Antithrombotics for ischemic heart disease

Question 1

Standard pharm intervention of ACS

Answer 1

Antiplatelets: COX inhibitor (Aspirin), ADP receptor inhib inhibitor (Clopidogrel, prasugrel, ticagrelor), Glycoprotein 2b/3a inhibitors (Abciximab, Eptifibatide)

Antithrombotic: unfractionated heparin, low molecular weight heparin, direct thrombin inhibitors

Exception: STEMI also thrombolytic

Question 2

Fibrinolysis (to dissolve intravascular clots)

Answer 2

Plasmin (plasma serine protease that cuts up the fibirn glue), non specific, also digests other plasma proteins

Plasminogen is the inactive precursor

t-PA activates plasmin
Plasminogen activator inhibitor-1 (PAI-1): preventing the formation of plasmin. Free plasmin is rapidly neutralized by serine proteinase inhibitor alpha-antiplasmin, fibrin bound plasmin is protected from rapid inhibition (promoting clot lysis)

Question 3

Use of fibrinolytics

Answer 3

accelerate lysis of occlusive intracoronary thrombosis in STEMI

Restore coronary blood flow, limit myocardial damage, translate to increased survival rate and fewer complication

Patients with UA or NSTEMI dont benefit from fibrinolytic therapy (recomb tissue type plasminogen activators) tPAs (alteplase, reteplase ,tenectaplase

MOA: binds fibrin in a thrombus, activates entrapped plasminogen to lyse clots, nneds to be administered ASAP (within 30 mins)

SE: bleeding, interferes with coag and general circulation

Question 4

Tenecteplase

Answer 4

modified alteplase, very fibirn specific, more resistant to plaminogen actovator inhibitor 1 (PAI-1)

longer duration of action compared to alteplase

single bolus over 5 seconds

Question 5

Contraindication to thrombolytic therapy

Answer 5

30% contraindicated, active peptic ulcer, recent stroke, recent surgery, uncontrolled severe HTN

Question 6

coagulation cascade

Answer 6

transformation of proenzymes to activated enzymes resulting in the formation of thrombin (2a) to insoluble fibrin X–> Xa, 2–>2a,

synthesis dependent on vitK (Factors 2, 7, 9 10)–Warfarin

Question 7

Anticoagulants

Answer 7

interferes w/coag cascade. Impairs secondary hemostasis

goal is to inhibit activation of thrombin by Xa), directly inhibit thrombin, decrease production of functional prothrombin

Question 8

unfractionated heparin, low molecular weight heparin (enoxaparin, dalteparin and fondaparinux)

Answer 8

administered parenternally (not absorbed from GIT), SE: bleeding

UFH: has the added SE of heparin induced thrombocytopenia (HIT)

LMWH (and fondapirunux) longer half life and more predictable bioavailability (less risk of HIT)

Question 9

Direct thrombin inhibitors

Answer 9

bivalirudin, why leeches work independently of antithrombin

Acts on circulating and clot bound thrombin

No thrombocytopenia, IV admin, UA percutaneous coronary intervention, major adverse effect is bleeding

Thrombin bound to fibrin within a thrombus remains enzymatically active and protected from inactivation by antithrombin (Fibrin-bound thrombin can locally activate platelet and trigger coagulation thereby causing thrombus to grow)
Heparin only inactivates circulating thrombin, direc thrombin is both

Question 10

Antiplatelets

Answer 10

Thienopyridines: Clopidogrel, prasugrel, ticagrelor

GP2b/3a: receptor antagonists: Abciximab, eptifibatide

Question 11

Aspirin

Answer 11

Irreversibly acetylates COX-1 in platelets (no COX2 in platelets)

Blocks production of thromboxane

Platelets lack nuclei so permanent effect of aspirin

In ED give 325 mg chew and swallow

Secondary prevention: used in pt with UA, Acute MI, chronic SA w/o A, strokes, CABG

Question 12

Clopidogrel, prasugrel, ticagrelor

Answer 12

Inhibits ADP mediated activation of platelets (inhibits the platelet P2Y12 receptor)- permanent platelet-

Clopidugrel and Prasugrel- prodrufs (bleeding

Clopidugrel (CYP2C19) metabolizm, give with omeprazole

Better than aspirin in MI risk (Clop+aspirin)

Question 13

Gp 2b/3a receptor antagonists

Answer 13

abciximab, eptifibatide

Reversibly inhibit platelet aggregation (binding of GP2b/3a receptors to fibrinogen and vWF)

Platelets cant stick to each other- no hemostatic plug

Abciximab: blocks access of fibrinogen (vWF) and other adhesive molecules to the Gp 2 b 3a, noncompetitive, Ivadmin
Eptifibatide: binds to GP competiitive inhibition, renal clearance

Question 14

dipyridamole

Answer 14

patients that cannot tolerate aspirin, ineffective

Mechanism of action unclear (increase in platelet cAMP) blocking PDE, blocking cell uptake and destruction of adenosine

Given alone, drug has no proven cardiac benefits