The pathway to cardiovascular disease (arterial thrombosis) is dependent upon what?
the activation and proper functioning of circulating platelets
For < 50 yrs, med therapy has been targeted at the platelet in an attempt to do what?
to limit thrombosis w/o the side effect of excessive bleeding
Initial platelet adhesion is mediated through what?
exposed collagen fibers on the endothelium binding to receptor sites on the platelet (both directly and with the aid of von Willebrand factor)
What additional stimulator of platelets is circulating?
circulating thrombin (generated by the coag cascade) is an additional stimulator of platelets that prompts the release of adenosine triphosphate (ATP) from the platelet itself, which provides positive feedback for activation through P2Y1, P2Y12, and 5-HT2A receptors.
The above activated platelet also produces what?
arachidonic acid (AA) that acts through the cycloxygenase-1 (COX-1) dependent signaling pathway to produce thromboxane A2 (TXA2) that then stimulates comtinued platelet activation
What enzymes are responsible for generating the activated adenosine monophosphate (AMP) and guanine monophosphate (GMP) needed for signal amplication within the platelet?
phosphodiesterase enzymes (PDE and PDE3)
Additional receptors are responsible for what type of aggregations?
What two anti-thrombotic drugs have been used for > 50 years and remain an important therapy due to its efficacy and low cost?
1) ASA 2) acetylsalicylic acid
Describe the pathway that ASA goes through?
ASA permanently inactivates the COX enzyme so its effects can only be reversed by the generation of new platelets.
Endothelilal TXA2 production is not affected by ASA so what is the result?
there is little effect on arterial blood pressure regulation, renal function or the effectiveness of diuretics or ACEI
What is the major risk of ASA?
bleeding (esp in the upper GI tract)
This bleeding can be reduced by concomitant use of what?
Only a small percentage (1-2%) of pts have true ASA resistance, but up to e1/3 of patients may have what?
inadequate response to low doses of the drug
*** The USPSTF recommends that men ____ to ____ years of age should take a daily low dose ASA to prevent MI and women ____ to ____ y.o. should take daily low dose ASA to prevent ischemic stroke?
What is clopidogrel?
a thienopyridine with no inherent anti-platelet activity. When metaoblized by cytochrome P450 in the liver, its metabolite is an active antagonist of the P2Y12 platelet receptor
The addition of clopidogrel to ____ was proven beneficial for SECONDARY prevention following cardiovascular events?
***In the CHARISMA trial, comment on the the effectiveness compared to clopidogrel AND ASA with ASA alone in the PRIMARY prevention of cardiovascular events?
clopidogrel and ASA was not better than ASA alone
Pts with reduced functioning of what allele have lower levels of the active metabolite of clopidogrel (so-called "clopidogrel resistance") and a higher rate of major adverse cardiovascular events than noncarriers?
Future ____ testing may allow identification of patients of risk of clopidogrel resistance?
The simultaneous use of clopidogrel and omeprazole which are both metabolized through cytochrome ____ reduces the antiplatelet effects of clopidogrel?
it is a thienopyridine that is actively metabolized by cytochrome P450 to a metabolite that irreversibly inhibits the platelet P2Y12 receptor. Its metabolism is more efficient, resulting in a more rapid, potent and consistent inhibition of platelet function that with clopidogrel
In the TRITON-TIMI 38 Trial, what were to findings when comparing prasugrel (Effient) to clopidogrel?
significantly reduced rates of stent thrombosis with prasurgrel when compared to clopidogrel. However, more episodes of major bleeding (including fatal bleeding) was noted with prasugrel
***Patients who were older (> ____ years), smaller (<____ kg) or who had a hx of ____ or _____ were more likely to have less clinical efficacy or more adverse events? : > 75; < 60 kg, CVA, TIA
What is Ticagrelor?
a reversible, direct-acting oral P2Y12 receptor antagonist. Unlike clopidogrel and prasugrel, it does NOT require metabolism to an active form
What did the PLATO trial conclude about ticagrelor (Brilinta)?
a decreased rate of death from vascular causes, MI and CVA compared to use of clopidogrel. There was no increased rate of overall major bleeding, but there was an increase in nonprocedure-related bleeding. There was no difference in coronary flow or myocardial perfusion after stenting betweene pts treated with ticagrelor or clopidogrel
has BOTH antiplatelet and vasodilator properties through its inhibition of PDE and blockade of adenosine uptake.
The combination of dipyridamole and ASA is approved for prevention of ______. It is dosed ____ daily. It was not shown to be superior to ______. It is not approved for use in ____disease?
The combination of dipyridamole and ASA side effects include?
increased risk of bleeding and headaches
oral selective PED3 inhibitor for the treatment of intermittent claudication. There is insufficient evidence to recommend it for pts undergoing percutaneous coronary intervention
Cilostazol side effects?
increased risk of bleeding, rash, HA, GI symptoms
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