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Cardiovascular II Final Exam > Drugs for thromboembolic disorders (Konorev) > Flashcards

Drugs for thromboembolic disorders (Konorev) Flashcards

1
Q

All clots involve both

A

platelets and fibrin but thee degree of involvement of platelet/fibrin in thrombus formation depends on the vascular location

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2
Q

White thrombus

A
  • platelet rich
  • Forms in high pressure arteries and is a result of platelet binding to the damaged endothelium and aggregation with little involvement of fibrin
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3
Q

Pathologic condition associated with white thrombi

A

-local ischemia due to arterial occlusion

in coronary arteries: myocardial infarction/unstable angina

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4
Q

Red thrombus

A
  • fibrin rich with trapped RBC
  • Forms in low-pressure veins and in the heart; result of platelet binding and aggregation followed by formation of bulky fibrin tails in which RBCs become enmeshed
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5
Q

Pathologic conditions associated with red thrombus

A

-pain and severe swelling, embolism and distal pathology (embolic stroke)

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6
Q

Drugs used in thromboembolic disorders

A
  • Anticoagulants
  • Antiplatelet drugs
  • Thrombolytics
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7
Q

Anticoagulants

A

regulate the function and synthesis of clotting factors

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8
Q

Antiplatelet drugs

A

inhibit platelet function

-Primarily used to prevent clots from forming in the arteries (white thrombi)

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9
Q

Thrombolytics

A
  • destroy blood clots after they are formed

- Re-establish blood flow through vessels once clots have formed

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10
Q

Thrombin

A
  • converts soluble fibrinogen into fibrin; it also interconnects the blood coagulation cascade with platelet aggregation
  • so thrombin also involved in platelet activation and aggregation
  • on the other hand it can accelerate the clotting cascade by inducing proteolytic cleavage of upstream of thrombin (Xa)
  • this is why thrombin and Factor Xa are major drug targets
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11
Q

Which organ will be affected by an embolism as a result of the primary thrombus formation in veins of lower extremities or pelvis

A

-Lung

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12
Q

Parenteral anticoagulants

A

Indirect thrombin and factor Xa (FXa) inhibitors:

  • Unfractionated heparin (UFH or HMW)
  • Low molecular weight heparins (LMW)
  • Synthetic pentasaccharide

Direct thrombin inhibitors: Lipirudin, Bivalirudin, Argatroban

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13
Q

UFH (HMW)

A

Heparin sodium

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14
Q

LMW Heparin

A

Enoxaprin
Tinzaparin
Dalteparin

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15
Q

Synthetic pentasaccharide

A

Fondaparinux

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16
Q

Direct thrombin inhibitors

A

Lepirudin
Bivalirudin
Argatroban

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17
Q

Indirect thrombin and FXa inhibitors MOA

A
  • Indirect thrombin FXa inhibitors–bind plasma serine protease inhibitor ANTITHROMBIN III
  • Antithrombin III inhibits several clotting factor proteases, especially IIa, IXa and Xa
  • In the absence of heparin, these reactions are slow; heparin increases the antithrombin III activity by 1000 fold
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18
Q

HMW heparin inhibits

A
  • the activity of both thrombin and factor Xa
  • provides scaffold for both antithrombin as an inhibitor and thrombin itself
  • binds to antithrombin III and thrombin (inactivates thrombin)
  • binds via pentasaccharide (sufficient to inactivate Xa)
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19
Q

LMW heparin inhibits

A
  • factor Xa with little effect on thrombin
  • shorter chains so cant effect thrombin but inhibits Xa because scaffolding is not required
  • Binds to antithrombin III via pentasaccharide but NOT to thrombin (poorly inactivates thrombin)
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20
Q

Fondaparinux inhibits

A

factor Xa activity with NO effect on thrombin

-Binds to antithrombin III via pentasaccharide (sufficient to inactivate Xa)

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21
Q

Direct thrombin inhibitors MOA (parenteral)

A

-Direct inhibition of the protease activity of thrombin

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22
Q

-Bivalent direct thrombin inhibitors (direct thrombin inhibitors)

A

bind at both active site and substrate recognition site

  • Lepirudin
  • Bivalirudin
  • -found in saliva of leeches??
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23
Q

Oral anticoagulants

A
  • coumarin anticoagulants: warfarin

- NOAC (novel oral anticoagulants): Factor Xa inhibitors and direct thrombin inhibitors

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24
Q

NOAC (novel oral anticoagulants)

A
  • Factor Xa inhibitors: Rivaroxaban, Apixaban, Edoxaban

- Direct thrombin inhibitors: Dabigatran

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25
Q

Coumarin anticoagulants

A
  • Warfarin

- Most commonly prescribed anticoagulant in US

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26
Q

MOA of warfarin (coumarin anticoagulant)

A
  • Inhibits reactivation of vitamin K, by inhibiting enzyme vit K epoxide reductase
  • Inhibits carboxylation of glutamate residues by GGCX (gamma-glutamyl carboxylase) in prothrombin and factors VII, IX and X making them inactive
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27
Q

Warfarin dosing

A
  • High individual variability in the optimal Warfarin dose based on:
  • Genetics, disease states, drug-drug interaction, diet
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28
Q

Drug therapeutic window for warfarin is

A

narrow

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29
Q

Warfarin dose is titrated based on

A

Laboratory testing: prothrombin time (INR)

  • 2.0-3.0 range for patients on warfarin
  • INR is monitored as patients visit the clinic regularly
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30
Q

Oral anticoagulants that inhibit factor Xa

A
  • Rivaroxaban
  • Apixaban
  • Edoxaban
31
Q

Parenteral anticoagulants that inhibit factor Xa

A
  • Fondaparinux

- LMWH

32
Q

Oral anticoagulants that target factor IIa

A

-Dabigatran

33
Q

Parenteral anticoagulants that target factor IIa

A

Argatroban

Bivalirudin

34
Q

Clinical use of parenteral anticoagulants

A

-Administer to patients with deep vein thrombosis, atria arrhythmias and other CONDITIONS THAT PREDISPOSE TOWARDS RED THROMBI

35
Q

Parenteral anticoagulants are used in the treatment/prevention of

A
  • embolic stroke
  • pulmonary embolism
  • used for prevention of emboli during surgery or in hospitalized patients (reduces risk of emboli)
36
Q

Parenteral anticoagulants: heparin locks used to

A

prevent clots from forming in catheters

37
Q

Clinical uses of oral anticoagulants

A
  • used to prevent thrombosis or prevent/treat thromboembolism
  • Atrial fibrillation
  • Prosthetic heart valves
38
Q

Antidotes for HMW and LMW heparins

A

Protamine sulfate

39
Q

When are antidotes for anticoagulants used

A

-used in situations of bleeding complication or traumatic injury causing bleeding or surgery–need to stop the action of anticoagulants to prevent excessive bleeding

40
Q

Antidotes for Foxaparinux and DTI (parenteral drugs)

A
  • Not available
  • DTIs are generally very short acting drugs so antidote usually not necessary but need to be careful about Foxaparinux because no antidote but long lasting
41
Q

Antidote to warfarin (oral)

A
  • Vitamin K

- Prothrombin complex concentrate

42
Q

Antidote to NOAC–DTI

A

Idarucizumab

43
Q

Antidote to NOAC FXa inhibitors

A

-not out yet but most likely Andexanet alfa will get approved soon

44
Q

Blood coagulation test used to monitor patients on heparins

A

aPTT
anti Xa
-measures intrinsic and common pathway

45
Q

Blood coagulation test used to monitor patients on warfarin

A

PT-based (INR)

-measures activity of extrinsic and common pathway

46
Q

Blood coagulation test used to monitor patients on NOAC–FXa inhibitors

A

Anti-Xa

-measures common pathway

47
Q

Blood coagulation test used to monitor patients on NOAC–DTI

A

Diluted thrombin time (TT)

-measures activity of common pathway

48
Q

Categories of antiplatelet drugs

A
  • Inhibitors of thromboxane A2 synthesis
  • ADP receptor blockers
  • Platelet glycoprotein receptor blockers
  • Inhibitors of phosphodiesterases
49
Q

Antiplatelet drugs: Inhibitors of thromboxane A2 synthesis

A

-Aspirin (acetylsalicylic acid)

50
Q

Antiplatelet drugs: ADP receptor blockers

A
  • Clopidogrel
  • Prasugrel
  • Ticlopidine
  • Ticagrelor
51
Q

Antiplatelet drugs: Platelet glycoprotein receptor blockers

A

Abciximab
Eptifibatide
Tirofiban

52
Q

Antiplatelet drugs: Inhibitors of phosphodiesterases

A

Dipyridamole

Cilostazol

53
Q

Platelet aggregation/activation–many different molecules but all eventually converge on what pathway?

A
  • Activation of GP IIb/IIIa
  • is an integrin–dimer and has both a cytoplasmic part and EC domain
  • EC domain is able to bind to adhesion fibrous proteins (fibronectin, fibrinogen)
  • activated as a result of inside out signaling–events happening inside the cell will activate integrin to bind to EC fibrous adhesive protein
54
Q

Compounds that inhibit platelet aggregation

A
  • NO–inhibits platelets via cGMP

- Prostacyclin–inhibits platelet aggregation by producing cyclic nucleotides–increases cAMP

55
Q

PDE inhibitors

A
  • prevents the composition of cyclic nucleotides

- cAMP

56
Q

GPIIb/IIIa inhibitors

A
  • blocks the site at which GPIIb/IIIa interacts with the ligand
  • The ligand has the amino acid sequence RGD
  • So these drugs block the integrin from interacting with the RGD sequence
57
Q

COX inhibitors

A

-Inhibit cyclooxygenase and eventually blocks production of TxA2 (a potent platelet aggregator)

58
Q

ADP receptor blockers

A
  • Normally, platelets contain vesicles with ADP, serotonin and other compounds in them and are released upon activation of platelets and serotonin and ADP can interact with receptors and induce platelet aggregation
  • These drugs block ADP from binding to the receptors irreversibly blocking platelet aggregation
59
Q

Aspirin MOA

A
  • Inhibition of cyclooxygenase
  • Decreased TxA2 production
  • TxA2 receptor is a GPCR coupled to Gq protein–>increases Ca conc and platelets and activates protein kinase C which signals and activates integrin to bind to exogenous fibrinogen
  • so aspirin blocks this process
60
Q

Clopidogrel, Ticlopidin, prasugrel MOA

A
  • ADP receptor blockers
  • Inhibition of AC by ai
  • normally, coupled to Gi which inhibits adenyl cyclase and decreases conc of cAMP and induces platelet aggregation so ADP receptors block this and will increase cAMP and prevent platelet aggregation
61
Q

Dipyradamole (phosphodiesterase inhibitors)

A
  • Blocks the degradation of cAMP
  • Inhibition of cAMP degredation
  • Levels of cAMP in platelets are increased
62
Q

Platelet glycoprotein GP IIb/IIIa is

A

an integrin binding to EC ligands: fibrinogen, vitronectin, fibronectin, von Willebrand factor

63
Q

Platelet GP receptor antagonists

A
  • Target Arg-Gly-Asp (RGD) sequence

- Prevent binding of ligands to the GP IIb/IIIa receptor to inhibit platelet aggregation

64
Q

GPIIb/IIIa antagonists

A
  • Abciximab (monoclonal Ab)
  • Tirofiban
  • Eptifibatide
  • inhibits interaction with fibrinogen (exogenous fibrous proteins)
65
Q

Clinical use of antiplatelet drugs

A
  • prevention of thrombosis in unstable angina and other acute coronary syndromes
  • Prevention of ischemic stroke and arterial thrombosis in peripheral vascular disease
  • In patients undergoing percutaneous coronary angioplasty and stenting
66
Q

-Inhibitors of phosphodiesterase are considered

A

adjunct antiplatelet agents and used in combination with other antiplatelet agents or anticoagulants

67
Q

Drug combinations using PDE inhibitors

A

-Dipyridamole with aspirin to prevent cerebrovascular ischemia
-dipyradamole with warfarin in patients with prosthetic heart valves
Cilostazol is primarily used to treat intermittent claudication

68
Q

Thrombolytic (fibronolytic) drugs MOA

A
  • induce fibriolysis (lyse fibrin in thrombi after they have formed)
  • activate endogenous fibrinolytic system by converting plasminogen into plasmin
69
Q

tpA: tissue type plasminogen activator drugs (fibrinolytic drug)

A
  • Alteplase: recombinant human protein
  • Reteplase: recombinant modified human protein
  • Tenecteplase: recombinant mutated human protein
70
Q

uPA: urokinase type plasminogen activator (fibrinolytic drug)

A

-Urokinase

71
Q

Streptokinase preparations (fibrinolytic drug)

A

-streptokinase–purified from bacteria

72
Q

Clinical uses of thrombolytic drugs

A
  • Acute embolic/thrombotic stroke (within 3 hours)
  • Acute myocardial infarction (within 3-6 hrs)
  • Pulmonary embolism
  • Deep venous thrombosis
  • Ascending thromboplebitis
73
Q

Treat with tPA to do what? Most effective when? Adverse effects?

A
  • treat with tPA to break down the clot and open up artery
  • most effective within 3 hours after embolic and thrombotic stroke
  • can exacerbate the damage produced by hemorrhagic stroke

Cardiovascular II Final Exam (13 decks)

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