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

Drugs for thromboembolic disorders (Konorev) Flashcards

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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
Coumarin anticoagulants
- Warfarin | - Most commonly prescribed anticoagulant in US
26
MOA of warfarin (coumarin anticoagulant)
- 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
27
Warfarin dosing
- High individual variability in the optimal Warfarin dose based on: - Genetics, disease states, drug-drug interaction, diet
28
Drug therapeutic window for warfarin is
narrow
29
Warfarin dose is titrated based on
Laboratory testing: prothrombin time (INR) - 2.0-3.0 range for patients on warfarin - INR is monitored as patients visit the clinic regularly
30
Oral anticoagulants that inhibit factor Xa
- Rivaroxaban - Apixaban - Edoxaban
31
Parenteral anticoagulants that inhibit factor Xa
- Fondaparinux | - LMWH
32
Oral anticoagulants that target factor IIa
-Dabigatran
33
Parenteral anticoagulants that target factor IIa
Argatroban | Bivalirudin
34
Clinical use of parenteral anticoagulants
-Administer to patients with deep vein thrombosis, atria arrhythmias and other CONDITIONS THAT PREDISPOSE TOWARDS RED THROMBI
35
Parenteral anticoagulants are used in the treatment/prevention of
- embolic stroke - pulmonary embolism - used for prevention of emboli during surgery or in hospitalized patients (reduces risk of emboli)
36
Parenteral anticoagulants: heparin locks used to
prevent clots from forming in catheters
37
Clinical uses of oral anticoagulants
- used to prevent thrombosis or prevent/treat thromboembolism - Atrial fibrillation - Prosthetic heart valves
38
Antidotes for HMW and LMW heparins
Protamine sulfate
39
When are antidotes for anticoagulants used
-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
Antidotes for Foxaparinux and DTI (parenteral drugs)
- 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
Antidote to warfarin (oral)
- Vitamin K | - Prothrombin complex concentrate
42
Antidote to NOAC--DTI
Idarucizumab
43
Antidote to NOAC FXa inhibitors
-not out yet but most likely Andexanet alfa will get approved soon
44
Blood coagulation test used to monitor patients on heparins
aPTT anti Xa -measures intrinsic and common pathway
45
Blood coagulation test used to monitor patients on warfarin
PT-based (INR) | -measures activity of extrinsic and common pathway
46
Blood coagulation test used to monitor patients on NOAC--FXa inhibitors
Anti-Xa | -measures common pathway
47
Blood coagulation test used to monitor patients on NOAC--DTI
Diluted thrombin time (TT) | -measures activity of common pathway
48
Categories of antiplatelet drugs
- Inhibitors of thromboxane A2 synthesis - ADP receptor blockers - Platelet glycoprotein receptor blockers - Inhibitors of phosphodiesterases
49
Antiplatelet drugs: Inhibitors of thromboxane A2 synthesis
-Aspirin (acetylsalicylic acid)
50
Antiplatelet drugs: ADP receptor blockers
- Clopidogrel - Prasugrel - Ticlopidine - Ticagrelor
51
Antiplatelet drugs: Platelet glycoprotein receptor blockers
Abciximab Eptifibatide Tirofiban
52
Antiplatelet drugs: Inhibitors of phosphodiesterases
Dipyridamole | Cilostazol
53
Platelet aggregation/activation--many different molecules but all eventually converge on what pathway?
- 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
Compounds that inhibit platelet aggregation
- NO--inhibits platelets via cGMP | - Prostacyclin--inhibits platelet aggregation by producing cyclic nucleotides--increases cAMP
55
PDE inhibitors
- prevents the composition of cyclic nucleotides | - cAMP
56
GPIIb/IIIa inhibitors
- 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
COX inhibitors
-Inhibit cyclooxygenase and eventually blocks production of TxA2 (a potent platelet aggregator)
58
ADP receptor blockers
- 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
Aspirin MOA
- 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
Clopidogrel, Ticlopidin, prasugrel MOA
- 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
Dipyradamole (phosphodiesterase inhibitors)
- Blocks the degradation of cAMP - Inhibition of cAMP degredation - Levels of cAMP in platelets are increased
62
Platelet glycoprotein GP IIb/IIIa is
an integrin binding to EC ligands: fibrinogen, vitronectin, fibronectin, von Willebrand factor
63
Platelet GP receptor antagonists
- Target Arg-Gly-Asp (RGD) sequence | - Prevent binding of ligands to the GP IIb/IIIa receptor to inhibit platelet aggregation
64
GPIIb/IIIa antagonists
- Abciximab (monoclonal Ab) - Tirofiban - Eptifibatide - inhibits interaction with fibrinogen (exogenous fibrous proteins)
65
Clinical use of antiplatelet drugs
- 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
-Inhibitors of phosphodiesterase are considered
adjunct antiplatelet agents and used in combination with other antiplatelet agents or anticoagulants
67
Drug combinations using PDE inhibitors
-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
Thrombolytic (fibronolytic) drugs MOA
- induce fibriolysis (lyse fibrin in thrombi after they have formed) - activate endogenous fibrinolytic system by converting plasminogen into plasmin
69
tpA: tissue type plasminogen activator drugs (fibrinolytic drug)
- Alteplase: recombinant human protein - Reteplase: recombinant modified human protein - Tenecteplase: recombinant mutated human protein
70
uPA: urokinase type plasminogen activator (fibrinolytic drug)
-Urokinase
71
Streptokinase preparations (fibrinolytic drug)
-streptokinase--purified from bacteria
72
Clinical uses of thrombolytic drugs
- Acute embolic/thrombotic stroke (within 3 hours) - Acute myocardial infarction (within 3-6 hrs) - Pulmonary embolism - Deep venous thrombosis - Ascending thromboplebitis
73
Treat with tPA to do what? Most effective when? Adverse effects?
- 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

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