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First Aid > Hematology and Oncology - Pharmacology > Flashcards

Hematology and Oncology - Pharmacology Flashcards

1
Q

Heparin

  • Mechanism
  • Clinical use
  • Toxicity
  • Low-molecular-weight heparins
  • Heparin-induced thrombocytopenia (HIT)
A
  • 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.
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2
Q

Argatroban, bivalirudin

A
  • Derivatives of hirudin, the anticoagulant used by leeches
  • Inhibit thrombin directly.
  • Used instead of heparin for anticoagulating patients with HIT.
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3
Q

Warfarin (Coumadin)

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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4
Q

Direct factor Xa inhibitors

  • Examples
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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).
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5
Q

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?
A
  • 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)
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6
Q

Thrombolytics

  • Examples
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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7
Q

Aspirin (ASA)

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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8
Q

ADP receptor inhibitors

  • Examples
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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9
Q

Cilostazol, dipyridamole

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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10
Q

GP IIb/IIIa inhibitors

  • Examples
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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11
Q

Cancer drugs—cell cycle

A
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12
Q

Antineoplastics (402)

A
  • 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
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13
Q

Methotrexate (MTX)

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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14
Q

5-fluorouracil (5-FU)

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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15
Q

Cytarabine (arabinofuranosyl cytidine)

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
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16
Q

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

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
17
Q

Dactinomycin (actinomycin D)

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
18
Q

Doxorubicin (Adriamycin), daunorubicin

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
19
Q

Bleomycin

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
20
Q

Cyclophosphamide, ifosfamide

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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).
21
Q

Nitrosoureas (carmustine, lomustine, semustine, streptozocin)

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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).
22
Q

Busulfan

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
23
Q

Vincristine, vinblastine

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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).
24
Q

Paclitaxel, other taxols

  • Type of drug
  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
25
Q

Cisplatin, carboplatin

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
26
Q

Etoposide, teniposide

  • Mechanism
  • Clinical use
  • Toxicity
A
  • Mechanism
    • Etoposide inhibits topoisomerase II –>Ž increased DNA degradation.
  • Clinical use
    • Solid tumors (particularly testicular and small cell lung cancer), leukemias, lymphomas.
  • Toxicity
    • Myelosuppression, GI irritation, alopecia.
27
Q

Irinotecan, topotecan

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
28
Q

Hydroxyurea

  • Mechanism
  • Clinical use
  • Toxicity
A
  • Mechanism
    • Inhibits ribonucleotide reductase Ž–> decreased DNA Synthesis (S-phase specific).
  • Clinical use
    • Melanoma, CML, sickle cell disease (increased HbF).
  • Toxicity
    • Bone marrow suppression, GI upset.
29
Q

Prednisone, prednisolone

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
30
Q

Tamoxifen, raloxifene

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
31
Q

Trastuzumab (Herceptin)

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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 (tras2zumab).
  • Toxicity
    • Cardiotoxicity.
    • “HEARTceptin” damages the HEART
32
Q

Imatinib (Gleevec)

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
33
Q

Rituximab

  • Mechanism
  • Clinical use
  • Toxicity
A
  • 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.
34
Q

Vemurafenib

  • Mechanism
  • Clinical use
A
  • Mechanism
    • Small molecule inhibitor of forms of the B-Raf kinase with the V600E mutation.
  • Clinical use
    • Metastatic melanoma.
35
Q

Bevacizumab

  • Mechanism
  • Clinical use
  • Toxicity
A
  • Mechanism
    • Monoclonal antibody against VEGF.
    • Inhibits angiogenesis.
  • Clinical use
    • Solid tumors (colorectal cancer, renal cell carcinoma).
  • Toxicity
    • Hemorrhage and impaired wound healing.
36
Q

Common chemotoxicities

  • Cisplatin/Carboplatin
  • Vincristine
  • Bleomycin, Busulfan
  • Doxorubicin
  • Trastuzumab
  • Cisplatin/Carboplatin
  • Cyclophosphamide
  • 5-FU
  • 6-MP
  • Methotrexate
A
  • Cisplatin/Carboplatin Ž–> acoustic nerve damage (and nephrotoxicity)
  • Vincristine –>Ž peripheral neuropathy
  • Bleomycin, Busulfan –>Ž pulmonary fibrosis
  • Doxorubicin –>Ž cardiotoxicity
  • Trastuzumab –>Ž cardiotoxicity
  • Cisplatin/Carboplatin–> Ž nephrotoxic (and acoustic nerve damage)
  • CYclophosphamide –>Ž hemorrhagic cystitis
  • 5-FU –>Ž myelosuppression
  • 6-MP –>Ž myelosuppression
  • Methotrexate –>Ž myelosuppression

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