  • Have better bioavailability and 2–4 times longer half-life.
  • Can be administered subcutaneously and without laboratory monitoring.
  • Not easily reversible.
• Heparin-induced thrombocytopenia (HIT)
  
  • Development of IgG antibodies against heparin bound to platelet factor 4 (PF4).
  • Antibody-heparin-PF4 complex activates platelets –>Ž thrombosis and thrombocytopenia.

Question 2

Argatroban, bivalirudin

Answer 2

• Derivatives of hirudin, the anticoagulant used by leeches
• Inhibit thrombin directly.
• Used instead of heparin for anticoagulating patients with HIT.

Question 3

Warfarin (Coumadin)

• Mechanism
• Clinical use
• Toxicity

Answer 3

• Mechanism
  
  • Interferes with normal synthesis and γ-carboxylation of vitamin K–dependent clotting factors II, VII, IX, and X and proteins C and S.
  • Metabolized by the cytochrome P-450 pathway.
  • In laboratory assay, has effect on EXtrinsic pathway and increases PT.
    
    • The EX-PresidenT** went to war(farin).**
  • Long half-life.
• Clinical use
  
  • Chronic anticoagulation (after STEMI, venous thromboembolism prophylaxis, and prevention of stroke in atrial fibrillation).
  • Not used in pregnant women (because warfarin, unlike heparin, can cross the placenta).
  • Follow PT/ INR values.
• Toxicity
  
  • Bleeding, teratogenic, skin/tissue necrosis [A], drug-drug interactions.
  • For reversal of warfarin overdose, give vitamin K.
  • For rapid reversal of severe warfarin overdose, give fresh frozen plasma.

Question 4

Direct factor Xa inhibitors

• Examples
• Mechanism
• Clinical use
• Toxicity

Answer 4

• Examples
  
  • Apixaban, rivaroxaban.
• Mechanism
  
  • Bind and directly inhibit the activity of factor Xa.
• Clinical use
  
  • Treatment and prophylaxis of DVT and PE (rivaroxaban), stroke prophylaxis in patients with atrial fibrillation.
  • Oral agents do not usually require coagulation monitoring.
• Toxicity
  
  • Bleeding (no specific reversal agent available).

Question 5

Heparin vs. warfarin

• Structure
• Route of administration
• Site of action
• Onset of action
• Mechanism of action
• Duration of action
• Inhibits coagulation in vitro?
• Treatment of acute overdose
• Monitoring
• Crosses placenta?

Answer 5

• Structure
  
  • H: Large anionic, acidic polymer
  • W: Small lipid-soluble molecule
• Route of administration
  
  • H: Parenteral (IV, SC)
  • W: Oral
• Site of action
  
  • H: Blood
  • W: Liver
• Onset of action
  
  • H: Rapid (seconds)
  • W: Slow, limited by half-lives of normal clotting factors
• Mechanism of action
  
  • H: Activates antithrombin, which decreases the action of IIa (thrombin) and factor Xa
  • W: Impairs the synthesis of vitamin K–dependent clotting factors II, VII, IX, and X (vitamin K antagonist)
• Duration of action
  
  • H: Acute (hours)
  • W: Chronic (days)
• Inhibits coagulation in vitro?
  
  • H: Yes
  • W: No
• Treatment of acute overdose
  
  • H: Protamine sulfate
  • W: IV vitamin K and fresh frozen plasma
• Monitoring
  
  • H: PTT (intrinsic pathway)
  • W: PT/INR (extrinsic pathway)
• Crosses placenta?
  
  • H: No
  • W: Yes (teratogenic)

Question 6

Thrombolytics

• Examples
• Mechanism
• Clinical use
• Toxicity

Answer 6

• Examples
  
  • Alteplase (tPA), reteplase (rPA), tenecteplase (TNK-tPA).
• Mechanism
  
  • Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots. 
  • Increase PT, increase PTT, no change in platelet count.
• Clinical use
  
  • Early MI, early ischemic stroke, direct thrombolysis of severe PE.
• Toxicity
  
  • Bleeding.
  • Contraindicated in patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension.
  • Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis.
  • Fresh frozen plasma and cryoprecipitate can also be used to correct factor deficiencies.

Question 7

Aspirin (ASA)

• Mechanism
• Clinical use
• Toxicity

Answer 7

• Mechanism
  
  • Irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) enzyme by covalent acetylation.
  • Platelets cannot synthesize new enzyme, so effect lasts until new platelets are produced: 
    
    • Increased bleeding time, decreased TXA2 and prostaglandins.
    • No effect on PT or PTT.
• Clinical use
  
  • Antipyretic, analgesic, anti-inflammatory, antiplatelet (decreased aggregation).
• Toxicity
  
  • Gastric ulceration, tinnitus (CN VIII).
  • Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding.
  • Reye syndrome in children with viral infection.
  • Overdose causes respiratory alkalosis initially, which is then superimposed by metabolic acidosis.

Question 8

ADP receptor inhibitors

• Examples
• Mechanism
• Clinical use
• Toxicity

Answer 8

• Examples
  
  • Clopidogrel, ticlopidine, prasugrel, ticagrelor.
• Mechanism
  
  • Inhibit platelet aggregation by irreversibly blocking ADP receptors.
  • Inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa from binding to fibrinogen.
• Clinical use
  
  • Acute coronary syndrome
  • Coronary stenting. 
  • Decreased incidence or recurrence of thrombotic stroke.
• Toxicity
  
  • Neutropenia (ticlopidine).
  • TTP/HUS may be seen.

Question 9

Cilostazol, dipyridamole

• Mechanism
• Clinical use
• Toxicity

Answer 9

• Mechanism
  
  • Phosphodiesterase III inhibitor
  • Increases cAMP in platelets, thus inhibiting platelet aggregation
  • Vasodilators.
• Clinical use
  
  • Intermittent claudication, coronary vasodilation, prevention of stroke or TIAs (combined with aspirin), angina prophylaxis.
• Toxicity
  
  • Nausea, headache, facial flushing, hypotension, abdominal pain.

Question 10

GP IIb/IIIa inhibitors

• Examples
• Mechanism
• Clinical use
• Toxicity

Answer 10

• Examples
  
  • Abciximab, eptifibatide, tirofiban.
• Mechanism
  
  • Bind to the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation.
  • Abciximab is made from monoclonal antibody Fab fragments.
• Clinical use
  
  • Unstable angina, percutaneous transluminal coronary angioplasty.
• Toxicity
  
  • Bleeding, thrombocytopenia.

Question 11

Cancer drugs—cell cycle

Answer 11

Question 12

Antineoplastics (402)

Answer 12

• Nucleotide synthesis
  
  • MTX, 5-FU: decreased thymidine synthesis
  • 6-MP: decreased purine synthesis
• DNA
  
  • Alkylating agents, cisplatin: cross-link DNA
  • Dactinomycin, doxorubicin: DNA intercalators
  • Etoposide: inhibits topoisomerase II
• RNA
• Protein
• Cellular division
  
  • Vinca alkaloids: inhibit microtubule formation
  • Paclitaxel: inhibits microtubule disassembly

Question 13

Methotrexate (MTX)

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 13

• Type of drug
  
  • Antimetabolite
• Mechanism
  
  • S-phase specific
  • Folic acid analog that inhibits dihydrofolate reductase –>Ž decreased dTMP –> decreased DNA and decreased protein synthesis.
• Clinical use
  
  • Cancers: leukemias, lymphomas, choriocarcinoma, sarcomas.
  • Non-neoplastic: abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis, IBD.
• Toxicity
  
  • Myelosuppression, which is reversible with leucovorin (folinic acid) “rescue.”
  • Macrovesicular fatty change in liver.
  • Mucositis.
  • Teratogenic.

Question 14

5-fluorouracil (5-FU)

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 14

• Type of drug
  
  • Antimetabolite
• Mechanism
  
  • S-phase specific
  • Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid.
  • This complex inhibits thymidylate synthase Ž–> decreased dTMP Ž–> decreased DNA and decreased protein synthesis.
• Clinical use
  
  • Colon cancer, pancreatic cancer, basal cell carcinoma (topical).
• Toxicity
  
  • Myelosuppression, which is not reversible with leucovorin.
  • Overdose: “rescue” with uridine.
  • Photosensitivity.

Question 15

Cytarabine (arabinofuranosyl cytidine)

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 15

• Type of drug
  
  • Antimetabolite
• Mechanism
  
  • S-phase specific
  • Pyrimidine analog –>Ž inhibition of DNA polymerase.
• Clinical use
  
  • Leukemias, lymphomas.
• Toxicity
  
  • Leukopenia, thrombocytopenia, megaloblastic anemia.
  • CYTarabine causes panCYTopenia.

Question 16

Azathioprine 6-mercaptopurine (6-MP) 6-thioguanine (6-TG)

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 16

• Type of drug
  
  • Antimetabolite
• Mechanism
  
  • S-phase specific
  • Purine (thiol) analogs –>Ž decreased de novo purine synthesis.
  • Activated by HGPRT.
• Clinical use
  
  • Preventing organ rejection, RA, SLE (azathioprine).
  • Leukemia, IBD (6-MP, 6-TG).
• Toxicity
  
  • Bone marrow, GI, liver.
  • Azathioprine and 6-MP are metabolized by xanthine oxidase
    
    • Thus both have increased toxicity with allopurinol, which inhibits their metabolism.

Question 17

Dactinomycin (actinomycin D)

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 17

• Type of drug
  
  • Antitumor antibiotic
• Mechanism
  
  • Intercalates in DNA.
• Clinical use
  
  • Wilms tumor, Ewing sarcoma, rhabdomyosarcoma.
  • Used for childhood tumors
    
    • “Children act out”
• Toxicity
  
  • Myelosuppression.

Question 18

Doxorubicin (Adriamycin), daunorubicin

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 18

• Type of drug
  
  • Antitumor antibiotic
• Mechanism
  
  • Generate free radicals.
  • Intercalate in DNA –>Ž breaks in DNA –>Ž decreased replication.
• Clinical use
  
  • Solid tumors, leukemias, lymphomas.
• Toxicity
  
  • Cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia.
    
    • Toxic to tissues following extravasation.
  • Dexrazoxane (iron chelating agent), used to prevent cardiotoxicity.

Question 19

Bleomycin

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 19

• Type of drug
  
  • Antitumor antibiotic
• Mechanism
  
  • Induces free radical formation, which causes breaks in DNA strands.
• Clinical use
  
  • Testicular cancer, Hodgkin lymphoma.
• Toxicity
  
  • Pulmonary fibrosis, skin changes, mucositis.
  • Minimal myelosuppression.

Question 20

Cyclophosphamide, ifosfamide

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 20

• Type of drug
  
  • Alkylating agent
• Mechanism
  
  • Covalently X-link (interstrand) DNA at guanine N-7.
  • Require bioactivation by liver.
• Clinical use
  
  • Solid tumors, leukemia, lymphomas, and some brain cancers.
• Toxicity
  
  • Myelosuppression
  • Hemorrhagic cystitis, partially prevented with mesna (thiol group of mesna binds toxic metabolites).

Question 21

Nitrosoureas (carmustine, lomustine, semustine, streptozocin)

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 21

• Type of drug
  
  • Alkylating agent
• Mechanism
  
  • Require bioactivation.
  • Cross blood-brain barrier –>Ž CNS.
  • Cross-links DNA.
• Clinical use
  
  • Brain tumors (including glioblastoma multiforme).
• Toxicity
  
  • CNS toxicity (convulsions, dizziness, ataxia).

Question 22

Busulfan

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 22

• Type of drug
  
  • Alkylating agent
• Mechanism
  
  • Cross-links DNA.
• Clinical use
  
  • CML.
  • Also used to ablate patient’s bone marrow before bone marrow transplantation.
• Toxicity
  
  • Severe myelosuppression (in almost all cases), pulmonary fibrosis, hyperpigmentation.

Question 23

Vincristine, vinblastine

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 23

• Type of drug
  
  • Microtubule inhibitors
• Mechanism
  
  • Vinca alkaloids that bind β-tubulin, inhibit its polymerization into microtubules, thereby preventing mitotic spindle formation (M-phase arrest).
• Clinical use
  
  • Solid tumors, leukemias, and lymphomas.
• Toxicity
  
  • Vincristine—neurotoxicity (areflexia, peripheral neuritis), paralytic ileus.
  • Vinblastine blasts bone marrow (suppression).

Question 24

Paclitaxel, other taxols

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 24

• Type of drug
  
  • Microtubule inhibitors
• Mechanism
  
  • Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur).
  • “It is taxing to stay polymerized.”
• Clinical use
  
  • Ovarian and breast carcinomas.
• Toxicity
  
  • Myelosuppression, alopecia, hypersensitivity.

Question 25

Cisplatin, carboplatin * Mechanism * Clinical use * Toxicity

Answer 25

* Mechanism * Cross-link DNA. * Clinical use * Testicular, bladder, ovary, and lung carcinomas. * Toxicity * Nephrotoxicity and acoustic nerve damage. * Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride diuresis.

Question 26

Etoposide, teniposide * Mechanism * Clinical use * Toxicity

Answer 26

* Mechanism * E**_topo_**side inhibits **_topo_**isomerase II --\>Ž increased DNA degradation. * Clinical use * Solid tumors (particularly testicular and small cell lung cancer), leukemias, lymphomas. * Toxicity * Myelosuppression, GI irritation, alopecia.

Question 27

Irinotecan, topotecan * Mechanism * Clinical use * Toxicity

Answer 27

* Mechanism * Inhibit topoisomerase I and prevent DNA unwinding and replication. * Clinical use * Colon cancer (irinotecan) * Ovarian and small cell lung cancers (topotecan). * Toxicity * Severe myelosuppression, diarrhea.

Question 28

Hydroxyurea * Mechanism * Clinical use * Toxicity

Answer 28

* Mechanism * Inhibits ribonucleotide reductase Ž--\> decreased DNA **_S_**ynthesis (**_S_**-phase specific). * Clinical use * Melanoma, CML, sickle cell disease (increased HbF). * Toxicity * Bone marrow suppression, GI upset.

Question 29

Prednisone, prednisolone * Mechanism * Clinical use * Toxicity

Answer 29

* Mechanism * May trigger apoptosis. * May even work on nondividing cells. * Clinical use * Most commonly used glucocorticoids in cancer chemotherapy. * Used in CLL, non-Hodgkin lymphomas (part of combination chemotherapy regimen). * Also used as immunosuppressants (e.g., autoimmune diseases). * Toxicity * Cushing-like symptoms * Weight gain, central obesity, muscle breakdown, cataracts, acne, osteoporosis, hypertension, peptic ulcers, hyperglycemia, psychosis.

Question 30

Tamoxifen, raloxifene * Mechanism * Clinical use * Toxicity

Answer 30

* Mechanism * Selective estrogen receptor modulators (SERMs)—receptor antagonists in breast and agonists in bone. * Block the binding of estrogen to ER (+) cells. * Clinical use * Breast cancer treatment (tamoxifen only) and prevention. * Raloxifene also useful to prevent osteoporosis. * Toxicity * Tamoxifen—partial agonist in endometrium, which increases the risk of endometrial cancer; “hot flashes.” * Raloxifene—no increase in endometrial carcinoma because it is an endometrial antagonist.

Question 31

Trastuzumab (Herceptin) * Mechanism * Clinical use * Toxicity

Answer 31

* Mechanism * Monoclonal antibody against HER-2 (c-erbB2), a tyrosine kinase receptor. * Helps kill breast cancer cells that overexpress HER-2, through inhibition of HER2-initiated cellular signaling and antibody-dependent cytotoxicity. * Clinical use * HER-**_2_** (+) breast cancer and gastric cancer (tras**_2_**zumab). * Toxicity * Cardiotoxicity. * **“**_HEART_**ceptin” damages the _HEART_**

Question 32

Imatinib (Gleevec) * Mechanism * Clinical use * Toxicity

Answer 32

* Mechanism * Tyrosine kinase inhibitor of bcr-abl (Philadelphia chromosome fusion gene in CML) and c-Kit (common in GI stromal tumors). * Clinical use * CML, GI stromal tumors. * Toxicity * Fluid retention.

Question 33

Rituximab * Mechanism * Clinical use * Toxicity

Answer 33

* Mechanism * Monoclonal antibody against CD20, which is found on most B-cell neoplasms. * Clinical use * Non-Hodgkin lymphoma, rheumatoid arthritis (with MTX), ITP. * Toxicity * Increased risk of progressive multifocal leukoencephalopathy.

Question 34

Vemurafenib * Mechanism * Clinical use

Answer 34

* Mechanism * Small molecule inhibitor of forms of the B-Raf kinase with the V600E mutation. * Clinical use * Metastatic melanoma.

Question 35

Bevacizumab * Mechanism * Clinical use * Toxicity

Answer 35

* Mechanism * Monoclonal antibody against VEGF. * Inhibits angiogenesis. * Clinical use * Solid tumors (colorectal cancer, renal cell carcinoma). * Toxicity * Hemorrhage and impaired wound healing.

Question 36

Common chemotoxicities * Cisplatin/Carboplatin * Vincristine * Bleomycin, Busulfan * Doxorubicin * Trastuzumab * Cisplatin/Carboplatin * Cyclophosphamide * 5-FU * 6-MP * Methotrexate

Answer 36

* **_C_**isplatin/**_C_**arboplatin Ž--\> acoustic nerve damage (and nephrotoxicity) * **_V_**incristine --\>Ž peripheral neuropathy * **_B_**leomycin, **_B_**usulfan --\>Ž pulmonary fibrosis * **_D_**oxorubicin --\>Ž cardiotoxicity * **_T_**rastuzumab --\>Ž cardiotoxicity * **_C_**isplatin/**_C_**arboplatin--\> Ž nephrotoxic (and acoustic nerve damage) * **_CY_**clophosphamide --\>Ž hemorrhagic cystitis * **_5_**-FU --\>Ž myelosuppression * **_6_**-MP --\>Ž myelosuppression * **_M_**ethotrexate --\>Ž myelosuppression