6 - Thrombolytic Agents Flashcards
What is usually the triggering event in an MI? What is needed to treat this?
Obstruction of coronary artery by thrombus.
Thrombolytics for reperfusion.
What is fibrinolysis and how is it done?
Dissolving intracellular clots.
Plasminogen converted to active plasmin to break down clots.
What is the mechanism of activation of plasminogen to plasmin?
Cleavage of a single peptide Arg560 bond generates two chain disulfide linked molecules and exposes kringles that can bind fibrin to degrade it.
What endogenous molecules activate plasminogen to plasmin? What exogenous drugs activate plasminogen to plasmin?
Endogenous: t-PA and Prourokinase
Exogenous: Alteplase (recombinant t-PA) and Tenecteplase (recombinant t-PA).
What is the action of tissue-type plasminogen activator (t-PA)? What occurs in the early stages of clot formation?
Cleaves plasminogen to plasmin.
Early stages of clot formation: inhibitor of plasminogen activator called t-PA-I present (prevents plasmin from being made when you wanna clot.)
What happens to free plasmin?
Inactivated by alpha2-antiplasmin.
What tissue plasminogen activator is produced by recombinant DNA technology, has a very short half life, and requires IV infusion?
Alteplase.
What tissue plasminogen activator is produced by recombinant DNA technology, has a longer half life, requires a single bolus administration, and is resistant to inhibition by PAI-1?
Tenecteplase
What is the advantage of fibrin specificity?
It limits systemic lysis/increases bleeding risk.
What are complications of thrombolytic therapy?
Hemorrhage (just as common with t-PA)
More bleeding complications when combined with heparin a/o aspirin.
What are therapeutic indications for thrombolytic therapy?
Acute MI (STEMI).
Complete occlusion of an epicardial coronary vessel caused by an acute thrombotic obstruction. (the earlier the better)
Stroke (only alteplase) - within first 3 hours.
What drug inhibits fibrinolysis? How does it do this?
Aminocaproic acid: blocks the binding of plasmin to fibrin.
How does platelet aggregation occur?
- GP1b, GP1a/IIa glycoprotein receptor proteins (integrins) bind collagen,
- GPIIb/GPIIIa glycoprotein receptor binds fibrinogen
- P2Y/P2Y12: purinergic receptors for ADP
- COX mediated production of TXA2.
What is the function of low-dose aspirin in platelets? What about in endothelial cells?
Irreversibly acetylates COX1 in platelets (no COX2 in platelets) and thereby blocks thromboxane production.
In endothelial cells it irreversibly inhibits COX1 and COX2. Endothelial ells produce prostacyclin which inhibit platelet agreggation.
Patients with cardiovascular disease taking aspirin experienced ____% fewer deaths. For combined fatal and nonfatal events the aspirin group was ____% lower than the placebo.
30%
21%
What are the therapeutic uses of low dose aspirin?
MI prophylaxis
Stroke prophylaxis
What is the function of dipyridamole?
Vasodilator and inhibitor of platelet aggregation.
What drug inhibits phosphodiesterase, thereby increasing cAMP in platelets and inhibiting platelet aggregation? What is the therapeutic use?
Dipyridamole
Used in combo with aspirin for secondary prevention or MI or stroke.
What drugs act through P2Y1/P2Y12 receptors to inhibit ADP-induced platelet aggregation? Which are irreversible?
Clopidogrel
Ticlopidine
Prasugrel
Ticagrelor
All irreversible except ticagrelor is reversible.
Two patients need treatment for acute coronary syndrome. Patient 1 is given clopidogrel. Patient 2 is given ticagrelor. Which drug provides the advantage if the patient requires coronary bypass surgery?
Ticagrelor, because it’s reversible.
The patients taking clopidogrel would need to wait until their platelet function returns to normal before having surgery otherwise they could have bleeding complications.
How are Clopidogrel, Ticlopidine, Prasugrel and Ticagrelor given? Which are prodrugs and how are they activated?
Oral admin.
Prasugrel prodrug: activated via hydrolysis then CYP3A4 and 2B6 activation.
Clopidogrel and Ticlopidine prodrugs: activated by CYP2C19.
How does Prasugrel differ from the other drugs act through P2Y1/P2Y12 receptors to inhibit platelet aggregation?
It has increased potency because there’s more efficient generation of active metabolite.
More predictable effects on platelets than other P2Y antagonist drugs.
What adverse effects are associated with clopidogrel?
CYP2C19 polymorphisms cause poor metabolizers that don’t get as much active drug (because clopidogrel is a prodrug).
What drugs are given via IV preparations and antagonize GbIIb/IIIa (integrin) receptors?
Abciximab and Eptifibatide
