Product Information
ReoPro is a GP IIb/IIIa inhibitor that blocks the GP IIb/IIIa receptor, blocking interaction of fibrinogen with the receptor, the final common pathway to platelet aggregation.
There are many steps involved in platelet activation, but all ultimately lead to aggregation. Binding of fibrinogen to the GP IIb/IIIa receptor is the final common pathway to platelet aggregation, and inhibitors of this receptor act as potent inhibitors of platelet aggregation (Fig. 1).
Figure 1. Pathways of platelet aggregation. The parameters presented here are based on the known or believed mechanism of action for each product and are not intended to convey comparative safety or efficacy.
GP IIb/IIIa inhibitors bind to the GP IIb/IIIa receptor on platelets; they stop fibrinogen from binding and forming links between platelets. This prevents platelet aggregation and subsequent thrombus formation. Fibrinogen has a relatively weak affinity for the GP IIb/IIIa receptor and GP IIb/IIIa antagonists take advantage of this. The binding of fibrinogen is a dynamic process and, in the early phase of interaction, fibrinogen continually binds to, and dissociates from, the GP IIb/IIIa receptor. (Click here to see the mechanism of thrombus formation.) The fibrinogen saturates the GP IIb/IIIa receptor, so that as soon as one fibrinogen molecule leaves the receptor, another is there to attach to it. Although an excess of fibrinogen normally maintains the binding of any given GP IIb/IIIa receptor, GP IIb/IIIa inhibitors have a clear opportunity to bind to the receptor instead of fibrinogen.
ReoPro binds rapidly and with high affinity to the GP IIb/IIIa receptor on the platelet to inhibit platelet aggregation, the first stage in the formation of thrombus.
ReoPro binds non-competitively and with a high degree of affinity to the GP IIb/IIIa receptor. ReoPro, as a non-competitive inhibitor, does not compete with fibrinogen for access to the RGD (arginine–glycine–aspartic acid)-binding site in the receptor that fibrinogen uses, but instead attaches elsewhere on the GP IIb/IIIa receptor. ReoPro has greater affinity for the GP IIb/IIIa receptor than fibrinogen. More than 80% of GP IIb/IIIa receptors on the platelet are blocked after bolus ReoPro administration. Platelet aggregation is reduced to less than 20% in most patients by 10 minutes after bolus administration.
ReoPro's long biologic half-life.
ReoPro has a bi-phasic plasma half-life, with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes. However, ReoPro has a biologic half-life of 12-24 hours as a result of its high affinity for the receptor.
The different half-lives can be thought of as follows: the plasma half-life is the half-life of the drug as it remains free floating and unbound in the plasma; the biologic half-life is the half-life of the pharmacodynamic effect of the drug.
ReoPro has a very short plasma half-life because, in the unbound state, it is rapidly cleared from the blood through binding rapidly to platelets. The very small remainder is eliminated by the kidney. However, once ReoPro is bound to the GP IIb/IIIa receptor, it is removed from the body in the bound state when the platelets are cleared from the blood by the spleen. This accounts for the longer biologic half-life. Low levels of GP IIb/IIIa receptor blockade are present for more than 10 days after completion of the ReoPro infusion. At 8 days after completion of infusion, 24% of ReoPro molecules are still bound to platelets, falling to 10% at 15 days -- long after the initial platelets are cleared from the bloodstream, with residual binding seen as late as 21 days.
ReoPro also binds to the vitronectin and MAC-1 receptors
In addition to the GP IIb/IIIa receptor, ReoPro also binds to the vitronectin (alpha-v, beta-3) receptor and the leukocyte receptor, MAC-1. Vitronectin receptors on smooth muscle cells have been associated with the intimal hyperplasia that occurs following vascular injury from coronary interventions and may contribute to restenosis. The MAC-1 receptor accelerates the inflammatory response following vascular injury.
The relationship of these in vitro data to clinical efficacy is unknown.
The dethrombotic effect of ReoPro diminishes fresh thrombus
ReoPro has demonstrated an ability to diminish freshly-formed platelet aggregates. ReoPro causes the outermost platelets to break away from the collected aggregates, and the thrombus starts to diminish.
ReoPro administration may help relieve the vessel of some obstructive thrombus and improve blood flow by reducing the size of platelet aggregates and increasing the accessibility of fibrin.
