Pharmacology I - 10/30

Front 1

What are the normal processes of blood clot formation and breakdown referred to as?

Back 1

Hemostasis
Fibrinolysis

Front 2

What is Thrombosis?

Back 2

Inappropriate activation of the normal hemostatic process within the normal non-interrupted vascular system.

Front 3

What are the 4 main steps in the normal sequence of hemostasis?

Back 3

Arteriolar vasoconstriction
Exposure of sub-endothelial ECM
Tissue Factor released at injury site
Formation of Permanent Plug

Front 4

What occurs during the first step of hemostasis (vasoconstriction)?

Back 4

Vasoconstriction (transient)

Front 5

What occurs during the second step of hemostasis (platelet adhesion)?

Back 5

Sub-endothelial ECM is exposed (has collagen which is highly thrombogenic)
Platelets adhere and become activated (they change shape and release secretory products Thromboxane, ADP, Serotonin)

Front 6

What does this second step lead to?
What is this called?

Back 6

Hemostatic plug
Primary Hemostasis

Front 7

What occurs in the third step (TF release)?

Back 7

It works with secreted platelet factors
Activates coagulation cascade
Thrombin is activated
Fibrin is formed

Front 8

What is this third step referred to as?

Back 8

Secondary Hemostasis

Front 9

What occurs in the fourth step (permanent plug)?

Back 9

Fibrin polymerizes and further platelet aggregation occurs
Counter regulatory mechanisms (t-PA) limit the plug to the site of injury.

Front 10

Describe the basics of the Intrinsic Cascade.

Back 10

It is activated by surface contact with a foreign body
Factor 9a converts 10 to 10a
10a converts prothombin to thrombin and thrombin converts fibrinogen to fibrin

Front 11

Describe the main points of the extrinsic pathway.

Back 11

Activated by Tissue Injury
Factor 7a/Tissue Factor convert 10 to 10a
10a (activated) converts prothrombin to thrombin
Thrombin converts fibrinogen to fibrin

Front 12

What are antithrombins?
What is the effect of Heparin on these molecules?

Back 12

They are molecules that inhibit clotting by inactivating various clotting factors, factor 10a, and thrombin.
Heparin greatly increases thrombin inactivation

Front 13

What are proteins C and S?

Back 13

Vitamin K dependent factors that inactivate cofactors 5a and 8a.

Front 14

What is the role of the plasminogen-plasmin system?

Back 14

It breaks down fibrin and inhibits its polymerization
Split fibrin products are anticoagulants

Front 15

What is vWF?

Back 15

vonWillebrand factor - produced by normal endothelium, found in plasma, essential for platelet binding to collagen and other surfaces

Front 16

What other factor is secreted by the endothelial cells?
What induces this factor?

Back 16

Tissue Factor
Cytokines TNF and IL-1

Front 17

Endothelial cells have pro-thrombotic (vWF, TF) and anti-thrombotic effects.
Describe the anti-thrombotic effects.

Back 17

Anti-platelet - Intact cells are a barrier to sub-endothelial ECM, PGI-2 and NO prevent platelet adhesion

Fibrinolytic - t-PA promotes fibrin clearing

Anti-coagulant - Heparin like molecules on endothelium inactivate thrombin and several coagulation factors

Front 18

What are the 4 major classes of drug that prevent or diminish thrombus formation?

Back 18

Anticoagulants - prevent clot
Direct Thrombin Inhibitors - lyse thrombi via catalyzing formation of plasmin
Fibrinolytic - dissolve existing thrombi
Anti-platelet - interfere with platelet activity

Front 19

What is the specific effect of anti-platelet agents?

Back 19

They inhibit platelet activation and adhesion and therefore prevent activation of clotting factors and fibrin formation

Front 20

What is the specific effect of anti-coagulants?

Back 20

They inhibit the coagulation cascade and therefore fibrin formation.

Front 21

How do Fibrinolytic agents work?

Back 21

They activate plasminogen to plasmin

Front 22

What are the 3 classes of anticoagulant?

Back 22

Heparins
Vitamin K antagonists
Direct thrombin inhibitors

Front 23

What is the unique sequence responsible for Heparin's activity?

Back 23

pentasaccharide

Front 24

How do all Heparin's work?

Back 24

By enhancing the activity of the antithrombin and increasing its affinity for thrombin
The thrombin-antithrombin complex also inhibits factors 10a, 9a, and 11a.

Front 25

What are some important characteristics of Unfractionated Heparin?

Back 25

Half life = 60-90 minutes
Does not cross BBB
Not absorbed orally
Does not cross placenta
Dose dependent kinetics

Front 26

What are the adverse effects?

Back 26

Bleeding
Thrombocytopenia
Long term = osteoporosis, alopecia

Front 27

How does LMWH work?

Back 27

It selectively inhibits factor 10a

Front 28

What are some important characteristics of LMWH?

Back 28

Better sc bioavailability
Longer acting
Lab monitoring not required
Lower risk of thrombocytopenia and osteoporosis.

Front 29

Name 3 Vitamin K antagonists

Back 29

Warfarin
Dicoumoral
Phenindione

Front 30

How does Warfarin work?

Back 30

It inhibits the synthesis of vitamin k dependent clotting factors and protein C
Synthesis requires gamma-carboxylation which oxidizes vitamin K (therefore it must be reduced)
Warfarin inhibits vitamin K epoxide reductase and therefore reduction of Vitamin K.

Front 31

Does warfarin have a fast or slow onset of action?

Back 31

slow - 3 to 5 days

Front 32

What is important to realize when considering co-administration with Warfarin?

Back 32

That 97-99.9% is bound to plasma proteins and therefore inactive. Co-administration may displace some of the warfarin and lead to greater amounts in the blood.

Front 33

What is Pro-thrombin Time?

Back 33

The time plasma takes to clot after tissue factor is added. Measures the quality of the extrinsic pathway.

Front 34

What is the problem with PTT?

Back 34

Different labs may have different results based on batches of TF used.
INR is used to standardize the results.

Front 35

Describe the different tests reviewed based on anticoagulant given.

Back 35

Heparin = PTT
Warfarin = PT/INR
LMWH = Anti- 10a

Front 36

Describe the conversion of Heparin to Warfarin.

Back 36

Use concomitantly for a minimum of 4 days which is the time to peak therapeutic effect of warfarin

Front 37

What is the reversal agent for Heparin?

Back 37

Protamine sulfate

Front 38

What is the reversal agent for LMWH (Lovenox)?

Back 38

Protamine sulfate

Front 39

What is the reversal agent for Warfarin?

Back 39

Vitamin K

Front 40

What is the MOA for Direct Thrombin Inhibitors?

Back 40

Direct binding of Thrombin active site.
Inhibit Fibrinogen to Fibrin
Not mediated via anti-thrombin or vitamin K

Front 41

What is the MOA for Fibrinolytic drugs?

Back 41

They are plasminogen activators which convert plasminogen into plasmin that catalyzes the degradation of fibrin

Front 42

What are they used for?

Back 42

Lysis of already formed clots
PE
MI

Front 43

Name 4 Fibrinolytic agents?

Back 43

Streptokinase (1) -bacterial protein
Urokinase (1) - Human enzyme
Alteplase (2) - Human t-PA
Reteplase/Tenecteplase (3) - Mutant variants of t-PA with increased plasma half lifes

Front 44

What is unique about Alteplase?

Back 44

It preferentially binds activates plasminogen bound to fibrin confining fibrinolysis to formed thrombi.
It avoids systemic activation