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Coagulation Corner
Wednesday, July 1, 2009
ANTI-PLATELET DRUGS
ANTI-PLATELET DRUGS:
You can't open a journal today without seeing an article about anti-platelet drugs. It is overwhelming- and confusing. So this month I will try to sort out the differences among the choices out there.
No article on anti-platelet drugs would be complete without mentioning the queen of all anti-platelet drugs- aspirin. Almost everyone is aware of how it works and the advantages of this product. Medical historians give 1897 as the date Aspirin was developed, however there are recipes that date back over 3,500 years ago when Egyptians used myrtle leaves to relieve pain. Hippocrates, the father of all doctors prescribed a juice from the bark of the willow tree for fever and pain. The active ingredient in that juice is salicylic acid, which is derived from the Latin word for willow Salix. This is also contained in the myrtle leaves used by the Egyptians. It was used throughout history but in 1897 Dr. Felix Hoffman purified acetylsalicylic acid and in 1899 the first clinical publication referred to this compound as Aspirin.
So how does Aspirin work?
Aspirin is rapidly absorbed from the proximal gastrointestinal tract and irreversibly binds to cyclooxygenase-1,or as it is referred to a COX-1 inhibitor. This impairs thromboxane A2 (TXA2) synthesis and platelet aggregation in response to collagen, adenosine diphosphate (ADP), and thrombin.
The most studied and best-established antiplatelet treatment is aspirin. Based on the time-honored balance between efficacy and safety, lifelong aspirin treatment is recommended for all patients with atherosclerotic vascular disease; exceptions are patients at high risk of bleeding and those with aspirin allergy
It is very effective. If you are a responder it will affect platelet function within 45 minutes. If someone is having a heart attack, crush the aspirin it will work even quicker. Aspirin can have a 25% risk reduction of nonfatal MI, stroke or death. Carry some at all times!
What about Aspirin Resistance? Some people believe it is just non-compliance, others inadequate dosing, or can occur in people concurrently taking NSAIDs. Anti-inflammatory drugs may interfere with the irreversible inactivation of platelet - COX-1 by competing with Aspirin for a common docking site- Naproxen can also compete. Aspirin resistance is difficult to define, but with pharmacokinetics, we have learned that there are many genetic polymoprphisms that can cause either a hyper or hypo response. Approximately 20-25% of the population can fall into this category. It has also been demonstrated that females need higher doses than males for cardio-vascular protection. This may be due to the process in which estrogen up-regulates prostaglyandin production by receptor redirection.
Clopidogrel is a prodrug metabolized in the liver by cytochrome P450
isoenzyme A4 (CYP3A4) after its intestinal absorption. Clopidogrel is an Adenosine 5'-diphosphate (ADP) receptor antagonist indicated for the reduction of atherosclerotic events including stroke or myocardial infarction. (ADP) is an important physiological and pathological platelet agonist. Upon vascular injury, ADP is released into the bloodstream from damaged cells and activated platelets, and in turn acts on other platelets. ADP induces a number of platelet responses, including shape change from disc to sphere, aggregation and secretion of granule contents. These ADP-induced platelet responses contribute to hemostasis, pathological thrombus formation and vascular occlusion. These responses are considered to be mediated by the interaction of ADP with specific binding sites on the platelet membrane designated as P2Y12 (or P2T) receptors. This is a selective and irreversible inhibitor of ADP-induced platelet aggregation, but does not interfere with ADP platelet induced shape changes. It inhibits the binding of fibrinogen without affecting the GPIIb/IIIa complex. Dosage is 75mg 1/day, with a half life of 7-8 hours and will affect platelets within 2 hours. Clopidogrel has transient effects on thrombin and collagen aggregation. The active thiol metabolite irreversibly binds to the P2Y12 receptor and inhibits ADP-induced platelet aggregation, ADP-stimulated P-selectin and CD40L expression, as well as platelet-leukocyte aggregate formation.
Concurrent therapy:
Aspirin and clopidogrel affect different platelet activation pathways, so they are frequently used in combination. Dual antiplatelet therapy may be most beneficial in patients with acute events, There are sever conditions in which combined therapy offers no benefits over monotherapy such as in primary prevention of coronary or cerebral events in patients at high risk.. Aspirin,is the preferred treatment for primary prevention; clopidogrel alone is useful in patients with an aspirin allergy] Likewise, combination therapy is inappropriate in patients with a recent stroke or transient ischemic attack because it increases the incidence of major and minor bleeds without offering any therapeutic benefit over clopidogrel alone. The most appropriate indications for the use of combined clopidogrel and aspirin therapy are the treatment of acute coronary syndromes and the prevention of coronary events after placement of a stent.
Prasugrel is a new prodrug-type antiplatelet agent that acts as a P2Y12 receptor antagonist via its active metabolite R-138727. Plasma levels of the active metabolite of prasugrel were also 10 times higher than those of the active metabolite of clopidogrel, suggesting that prasugrel's greater potency may be due to a faster metabolization rate.
The JUMBO-TIMI 26 (Joint Utilization of Medication to Block Platelets Optimally - Thrombolysis in Myocardial Infarction 26) was a multicenter, double-blind, randomized, phase II clinical trial that evaluated the effects and safety of prasugrel. A total of 904 patients undergoing elective or urgent percutaneous coronary intervention were given the standard clopidogrel regimen above or one of three prasugrel regimens (loading doses of 40 or 60 mg, followed by 7.5, 10 or 15 mg/day) for 29-34 days, starting after the diagnostic angiogram. Prasugrel-treated patients showed a lower incidence of major adverse cardiac events than clopidogrel-treated patients, although the difference among study regimens did not reach statistical significance. Only 0.7% of patients had major bleeding, whereas 1.1% had minor bleeding and 2.4% experienced minimal bleeding in all study groups combined. No significant differences among study treatments were found in the incidence of an endpoint combining major and minor hemorrhage unrelated to coronary artery bypass graft. Hemorrhage rates were lower than those expected from historical controls (Wiviott, S.D. et al., Circulation 2005, 111(25): 3366).
Glycoprotein IIb/IIIa Inhibitors:
These IIb/IIIa antagonists receptors are critical to the process of platelet thrombus formation and work by blocking fibrinogen binding to the receptor. It serves as the final common pathway for platelet aggregation. Effectiveness has been established for precutaneous coronary intervention (PCI).It is administered by IV Bolus,and infused for 20-24 hours. Bleeding is an adverse event, but, no increased risk of intracranial hemorrhage, Thrombocytopenia can occur 0.4-1% of the time.Due to the risk of possible thrombocytopenia, platelet counts should be monitored at 1, 2 and 12 hours. ABCIXIMAB - (REPRO) is a chimeric monoclonal antibody that binds non-specifically to the Gp IIb/IIIa receptor.and is cleared between the RE system. The anti-platelet effect can last several days. Non-specific action can also bind to vitronectin and MAC 1-receptors, as a result may have an anticoagulant effect.
EPTIFBATIDE is a cyclic heptapeptide that selectively binds to the GpIIb/III a receptor. The effect is short acting, 50% of platelet function returns within 4 hours of cessation of infusion. Triofiban hydrochloride is a short acting non-peptide derivative of tyrosine that binds selectively to the GpIIb/IIIa receptor.
So, there are several options regarding antiplatelet drugs. Aspirin is still considered as one of the best anti-platelet drugs, however their are, several others that can provide options and decrease function. The challenge in using these agents is to maximize their effectiveness while minimizing the risk of bleeding.
Antiplatelet drugs
Glycoprotein IIb/IIIa inhibitors
Abciximab - Eptifibatide - Tirofiban
ADP receptor/P2Y12 inhibitors
(Thienopyridines) Clopidogrel - Ticlopidine - Prasugrel
Prostaglandin analogue (PGI2)
Beraprost - Prostacyclin - Iloprost - Treprostinil
COX inhibitors
Acetylsalicylic acid/Aspirin # - Aloxiprin - Carbasalate calcium
Other
Ditazole - Cloricromen - Dipyridamole - Indobufen - Picotamide - Triflusal
Donna Castellone
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About the Author
Donna Castellone,
MS, MT(ASCP)SH
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