Heme/Onc Drugs Flashcards Preview

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Flashcards in Heme/Onc Drugs Deck (105):
1

Heparin: Mechanism

- cofactor for activation of antithrombrin
- decreased thrombrin
- decreased factor Xa
- Short half life

2

Heparin: Clinical Use

Immediate anticoagulation for pulmonary embolism, acute coronary syndrome, MI, DVT
- Used during pregnancy (does not cross placenta)
- Follow PTT

3

Heparin: Toxicity

Bleeding, thrombocytopenia (HIT), osteoporisis, drug-drug interactions.

4

Antidote for heparin toxicity (not to be confused with HIT)

Protamine sulfate - positively charged molecule that binds negatively charged heparin

5

Low molecular heparin (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

6

Lepirudin, Bivalirudin

derivatives of hirudin (anti-coagulant used by leeches)
- inhibit thrombrin
- used as an alternative to heparin for anti-coagulating patients with HIT

7

Heparin-induced thrombocytopenia

development of IgG antibodies against heparin bound to platelet factor 4 (PF4).
Antibody-heparin-PF4 activates platelets --> thrombosis and thrombocytopenia

8

Warfarin: Mechanism

interferes with normal synthesis and gamma carboxylation of vitamin K-dependent clotting factors II, VII, IX, and X and proteins C and S.
- BLOCKS Vitamin K
- Metabolized by the cytochrome P-450 pathway
- has effect on EXTRINSIC pathway and increase in PT
- Long half-life

9

Warfarin: Clinical Use

Chronic anticoagulation (after STEMI, venous thromboembolism prophylaxis, and prevention of stroke in atrial fibrillation).

Follow PT/ INR values

** Don't use in pregnncy, because unlike heparin, warfarin can cross placents

10

Warfarin: Toxicity

Bleeding, teratogenic, skin/tissue necrosis, drug-drug interactions

11

Treatment to reverse warfarin overdose

- Give vitamin K
- For rapid reversal of severe warfarin overdose, give fresh frozen plasma

12

Heparin

- large anionic, acidic polymer
- given parentally (IV, SC)
- acts on blood
- rapid onset
- activates thrombrin, by decreasing action of IIa (thrombrin) and factor Xa
- lasts for hours
- inhibits coagulation in vitri
- overdose treated with protamine sulfate
- monitor PTT
- doesn't cross placenta

13

Warfarin

- small lipid-soluble molecule
- given orally
- acts on liver
- slow onset, limited by half lives of normal clotting factors
- impairs synthesis of vitamin K-dependent clotting factors (II, VII, IX, X, proteins C and S)
- Vitamin K antagonist
- Lasts for DAYS
- overdose treated with IV Vitamin K or fresh frozen plasma
- Monitor extrinsic pathway (PTT/INR)
- Teratogenic

14

Thrombolytics

Altepase (tPa), reteplase (rPA), tencteplase (TNK-tPA)

15

Thrombolytic: Mechanism

Directly or indirectly aid conversion of plasminogen to plasmi, which cleaves thrombin and fibrin clots.

Increases PT and PTT. NO CHANGE IN PLATELETS

16

Thrombolytics ("-eplase"): Clinical Use

Early MI, early ischemic stroke, direct thrombolysis of severe pulmonary embolism

17

Thrombolytics ("-eplase"): Toxicity

Bleeding.
Contraindicated in patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diathesis, or severe hypertension

18

Tx of thrombolytic ("-eplase") toxicity:

Aminocaproic acid - inhibitor of fibrinolysis

19

Aspirin: 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 produce

- Increased bleeding time, decreased thromboxane and prostaglandins

- NO EFFECT on PT and PTT

20

Aspirin: Clinical Use

Antipyretic, analgesic, anti-inflammatory, antiplatelet (decreased aggregation)

21

Aspirin: Toxicity

Gastric ulceration, tinnitus (CN VIII).
Chronic used can lead to acute renal falire, interstitial nephritis, and upper GI bleeding

** Reye's syndrome in children with with viral effection

22

Treatment of Apsitin toxicity

N-acetylation -
Aspirin toxicity is respiratory alkaltois and metabolic acidosis

23

ADP receptor inhibitos

Clopidogrel, Ticlipidine, Prasugrel, Ticagrelor

24

ADP Receptor Inhibitor: Mechanism

Inhibit platelet AGGREGATION by irreversibly binding ADP receptors. Inhibit fibrinogen binding by preventing glycoprotein IIb/IIIa from binding to fibrinogen

25

ADP receptor inhibitor: Clinical Use

Acute coronary syndrome
Coronary stenting
Decreased incidence or recurrence of thrombotic stroke

26

ADP Receptor Inhibitior: Toxicity

Neutropenia (ticlopidine)

27

Cliostazol, Dipyridamole: Mechanism

Phosphodiesterase III inhibitor;
Increased cAMP in platelets, thus inhibiting platelet aggregation
Vasodilators

28

Cliostazol, Dipyridamole: Clinical Use

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

29

Cliostazol, Dipyridamole: Toxicity

Nausea, headache, facial flushing, hypotension, abdominal pain

30

GP IIb/IIIa inhibitors

Abciximab, Eptifibatide, Tirofiban

31

GP IIb/IIIa Inhibitors (Abciximab, Eptifibatide, Tirofiban): Mechanism

Bind to the glycoprotein receptor IIb/IIa on activated platelets, preventing aggregation.

Abciximab is made from monoclonal antibody Fab fragments

32

GPIIb/IIIa inhibitors (Abciximab, Eptifibatide, Tirofiban): Clinical USe

Acute coronary syndromes, percutaneous transluminal coronary angioplasty

33

GPIIb/IIIa inhibitors (Abciximab, Eptifibatide, Tirofiban)

Bleeding, thrombocytopenia

34

Methotrexate (MTX): Mechanism

Folic acid analog that inhibits dihydrofolate reductase --> less dTMP --> less DNA and less protein synthesis

35

Methotrexate (MTX): Clinical Use

Cancers: leukemias, lymphomas, choriocarcinoma, sarcomas

Non-neoplastic: abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis

36

Methotrexate (MTX): Toxicity

Myelosuppression, which is reversible with leucorvorin (folinic acid) "rescue"

Macrovesicular fatty chain in liver

- Mucositis
- Teratogenic

37

5-Fluorouracil (5-FU): Mechanism

Pyrimadine analog bioactivated to 5F-dUMP which covalently complexes folic acid.

This complex inhibits thymidylate synthase --> dTMP --> less DNA and protein synthesis

38

5-Fluorouracil (5-FU): Clinical Use

Colon cancer, basal cell carcinoma (topical)

39

5-Fluorouracil (5-FU): Toxicity

Myelosuppression, which is NOT reversible with leucorvorin

Overdose: "rescue" with thymidine

Photosensitivity

40

Cytarabine (arabinofuranoysl cytidine): Mechanism

Pyrimidine analog --> inhibition of DNA polymerase

41

Cytarabine: Clinical Use

Leukemias, lymphomas

42

Cytarabine: Toxicity

Leukopenia, thrombocytopenia, megaloblastic anemia

43

Azathoprine ; 6-mercaptopurine; 6-thioguanine : Mechanism

Purine (thiol) analogs --> decreased de novo purine synthesis

- Activated by HGPRT

44

Azathoprine; 6-mercaptopurine; 6-thioguanine: Clinical Use

Leukemias

45

Azathoprine; 5-mercaptopurine; 6-thioguanine: Toxicity

Bone marrow, GI, liver

Metabolized by xanthine oxidase --> thus increase toxicity with allopurinol

46

Dactinomycin (actinomycin D): Mechanism

Intercalates in DNA

47

Dactinomycin (actinomycin D): Clinical Use

Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma

Used for childhood tumors ("children ACT out")

48

Dactinomycin (actinomycin D): Toxicity

Myelosuppression

49

Doxorubicin (Adriamycin), Daunorubicin: Mechanism

Generate free radicals
Noncovalently interalate in DNA --> breaks in DNA --> decreased replication

50

Doxorubicin (Adriamycin), Daunorubicin: Clinical Use

Solid tumors, leukemias, lymphomas

51

Doxorubicin (Adriamycin), Daunorubicin: Toxicity

Cardiotoxicity (dilated cardiomyopathy), myelosuppression, Alopecia

Toxic to tissues following extravasation

Dexrazozane (Fe chelating agent), used to prevent cardiotoxicity

52

Bleomycin: Mechanism

Induces free radical formation , which causes breaks in DNA

53

Bleomycin: Clinical Uses

Testicular cancer, Hodgkin's lymphoma

54

Bleomycin: Toxicity

Pulmonary fibrosis, skin changes.

Minimal myelosuppression

55

Cyclophosphamide; Ifosfamide: Mechanism

Covalently X-link (interstrand) DNA at guanine N-7. Require bioactivation by liver

56

Cyclophosphamide; Ifosfamide: Clinical Use

Solid tumors, leukemia, lymphomas, and some brain cancers

57

Cyclophosphamide; Ifosfamide: Toxicity

Myelosuppression;
Hemorrhagic cystitis, partially prevented with mesna (thiol group of mesna binds toxic metabolite)

58

Nitrosoureas (carmustine, lomustine, semustine, streptozocin): Mechanism

Alkylating agent
Require bioactivation
Cross blood-brain barrier --> CNS

59

Nitrosoureas (carmustine, lomustine, semustine, streptozocin): Clinical Use

Brain tumors (including glioblastoma multiforme)

60

Nitrosoureas (carmustine, lomustine, semusine, streptozocin): Toxicity

CNS toxicity (dizziness, ataxia)

61

Bulsulfan: Mechanism

Alkylates DNA

62

Bulsulfan: Clinical Use

CML. Also used to ablate patient's bone marrow before bone marrow before transplantation

63

Bulsulfan: Toxicity

Pulmonary fibrosis, hyperpigmentation

64

Vincristine, Vinblastine: Mechanism

Alkaloids that bind to tubulin in M phase and block polymerization of microtubules so that mitotic spindle cannot form.

"Microtubules are the vines of your cells"

65

Vincristine, Vinblastine: Clinical Use

Solid tumors, leukemias, and lymphomas

66

Vincristine, Vinblastine: Toxicity

Vincristine - nephrotoxicity ( areflexia, peripheral neuritis), paralytic ileus

Vinblastine - myelosuppression

67

Paclitaxel, other taxols: Mechanism

Hyperstabilize polymerized microtubules in M phase so that mitotic spindle cannot breakdown (anaphase cannot occur)

68

Paclitaxel, other taxols: Clinical Use

Ovarian and breast carcinomas

69

Paclitaxel, other taxols: Toxicity

Myelosuppression and hypersensitivity

70

Cisplatin, carboplatin: Mechanism

Cross-link DNA

71

Cisplatin, carboplatin: Clinical Use

Testicular, bladder, ovary, and lung carcinomas

72

Cisplatin, carboplatin: Toxicity

Nephrotoxicity and acoustic nerve damage. Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride diuresis

73

Etoposide, Tenoposide: Mechanism

Inhibit DNA topoisomerase II --> increased DNA degradation

74

Etoposide: Tenoposide: Clinical Use

Solid tumors, leukemias, lymphomas

75

Etoposide, Tenoposide: Toxicity

Myelosuppression, GI irritation

76

Hydroxyurea: Mechanism

Inhibits ribonucleotide reductase --> less DNA Synthesis (S phase specific)

77

Hydroxyurea: Clinical Use

Melanoma, CML, sickle cell disease (increase HbF)

78

Hydroxyurea: Toxicity

Bone marrow suppression, GI upset

79

Prednisone, Prenisolone: Mechanism

May trigger apoptosis. May even work on non-dividing cells.

80

Prednisone, Prenisolone: Clinical Use

Most commonly used glucocorticoid in cancer chemotherapy. Used in CLL, non-Hodgkin's lymphoma (part of combination chemotherapy regimen).

- Also used as an immunosuppressant (e.g. autoimmune disease)

81

Prednisone, Prenisolone: Toxicity

Cushing-like symptoms; immunosuppression, cataracts, acne, osteoporosis, hypertension, peptic ulcers, hyperglycemia, psychosis

82

Tamoxifen, Raloxifene: Mechanism

SERMs- receptor antagonist in breast and antagonist in bone. Block the binding of estrogen to estrogen-positive cells

83

Tamoxifen, Raloxifene: Clinical Use

Breast cancer treatment and prevention. Also useful to prevent osteoporosis

84

Tamoxifen Toxicity

Partial agonist in endometrium, which increases risk of endometrial cancer , "hot flashes"

85

Raloxifene: Toxicity

No increased risk of endometrial cancer because it is an endometrial antagonist

86

Trastuzumab (Herceptin): Mechanism

Monoclonal antibody against HER-2 (cerbB2), tyrosine kinase. Helps kill breast cancer that overexpress HER-2, possibly through antibody-dependent cytotoxicity

87

Trastuzumab (Herceptin): Clinical Use

HER-2 positive breast cancer

88

Trastuzumab (Herceptin): Toxicity

Cardiotoxicity

89

Imatinib (Gleevac): Mechanism

Philadelpha chromosome bcl-acr tyrosine kinase inhibitor

90

Imatinib (Gleevac): Clinical Use

CML, GI stromal tumors

91

Imatinib (Gleevac): Toxicity

Fluid retention

92

Rituximab: Mechanism

Monoclonal antibody against CD20, which is found in B cell neoplasms

93

Rituximab: Clinical Use

Non-Hodgkin's lymphoma, rheumatoid arthritis (with methotrexate)

94

Vemurafenib: Mechanism

Small molecule inhibitor of forms of B-RAF kinase with V600E mutation

95

Vemurafenib: Clinical Use

Metastatic melanoma

96

Bevacizumab: Mechanism

Monoclonal antibody against VEGF angiogenesis

97

Bevacizumab: Clinical Use

Solid tumors

98

Cisplatin/Carboplatin Toxicity

Acoustic nerve damage (and nephrotoxicity)

99

Vinecristine: toxicity

Peripheral neuropathy

100

Belomycin, Busulfan: Toxicity

Pulmonary fibrosis

101

Doxorubicin: Toxicity

Cardiotoxicity

102

Trastuzumab: Toxicity

Cardiotoxicity

103

Cyclophosphamide

Hemorrhagic cystitis

104

5-FU and 6-MP: Toxicity

Myelosuppression

105

Methotrexate: Toxicity

Myelosuppression