Drugs Used in Thromboembolic Disorders: An Insight into Their Mechanisms

In the United States alone, more than 6 million patients receive long-term anti-platelet and anticoagulation therapy. The hemostatic system must maintain a balance between fibrin formation (coagulation) and fibrin dissolution (fibrinolysis). Thrombin and Factor Xa are two of the most important components of the coagulation cascade. Any disruption in this cascade can lead to either thrombosis, hemorrhage or both. The clotting process is a dynamic, highly interwoven array of multiple processes. There are four different phases involved in the response of activated platelets: Adhesion, aggregation, secretion and the procoagulant activity. The coagulation cascade is a coordinated sequence of linked enzymatic reactions in which each reaction product converts the subsequent inactive zymogen into an active serine protease that are responsible for the conversion of soluble plasma fibrinogen into insoluble fibrin. Several antithrombotic factors regulate coagulation and limit the production of thrombin to prevent the perpetuation of coagulation and thrombus formation; these include protein C/protein S, antithrombin, heparin cofactor and tissue factor pathway inhibitor. Antiplatelet agents play a major role in the management of cerebrovascular, peripheral vascular and cardiovascular diseases. Aspirin is a non-steroidal anti-inflammatory drug that works by irreversibly inhibiting cyclo-oxygenase 1 and 2 by covalent acetylation. Cilostazol, a specific and strong inhibitor of PDE3 in platelets and smooth muscle cells was approved in the USA in 1999 for the treatment of intermittent claudication. Dipyridamole affects platelet function by inhibiting the reuptake of adenosine by red blood cells, in this way enhancing plasma levels of this vasodilator and platelet inhibitory nucleoside; it acts as an inhibitor of PDE5 and PDE3, thus increasing intraplatelet cAMP and/or cGMP; and it also acts as an antioxidant by scavenging free radicals that inactivate cyclo-oxygenase, thus enhancing PGI2 biosynthesis. Vorapaxar, a first in its class, is an orally available PAR-1 antagonist approved for patients with prior myocardial infarction or peripheral arterial disease with no previous history of stroke or TIA, and is added to standard therapy for long‐term secondary prevention of thrombotic CV events. Abciximab, eptifibatide, tirofiban all bind the glycoprotein receptor IIb/IIIa on activated platelets, preventing aggregation. Warfarin is a Vitamin K antagonist that interferes with γ-carboxylation of vitamin K–dependent clotting factors II, VII, IX, and X, and proteins C and S. Dabigatran is a potent, competitive inhibitor of thrombin, while Apixaban, edoxaban and rivaroxaban all selectively inhibit factor Xa. Heparins, acts indirectly by binding to anti-thrombin (AT) rather than acting directly on the coagulation factors. This interaction converts AT to a rapid inactivator of factor IIa and factor Xa. Unfractionated heparin, LMW heparin (enoxaparin, dalteparin) and fondaparinux all inactivate factor Xa, but unfractionated heparin is a much more efficient inactivator of thrombin. Drugs such as anti-platelet therapy and anti-coagulants are frequently used in clinical settings. It is imperative that the physicians have a thorough understanding of these agents. An insight into the mechanism of how these medications act serves as a prelude to understanding the pharmacology of these drugs.