Thrombin pharmacology

The 2(lH)-pyrazinone system has received increased interest in the past two decades by both synthetic and biological research, due to its presence in a variety of natural and non-natural products as well as pharmacologically active compounds. The easy and diverse methods for the generation of this versatile scaffold make it a prime choice for the current pharmaceutical research hke thrombin inhibitors, substance P antagonists, etc. The rich 1,4-azadiene... 

Given that thrombin is the central mediator of coagulation and amplifies its own production, it is a natural target for pharmacologic intervention. Direct thrombin inhibitors (DTIs) bind thrombin and prevent interactions with its substrates (Fig. 7-7). Several injectable DTIs are approved for use in the United States including lepirudin, bivalirudin, arga-troban, and desirudin. Several oral DTIs are currently in... 

Fareed J., Callas D. D. Pharmacological aspects of thrombin inhibitors A developmental perspective. Vessels 1995 1,15-24. 

Pharmacology Enoxaparin, tinzaparin, and dalteparin are LMWHs. These agents enhance the inhibition of Factor Xa and thrombin by binding to and accelerating antithrombin activity. They preferentially potentiate the inhibition of Factor Xa, while only slightly affecting thrombin and clotting time (activated partial thromboplastin time [APTT] or PT). 

Pharmacology Lepirudin (rDNA), a recombinant hirudin derived from yeast cells, is a highly specific direct inhibitor of thrombin. 

Pharmacology Bivalirudin directly inhibits thrombin by specifically binding to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin. The binding of bivalirudin to thrombin is reversible. 

Pharmacology The antithrombotic activity is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. 

Fitzgerald, G. (1996). The human pharmacology of thrombin inhibition. Coronary Artery Dis. 7(12), 911-918. Markwardt, F. (1991). Hirudin and its derivatives as anticoagulant agents. Thromb. Haemost. 66, 141-152. 

Chemical Class L-Arginine derivative thrombin inhibitor Clinical Pharmacology ... 

Clinical pharmacology Activated factor IX in combination with activated factor VIII activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, and a clot can be formed. Factor IX is the specific clotting factor deficient in patients with hemophilia B and in patients with acquired factor IX deficiencies. The administration of Coagulation Factor IX (Recombinant) increases plasma levels of factor IX and can temporarily correct the coagulation defect in these patients. 

Unfractionated heparin (UFH) has long been the only thrombin inhibitor used during PCI. As will be developed further, several pharmacological characteristics limit the antithrombin activity of UFH and encourage the development of alternative antithrombin strategies. 

White CM, Thrombin-directed inhibitors pharmacology and clinical use, Am Heart J 2005 I49 S54-S60. 

Gurm HS, Bhatt DL. Thrombin, an ideal target for pharmacological inhibition a review of direct thrombin inhibitors. Am Heart J 2005 I49 S43-S53. 

Linkins LA, Weitz Jl, Pharmacology and clinical potential of direct thrombin inhibitors, Curr Pharm Des 2005 ... 

The pharmacological treatment options for ACS include agents that either reduce oxygen demand (beta blockers) or increase oxygen supply (nitrates, potassium channel activators, calcium channel blockers) to the heart and antiplatelet (aspirin, ADP-receptor antagonists, GPIIb/llla receptor blockers) and antithrombin therapy (unfractionated heparin, low molecular weight heparin, direct thrombin inhibitors) (10). 

Bivalirudin is a direct thrombin inhibitor that has found utility for reducing the rate of acute reocclusion in patients treated with PCI. It is preferential to heparin in PCI when HIT is present. This drug is a derivative of hirudin, which is a dedicated thrombin inhibitor with no other in vivo activities of significance. The molecule is semisynthetic the C-terminal of hirudin is linked by a polyglycine spacer to the tetrapeptide region of the N-terminal that reacts with the thrombin active site (22). It is monitored by the activated clotting time test. Its pharmacologic properties are shown in Table I. 

Pharmacologic inhibitors of thrombin. Thrombin is a key enzyme in the hemostatic system in that it leads to the formation of fibrin strands and is a potent stimulus for platelet activation. Thrombin inhibitors, factor Xa inhibitors, and antiplatelet drugs act at different points in the hemostatic system to regulate the amount of thrombin that is generated. 

Recently, there has been in the use of other pharmacologic agents to modify the chronic total occlusion and render it more suitable for treatment (38-40). An animal model has been developed for testing these new approaches. In this rabbit model, thrombin is injected into an isolated portion of the femoral artery. After recovery, during the next two to four month, the thrombus is replaced by collagen which results in a chronic total occlusion. 

Platelet aggregation proceeds like an avalanche because, once activated, one platelet can activate other platelets. On the injured endothelial cell a thrombus is formed, which obstructs blood flow. Ultimately, the vascular lumen is occluded by the thrombus as the latter is solidified by vasoconstriction promoted by the release of serotonin and thromboxane A2 from the aggregated platelets and by locally activated thrombin. Thrombin plays a twofold part in thrombus Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms... 

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