Pharmacology of Fibrinolytics

Question 1

What is the MOA of fibrinolytic agents?

Answer 1

-degrade fibrin matrix of thrombi -> soluble fibrin degradation products -> thrombolysis
-unregulated plasmin degrades fibrinogen and other clotting factors (not ideal) because it may lead to systemic lytic syndrome= delayed wound healing, increased bleed risk

Question 2

What is the undesired effect of fibrinolytics?

Answer 2

unregulated plasmin degrades fibrinogen and other clotting factors resulting in systemic lytic syndrome= delayed wound healing, increased bleed risk

Question 3

What drugs are recombinant t-PAs?

Answer 3

-alteplase
-reteplase
-tenecteplase
-anistreplase
-urokinase

Question 4

Which recombinant t-PAs drugs are relatively fibrin specific?

Answer 4

-alteplase
-reteplase
-tenecteplase

Question 5

What is the MOA of t-PA?

Answer 5

binds to the fibrin on the surface of the clots which activated fibrin bound plasminogen resulting in plasmin being cleaved and fibrin is broken down = clot dissolves

Question 6

What is the t1/2 of Alteplase?

Answer 6

short= 5-30 mins

Question 7

Describe the binding affinity of Alteplase:

Answer 7

-fibrin&raquo_space;> fibrinogen
-more fibrin selective at low doses
-fibrinogen may also be degraded due to soluble fibrin degradation products

Question 8

What are the FDA indications of Alteplase?

Answer 8

-acute ischemic stroke
-acute massive pulmonary embolism
-patients with central venous access devices (CVAD)
-MI with ST elevation (STEMI) within 12h (6h ideal) as an alternative to percutaneous coronary angioplasty

Question 9

What are the adverse effects of Alteplase?

Answer 9

-bleeding, cerebral hemorrhage (very serious!)
-angioedema (increased risk with ACEI use)

Question 10

Where on Alteplase molecule does it interact with fibrin?

Answer 10

Finger (F) domain and KR2/K2

Question 11

How does the structure of Tenecteplase differ from Alteplase?

Answer 11

-glycosylation site on K1 has been repositioned
-tetra-alanine sub in P domain where t-PA interacts with type 1 plasminogen activator inhibitor (PIA-1)

Question 12

How does the affinity of fibrin of Tenecteplase differ from Alteplase?

Answer 12

higher affinity for fibrin

Question 13

What are the FDA approved indications of Tenecteplase?

Answer 13

acute MI if percutaneous transluminal coronary angioplasty would be delayed 1-2h

Question 14

How does the structure of Reteplase differ from Alteplase and Tenecteplase?

Answer 14

-lacks F domain
-not glycosylated (made in E. coli)

Question 15

What are the unique pharmacological properties of Reteplase?

Answer 15

-faster onset than rt-PA (Alteplase)
-long t1/2 than rt-PA

Question 16

What are the FDA Indications of Urokinase?

Answer 16

catheter-directed lysis of thrombi in the deep veins or the peripheral arteries

Question 17

What is the MOA of Urokinase?

Answer 17

coverts plasminogen to plasmin by cleavage of Arg-Val bond (acts like t-PA)

Question 18

What is the MOA of streptokinase (Anistreplase)?

Answer 18

1. forms 1:1 complex with plasminogen
2. induce conformational changes in plasminogen to expose the active site
3. streptokinase-plasmin complex converts plasminogen to plasmin

Question 19

What are the issues with using streptokinase (Anistreplase)?

Answer 19

-not fibrin selective
-cannot be given to a patient more than once due to antibody formation and allergic reactions

Question 20

What are the unique pharmacokinetics of Anistreplase?

Answer 20

-IV infusion with slow activation in vivo
-long complex half life

Question 21

What drugs are antifibrinolytics?

Answer 21

-epsilon-aminocaproic acid (EACA)
-tranexamic acid (TXA)

Question 22

What are the FDA indications of Epsilon-Aminocaproic acid (EACA)?

Answer 22

-reduced bleeding after prostatic surgery (IV)
-reduce bleeding after tooth extraction in hemophiliacs

Question 23

What are the FDA indications of Tranexamic acid (TXA)?

Answer 23

reduce operative bleeding in patients undergoing hip or knee arthroplasty or cardiac surgery