Thrombolytic Drugs Flashcards
What is the role of plasmin?
Degrades the fibrin clot and clears in from the blood vessel
(Fibrinolysis and clot degradation)
What does the fibrinolytic pathway do?
Dissolves a blood clot after the blood vessel has healed
What is the mechanism of action of thrombolytics?
Increase the conversion of plasminogen to plasmin
What is the function of plasmin?
Degrades fibrin and dissolves clots
*digests fibrin and fibrinogen
What enzyme activates plasminogen to plasmin?
t-PA or u-PA
*what we target to break down clots
What does PAI-1 do?
bind t-PA or u-PA and inhibits activity
(prevents activation of plasminogen to plasmin)
What does a2AP do?
Degrades plasmin
What does TAFI do?
Prevents plasmin from binding fibrin which inhibits fibrinolysis
How does t-PA work?
Cleaves the arg-val bond to activate plasminogen to plasmin
(serine protease)
What does a2-antiplasmin do?
Inactivates plasmin
What is t-PA inhibited by?
PAI-1 and PAI-2
What are the indications for thrombolytic therapy?
-Acute MI
-Acute ischemic thrombotic stroke
-PE
What is the standard of care acute myocardial infarction (MI)?
STENT placement
What are the two types of STENTs?
Bare-metal
Drug-coated
What is the purpose of drug-coated STENTs
Drugs prevent restenosis (when an artery opened through a medical procedure re-narrows)
-by inhibiting smooth muscle cell proliferation
-increase risk of subsequent thrombosis
What is the structure/ function of Alteplase?
-Recombinant human t-PA
527 amino acid residues
*Binds fibrin to activate plasminogen
What is the structure/function of Reteplase?
-Recombinant human t-PA with deletion of aa (355/527)
**More potent
**Faster onset
*Lacks fibrin binding domain, less fibrin-specific than alteplase
What is the structure/ function Tenecteplase?
-Recombinant, mutant form of t-PA
*Longer half-life
*Given by single IV bolus
*More fibrin specific than t-PA
What domains in Alteplase and Tenecteplase are part of fibrin binding?
Finger
Kringle 1/2
What are the mutations present in tenecteplase?
-Increased half-life
-Reduced inhibition by PAI
-Enhanced activity at thrombi
What is the mechanism of action of alteplase, reteplase, and tenecteplase?
Tissue Plasminogen Activator (t-PA)
What tPA is the target of alteplase and tenecteplase?
tPA bound to a fibrin clot
What tPA is the target of reteplase?
tPA in the plasma OR bound to a fibrin clot
How are tissue plasminogen factors administered?
IV
What is the duration of actions of the tissue plasminogen activators?
Alteplase: 5-10min
Reteplase: 13-16min
Tenecteplase: 90-130min
What are the adverse effects of tissue plasminogen activators?
-Bleeding
-internal bleeding
-Superficial or surface bleeding
(can dissolve more than just the targeted clot)
What are anti-fibrinolytic agents used for?
-To stop bleeding caused by thrombolytic drugs
-Adjunct therapy in hemophilia
-re-bleeding from intracranial aneurysms
How do anti-fibrinolytic agents work?
-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
What are the anti-fibrinolytic drugs?
Aminocaproic acid
Tranexamic acid
Lysine
Which anti-fibrinolytic drug is most potent?
Tranexamic acid
(10x more potent than aminocaproic acid_
What are the risks associated with anti-fibrinolytic agents?
Intravascular thrombosis formation as a result of fibrinolysis inhibition
Thrombi formed during therapy are not easily lysed
