Aspirin and Antiplatelet Medications (cont.)

These agents differ in the way they work, their potency (how strongly they prevent clumping), how rapidly they work, and their cost.

What are platelets?

Platelets are particles (actually, remnants of cells) circulating in the blood that are needed in order for blood clots to form. Platelets initiate the formation of blood clots by sticking together (clumping or aggregating), a process called platelet aggregation. Clumps of platelets then are further bound together by a protein (fibrin) formed by clotting factors present in the blood. The clumps of platelets and fibrin make up the blood clot.

Blood clots are important because they stop bleeding (for example, a cut or laceration on the skin). When bleeding occurs from a cut, platelets become activated and form a network by attaching to the blood vessel wall at the site of bleeding, and by also attracting other clotting factors in the blood (such as fibrin) to stop ongoing bleeding rapidly.

However, if a blood clot forms inside an artery, it blocks the flow of blood to the tissue that the artery supplies, which can damage the tissue. For example, a blood clot that forms in a coronary artery supplying blood to the muscle of the heart causes a heart attack, and a blood clot that forms in an artery supplying blood to the brain causes a stroke.

How do antiplatelet agents work?

Aspirin

Aspirin prevents blood from clotting by blocking the production by platelets of thromboxane A-2, the chemical that causes platelets to clump. Aspirin accomplishes this by inhibiting the enzyme cyclo-oxygenase-1 (COX-1) that produces thromboxane A-2. While other NSAIDs also inhibit the COX-1 enzyme, aspirin is the preferred NSAID for use as an antiplatelet agent because its inhibition of the COX-1 enzyme lasts much longer than the other NSAIDs (aspirin's antiplatelet effect lasts days while the other NSAIDs' antiplatelet effects last only hours).

Thienopyridines

In addition to thromboxane A-2, platelets also produce adenosine diphosphate (ADP). When ADP attaches to receptors on the surface of platelets, the platelets clump. The thienopyridines, for example, ticlopidine (Ticlid) and clopidogrel (Plavix), block the ADP receptor. Blocking the ADP receptor prevents ADP from attaching to the receptor and the platelets from clumping.

Glycoprotein IIb/IIIa inhibitors

The glycoprotein IIb/IIIa inhibitors, such as abciximab (Reopro) and eptifibatide (Integrilin), prevent clumping by inhibiting a different receptor on the surface of platelets, the receptor for glycoprotein IIb/IIIa. The glycoprotein IIb/IIIa inhibitors that are approved by the FDA must be given intravenously (in the veins).

What is the relative potency of the antiplatelet agents?

  • Since aspirin blocks only one of the several pathways by which platelet aggregation can occur, aspirin is a weak antiplatelet agent because platelet aggregation can be stimulated via another pathway.

  • Since glycoprotein IIb/IIIa inhibitors block the final common pathway for platelet aggregation (platelet aggregation is blocked regardless of the nature of the initial stimuli), glycoprotein IIb/IIIa inhibitors are the most potent antiplatelet agents. The maximal antiplatelet effect of glycoprotein IIb/IIIa inhibitors is approximately nine times that of aspirin.

  • The maximal antiplatelet effect of thienopyridines is in between that of aspirin and the glycoprotein IIb/IIIa inhibitors.

How quickly do antiplatelet agents work?

Aspirin

When aspirin is given in low doses (75 mg/day), the complete inhibition of the COX-1 enzyme and hence maximal antiplatelet effect may take several days. At a dose of 160-325 mg/day, the maximal antiplatelet effect of aspirin occurs within 30 minutes. Thus, aspirin at low doses (75-150 mg/day) is used for the long term prevention of heart attacks and strokes, whereas moderate doses (160-325 mg/day) of aspirin are given in situations where an immediate anti-clotting effects are needed (such as in the treatment of acute heart attacks and unstable angina).

Thienopyridines

Like aspirin, the onset of action of clopidogrel (Plavix) is dose related. Maximal antiplatelet effect occurs several days after initiation of clopidogrel (75 mg/daily), but can occur within hours after larger doses of 300 or 600 mg. Therefore, larger doses of clopidogrel are used initially when immediate antiplatelet actions are needed (such as after placement of intracoronary stents) while the lower doses are used as maintenance.

Glycoprotein IIb/IIIa inhibitors

The glycoprotein IIb/IIIa inhibitors have a rapid onset of action. Their maximal antiplatelet effect occur within minutes after an intravenous infusion, and are used mainly in patients with unstable angina or acute heart attack (myocardial infarction).

What is dipyridamole?

Dipyridamole (Persantine IV, Persantine) is another medication that decreases platelet aggregation, though the exact mechanism of its antiplatelet action is not well understood. Dipyridamole is not commonly used in heart attack prevention, although it is sometimes used with aspirin to lessen the chance of stroke.



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