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Owenpharm Block 2 > Anticoagulants, Thrombolytics & Ant-platelets > Flashcards

Anticoagulants, Thrombolytics & Ant-platelets Flashcards

1
Q

What substances are associated with venous thrombosis

A

Red blood cells enmeshed in fibrin

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2
Q

What differentiates arterial thrombi from venous thrombi in their composition? How does this affect their appearance

A

Composed of platelets with little fibrin or red cells. This gives appearance of “white thrombi.”

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3
Q

What event usually initiates an arterial thrombus formation?

A

Erosion or rupture of an atherosclerotic plaque

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4
Q

What effect does the activation of factor X to Xa have?

A

Conversion of factor II (prothrombin) to IIa (thrombin)

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5
Q

What effect does the activation of factor II (prothrombin) to IIa have?

A

Transformation of fibrinogen to fibrin (clot glue)

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6
Q

What coagulation factors are dependent on vitamin K for their synthesis?

A

II, IX, X, VII

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7
Q

What is the pro-coagulant effect of thrombin regarding crosslinking of fibrin?

A

Transforms fibrinogen to fibrin which involves conversion of XIII to XIIIa. This promotes crosslinking of fibrin.

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8
Q

How does thrombin promote platelet aggregation? (3 points)

A

Via thrombin specific receptors located on platelets (PAR4/PAR1).
It cleaves the receptor at the N-terminus.
This causes conformational change and activation of G protein.

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9
Q

Which factors does thrombin activate?

A

V and VIII

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10
Q

What is the 5 step process in anti-coagulation by thrombin?

A
  1. Thrombin binds to thrombomodulin on endothelial cells
  2. Elicits activation of protein C to Ca (vit. K dependent)
  3. Protein Ca combined with Protein S degrades Va & VIIIa
  4. Decreases the rate of activation of prothrombin
  5. Limits the further production of thrombin (negative feedback)
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11
Q

What is Factor V Leiden? (3 points)

A
  1. Genetic disease of hypercoagulation
  2. Patients have resistance to activated protein C
  3. Unable to degrade clots
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12
Q

What are the physical properties of Heparin? (4 points)

A
  1. Heterogenous mixture of sulfated polysaccharides
  2. Highly negatively charged
  3. Molecular weight 15kDa
  4. Sourced from porcine intestine (heterogeneity in composition from different sources)
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13
Q

What is the mechanism of action for Heparin?

A
  1. Catalyzes antithrombin’s inhibition of coag. proteases
  2. Serves as catalytic template for antithrombin and thrombin to interact.
  3. Causes a conformation change in active site of antithrombin making it more accessible.
  4. Creates 1000 fold increase in reaction rate
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14
Q

What 2 main actions does Heparin do?

What 2 main actions does Heparin not do?

A
  1. It does prevent further clot formation
  2. It does prevent the further extension of a clot
  3. It does NOT affect the synthesis of clotting factors
  4. It does NOT lyse an existing clot
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15
Q

Why isn’t Heparin absorbed orally? (2 points)

A
  1. It is very negatively charged

2. It is a very large molecule

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16
Q

Why is the kinetics of Heparin complicated? (2 points)

A
  1. The half-life is dependent on dose

2. It is cleared and degraded by reticuloendothelial system AND the liver.

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17
Q

Is Heparin safe in pregnancy? Why or why not?

A

Yes. It does not cross the placental barrier.

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18
Q

How is the efficacy of Heparin measured?

A

Prolonged activated partial thromboplastin time (aPTT).
Normal aPTT value 26-33 seconds.
Therapeutic aPTT usually 50-80 seconds.

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19
Q

What is the mechanism for Heparin induced Thrombocytopenia?

A

IgG antibodies form against heparin-platelet factor 4.

This causes increased platelet aggregation and a fall in platelet number.

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20
Q

What are the contraindications for the use of Heparin? (3 points)

A
  1. Active bleeding
  2. Severe uncontrolled hypertension
  3. Recent surgery of eye, brain, spinal cord.
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21
Q

What are the clinical indications for Heparin? (5 points)

A
  1. DVT or PE
  2. Initial management of unstable angina or acute MI
  3. Coronary angioplasty or stent replacement
  4. Surgery requiring cardiopulmonary bypass
  5. Anticoagulation during pregnancy
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22
Q

What are the two prototype low molecular weight heparins?

A
  1. Enoxaparin

2. Dalteparin

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23
Q

What is the difference between Low-MW heparin and standard heparin? (3 points)

A
  1. 15 monosaccharide units instead of 40
  2. Low-MW heparins don’t fully inactivate thrombin because they aren’t as efficient catalysts.
  3. Low-MW heparins have a longer half-life
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24
Q

What are the major pharmacokinetic points for Enoxaparin/Dalteparin? (4 points)

A
  1. Parenteral administration
  2. Absorbed more uniformly than Heparin
  3. Longer half-life than Heparin
  4. Renal elimination (risk in patients with ESRD)
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25
Q

What is the relative risk of thrombocytopenia with Enoxaparin/Dalteparin compared to Heparin?

A

Lower

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26
Q

What are the contraindications of LMWH is not present with Heparin?

A

Renal impairment

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27
Q

What are the therapeutic uses for Enoxaparin/Dalteparin?

A
  1. Acute DVT
  2. Prophylaxis of DVT
  3. Hip replacement surgery (or other orthopedic surgeries)
  4. Acute unstable angina and MI
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28
Q

What are two parenteral direct thrombin inhibitors other than Heparin?

A

lepIRUDIN and bivalIRUDIN

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29
Q

Name the prototype parenteral direct factor Xa inhibitor.

A

fondaparinux

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30
Q

What is the mechanism of action of lepIRUDIN and bivalIRUDIN?

A

Inactivates thrombin by blocking the substrate binding site

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31
Q

What is the route of admin. and excretion of lepirudin and bivalirudin?

A
  1. IV administration

2. Renal excretion

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32
Q

What is the therapeutic use for lepirudin and bivalirudin?

A

Alternative to heparin for patients who have heparin induced thrombocytopenia.

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33
Q

What is the route of admin and excretion of fondaparinux?

A
  1. SQ administration

2. Renal excretion

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34
Q

What is the therpeutic use/clinical indication for fondaparinux? (3 points)

A
  1. Prevention of DVT in patients undergoing surgery
  2. Treatment of acute PE
  3. Treatment of acute DVT w/o PE
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35
Q

What is the prototype Heparin antagonist?

A

Protamine Sulfate

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36
Q

What is the mechanism of action for protamine sulfate? (2 points)

A
  1. High affinity for negatively charged molecules

2. 1:1 binding with heparin results in formation of inactive complex

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37
Q

What are the adverse effects of protamine sulfate? (3 points)

A
  1. Weak anticoagulation in high doses used alone
  2. Anaphylaxis in fish and insulin hypersensitive patients
  3. Severe pulmonary hypertension
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38
Q

What are the therapeutic uses of protamine sulfate? (2 points)

A
  1. Heparin overdose

2. Reversal of heparin following cardiopulmonary bypass

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39
Q

What are the three prototype oral anticoagulants for this course?

A
  1. Warfarin
  2. Dabigatran
  3. Rivaroxaban
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40
Q

What are the three types of Warfarin?
Which is the administered form?
Which is the most active form?

A

Racemic mixture, S-Warfarin, R-Warfarin
Racemic mixture is administered
S-Warfarin is most active

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41
Q

What is the mechanism of action of Warfarin?

A

Prevention of reduction of inactive Vit. K into active form (reduced form) through inhibition of VKORC1 (vitamin K reductase). This impairs coag. factor synthesis by impairing the gamma-carboxylation of Prothrombin, VII, IX, and X.

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42
Q

How is efficacy of Warfarin measured?

A

PT between 15 and 26 seconds

INR between 2 and 3

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43
Q

Why is the therapeutic effect of Warfarin delayed?

A

Factors circulating prior to administration are not inhibited (only synthesis of new factors prevented)
This makes Warfarin’s action dependent on half-life of circulating clotting factors

44
Q

What is the route of admin, level of protein binding, and metabolism of Warfarin?

A

Oral administration
High plasma protein binding
CYP2C9 inactivation of S-Warfarin

45
Q

What are the contraindications for Warfarin administration? (5 points)

A
  1. Active bleeding
  2. CYP2C9 polymorphism
  3. Genetic variation in Vit K epoxide reductase
  4. Pregnancy (teratogenic-bone metabolism/vit K dependent)
  5. Liver/renal disease, vit K deficiency (prolonged effects)
46
Q

What are two rare adverse reaction of Warfarin?

A
  1. Purple toe syndrome (blue-tinged plantar surfaces 3-8 weeks after initiation)
  2. Skin necrosis/gangrene (widespread microthrombosis related to protein C deficiency)
47
Q

When should Warfarin be reversed and how is it reversed?

A

INR >5

Administration of Vit K for delayed reversal. Administration of FFP for immediate reversal (consideration in trauma).

48
Q

What are the therapeutic uses/clinical indications for Warfarin use?

A
  1. Long term treatment of venous thromboembolic disease
  2. Atrial fibrillation
  3. Prosthetic heart valves
  4. Dilated cardiomyopathy
49
Q

Which genetic polymorphisms decrease activity of Warfarin?

A

CYP2C9*2 and *3

50
Q

How would Warfarin dose need to be adjusted for an increased VKORC1 variant?

A

Increased dose

51
Q

What is the prototype orally administered direct thrombin inhibitor that does not require INR monitoring?

A

Dabigatran

52
Q

Is oral dabigatran administered in its active form?

A

No. It is administered as dabigitran etexilate mesylate, a pro-drug that is metabolized to active dabigitran.

53
Q

What is the catalyst for dabigatran etexilate metabolism?

A

Esterase

54
Q

What is the mechanism of action for dabigatran?

A

It interacts with the active site of thrombin as a potent, reversible, competitive inhibitor that inhibits both fibrin-bound and free thrombin.

55
Q

What is specific/special about the activity of fibrin-bound thrombin? (2 points)

A
  1. Remains enzymatically active and protected from inactivation by antithrombin
  2. It can locally activate platelets and trigger coagulation causing thrombus growth.
56
Q

Which is more predictable in its pharmakokinetics, warfarin or dabigatran?

A

dabigatran

57
Q

What is the time to peak action and half-life of dabigatran?

A

2 hours and 14-17 hours

58
Q

What is dabigatran’s relationship to CYP450 enzymes?

A

None, it is not a substrate for CYP 450s

59
Q

How is dabigatran excreted?

A

kidney

60
Q

What limits the oral absorption of dabigatran? How?

A

P-glycoprotein which acts as an efflux transporter pumping dabigatran back into the GI lumen.

61
Q

What can be given for an overdose of dabigatran?

A

Nothing, there is no antidote for dabigatran. Reversal is solely dependent on physiology excretion.

62
Q

What are the contraindications for dabigatran administration? (3 points)

A

Renal impairment, Advanced liver disease, Valvular heart disease

63
Q

How does renal impairment affect dabigatran?

A

Increased concentrations with any degree of impairment

64
Q

Why is valvular disease a contraindication for dabigatran?

A

Significantly more thromboembolic events and an excess of major bleeding

65
Q

How does rifampin affect plasma levels of dabigatran?

A

Reduces plasma concentration by induction of P-glycoprotein

66
Q

How do verapamil, amiodarone, quinidine, and clarithromycin affect plasma levels of dabigatran?

A

Increases plasma concentration by inhibition of P-glycoprotein

67
Q

What is the prototype oral direct factor Xa inhibitor?

A

RivaroXaban

68
Q

What is the primary site of amplification of thrombin generation?

A

Factor Xa, approximately 1:1000 amplification

69
Q

How is inhibition of Factor Xa favorable in preventing unwanted coagulation?

A

Inhibition decreases the amplified generation of thrombin without affecting existing thrombin levels. The remaining thrombin should be sufficient to ensure primary hemostasis.

70
Q

Why is RivaroXaban more effective in preventing clot extension than heparin?

A

It is capable of gaining access to clotbound Factor Xa and heparin is not.

71
Q

How is RivaroXaban metabolized?

A

CYP3A4/5 and CYP2J2 as well as CYP independent metabolism.

72
Q

How is RivaroXaban eliminated?

A

Half through kidneys and half through hepatobiliary tract. It is also a substrate for P-glycoprotein.

73
Q

What is the therapeutic indication for dabigatran or rivaroxaban? (2 points)

A
  1. Patients with nonvalvular atrial fibrillation at risk for stroke or systemic embolism.
  2. Prophylaxis in patients with knee or hip replacement
74
Q

According to our lecture, most cardiologists think that new oral anti-coagulants are better. Why? (5 points)

A
  1. Rapid onset/offset of action
  2. Limited food and drug interactions
  3. Greater convenience with no need for monitoring
  4. Wide therapeutic window allows fixed dosing
  5. Fewer adverse effects and bleeding events
75
Q

Why is warfarin used more often and why is it a “drug clinicians love to hate”? (3 points)

A
  1. Virtually every aspect is well known
  2. Universally available tool for monitoring in INR
  3. Highly effective reversal agent (vitamin k)
76
Q

What bond is cleaved to activate plasminogen to plasmin?

A

Arg-Val bond

77
Q

What endogenous factors cleave the Arg-Val bond of plasminogen?

A

t-PA and Prourokinase

78
Q

What drug cleaves plasminogen into activated plasmin?

A

Alteplase (recombinant t-PA)

79
Q

What is the name of a lysine analog that binds to plasminogen and plasmin thus blocking its binding to fibrin?

A

Aminocaproic acid

80
Q

What is aminocaproic acid used for?

A

Reversal of states that are associated with excessive fibrinolysis.

81
Q

Why is aminocaproic acid useful for treating urinary tract bleeding?

A

Concentration in urine can be 100x what it is in plasma.

82
Q

What drug is used for primary prophylaxis of thromboemboli in patients with prosthetic heart valves?

A

Dipyridamole

83
Q

What is the main mechanism of Dipyridamole?

A

Inhibition of phosphodiesterase which increases cAMP in platelets. This inhibits platelet aggregation.

84
Q

What is the mechanism of action of Clopidogrel, Ticlopidine, Prasurgrel and Ticagrelor?

A

Act through P2Y1/P2Y12 receptors to inhibit ADP-induced platelet aggregation. All are irreversible except Ticagrelor.

85
Q

The P2Y1 receptor for Clopidogrel is what type of G-protein coupled receptor and what is its effect?

A

Gq receptor which increases PLC and increases Calcium

86
Q

The P2Y12 receptor for Clopidogrel, Ticlopidine, Prasurgrel and Ticagrelor is what type of G-protein coupled receptor and what is its effect?

A

Gi which decreases adenyl cyclase, decreases cAMP, and decreases PKA

87
Q

How are Clopidogrel and Ticlopidine metabolized?

A

CYP2C19

88
Q

Which is the active drug, Clopidogrel or it’s metabolite?

A

Its metabolite

89
Q

What side effects are specific to Ticagrelor and not Clopidogrel or Prasurgrel and therefore decrease how often it is used?

A
  1. Dyspnea

2. Neutropenia

90
Q

If someone has a CYP2C19 polymorphism and is a poor metabolizer what does this mean for the activity of Clopidogrel?

A

The patient won’t get as much of the active drug.

91
Q

What is a common drug interaction scenario for Clopidogrel?

A

A patient will take both ASA and Clopidogrel.
Complain of GI irritation and is prescribed a PPI.
Omeprazole is also a substrate for CYP2C19 resulting in decreased activity of Clopidogrel.

92
Q

What are the therapeutic uses for Clopidogrel?

A

Unstable angina, NSTEMI, STEMI, Recent MI/Stroke, Peripheral arterial disease.

93
Q

What are the therapeutic uses for Prasurgrel?

A

Patients undergoing percutaneous coronary intervention for unastable angina, NSTEMI, STEMI.

94
Q

What are the therapeutic uses for Ticagrelor?

A

Used with ASA for secondary prevention in patients with unstable angina, NSTEMI, STEMI and to manage patients undergoing PCI and/or coronary artery bypass.

95
Q

Name two GbIIb/IIIa antagonists used for antiplatelet purposes.

A

Abciximab & Eptifibatide

96
Q

What effect does abciximab have on platelet function?

A

It prevents binding of fibrinogen, vW factor, and other adhesive molecules

97
Q

HOW does abciximab exert its effect on platelets? (4 points)

A

Through steric hindrance a/o conformational change.
It blocks access of the molecules to the receptor.
It is NOT a direct interaction with the binding site.
It is non-competitive inhibition.

98
Q

What natural substance is Eptifibatide a derivative of?

A

“Disintegrins” which are proteins from snake venoms that inhibit platelet aggregation.

99
Q

How does Eptifibatide work?

A

It contains a KGD (Lys-Gly-Asp) sequence motif that binds specifically to GP IIb-IIIa receptors on the platelet surface.
This blocks the binding of fibrinogen activated platelets.

100
Q

What type of antagonism does Eptifibatide create?

A

Competitive, reversible inhibition.

101
Q

Describe the relative onset of action and clearance of abciximab.

A

Quick onset of action but delayed clearance.

102
Q

How long is abciximab effective for?

A

Up to 7 days

103
Q

What is the relative onset/offset of Eptifibatide?

A

Quick onset, Quick offset (platelet aggregation is normal w/in 8 hrs of stopping drug)

104
Q

How is Eptifibatide cleared?

A

Renal clearance

105
Q

What are the adverse effects of abciximab and eptifibatide?

A

Bleeding, Thrombocytopenia, hypotension, bradycardia

106
Q

What are the clinical indications for Eptifibatide?

A

Patients with unstable angina and myocardial infarction often with LMWH
Patients undergoing PCI, including angioplasty or stent placement.

107
Q

What are the clinical indications for abciximab?

A

Patients undergoing PCI, including agioplasty or stent placement.
In combination with ASA and heparin.
Also used with Alteplase for thrombolysis.

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