Thrombolytic Drugs

Question 1

What is the role of plasmin?

Answer 1

Degrades the fibrin clot and clears in from the blood vessel

(Fibrinolysis and clot degradation)

Question 2

What does the fibrinolytic pathway do?

Answer 2

Dissolves a blood clot after the blood vessel has healed

Question 3

What is the mechanism of action of thrombolytics?

Answer 3

Increase the conversion of plasminogen to plasmin

Question 4

What is the function of plasmin?

Answer 4

Degrades fibrin and dissolves clots

*digests fibrin and fibrinogen

Question 5

What enzyme activates plasminogen to plasmin?

Answer 5

t-PA or u-PA

*what we target to break down clots

Question 6

What does PAI-1 do?

Answer 6

bind t-PA or u-PA and inhibits activity

(prevents activation of plasminogen to plasmin)

Question 7

What does a2AP do?

Answer 7

Degrades plasmin

Question 8

What does TAFI do?

Answer 8

Prevents plasmin from binding fibrin which inhibits fibrinolysis

Question 9

How does t-PA work?

Answer 9

Cleaves the arg-val bond to activate plasminogen to plasmin

(serine protease)

Question 10

What does a2-antiplasmin do?

Answer 10

Inactivates plasmin

Question 11

What is t-PA inhibited by?

Answer 11

PAI-1 and PAI-2

Question 12

What are the indications for thrombolytic therapy?

Answer 12

-Acute MI
-Acute ischemic thrombotic stroke
-PE

Question 13

What is the standard of care acute myocardial infarction (MI)?

Answer 13

STENT placement

Question 14

What are the two types of STENTs?

Answer 14

Bare-metal

Drug-coated

Question 15

What is the purpose of drug-coated STENTs

Answer 15

Drugs prevent restenosis (when an artery opened through a medical procedure re-narrows)

-by inhibiting smooth muscle cell proliferation
-increase risk of subsequent thrombosis

Question 16

What is the structure/ function of Alteplase?

Answer 16

-Recombinant human t-PA

527 amino acid residues

*Binds fibrin to activate plasminogen

Question 17

What is the structure/function of Reteplase?

Answer 17

-Recombinant human t-PA with deletion of aa (355/527)

**More potent
**Faster onset

*Lacks fibrin binding domain, less fibrin-specific than alteplase

Question 18

What is the structure/ function Tenecteplase?

Answer 18

-Recombinant, mutant form of t-PA

*Longer half-life
*Given by single IV bolus

*More fibrin specific than t-PA

Question 19

What domains in Alteplase and Tenecteplase are part of fibrin binding?

Answer 19

Finger

Kringle 1/2

Question 20

What are the mutations present in tenecteplase?

Answer 20

-Increased half-life

-Reduced inhibition by PAI

-Enhanced activity at thrombi

Question 21

What is the mechanism of action of alteplase, reteplase, and tenecteplase?

Answer 21

Tissue Plasminogen Activator (t-PA)

Question 22

What tPA is the target of alteplase and tenecteplase?

Answer 22

tPA bound to a fibrin clot

Question 23

What tPA is the target of reteplase?

Answer 23

tPA in the plasma OR bound to a fibrin clot

Question 24

How are tissue plasminogen factors administered?

Answer 24

IV

Question 25

What is the duration of actions of the tissue plasminogen activators?

Answer 25

Alteplase: 5-10min Reteplase: 13-16min Tenecteplase: 90-130min

Question 26

What are the adverse effects of tissue plasminogen activators?

Answer 26

-Bleeding -internal bleeding -Superficial or surface bleeding (can dissolve more than just the targeted clot)

Question 27

What are anti-fibrinolytic agents used for?

Answer 27

-To stop bleeding caused by thrombolytic drugs -Adjunct therapy in hemophilia -re-bleeding from intracranial aneurysms

Question 28

How do anti-fibrinolytic agents work?

Answer 28

-Plasmin binds fibrin through a lysine binding site to activate fibrinolysis -Drugs act as a lysine analog to bind receptor on plasminogen and plasmin -Results in block of plasmin binding to target fibrin

Question 29

What are the anti-fibrinolytic drugs?

Answer 29

Aminocaproic acid Tranexamic acid Lysine

Question 30

Which anti-fibrinolytic drug is most potent?

Answer 30

Tranexamic acid (10x more potent than aminocaproic acid_

Question 31

What are the risks associated with anti-fibrinolytic agents?

Answer 31

Intravascular thrombosis formation as a result of fibrinolysis inhibition Thrombi formed during therapy are not easily lysed