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Therapeutics 2 Exam 4 -Geriatric, Coagulation > Anticoagulant Drugs (Hock) > Flashcards

Anticoagulant Drugs (Hock) Flashcards

1
Q

What is the key enzyme in the coagulation pathway?

A

Thrombin

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2
Q

How do PRO-COAGULANT SERINE PROTEASES work and what factors are these?

A

-Cleave down-stream factors to activate them

Factors:
XII (12)
XI (11)
X (10)
IX (9)
VII (7)
II (2)

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3
Q

How do ANTI-COAGULANT SERINE PROTEASES work and what factors are these?

A

-Cleave factors Va (5) and VIIIa (8)

Factor:
Protein C

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4
Q

What glycoprotein factors activate proteases?

A

Factors:
VIII (8)
V (5)
III (3)(tissue factor)
Protein S

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5
Q

What glycoprotein factors bind and inhibit thrombin?

A

Factor:
Anti-thrombin III

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6
Q

What is factor IV (4) and what does it do?

A

Calcium

-Links certain factors to phospholipid membranes

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7
Q

what factor is transglutaminase and how does it contribute to clotting?

A

factor: XIII (13)
Cross-links fibrin fibers

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8
Q

What factor is prothrombin/thrombin?

A

II and IIa

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9
Q

What causes Hemophilia A?

A

Deficiency in Factor VIII (8)

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10
Q

What causes Hemphilia B?

A

Deficiency in factor IX (9)

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11
Q

What does the mutation Factor V Leiden cause?

A

Resistance to activated protein C

*increases chance of developing a clot

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12
Q

Where are clotting factors produced?

A

Liver
(except von Willebrand Factor)

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13
Q

Where is von Willebrand factor produced?

A

In the endothelium, subendothelium, and megakaryocytes

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14
Q

Besides von Willebrand Factor, what other factor is produced in the endothelium?

A

Factor VIII (8)

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15
Q

What affect can liver disease have on coagulation?

A

Since clotting factors are produced in the liver, liver disease has an unpredictable effect on coagulation

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16
Q

When is the extrinsic pathway for coagulation triggered?

A

A factor extrinsic to the blood (tissue factor) encounters blood and initiates coagulation

*important when vessel is damaged and blood leaks out

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17
Q

When is the intrinsic pathway for coagulation triggered?

A

Inside of blood vessel is damaged and collagen is exposed on the wall of the blood vessel

*factors then bind to collagen

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18
Q

Activation of which factor is the important step for the intrinsic pathway?

A

Factor 9

*this factor is activated by both the extrinsic and intrinsic pathways to activate factor X

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19
Q

What is the first factor recognized by the extrinsic pathway?

A

Factor 7

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20
Q

What pathway allows blood to clot in a test tube?

A

Intrinsic pathway
(glass acts like collagen)

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21
Q

What makes up the intrinsic pathway?

A

All components in blood

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22
Q

What initiates the intrinsic pathway?

A

Contact with negatively charged collagen of a diseased of injured vessel

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23
Q

What does the extrinsic pathway rely on for activation?

A

Factors outside the bloodstream

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24
Q

What activates the extrinsic pathway?

A

The release of tissue thromboplastin

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25
Q

How long does it take the extrinsic pathway to start clot formation?

A

About 15 seconds (rapid)

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26
Q

Where is tissue factor expressed?

A

On the surface of cells outside but near blood vessels

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27
Q

Where does Factor VII (the initiating factor of the extrinsic pathway) reside?

A

In the blood

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28
Q

How are Factor VII and Factor X initiated in the extrinsic pathway?

A

Tissue Factor (TF) binds Factor VII in the blood and activates it

Factor VIIa binds and cleaves Factor X which activates it

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29
Q

What affect does ketylating calcium have on coagulation?

A

Ketylating calcium inhibits coagulation

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30
Q

Once Factor X is activated, what does it do?

A

Factor Xa is the initiator of the “common pathway” (where the intrinsic and extrinsic pathways meet)

Factor X is responsible for cleaving prothrombin to thrombin

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31
Q

What does Thrombin do?

A

-Converts fibrinogen to fibrin

-Activates Factor XIII which cross-links fibrin to form a stable clot incorporated into a platelet plug

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32
Q

What 2 feedback mechanisms increase coagulation?

A

Thrombin
-Activates Factor V and VIII
-Enhances platelet activation

Platelet Activation
-Increases activation of factor VII, Factor X, and cleavage of prothrombin

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33
Q

What 3 feedback mechanisms decrease coagulation?

A

Antithrombin
-Neutralizes procoagulant serine proteases (thrombin, Xa, IXa) *accelerated by heparin

Protein C System
-Activated by thrombin binding to thrombomodulin
-Activated protein C complex (APC) forms complex with protein S to inactivate factors Va and VIIIA

Factor Xa
-Activates tissue factor pathway inhibitor to block initial activation of factor VII

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34
Q

What clotting factors are inhibited by warfarin?

A

II, VII, IX, X

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35
Q

What is the mechanism of action of warfarin?

A

Inhibits Vitamin K-epoxide reductase (VKORC1) which blocks the reduction of vitamin K

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36
Q

What is the role of gamma-carboxylation for clotting factors?

A

Factors need to bind to the phospholipid membrane in order to find each other

-They do this by binding to Ca+ which can then bind to the negatively charged phospholipid membrane

-The calcium binds to the two negatively charged oxygens located on the factors

-This process is done by the y-glutamyl carboxylase

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37
Q

What CYP metabolizes warfarin?

A

CYP2C9

**this is one of the most variable CYPs

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38
Q

How is warfarin inactovated?

A

Warfarin is inactivated when it is metabolized by CYP2C9

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39
Q

The termination of action of warfarin is based on what?

A

Termination of action of warfarin is not related to plasma warfarin levels, but instead the reestablishment of clotting factors in the blood

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40
Q

What happens when a patient overdoses on warfarin?

A

-Can lead to lactogenic hemorrhage

41
Q

If a patient overdoses on warfarin what should you do?

A

-Discontinue warfarin therapy
-Administer Vitamin K1 (activates resistance)

*In serious hemorrhage: Giving plasma replaces clotting factors faster than Vit K

42
Q

What is Protein C?

A

An innate coagulant that requires vitamin K-dependent carboxylation for its activity

43
Q

What causes warfarin necrosis?

A

-Some patients have protein C deficiency

-Warfarin initially decreases protein C levels faster than coagulation factors do which can paradoxically increase coagulation when treatment is first begun

***Deficiency in protein S would lead to the same necrosis

44
Q

What is used to prevent warfarin necrosis?

A

Patients are started on heparin at the same time as warfarin to combat this

45
Q

Can you take warfarin during pregnancy?

A

NO
-crosses placenta, teratogen

46
Q

What drugs reduce the anticoagulation effect of warfarin?

A

Vitamin K:
(bypasses warfarin-induced epoxidise reductase inhibition)

Broad-Spectrum Antibiotics:
(reduce availability of vitamin K in the GI tract)

47
Q

What is Vitamin K and what does it do?

A

Fat-soluble vitamin

-Involved in post-translational modification of prothrombin, factors VII, IX, and X

48
Q

What does a vitamin K deficiency cause?

A

Abnormalities in fat absorption

49
Q

What is the single vitamin K antagonist?

A

Warfarin

50
Q

What are the indirect factor IIA/Xa Inhibitor medications?

A

-Unfractionated heparin
-Enoxaparin
-Daltaparin

-Fondaparinux (non-heparinoids)

51
Q

What is the mechanism of action of heparin?

A

-Free antithrombin inactivates clotting factors (Activity is 3:1 thrombin:factor Xa)

-Heparin binds AT and changes its conformation to form a ternary complex

LMWH:
-LMWH are too small to bind antithrombin and thrombin so they have greater specificity for inhibition of Factor Xa

***Heparin accelerates AT reactions to inactivate thrombin and factor Xa

52
Q

How long does it take heparin to become effective?

A

Heparin is effective immediately

53
Q

How is heparin administred?

A

-Intermittent IV injection
-Continuous IV infusion (*easiest to control)
-SubQ injection

54
Q

What are the adverse effects of heparin?

A

Latrogenic Hemorrhage
(hemorrhage can occur at any site)

Thrombocytopenia (HIT)

Osteoporosis

55
Q

What is the treatment for latrogenic hemorrhage resulting from heparin?

A

-Stop heparin

-Life threatening bleeding:
(administer antagonist protamine sulfate which binds tightly to heparin to neutralize the anticoagulation action)

56
Q

What is protamine sulfate?

A

Heparin inhibitor

-low molecular weight polycationic protein that forms a stable complex with heparin through electrostatic interactions

57
Q

How is protamine sulfate administered?

A

IV
**not as effective as LMWH
**does not reverse the effects of fondaparinux

58
Q

How does heparin bind to antithrombin?

A

Through negatively charged sulfate groups (SO3-)

59
Q

What are the low molecular weight heparins?

A

-Dalteparin
-Enoxaparin

60
Q

How do LMWH’s compare to heparin?

A

-Equal efficacy

-Increased SubQ bioavailability (only route)

-Less frequent dosing

-Longer half-life

No monitoring needed!

61
Q

What are the advantages of LMWH over Heparin?

A

-More predictable

-Lower incidence of thrombocytopenia and osteoporosis (more specificity)

62
Q

Can UFH and LMWH be given in patients with renal failure?

A

UFH: YES

LMWH: NO

63
Q

How are LWMH administered?

A

SubQ only

64
Q

What is the only Factor Xa inhibitor?

A

Fondaparinux Sodium

65
Q

What is the structure of Fondaparinux Sodium?

A

synthetic sulfated pentasaccharide
(active part of heparins)

66
Q

What is the mechanism of action of fondaparinux sodium?

A

Indirectly inhibits factor Xa by selectively binding antithrombin (AT)

67
Q

How is fondaparinux sodium administered?

A

SubQ, can be given at home

68
Q

How often is fondaparinux sodium administered?

A

Once daily
(half life around 1 day)

69
Q

What monitoring is used for fondaparinux sodium?

A

NONE
-has a predictable dose response

70
Q

What is fondaparinux used for?

A

-VTE

-Prophylaxis in patients undergoing knee OR hip surgery OR abdominal surgery

71
Q

Can fondaparinux sodium be reversed by protamine sulfate?

A

No, only heparin and LMWH

72
Q

What medication is a non-heparinoid?

A

Fondaparinux sodium

73
Q

What is an advantage of fondaparinux sodium relating to possible side effects?

A

Low potential for thrombocytopenia

74
Q

What are the Direct Factor Xa Inhibitors?

A

Rivaroxaban
Apixaban
Edoxaban

75
Q

How is dosing of Direct Factor Xa Inhibitors changed with impaired renal function?

A

-Need a dose reduction

76
Q

What procedure poses an added risk with Direct Factor Xa Inhibitors?

A

Spinal punctures or epidural anesthesia procedures increase the risk for hematoma and paralysis

77
Q

True or False: Factor Xa Inhibitors have an increased risk of thrombosis upon discontinuation

A

True

78
Q

What are Factor Xa Inhibitors used to treat?

A

-VTE and PE

-Prevent thrombosis in afib

79
Q

At what CrCl should Edoxaban (Savaysa) not be used?

A

CrCl > 95 ml/min

80
Q

Upon premature discontinuation of Edoxaban, the risk for what increases?

A

Ischemic events

81
Q

What is the antidote for Factor Xa inhibitors?

A

Andexanet

(only inhibits apixaban and rivaroxaban)

82
Q

What Factor Xa Inhibitors does andexanet inhibit?

A

Apixaban and Rivaroxaban

83
Q

What is the black box warning for andexanet?

A

Increased thromboembolic events

84
Q

What is the mechanism of action of direct thrombin inhibitors?

A

-Bind active site of thrombin, to exosites of thrombin or both (bivalent)

-Inhibit BOTH soluble and fibrin-bound thrombin

-Also reduce platelet activation

85
Q

What type of fibrin can direct thrombin inhibitors inhibit?

A

BOTH soluble and fibrin-bound

86
Q

What is the mechanism of action of non-heparinoid parenteral agents?

A

Do not act through AT-III

*inhibit both free and fibrin-bound thrombin

87
Q

What is hirudin?

A

-Peptide from saliva gland of medicinal leaches

-Non-heparinoid parenteral agent

-Prevents thrombin from cleaving fibrinogen and coagulation

88
Q

What is Lepirudin (Refludan)?

A

Direct Thrombin Inhibitor
-Recombinant hirudin grown in yeast
*Given IV
*Inhibition of thrombin is reversible
-Increase aPTT dose-dependently

89
Q

What is lepiruden used to treat/

A

HIT

90
Q

What is the mechanism of action of Bivalirudin?

A

*Direct thrombin inhibitor

-Binds catalytic site and exosite I of thrombin

91
Q

Is the binding of bivaliruden to thrombin reversible or irreversible?

A

Reversible

92
Q

What part of bivaliruden is cleaved by thrombin?

A

Between the Arg - Pro

*this part binds the catalytic site of thrombin
-dissociates after being cleaved

93
Q

When is bivaliruden given?

A

Given IV during percutaneous coronary angioplasty (PCI) placement

94
Q

What is the mechanism of action of argatroban?

A

*Direct Thrombin inhibitor

-Binds reversibly to active site of thrombin

***Inhibits both free and clot-associated thrombin

95
Q

What is argatroban used to treat?

A

HIT or Coronary artery thrombosis in patients with HIT

*Also prophylaxis in PCI procedures

96
Q

What is argatroban derived from?

A

L-arginine

97
Q

Can dabigatran be used in severe renal impairment?

A

NO

98
Q

What is the antagonist of dabigatran?

A

Praxbind

(humanized IgG1 FAB fragment)

99
Q

What is Idarucizumab (Praxbind) use to reverse?

A

Dabigatran

**does not bind other thrombin inhibitors

Therapeutics 2 Exam 4 -Geriatric, Coagulation (8 decks)

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