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Cardio Module > 8. Olah - Anticoagulants > Flashcards

8. Olah - Anticoagulants Flashcards

1
Q

What is the key sequence of unfractionated heparin (UFH)?

A

The pentasaccharide sequence, it is often sulfonated w/ lots of negative charges

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2
Q

Is heparin present in the human body?

A

Yes, in mast cells, but does not act as an endogenous anticoagulant

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3
Q

What is heparan sulfate?

A

An anticoagulant found on the outside of blood vessels, and it is an endogenous anticoagulant.

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4
Q

What kind of mixture is UFH?

A

UFH is a heterogenous mixture of varying sizes, meaning it contains a collection of repeating saccharide units in all sorts of sizes.

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5
Q

What is the MOA of UFH?

A

UFH bind and activates antithrombin, which will inhibit the activity of factor IIa (thrombin) and factor Xa

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6
Q

What does SERPIN stand for?

A

Serine Protease Inhibitor, antithrombin is the endogenous SERPIN

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7
Q

How is UFH considered an indirect thrombin inhibitor?

A

UFH causes clotting factor to attack antithrombin and become trapped in a complex

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8
Q

What are the 2 steps of UFH binding to antithrombin?

A
  1. 3 residues of UFH bind w/ low affinity
  2. Conformational change in antithrombin allows for additional high affinity binding and antithrombin activation - allows more binding to antithrombin to increase its activation
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9
Q

Why does binding of UFH make antithrombin more active?

Hint there’s 2 reasons

A
  1. UFH cause a conformational change in antithrombin, causing the active site to become more accessible (to thrombin or Xa)
  2. Proximity effect - UFH provides a scaffold for both antithrombin and thrombin
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10
Q

SERPIN MOA is also called what?

A

Suicide inhibition

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11
Q

What are the 5 steps of Suicide Inhibition?

A
  1. Antithrombin is recognized by protease (IIa and Xa)
  2. Protease attacks Antithrombin
  3. Conformational change in protease disrupts its catalytic triad and deacylation is prevented
  4. Prevented deacylation- no free active protease is generated
  5. “Receptor” proteins recognize trapped complex and is cleared from circulation by the liver
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12
Q

What is the quick summary of Suicide Inhibition?

A

Major anticoagulant effect of UFH results from its ability to promote the antithrombin-mediated inhibition of thrombin and factor Xa

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13
Q

What is the purpose of anticoagulant drugs?

A

To prevent the formation of new clots and inhibit the existing clot from becoming bigger. They will not disrupt or lose an existing clot.

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14
Q

What type of pharmacokinetic response does UFH have?

A

Unpredictable/varying response, requires lots of pt monitoring, binds to plasma and other proteins

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15
Q

What are the two big side effects/toxicity of UFH? What are the other 2 side effects?

A
  1. Bleeding
  2. Heparin-Induced Thrombocytopenia
  3. Osteoperosis, from long time, high dose use
  4. Mild changes in hepatic function
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16
Q

What is the antidote/reversal agent of bleeding from UFH? And what is its MOA?

A

Administration of protamine sulfate, which will bind to the negative charges preventing UFH-antithrombin interactions

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17
Q

What are the two types of HIT?

A

HIT type 1 and HIT type 2

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18
Q

What is HIT type 1?

A

Nonimmune, observed in early heparin exposure, causes platelet aggregation and consumption but a clinical effect may not be seen. Eventually, platelet counts often return to normal.

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19
Q

What is HIT type 2?

A

Immunologic, antibodies develop against heparin-platelet factor 4 complex. Leads to a 50% decrease in platelet counts, and thrombosis may also be seen.

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20
Q

What are the two low molecular weight heparin drugs?

A
  1. Enoxaparin

2. Dalteparin

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21
Q

What is the main difference between UFH and LMWH?

A

LMWH contains smaller weight mixtures of polysaccharides

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22
Q

What is the same between UFH and LMWH?

A
  1. Heterogenous mixture of polysaccharides
  2. Retains the pentasaccharide sequence (necessary for antithrombin activation)
  3. ~1/3 of LMWH and UFH are the pentasaccharide sequence
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23
Q

What is the MOA of LMWH?

A

Inhibition of factor Xa

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24
Q

Can LMWH inhibit thrombin?

A

LMWH lacks the scaffold necessary for thrombin, but since LMWH inhibits Xa, it will indirectly inhibit thrombin.

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25
Q

What are the pharmacokinetic advantages of LMWH over UFH?

A
  1. Higher bioavailability

2. More predictable response w/ less pt-pt variations

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26
Q

What are the indications for LMWH usage?

Hint, there’s 2

A
  1. Prophylaxis and treatment of DVT/PE - useful post-op

2. Management of ACS

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27
Q

What is fondaparinux?

A

A synthetic pentasaccharide, based on the active moiety of heparin - contains only a single molecule, no heterogeneous mixture

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28
Q

What is the MOA of fondaparinux?

A

Promotes a conformational change in antithrombin, enhancing activity against Xa. No direct activity is seen on thrombin.

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29
Q

What are the advantages of fondaparinux vs. heparins?

Hint, there’s 5

A
  1. Synthetic
  2. Homogenous prep
  3. Longer half life
  4. More predictable anticoagulant effects
  5. Unlikely to induce HIT - no interaction w/ platelets and platelet-factor 4
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30
Q

What is the unfavorable characteristic of fondaparinux vs. heparins?

A

Cannot be reversed, protamine sulfate will not work

31
Q

What are the 3 domains necessary for thrombin activity? What do they regulate?

A
  1. Active site - the catalytic domain, proteolysis of substrate
  2. Exosite I - substrate binding pocket, activates the catalytic triad
  3. Exosite II - where heparins will bind
32
Q

What is the MOA of direct thrombin inhibitors?

A

DTIs bind to thrombins active site (and possibly exosite) to inhibit proteolytic activity of thrombin.
Inhibit thrombin molecules that are free in plasma and bound to clot.

33
Q

What are the 3 DTIs mentioned?

A
  1. Lepirudin
  2. Argatroban
  3. Dabigatran
34
Q

What is the MOA of lepirudin?

A

Binds irreversibly (or slowly reversible) to both exosite I and active site of thrombin

35
Q

What is the main usage of lepirudin?

A

Used in HIT and/or other thrombotic events

36
Q

What is the MOA of argatroban?

A

Bind reversible to thrombins active site w/ no exosite binding

37
Q

What is the MOA of dabigatran?

A

The only oral DTI, it’s a prodrug converted via plasma esterases and is a reversible inhibitor of the thrombin site

38
Q

What kind of drug is warfarin?

A

Oral anticoagulant, it’s a competative inhibitor of VKOR

39
Q

Why is vitamin K needed for coagulation?

A

Necessary for carboxylation of factors II, VII, IX, and X.

40
Q

What is the MOA of warfarin?

A

Competitive inhibitor of VKOR, preventing the regeneration of active vitamin K (the oxidized form cannot be reduced)

41
Q

What are the results of warfarin? How long until effects are seen?

A
  1. ~30-50% reduction in circulations II, VII, IX and X
  2. Decreased levels of protein C and S
  3. Anticoagulant effects seen in 3-6 days after initiation of therapy
42
Q

What are the 3 effects/contraindications of warfarin?

A
  1. Bleeding
  2. Skin lesions/tissue necrosis
  3. Contraindicated in pregnancy
43
Q

How should bleeding from warfarin be monitored?

A
  1. INR and observing clinical status

2. Watching drug interactions, food interactions, disease states

44
Q

What are the 3 tx/response to bleeding from warfarin?

A
  1. D/C warfarin
  2. D/C warfarin + vitamin K1
  3. D/C warfarin + fresh frozen plasma + vitamin K
45
Q

When are skin lesions/tissue necrosis seen from warfarin pts?

A

When pts are deficient in protein C and S

46
Q

Why should warfarin not be used in pregnancy?

A
  1. Spontaneous abortion

2. Birth defects

47
Q

What are direct and indirect interactions of warfarin (generalized)?

A

Direct - affect warfarin itself, displacement from plasma protein binding, altering metabolism
Indirect - affect coagulation status

48
Q

What is the reversal agent for dabigatran?

A

Idarucizumab, a MAB directed against dabigatran

49
Q

What are the 3 main direct Xa inhibitors?

A
  1. Rivaroxaban
  2. Apixaban
  3. Edoxaban
50
Q

What is the MOA of Direct Xa inhibitors?

A

Bind directly at factor Xa active site, antithrombin is not needed
Binding w/ high affinity, and is reversible

51
Q

What is the major concern of direct Xa inhibitors?

A

GI bleeds, plus other bleeding since no antidote is available

52
Q

What is aspirin’s MOA?

A

Irreversible inhibitor of COX-1, leading to decrease in TXA2 production –>decrease platelet activation and aggregation

53
Q

What are the 3 P2Y12 antagonists?

A
  1. Clopidogrel
  2. Prasugrel
  3. Ticagrelor
54
Q

Since Clopidogrel is a pro-drug how much is actually converted to the active form?

55
Q

What is clopidogrel’s MOA?

A

Irreversible inhibitor of P2Y12, inhibiting platelet aggregation and secretion

56
Q

What are the 2 big adverse effects of Clopidogrel?

A
  1. Bleeding - obvi

2. Thrombotic Thrombocytopenic Purpura

57
Q

Since Prasugrel is a prodrug, how much is converted to its active form?

A

~85%, making it a more potent inhibitor of platelet activity

58
Q

How is prasugrel “better” than Clopidogrel?

A
  1. More potent
  2. Faster onset of activity
  3. More consistent patient to patient response
59
Q

What is the main side effect of Prasugrel?

A

Bleeding, seen in higher incidences that Clopidogrel

60
Q

What is the MOA of Ticagrelor?

A

A noncompetative, reversible antagonist at the P2Y12 receptor

61
Q

What class is Vorapaxar?

A

A thrombin receptor antagonist

62
Q

What is the MOA of Vorapaxar?

A

Nonpeptide inhibitor of protease activated receptor-1 (PAR-1)

63
Q

What are the two GP IIb/IIIa antagonists?

A
  1. Abciximab

2. Tirofiban

64
Q

What is the MOA of abciximab?

A

Antibody directed against GP IIb/IIIa and inhibits fibrinogen binding - inhibits platelet activity

65
Q

What is the MOA of Tirofiban?

A

Reversible antagonist of GP IIb/IIIa, mimics the sequence of the endogenous ligands for GP IIb/IIIa and blocks binding

66
Q

What are the 3 limitations of GP IIb/IIIa inhibitors?

A
  1. Only IV adminstration
  2. Associated w/ severe bleeding
  3. Ligands partially activate GP IIb/IIIa
67
Q

What is dipyridamole’s MOA?

Hint, there’s 2 parts

A
  1. Inhibitor of adenosine transport - increasing cAMP
  2. Inhibitor of PDE - increase cAMP
    Increase in cAMP inhibits platelet activity
68
Q

What are the 3 thrombolytic drugs?

A
  1. Tissue Plasminogen Acitvator (t-PA, Alteplase)
  2. Reteplase
  3. Tenecteplase
69
Q

What is plasminogen activator inhibitor-1 (PAI-1)?

A

A SERPIN inhibitor of t-Pa, keeps the fibrinolytic system in check

70
Q

What is plasminogen activator inhibitor-2 (PAI-2)?

A

A SERPIN inhibitor w/ significant levels seen in pregnancy

71
Q

What is the difference between Reteplase and Tenecteplase compared to PAI-1?

A

R and T have longer half lives and there is not follow up infusion needed

72
Q

What is the main toxicity of thombolytic drugs? What 2 mechanisms cause it?

A

Bleeding! - duh

  1. Lose physiologic thrombi
  2. Systemic lysis from degredation of fibrinogen and factors V and VIII
73
Q

What is the antidote for thrombolytic drugs?

A

Aminocaproic acid - binds plasminogen and blocks binding to fibrin residues - no activation to plasmin

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