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Ranolazine Antithrombotic Agents

Platelet activation and platelet aggregation play an important role in the pathogenesis of thromboses. These, in turn, play an important role in unstable angina, myocardial infarction, stroke, and peripheral vascular thromboses. Because many cardiovascular diseases are associated with platelet activation, many agents possessing antiplatelet or antithrombotic effects have been investigated. This has revolutionized cardiovascular medicine, in which vascular stenting or angioplasty can be used without compromising normal hemostasis or wound healing. Although most of these agents act by different mechanisms, many of the newer agents are being developed to antagonize the GPIIb/IIIa receptors of platelets.

Aspirin. Aspirin, acetylsalicylic acid, has an inhibitory effect on platelet aggregation not only because of its ability to inhibit cyclooxygenase (COX) but also because of its ability to acetylate the enzyme. Aspirin irreversibly inhibits COX (prostaglandin H synthase), which is the enzyme involved in converting arachidonate to prostaglandin G2 and ultimately thromboxane 2, an inducer of platelet aggregation. Aspirin's mechanism of action includes not only the inhibition in the biosynthesis of thromboxane 2, but also its ability to acetylate the serine residue (529) in the polypeptide chain of platelet prostaglandin H synthetase-1. This explains why other nonsteroidal anti-inflammatory agents that are capable of inhibiting the COX enzyme do not act as antithrombotics—they are not capable of acetylating this enzyme. Because platelets cannot synthesize new enzymes, aspirin's ability to acetylate COX lasts for the life of the platelet (7-10 days) and is, thus, irreversible.

Dipyridamole. Dipyridamole, 2,2',2",2"'-[(4,8-di-1piperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl)dinitrilo]-tetrakisethanol (Persantine), may be used for coronary and myocardial insufficiency. Its biggest use today, however, is as an antithrombotic in patients with prosthetic heart valves. It is a bitter, yellow, crystalline powder, soluble in dilute acids, methanol, or chloroform. A formulation containing dipyridamole and aspirin (Aggrenox) is currently being marketed as an antithromobotic.

Dipyridamole is a long-acting vasodilator. Its vasodilat-ing action is selective for the coronary system; it is indicated for long-term therapy of chronic angina pectoris. The drug also inhibits adenosine deaminase in erythrocytes and interferes with the uptake of the vasodilator adenosine by erythrocytes. These actions potentiate the effect of prostacyclin (PGI2), which acts as an inhibitor to platelet aggregation.

management of secondary ischemic events, including myocardial infarction, stroke, and vascular deaths. It may be classified as a thienopyridine because of its heterocyclic system. Several agents possessing this system have been evaluated as potential antithrombotic agents. These agents have a unique mechanism, in that they inhibit the purinergic receptor located on platelets. Normally, nucleotides act as agonists on these receptors, which include the P2Y type. Two P2Y receptor subtypes (P2Y1 and P2Y2) found on platelets, when stimulated by adenosine diphosphate (ADP), cause platelet aggregation. Clopidogrel acts as an antagonist to the P2Y2 receptor. It is probably a prodrug that requires metabolic activation, because in vitro studies do not interfere with platelet aggregation. Although platelet aggregation is not normally seen in the first 8 to 11 days after administration to a patient, the effect lasts for several days after the drug therapy is discontinued. Unlike other thienopyridines currently used, clopidogrel does not seriously reduce the number of white cells in the blood, and therefore, routine monitoring of the white blood cell count is not necessary during treatment.

Ticlopidine. Ticlopidine, 5-[(2-chlorophenyl)methyl]-4,5,6,7-tetrahydrothieno [3,2-c]pyridine hydrochloride (Ticlid), is useful in reducing cardiac events in patients with unstable angina and cerebrovascular events in secondary prevention of stroke. It belongs to the thienopyridine class and facilitated the development of clopidogrel. One of the drawbacks to this agent is its side effect profile, which includes neutropenia, and patients receiving this antithrom-botic should have their blood levels monitored. Its mechanism of action is similar to that of clopidogrel, in that it inhibits the purinergic receptors on platelets.

Clopidogrel. Clopidogrel, methyl ( + )-(s)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (Plavix), is useful for the preventative

GPIIB/IIIA RECEPTORS

Located on platelets is a site that serves to recognize and bind fibrinogen. This site is a dimeric glycoprotein that allows fibrinogen to bind, leading to the final step of platelet aggregation. The receptor must be activated before it will associate with fibrinogen, and this may be accomplished by thrombin, collagen, or thromboxane A2 (TXA2). Once the receptor is activated, fibrinogen most likely binds to the platelet through the arginine-glycine-aspartic acid (RGD) sequences at residues 95-96-97 and 572-573-574 of the a-chain of fibrinogen. This particular feature has been used in the design of nonpeptide antagonists that mimic the RGD system in which a distance of 15 to 17A (16-18 atoms) separates the amine group of arginine and the carbonyl oxygen of aspartic acid.

Eptifibatide. Eptifibatide (Integrilin) is a synthetic cyclic heptapeptide that acts as a GPIIb/IIIa receptor antagonist, thus causing inhibition of platelet aggregation. Its structure is based on the natural product barbourin, a peptide isolated from the venom of a pygmy rattlesnake (Sistrurus milarud barbouri). As part of the structure, there is a sequence RGD that can bind to the RGD receptor found on platelets and block its ability to bind with fibrinogen. This agent is used in the treatment of unstable angina and for an-gioplastic coronary interventions.

Tirofiban. Tirofiban is a nonpeptide that appears unrelated chemically to eptifibatide, but actually has many similarities. The chemical architecture incorporates a system that is mimicking the RGD moiety that is present in eptifibatide. This can be seen in the distance between the nitrogen of the piperidine ring, which mimics the basic nitrogen of arginine in the RGD sequence, and the carboxylic acid, which mimics the acid of aspartate in the RGD sequence. The basic nitrogen and the carboxylic acid of tirofiban are separated by approximately 15 to 17A (16-18 atoms). This is the optimum distance seen in the RGD sequence of the platelet receptor. Tirofiban is useful in treating non-Q wave myocardial infarction and unstable angina.

Abciximab. Abciximab (ReoPro) is a chimeric Fab fragment monoclonal antibody that can bind to the GPIIa/IIIb receptor of platelets and block the ability of fibrinogen to associate with the platelet. This results in less platelet aggregation. Abciximab is useful in treating unstable angina and as an adjunct to percutaneous coronary intervention (PCI). The half-life of abciximab is about 30 minutes, whereas its effects when bound to the GPIIa/IIIb may last up to 24 hours. A significant drawback to using abciximab lies in its cost, which is approximately $1,500 for a single dose.

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