Exam 2 Flashcards Preview

Pharmacology > Exam 2 > Flashcards

Flashcards in Exam 2 Deck (130):
1

Carcinomas

- Epithelial cell origin (ectodermal or endodermal tissues)
- Example: lung, colon, breast and prostate

2

Sarcomas


- Mesodermal tissue origin (predominantly CT)
- Example: bone cancer

3

Leukemia vs lymphomas


- Leukemia: neoplasms involving bone marrow and peripheral blood
- Lymphomas: neoplasms of B or T lymphocytes that commonly present as masses in lymph nodes or other soft tissue
o Hodgkin (abnml type of B lymphocyte)
o Non-Hodgkin

4

What are the hallmarks of cancer?


1. Evading growth suppressors (eg. P53)
2. Sustaining proliferative signaling (eg. Proto-oncogene)
3. Deregulating cellular energetics
4. Resisting apoptosis
5. Genome instability and mutation
6. Inducing angiogenesis
7. Activating invasion and metastasis
8. Tumor-promoting inflammation
9. Replicative immortality
10. Avoiding immune destruction

5

What are proto-oncogenes?


- Genes encoding proteins that facilitate normal cell growth. When mutated, these become oncogenes (= cancer).

6

Cancers resulting from IGF mutations

- Prostate, breast and colorectal

7

EGFR mutations can result in what cancers?

- Breast. Product of EGFR mutation = Her2, a product of the EGF-R proto-oncogene.

8

C-myc mutations can result in what cancers?

- Colorectal and lung cancers

9

3 mechanisms of oncogene formation


1. Point mutation = hyperactive gene product

2. Gene amplification = normal gene product in excess

3. Chromosomal translocations = fusion protein with oncogenic activity

10

Describe the cell cycle


- G1: synthesis of cell components needed for DNA synthesis

- S: replication of DNA genome

- G2: synthesis of cellular components needed for mitosis

- M: mitosis/cell division

11

What are the 3 cell cycle checkpoints? What are the goals of each checkpoint?


- G1/S: Are cells nutrition, size and environment favorable to enter DNA replication? Is all DNA intact? If so, cell can enter S phase and replicate DNA.

- G2/M: Is DNA completely replicated? If so, cell can enter mitosis.

- Metaphase/anaphase (w/in M phase): Is all DNA intact? Are all chromosomes attached to the mitotic spindle? If so, cell can begin chromatid separation and prepared for cytokinesis.

12

What are the implications of low therapeutic index of chemotherapeutics?


- D/t collateral damage, dosing is limited to a certain window.

- Problem with this: dosing may not kill all tumor cells and some can become resistant. Might need to use combo therapy to combat this.

13

Goals of CA drug therapy?


1. Curative: eg. ALL, testicular CA, AML

2. Adjuvant therapy: given after primary treatment (often surgery) to decrease chance that cancer will return.

3. Neoadjuvant therapy: shrink tumor before surgery.

4. Palliative care

14

Cell Kill Hypothesis. What is the clinical implication of this?


- Chemo drugs kill a constant PROPORTION (not #). This is first-order kinetics. Log kill curve. Eg. If a drug kills 99% of cells with dose 1, second dose won’t kill remaining 1%, but only 99% of that 1% remaining.

- Clinical implication: between doses, CA cells grow continuously, so next dose must be given quickly. Problem is toxic side-effects and also resistance development.

15

Mechanisms of resistance to chemotherapy


- Drug efflux

- DNA damage repair

- Cell death inhibition

- Epithelial-mesenchymal transition (EMT): process by which cells loose adhesive properties becoming motile and to become resistant.

- Drug target activation

- Drug inactivation

- Epigenetics

16

Common adverse effects to anti-neoplastic agents


- Hematologic: BM toxicity, anemia, immunosuppression, bleeding. Can tx with EPO and G-CSF.

- GI tract: diarrhea, nausea, vomiting, ulceration (leading to infection), irritation of oral cavity (oral mucositis)

- Carcinogenic

- Teratogenic

- Alopecia

- Impaired wound healing

17

General mechanisms of antineoplastic agents

1. Cytotoxic
a. Perturb normal DNA replication

b. Perturb mitosis

c. Starve cells of amino acids

2. Targeted
a. Perturb hormone and GF signaling

b. Inhibiting blood supply

c. Target proteins leading to tumor growth

18

Base vs Nucleoside vs nucleotide


- Base: A, G, C, T, U

- Nucleoside: base w/sugar

- Nucleotide: base w/sugar w/phosphate

19

Classes of antineoplastic agents, general mechanism and drug names.

1.) Antimetabolites: Block de novo nucleotide biosynthesis

- Drugs: purine analogs (6-mercaptopurine, 6-thioguanine, fludarabine, cladribine), pyrimidine analogs (cytarabine, 5-fluorouracil, gemcitabine, capecitabine) and folic acid analog (methotrexate)

2.) Alkylating agents: causes DNA cross-linking and strand breakage

- Drugs: nitrogen mustards (mechlorethamine, cyclophosphamide) and nitrosoureas (carmustine (BCNU))

3.) Non-classical alkylating agents: DNA cross-linking, no alkyl group like classic agents

- Drugs: platinum analogs (cisplatin, carboplatin, oxaliplatin) and other (procarbazine, decarbazine, temozolomide)

4.) Plant derivatives + similar: antimicrotubule for taxanes and camptothecans/others as topo inhibitors

- Drugs: taxanes (paclitaxel), vinca alkaloids (vinblastine, vincristine), camptothecans (irinotecan, topotecan) and other (etoposide)

5.) Cytotoxic antibiotics

- Drugs: anthracyclines (doxorubicin) and other (bleomycin)

6.) Hormones agonists/antagonists:

- Drugs: glucocorticoids (prednisone, dexamethasone), estrogen receptor antagonists (tamoxifen), androgen receptor antagonists (flutamide), aromatase inhibitors (anastrozole)

7.) Monoclonal antibodies (-ab):

- Drugs: VEGF inhibitor (bevacizumab), HER-2 inhibitor (trastuzumab), EGFR inhibitor (cetuximab)

8.) Small molecule kinase inhibitors:

- Drugs: lapatinib, erlotinib, imatinib

9.) Miscellaneous:

- Drugs: asparaginase, bortezomib, temsirolimus

20

Methotrextate. Class, MOA, indication, adverse effects (toxicities), resistance


- Class: antimetabolite (folic acid analog)

- MOA: DHFR (DIHYDROFOLATE REDUCTASE) INHIBITOR preventing dihydrofolate conversion to THF. This inhibits purine dTMP synthesis (from dUMP) via thymidylate synthetase. OVERALL: REDUCTION OF CELL PROLIFERATION AND INDUCES CELL DEATH BY REDUCING PRECURSORS FOR RNA AND DNA SYNTHESIS.

- Indication: ALL in children (sgl tx), Osteosarcomas (high dose), Choriocarcinoma (placental origin) – high cure rate, Combo therapy: lymphoma, leukemias and breast, head/neck, ovary, bladder

- Adverse effects: bone marrow suppression and intestinal epithelium death; hepatic dysfunction; interstitial pneumonitis; nephrotoxicity. Use leucovorin (folinic acid).

- Resistance: impaired transport, altered forms of DHFR with decreased affinity for drug, elevated DHFR expression

21

Drug used to reduce methotrexate toxicity.

- Leucovorin (folinic acid)

22

5-Fluorouracil (5-FU). Class, MOA, indication, adverse effects (toxicities), other

- Class: antimetabolite (pyrimidine analog)

- MOA: metabolized into FdUMP, which INHIBITS THYMIDYLATE SYNTHASE, REDUCING DNA PRECURSORS. This causes DNA damage by decreasing dTMP levels leading to cell death. Converted to FdUTP and FUMP and INCORPORATED INTO DNA AND RNA RESPECTIVELY = RNA and DNA damage = cell death.

- Indications: part of combo cocktail for breast, head, neck, colorectal and GI CAs

- Adverse effects: oral and GI ulcers and bone marrow suppression

- Other: capecitabine = prodrug of 5-FU with improved PO bioavailability

23

Cytarabine (cytosine arabinoside, ara-C). Class, MOA, indication, adverse effects (toxicities), resistance

- Class: antimetabolite (pyrimidine analog)

- MOA: DEOXYCYTIDINE KINASE converts ara-C into ara-CMP, which can then be converted to ara-CTP, an analog of cytosine, which is incorporated into DNA and INHIBITS DNA POL, halting DNA synthesis. Only active in s-phase.

- Indication: AML (most important antimetabolite in treating this), only used in tx of hematologic malignancies (not good at solid tumors)

- Adverse effects: CEREBELLAR SYNDROME (dysarthria, nystagmus, ataxia). Why? Cytidine deaminase inactivates drug. CNS has low levels of this. Toxicity also w/renal dysfunction, hepatic dysfunction and advancing age. Also myelosuppression.

- Resistance: downregulation/loss of deoxycytidine kinase = primary mechanism of resistance. Also cytidine deaminase upregulation in tumor = increase ara-C inactivation.

24

Most important anti-metabolite in treating AML

- Cytarabine (antimetabolite pyrimidine analog)

25

Gemcitabine. Class, MOA, indication, adverse effects (toxicities), resistance


- Class: antimetabolite (pyrimidine analog)

- MOA: DEOXYCYTIDINE ANALOGUE INCORPORATED INTO DNA INHIBITING SYNTHESIS AND FUNCTION. INHIBITS RIBONUCLEOTIDE REDUCTASE (RNR), REDUCING POOLS OF DNTPS NECESSARY FOR DNA SYNTHESIS.

- Indications: Wide-range of CAs: pancreatic, non-small cell lung, ovarian, bladder etc.

- Adverse effects: ?

- Resistance: reduced activity of deoxycytidine kinase, increasing production of deoxycytidine

26

6-Thioguanine (6-TG) and 6-Mercaptopurine (6-MP). Class, MOA, indication, adverse effects (toxicities), resistance

- Class: antimetabolites (purine analogs)

- MOA: activated into thio-GMP and thio-IMP via enzyme: HGPRT (HYPOXANTHINE-GUANINE PHOSPHORIBOSYL TRANSFERASE). These can INHIBIT PURINE SYNTHESIS, but also INCORPORATED INTO DNA leading to inhibition of DNA function via damage.

- Indication: ALL, largely replaced by newer fludarabine and cladribine

- Adverse effects: Thiopurine methyltransferase inactivates 6MP. Common gene variant of this leads to life-threatening toxicity. Must screen patient genomically.

- Resistance: decreased expression of HGPRT ez.

27

Fludarabine. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: antimetabolite (purine analog)

- MOA: activated by deoxycytidine kinase, INCORPORATED INTO DNA AND RNA, INHIBITS DNA POL AND RIBONUCLEOTIDE REDUCTASE (RNR), inhibits RNA function

- Indication: CLL as single agent or combo

- Adverse effects: ?

- Resistance: decreased activity of deoxycytidine kinase (necessary to activate drug), drug efflux

28

Cladribine. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: antimetabolite (purine analog)

- MOA: activated by deoxycytidine kinase, INCORPORATED INTO DNA CAUSING STRAND BREAKS, INHIBITOR OF RNR (RIBONUCLEOTIDE REDUCTASE)

- Indication: hairy cell leukemia (HCL) curatively

- Adverse effects: ?

- Resistance: commonly with decreased activity of deoxycytidine kinase (necessary for drug activation), drug efflux and increased RNR expression

29

Cyclophosphamide. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: alkylating agent (nitrogen mustard)

- MOA: causes DNA cross-linking and strand breakage

- Indication: ?

- Adverse effects: HEMORRHAGIC CYSTITIS CAUSED BY ACROLEIN (CO-ADMINISTER WITH MESNA TO INACTIVATE THIS), myelosuppression, nausea and vomiting.

- Resistance: see general flashcard

30

Carmustine (BCNU). Class, MOA, indication, adverse effects (toxicities), resistance

- Class: alkylating agent (nitrosurea)

- MOA: causes DNA cross-linking and strand breakage

- Indication: brain tumors (lipophilicity allows for crossing of BBB), secondary tx of Hodgkin’s or non-Hodgkin’s.

- Adverse effects: profound myelosuppression and other general adverse effects of alkylating agents

- Resistance: see general flashcard

31

What are general adverse effects of alkylating agents?


- Mutagenic, teratogenic and myelosuppressive

- Bone marrow suppression and intestinal mucosa damage

- Can cause leukemia

- Some have strong vesicant (blistering) properties that can damage veins with repeated use

32

What are the general resistance mechanisms for alkylating agents?

- Inactivation by glutathione and other nucleophiles,

- reduced uptake

- accelerated DNA repair

- increased expression of MGMT (methylguanine-DNA-methyltransferase): prevent DNA damage by removing alkyl groups from guanine before cross-links form

33

Cisplatin. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: non-classical alkylating agent (1st generation)

- MOA: transported into cell via Cu2+ transporter, targets N-7 on guanine

- Indication: wide range of cancers

- Adverse effects: PERIPHERAL MOTOR AND SENSORY NEUROPATHY, NEPHROTOXICITY (SIGNIFICANTLY REDUCED BY INCREASING HYDRATION, SO GIVE WITH SALINE), risk of leukemia, nausea/vomiting, mild myelosuppression, tinnitus/hearing loss, electrolyte disturbance, anaphylactic-like rxns

- Resistance: ?

34

Carboplatin


- Class: non-classical alkylating agent (2nd generation)

- MOA: transported into cell via Cu2+ transporter, targets N-7 on guanine

- Indication: wide range of cancers

- Adverse effects: risk of leukemia, myelosuppression, anaphylactic-like rxns

- Resistance: ?

35

Differences in toxicities between cisplatin and carboplatin

- Cisplatin: nausea, peripheral neuropathy, ototoxicity, nephrotoxicity. Mild myelosuppression.

- Carboplatin: less nausea and neuro/oto/nephro-toxicities. Myelosuppression more than cisplatin.

36

Procarbazine. Class, indication


- Class: non-classical alkylating agent

- Indication: Hodgkin’s dz

37

Decarbazine


- Class: non-classical alkylating agent

- Indication: part of combo curative tx for Hodgkin’s lymphoma; melanomas and sarcomas

38

Temozolomide


- Class: non-classical alkylating agent

- Indication: glioblastoma and metastatic melanoma

39

Vinblastine. Class, MOA, indication, adverse effects (toxicities), resistance


- Class: plant derivative Vinca alkaloid

- MOA: antimicrotubule agent blocks mitosis

- Indication: ?

- Adverse effects: significant myelosuppression

- Resistance: ?

40

Vincristine. Class, MOA, indication, adverse effects (toxicities), resistance


- Class: plant derivative Vinca alkaloid

- MOA: antimicrotubule agent blocks mitosis

- Indication: ?

- Adverse effects: neurolotoxicities (numbness/tingling, motor weakness), limited myelosuppression

- Resistance: ?

41

Compare and contrast adverse effects between vinblastine and vincristine. How does this compare with cisplatin and carboplatin?


- Vinblastine: significant myelosuppression

- Vincristine: neurotoxicities (numbness, tingling, motor weakness), limited myelosuppression.

- Cisplatin: nausea, peripheral neuropathy, ototoxicity, nephrotoxicity. Mild myelosuppression.

- Carboplatin: less nausea and neuro/oto/nephro-toxicities. Myelosuppression more than cisplatin.

- So, cisplatin like vincristine. Carboplatin like vinblastine.

42

Paclitaxel. Class, MOA, indication, adverse effects (toxicities), resistance


- Class: plant derivatives taxane

- MOA: antimicrotubule agent (prevents depolymerization of microtubules)

- Indication: ?

- Adverse effects: peripheral neuropathy, bone marrow toxicity, myelosuppression (use with filgrastim, which is a G-CSF to reduce it), hypersensitivity reaction (tx with dexamethasone and anti-histamines)

- Resistance: ?

43

Antineoplastic agents that have neurotoxicities as major adverse effects

- Vincristine , cisplatin, paclitaxel, bortezomib, cytarabine

44

Which drugs are topoisomerase I and II inhibitors?


- Irinotecan and topotecan: class I

- Etoposide: class II

- Also note: doxorubicin = topo II inhibitor

45

Doxorubicin. Class, MOA, indication, adverse effects (toxicities), resistance


- Class: cytotoxic abx (anthracyclines)

- MOA: intercalates with DNA = inhibition of DNA pol; inhibits topo II causing ds breaks = cell death. Also binds free iron = free radical = DNA and protein damage (not major mechanism).

- Indication: ?

- Adverse effects: irreversible cardiomyopathy (unique, co-administer with dexrazoxane and iron chelator), myelosuppression

- Resistance: ?

46

Bleomycin. Class, MOA, indication, adverse effects (toxicities), resistance


- Class: cytotoxic abx (other)

- MOA: small peptide that binds to DNA and causes ss and ds breaks CAUSES ARREST IN G2.

- Indication: part of combo for testicular CA and Hodgkin’s dz

- Adverse effects: irreversible and cumulative pulmonary toxicity (Bleo makes you blue)

- Resistance: ?

47

Antineoplastic drugs that are myelosuppressive?


- High toxicity = vinblastine, doxorubicin, cytarabine, carmustine, cyclophosphamide, carboplatin (high to med)

- Low = bleomycin, vincristine, methotrexate (+ leucovorin)

48

Prednisone/dexamethasone. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: hormone antagonist

- MOA: inhibits lymphocyte proliferation

- Indication: leukemias, lymphomas, reduces intracranial pressure associated w/brain tumors, also reduces effects of chemo such as nausea and vomiting

- Adverse effects:

- Resistance: ?

49

Tamoxifen. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: Partial estrogen receptor antagonist

- MOA: non-steroid agent that binds to ER and reduces growth of estrogen dependent breast cancers

- Indication: estrogen-dependent/sensitive breast cancers

- Adverse effects: increases risk for endometrial cancer

- Resistance: ?

50

Anastrozole. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: aromatase inhibitors

- MOA: inhibits aromatase activity, lowering estrogen levels

- Indication: estrogen-dependent/sensitive breast cancers (in post-meno women)

- Adverse effects: ?

- Resistance: ?

51

Flutamide. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: androgen receptor inhibitors

- MOA: prevent DHT from binding to androgen receptors

- Indication: prostate cancer

- Adverse effects: ?

- Resistance: ?

52

Leuprolide and goserelin. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: GnRH agonists

- MOA: causes desensitization of GnRH receptor on anterior pituitary

- Indication: prostate cancer

- Adverse effects: ?

- Resistance: ?

53

Degarelix. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: GnRH antagonist

- MOA: blocks GnRH receptor on anterior pituitary = decrease FSH, LH release = decrease testosterone

- Indication: prostate cancer

- Adverse effects: ?

- Resistance: ?

54

Trastuzumab (Herceptin). Class, MOA, indication, adverse effects (toxicities), resistance

- Class: monoclonal HER-2 ab

- MOA: binds to EC part of HER-2 receptor, blocking signaling. Also induces antibody-dependent cytotoxicity

- Indication: HER-2 amplified breast cancer

- Adverse effects: cardiotoxicity is most serious

- Resistance: ?

55

Antineoplastic drugs with cardiotoxicities

- Doxorubicin and trastuzumab (Herceptin)

56

Cetuximab. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: monoclonal EGFR ab

- MOA: binds to EGFR and blocks signaling

- Indication: in combo w/radiation to tx head and neck cancers

- Adverse effects: ?

- Resistance: activating mutations in RAS in colorectal tumors cause cells to be resistant, must perform routine tests of RAS status

57

Bevacizumab. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: monoclonal VEGF ab

- MOA: binds to VEGF and prevents it from binding to VEGF-R preventing angiogenesis

- Indication: colorectal (in combo), metastatic breast (in comb)

- Adverse effects: HTN, increase risk of thrombosis or bleeding, increase risk of GI perf, decrease wound healing

- Resistance: ?

58

Lapatinib. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: small molecule inhibitor

- MOA: inhibits both EGFR and HER-2 kinase

- Indication: HER-2 amplified, trastuzumab refractory breast cancer (in combo with capecitabine)

- Adverse effects: skin rashes, diarrhea, cramping, worse GI reflux

- Resistance: ?

59

Erlotinib. Class, MOA, indication, adverse effects (toxicities), resistance


- Class: small molecule EGFR inhibitor

- MOA: inhibits EGFR and ATP

- Indication: metastatic non-small lung carcinoma (first like) – must determine mutation status with and FDA approved – only certain deletions or substitution mutations

- Adverse effects: diarrhea, skin rash, anorexia, fatigue

- Resistance: acquired second mutation in EGFR or by amplification of MET oncogene

60

Imatinib (Gleevec). Class, MOA, indication, adverse effects (toxicities), resistance

- Class: small molecule inhibitor of BCR-ABL

- MOA: inhibits BCR-ABL. CML is caused by Philadelphia c/s translocation = fusion between BCR and ABL tyrosine kinase = constitutive activity of ABL

- Indication: CML

- Adverse effects: ?

- Resistance: point mutations in BCR-ABL cause a reduced affinity for drug – drug analogs can still work

61

Asparaginase. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: antineoplastic enzyme

- MOA: hydrolyzes plasma L-asparagine into L-aspartate. Tumor cells cannot synthesize (low synthetase) sufficient L-asparagine. Cancer cells now starved.

- Indication: childhood ALL

- Adverse effects: allergic hypersensitivity rxn (fever, chills, rash, hives) that can progress to severe with respiratory failure and hypotension

- Resistance: ?

62

Bortezomib. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: proteasome inhibitor

- MOA: inhibition of proteasome = elevated levels of p53 and inhibition of NF-kappaB

- Indication: relapsed or refractory multiple myeloma

- Adverse effects: thrombocytopenia, PERIPHERAL NEUROPATHY (chronic), neutropenia, anemia

- Resistance: ?

63

Temsirolimus. Class, MOA, indication, adverse effects (toxicities), resistance

- Class: mTOR complex 1 inhibitor

- MOA: inhibition of mTOR complex 1 = reduction in protein translation, promotes cell cycle inhibition and promotes apoptosis

- Indication: renal cell carcinoma

- Adverse effects: skin rash, mucositis, anemia, leukopenia, thrombocytopenia, hyperglycemia and hypertriglyceridemia

- Resistance: mTOR forms a complex called mTOR complex 2, which isn’t inhibited by this drug

64

Antineoplastic agents that are nephrotoxic

- Cisplatin, methotrexate

65

Antineoplastic agents that are cardiotoxic

- doxorubicin and trastuzumab

66

Antineoplastic agents that have pulmonary toxicities

- methotrexate, bleomycin, alkylating agents

67

Antineoplastic agents that have bladder toxicities

- cyclophosphamide cause hemorrhage cystitis

68

Antineoplastic agents that cause hypersensitivity reactions

- asparaginase and paclitaxel

69

Briefly describe platelet activation and formation of clot


- G1b (on platelet) binds to vWF (on collagen at injury) = activation of platelet

- They secrete ADP, TXA2, 5-HT = activation of GPIIb/IIIa

- GPIIb/IIIa binds fibrinogen = soluble temporary plug

- Intrinsic/extrinsic pathay activated = thrombin formation

- Thrombin cleaves fibrinogen to fibrin = insoluble plug. Thrombin also further activates more platelets through binding to PAR (protease activated receptor)

70

Two mechanisms used by anticoagulation system to prevent coagulation

- Preventing thrombin-mediated fibrin clot formation through coagulation factor inhibition

- Destroying thrombin already formed

71

Overview of anticoagulation system

- Thrombomodulin (on ECs) can bind thrombin. Complex cleaves protein C into activated form. With protein S, factors V and VIII are degraded preventing further formation of thrombin.

- Antithrombin in plasma inactivates thrombin and factor Xa slowly. Heparin sulfate on ECs can bind antithrombin significantly increasing rate of thrombin and factor Xa inactivation.

72

How does antithrombin/heparin function to inactivate thrombin? Does it work when thrombin is bound to fibrinogen?

- Thrombin binds to fibrin at its E1 site to prevent diffusion of thrombin from clot site.

- When bound, thrombin is not able to be inhibited by AT/heparin complex.

73

Define thrombosis and describe differences between arterial and venous thrombosis

- Thrombosis: inappropriate clot formation

- Venous: platelet poor/red thrombus, often at valve cusps where slow moving blood (coag system activated) leading to VTE, which can cause PE. Antiplatelets not useful d/t platelet poor thrombus.

- Arterial: platelet rich/white thrombus, typically occur on top of ruptured atherosclerotic plaques where thrombogenic material exposed leading to MI and ischemic strokes. Antiplatelets very useful.

74

Describe common causes of thrombosis

- Factor V leiden

- G20210A prothrombin gene mutation


- Deficiencies in protein C or S

- Deficiency of antithrombin

- other: cancer, afib, mechanical valves, major surgery, prolonged bed rest, OCPs

75

Classes of antiplatelet drugs, names

a) TXA2 inhibitors: aspirin

b) Phosphodiesterase inhibitor: dipyridamole

c) P2Y12 (ADP/receptor) inhibitors: clopidrogel, ticagrelor, cangrelor, prasugrel

d) GIIb/IIIa receptor inhibitors: abciximab, eptifibatide, tirofiban

e) PAR inhibitor: vorapaxar

76

Aspirin. Class, MOA, indication

- Class: COX / TXA2 inhibitor

- MOA: irreversibly blocks COX-1 in platelets reducing TXA2 production = block platelet activation, aggregation and vasoconstriction

- Indication: antiplatelet (prevent MI, stroke etc.)

77

Dipyridamole. Class, MOA, indication

- Class: antiplatelet, phosphodiesterase inhibitor

- MOA: inhibit phosphodiesterase, which normally degrades cAMP. Now increase cAMP = decrease Ca = activation and aggregation of platelets inhibited. Also inhibits reuptake of adenosine and promotes adenosine A2 receptor interaction causing same effect on Ca. Vasodilator

- Indication: combo with warfarin to inhibit embolization from mechanical heart valves. Also formulated with aspirin.

78

What are the P2Y12 antagonists? MOA/Function? Compare and contrast the metabolism of them.

- These are antiplatelet drugs that block ADP binding at the P2Y12 receptor preventing activation of platelet and aggregation.

- Clopidrogel (Plavix) and prasugrel = irreversible inhibitors. Are taken PO and must be metabolized by liver to become activated. Note: clopidrogel activation depends on CYP2C19. Polymorphisms in some patients and omeprazole (PPI) inhibit/reduce activity in this cytochrome.

- Ticagrelor and cangrelor = reversible inhibitors. Both don’t require liver metabolism to become activated. Cangrelor is newer and is given IV. Ticagrelor is given PO.

- Prasugrel and ticagrelor, although superior to clopidrogel in efficacy, have greater rates of fatal and life-threatening bleeding. Not recommended for use in patients with previous ICH.

79

Abciximab, eptifibatide and tirofiban. Class, MOA, indication, adverse effects

- Class: glycoprotein IIb/IIIa antagonists (anti-platelets)

- MOA:

a. Abciximab: monoclonal Fab segment directed against GPIIb/IIIa. Prevents platelet aggregation by preventing fibrinogen GPIIb/IIIa interaction. Can also bind receptors related to GPIIb/IIIa on leukocytes contributing to anti-inflammatory effects.

b. Eptifibatide: peptide that binds to and inhibits GPIIb/IIIa

c. Tirofiban: non-peptidic small molecules that binds to and inhibits GPIIb/IIIa

- Indications: see anti-platelet flashcard

- Adverse effects: thrombocytopenia and bleeding, lower risk for eptifibatide and tirofiban

80

Vorapaxar (zontivity). Class, MOA, indication, adverse effects

- Class: PAR (protease activated receptor) inhibitor

- MOA: PAR inhibitor, prevents thrombin from further activating platelets

- Indication: prevention of thrombotic CV events in pts with hx of MI or peripheral arterial dz

- Adverse effects: life-threatening IC bleed (contraindicated in pts with previous stroke or other bleeding)

81

Classes of anticoagulants, drug names

a) Indirect inhibitors of thrombin and/or factor Xa: heparin, enoxaparin, fondaparinux

b) Direct thrombin inhibitors (DTIs): lepirudin, bivalirudin, argatroban, dabigatran

c) Direct factor Xa inhibitors: rivaroxaban, apixaban

d) Vit K antagonists (VKA): warfarin

82

Indications for anticoagulants

- Tx and prevention of VTE/thrombosis: afib, surgeries, cancer, DVT and pulmonary thromboembolism

- Used w/antiplatelet drugs to tx MI

83

Indication for antiplatelet drugs

- Primary prevention level: patients at high risk for MI or stroke

- Acute: MI, coronary angioplasty, CABG, CVA

- Secondary prevention level: prevent recurrence

84

Heparin. Class, MOA, indications, adverse effects, other, antidote

- Class: indirect thrombin and factor Xa inhibitor (antithrombin enhancer), anticoagulant

- MOA: heparin binds to antithrombin = conformation change to AT = higher affinity for Xa & accelerated rate of Xa inhibition & also increases AT-induced inhibition of thrombin

- Indication: see anticoag flash card

- Adverse effects: bleeding, osteoporosis with long-term usage

- Other: parenterally (IV usually), cleared by kidneys/liver (non-saturable) or taken up by ECs (saturable), as dose increases, clearance and half-life increases (t1/2 = 0.693 x Vd/CL). Monitor via PTT (intrinsic).

- Antidote: protamine sulfate binds to and inactivates longer heparin molecules

85

Describe the mechanism of heparin-induced thrombocytopenia (type II). What is the treatment?

- Type I: mild transient thrombocytopenia – of little clinical consequence

- Type II: immune thrombocytopenia. Heparin binds platelet factor 4 (from platelets) forming complex to which antibodies are generated. These antibodies bind to platelets, activate them and cause them to be cleared by macrophages leading to thrombosis in venous and arterial system. So you are trying to anticoagulate someone, but you are actually coagulating them. Note: more common with unfractionated heparin than LMW heparin (enoxaparin). Occurs 5-10 days after starting heparin.

- Tx: use DTIs (bivalirudin, lepirudin and argatroban)

86

Enoxaparin (LMWH). Class, MOA, indication, adverse effects, other, antidote

- Class: indirect factor Xa inhibitor (antithrombin enhancer), anticoagulant

- MOA: binds to antithrombin = conformation change to AT = higher affinity for Xa & accelerated rate of Xa inhibition. NB to note: not long enough to facilitate binding of thrombin to AT

- Indication: see anticoagulant flashcard

- Adverse effects: contraindicated in patients with renal insufficiency as clearance by kidney mainly

- Other: advantages over heparin (unfractionated): better bioavailability, dose-independent clearance, predictable anticoag response, lower risk for HIT, lower risk for osteoporosis

- Antidote: protamine only partially reverses

87

How are LMWH (enoxaparin) and heparin different?

- Heparin is unfractionated heparin, enoxaparin is fractionated and LMW. Heparin = indirect inhibitor of factor Xa and thrombin, while LMWH is inhibitor of factor Xa only.

- Protamine only partially reverses LMWH overdose.

- Other benefits: better bioavailability, dose-independent clearance, predictable anticoag response, lower risk for HIT, lower risk for osteoporosis

88

Fondoparinux. Class, MOA, indication, adverse effects, antidote

- Class: indirect factor Xa inhibitor (antithrombin enhancer), anticoagulant

- MOA: synthetic analog of part of heparin (pentasaccharide sequence) that binds to antithrombin = onformation change to AT = higher affinity for Xa & accelerated rate of Xa inhibition. NB to note: not long enough to facilitate binding of thrombin to AT.

- Indication: see anticoag flash card

- Adverse effects: contraindicated in patients with severe renal insufficiency d/t main clearance by kidney


- Antidote: protamine doesn’t reverse

89

What is one of the clinical problems with using LMWH and fondaparinux?

- Can be a problem or advantageous depending on how you look at it. Cannot measure coag time using PTT.

- Can use anti-factor X assay (measure of factor Xa activity) to monitor thes.

90

Lepirudin. Class, MOA, indication, adverse effects, other, antidote

- Class: direct thrombin inhibitor, anticoagulant

- MOA: recombinant form of hirudin (from leach), binds at fibrin binding site and active site of thrombin preventing coagulation (fibrinogen cleavage to fibrin)

- Indication: Anticoagulation in HIT

- Adverse effects: bleeding

- Other: parenteral administration, doesn’t cause HIT

- Antidote: no specific antidote, must hemodialize and administer factor VII or PT complex to reverse bleeding

91

Bivalirudin. Class, MOA, indication, adverse effects, other, antidote

- Class: direct thrombin inhibitor, anticoagulant

- MOA: binds at fibrin binding site and active site of thrombin preventing coagulation (fibrinogen cleavage to fibrin)

- Indication: PCI anticoagulation in HIT

- Adverse effects: bleeding

- Other: parenteral administration, doesn’t cause HIT

- Antidote: no specific antidote, must hemodialize and administer factor VII or PT complex to reverse bleeding

92

Argatroban. Class, MOA, indication, adverse effects, other, antidote

- Class: direct thrombin inhibitor, anticoagulant

- MOA: small molecule inhibitors that bind only to active site of thrombin preventing fibrinogen cleavage to fibrin

- Indication: Anticoagulation in HIT

- Adverse effects: bleeding

- Other: parenteral administration, doesn’t cause HIT

- Antidote: no specific antidote, must hemodialize and administer factor VII or PT complex to reverse bleeding

93

Dabigatran (pradaxa). Class, MOA, indication, adverse effects, other, antidote

- Class: direct thrombin inhibitor, anticoagulant

- MOA: small molecule inhibitors that bind only to active site of thrombin preventing fibrinogen cleavage to fibrin

- Indication: stroke prevention

- Adverse effects: bleeding

- Other: oral

- Antidote: no specific antidote, must hemodialize and administer factor VII or PT complex to reverse bleeding

94

Identify the route of administration of direct thrombin inhibitors and the factor Xa inhibitors.

- DTIs given parenterally (IV) except for dabigatran, which is oral

- Factor Xa inhibitors: SC, except for heparin, which can be given IV

95

Describe the mechanism that explains why DTIs can inhibit thrombin bound to fibrin, while heparin/antithrombin complex cannot

- Both heparin/AT complex and DTIs can inhibit soluble thrombin

- DTIs (only lepirudin and bivalirudin) can inhibit thrombin bound to fibrin as they bind both the active site and the fibrin-binding site. Heparin/AT complex only binds active site and fibrin itself.

96

Blood coagulation study to monitor warfarin (coumadin)? Heparin? LMWH? Fondaparinux

- Warfarin monitored by PT

- Heparin monitored by PTT

- LMWH + fondaparinux by anti-factor Xa assay

97

Warfarin (coumadin). Class, MOA, indication, adverse effects, other, antidote

- Class: vit K antagonist (VKA), anticoagulant

- MOA: 1972 factors + protein C & S are vit K dependent. When vit K reduced, used as a co-factor in carboxylation rxn of these factors to allow Ca binding. Warfarin = small lipid soluble derivative of vit K that competes with vit K for vit K reductase preventing vit K from being put into reduction form.

- Indication: see flashcard on anticoagulant use, long-term mgmt d/t oral activity

- Adverse effects: hemorrhage, birth defect, necrosis (fall in protein C) = hypercoag state. Metabolized by CYP2C9 and others. Variants = lower activity of CYP and patients require low dosing. Drug interactions that increase effect (abx, NSAIDs, SSRI, statins) and lower effect (rifampin, barbs, carbamazepine). Liver dz = decrease clearance = increase INR. Intestine dz = reduced vit K absorption = increase INR. Kidney dz = hypoalbuminemia (where heparin carried) = increase INR.

- Other: takes 3-5 days w/no effect on previously synthesized factors, so must give with fast-acting anticoags (hep, LMWH, fondaparinux), has long half-life. Monitor clotting time via PT INR (extrinsic).

- Antidote: no real antagonists. Vit K administration (requires time d/t need for new factors). Emergency = FFP.

98

What drugs can reverse the actions of warfarin, heparin, DTIs and rivaroxaban/apixaban and the fibrinolytics?

- Warfarin: no real antagonists. Vit K administration (requires time d/t need for new factors). Emergency = FFP.

- Heparin: : protamine sulfate binds to and inactivates longer heparin molecules

- DTIs: no real antagonist, active factor VII or PT complex

- Rivaroxaban/apixaban: no real antagonist, active factor VII or PT complex

- Fibrinolytics:

99

Rivaroxaban. Class, MOA, indication, other, antidote

- Class: direct factor Xa inhibitor, anticoagulant

- MOA: inhibition of factor Xa

- Indication: see anticoagulant flash card

- Other: oral

- Antidote: no real antagonist, active factor VII or PT complex

100

Apixaban. Class, MOA, indication, other, antidote

- Class: direct factor Xa inhibitor, anticoagulant

- MOA: inhibition of factor Xa

- Indication: see anticoagulant flash card

- Other: oral

- Antidote: no real antagonist, active factor VII or PT complex

101

Why are the newer oral anticoagulants beneficial over warfarin? What agents?

- Agents = rivaroxaban (direct factor Xa inhibitor), apixaban (direct factor Xa inhibitor), dabigatran (DTI: direct thrombin inhibitor)

- Faster onset of action, larger therapeutic window, low potential for food and drug interactions, predictable anticoag effect removing need for routine monitoring, overall bleeding risk is similar to warfarin w/lower risk of IC/ICerebral bleeding than warfarin

102

Overview of fibrinolytic system

- tPA (from ECs) and plasminogen have high affinity for fibrin. When bound to fibrin, tPA cleaves plasminogen to plasmin leading to fibrin clot breakdown = FDPs.

103

What are the fibrinolytic drugs?

- Streptokinase (produced by bacteria)

- Urokinase (kidney and other cells)

- tPA (endogenous and recombinant)

104

What drugs can you use to reverse bleeding caused by fibrinolytic therapy?

- Aminocaproic acid (amicar) and tranexamic acid (Cyklokapron): block interaction of plasmin and fibrin preventing fibrin degradation.

- Also used in tx of hemophilia

105

What are the therapeutic uses of alteplase?

- Alteplase = recombinant human tPA.

- tPA cleaves plasminogen to plasmin. Plasmin cleaves fibrin to FPDs breaking up clot

- Use: acute MI (w/STE within 12 hours of onset) = main use. Other uses = acute thrombotic stroke (within 3 hours), clearing thrombose shunts and cannulae, acute arterial thromboembolism, life-threatening DVT and PE.

106

What are the contraindications for the use of fibrinolytics (alteplase)?

- >24 hours since onset of sx

- Prior ICH

- Stroke within past year

- IC neoplasm

- Active bleeding

- Suspected aortic dissection

- Significant closed-head or facial trauma w/in 3 months

107

Types and classes of hematological agents and drug names

1. Anticoagulants

a) Indirect inhibitors of thrombin and/or factor Xa: heparin, enoxaparin (LMW heparin), fondaparinux

b) Direct thrombin inhibitors (DTIs): lepirudin, bivalirudin, argatroban, dabigatran

c) Direct factor Xa inhibitors: rivaroxaban, apixaban

d) Vit K antagonists (VKA): warfarin (Coumadin)

2. Antiplatelet drugs

a) TXA2 inhibitors: aspirin

b) Phosphodiesterase inhibitor: dipyridamole

c) P2Y12 (ADP/receptor) inhibitors: clopidrogel, ticagrelor, cangrelor, prasugrel

d) GIIb/IIIa receptor inhibitors: abciximab, eptifibatide, tirofiban

e) PAR inhibitor: vorapaxar


3. Fibrinolytics

- Drugs: alteplase

108

Which lipoproteins are highest in TG:chol ratio?

- Chylomicron 10:1 TG:CE > VLDL > IDL (1:1)

- LDL primarily CE

- HDL CE and phospholipids

109

Mechanism through which lipids acquired exogenously? Mechanism by which chlyomicrons are synthesized and used in body?

- Lipids digested in stomach and small intestine into unesterified cholesterol, FFAs and monoglycerides – combine into micelles via bile salts

- Cholesterol enters enterocyte via NPC1L1, converted into cholesterol ester via ACAT (acetyl-coA cholesterol acyltransferase)

- Monoglycerides w/FFAs converted into triglycerides via DGAT (diglyceride acyltransferase)

- Small intestine synthesizes nascent chylomicrons which are filled with TG and CE, tagged with apo-B 48

- Chylomicrons released and tagged with Apo C-II and E from HDL. They enter circulation and extracellular LPL on tissue is activated by Apo C-II causing TAG degradation and release off FFAs (to tissue) and glycerol (to liver).

- Apo C-II is returned to HDL and chylomicron remnant binds to Apo E receptor on liver and endocytosed for recycling

110

Apo proteins associated with chylomicrons. Function?

- Apo B 48 in SI: structural protein

- Apo C II: activates extracellular LPL on tissue

- Apo E: binds liver and remnant re-uptaken into liver

111

Describe the mechanism by which lipoproteins of hepatic origin are synthesized. Describe the mechanism through which these are used in the body?

- Liver synthesizes VLDL containing Apo B 100 lipoprotein on it.

- This is released into the plasma and Apo C II and apo E are transferred to it (from HDL).

- VLDL enters capillaries and Apo C II binds and activates extracellular LPL causing TG to be degraded into FFAs (into tissue) and glycerol (to liver). Ultimately this converts VLDL to IDL. IDL can be re-uptaken by liver using apo E receptor.

- Apo C II and E are returned to HDL and LDL (primarily containing CEs) with apo B 100 remains.

- LDL binds to specific receptor (apo B 100) on extrahepatic tissue and on liver where they are endocytosed.

112

Apo proteins associated with VLDL, IDL and LDL. Function?

- VLDL: apo B 100, apo C II and apo E

- IDL: same as VLDL

- LDL: apo B 100

- Apo B 100 = structural protein, also ligand for binding to LDL receptor (liver and extra-hepatic)

- Apo C II = activation of extracellular LPL

- Apo E = ligand for binding to LDL receptor and remnant receptor

113

Apoproteins associated with HDL

- Apo A I: structural, activates LCAT, ligand for SR-B1 (to hand-off CE to liver)

- Apo A II: structural

- Apo C II: activation of extracellular LPL

- Apo E: ligand for binding to LDL receptor

114

Only place in body where cholesterol can be eliminated?

- Liver (converted to bile acids and salts and secreted into bile, also as free cholesterol). ~ 5% excreted in feces daily.

115

Describe reverse cholesterol transport

- Refers to taking excess cholesterol from peripheral tissues back to liver

- Nascent HDL with apo A I receives free cholesterol from tissue (including from macrophages). LCAT converts FC to CE, maturation of HDL – HDL binds to SR-B1 (scavenger receptor) on liver through Apo A-I and delivers CE.

116

What is dyslipidemia (hyperlipidemia)?

- Elevation of tot cholesterol, elevation in LDL, elevation in TG, low HDL in any combination or alone

- Types: primary (hypercholesterolemia, hypertrig, mixed hyperlipid) usually d/t defect in one gene; polygenic-environmental (hypercholesterolemia, mixed hyperlipid), secondary (etoh, DM, etc.)

117

Primary chylomicronemia. Defect/cause, manifestation, treatment?

- Defect/cause: decrease LPL activity

- Manifestation: increase chylomicrons and VLDL

- Tx: fibrates (gemfibrozil, fenofibrate), niacin

118

Familial hypertriglyceridemia. Defect/cause, manifestation, treatment?

- Defect/cause: impaired removal of VLDL and/or chylomicrons

- Manifestation: moderate to high VLDL and chylomicrons

- Tx: fibrates (gemfibrozil, fenofibrate), niacin

119

Familial combined hyperlipoproteinemia. Defect/cause, manifestation, treatment?

- Defect/cause: high VLDL production and conversion of VLDL to IDL (probably polygenic)

- Manifestation: high VLDL and LDL

- Tx: fibrates (gemfibrozil, fenofibrate), niacin, NPC1L1 inhibitor (ezetimibe), HMG-CoA reductase inhibitor (-statins)

120

Familial dysbetalipoproteinemia. Defect/cause, manifestation, treatment?

- Defect/cause: decreased clearance of VLDL, IDL and chylomicron remnants d/t dysfunction or absence of apo E

- Manifestation: high IDL and chylomicrons

- Tx: fibrates (gemfibrozil, fenofibrate), niacin

121

Familial hypercholesterolemia. Defect/cause, manifestation, treatment?

- Defect/cause: LDL-R impairment, high fat diet, inactivity

- Manifestation: high LDL

- Tx: bile acid sequestrants / resins (cholestyramine, colesevelam, colestipol), niacin, NPC1L1 inhibitor (ezetimibe), HMG-CoA reductase inhibitor (-statins)

122

Can fibrates be used to treat hypercholesterolemia?

- No, they decrease plasma TG, increase in plasma HDL. Don’t treat high cholesterol.

123

Familial ligand-defective Apo B. Defect/cause, manifestation, treatment?

- Defect/cause: mutation in apo B 100 = impaired endocytosis of LDL

- Manifestation: high LDL

- Tx: bile acid sequestrants / resins (cholestyramine, colesevelam, colestipol) – not in the list according to chart at end of lecture, niacin, HMG-CoA reductase inhibitor (-statins), NPC1L1 inhibitor (ezetimibe)

124

Gemfibrozil and fenofibrate. Class, MOA, indications, adverse effects

- Class: fibric acid derivatives (fibrates) – PPAR activators

- MOA: activation of PPAR (txn factor) = decrease in plasma TG, increase in plasma HDL, increase in reverse cholesterol transport, increase in oxidation of FAs

- Indications: primary chylomicronemia, familial hypertrig, familial combine hyperlipoproteinemia, secondary hypertrig

- Adverse effects: rarely – rashes, GI symptoms and myopathy (increased risk if combined with statins)

125

Cholestyramine, colesevelam, colestipol. Class, MOA, indications, adverse effects, other

- Class: bile acid sequestrant / resin

- MOA: bind to bile acids and bile salts in intestine disrupting enterohepatic circulation = excretion in feces, liver must increase synthesis of these requiring increased uptake of cholesterol (LDL-receptor upregulated on liver)

- Indications: hypercholesterolemia (familial hypercholesterolemia)

- Adverse effects: lowers LDL, but can increase plasma TGs (not generally used in pts with hypertrigs), bloating/constipation

- Other: drug of choice to lower cholesterol in children and women who are pregnant/lactating

126

Niacin. Class, MOA, indications, adverse effects

- Class: niacin, anti-hyperlipidemic med

- MOA: niacin binding = decrease in HSL = decrease in plasma FFAs = decrease in VLDL = decrease in LDL = decrease cholesterol delivery = increase in plasma HDL and cholesterol removal = increase excretion in bile

- Indication: all hypertrigs and hypercholesterolemias

- Adverse effects: cutaneous flushing, itching (most common), hyperuricemia, hepatotoxicity, slight increase risk of statin-induced myopathy

127

Ezetimibe. Class, MOA, indications, adverse effects

- Class: NPC1L1 protein inhibitor

- MOA: blocks uptake of dietary cholesterol and cholesterol reabsorption from bile = reduction of cholesterol incorporation into chylomicrons = reduced remnants = increase expression of LDL and reduced plasma LDL levels

- Indications: hypercholesterolemia (familial hyperlipoproteinemia, hypercholesterolemia and familial ligand-defective apoB)

- Adverse effects: ?

128

Statins. Class, MOA, indications, adverse effects, other

- Class: HMG-CoA reductase inhibitor

- MOA: blocks HMG-CoA reductase the RLS step of cholesterol synthesis, body increases number of LDL receptors promoting uptake of LDL from blood = lower LDL plasma

- Indications: elevated LDL, CVD and elevated CVD risk; treat hypercholesterolemia (familial, familial ligand-defective apo B, familial combined hyperlipoproteinemia, secondary hypercholesterolemia)

- Adverse effects: generally well tolerated, myopathy/myositis (higher risk in those with inherited variant of anion transporter), rhabdo, liver toxicity. Contraindicated in pregnancy.

- Other: pleitropic effects (decrease platelet activation, decrease coagulation etc.)

129

Purpose of adult tx panel IV guidelines

- Shift focus away of treating cholesterol to specific LDL goals

130

Classes, MOA and drug names of anti-hyperlipidemic medication

1. HMG-CoA reductase inhibitors (-statin)

- MOA:

- Drugs: atorvastatin (Lipitor), fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin

2. Fibrates/fibric acid derivatives (PPAR activators)

- MOA:

- Drugs: fenofibrate, gemfibrozil

3. Bile acid sequestrants / resins

- MOA:

- Drugs: cholestyramine, colestipol, colesevalam

4. Cholesterol absorption inhibitors

- MOA:

- Ezetimibe

5. Other

- Drug: niacin