Heparin, anticoagulant drug

The purpose of this paper is to illustrate how mathematical modeling and control theory can be applied to the problem of optimizing the administration of the anticoagulant drug heparin. 

A pharmacokinetic model which describes a patienf s response to the widely used anticoagulant drug, heparin, is discussed. The model contains several unknown parameters. A patients own past data can be used to identify these parameters and thus tailor-make a model for each individual under treatment. Once such a model is available it can be used to calculate optimum dosing policies to achieve a specified therapeutic goal. 

McAvoy, T. J., Modeling and Control of the Anticoagulant Drug Heparin, J. Process Control, 17, 590 (2007). 

Anticoagulant drugs include heparin and warfarin (Coumadin ) —agents used to prevent deep vein thrombosis. They are also used to prevent formation of emboli due to atrial fibrillation, valvular heart disease, and other cardiac disorders. Heparin, which is not absorbed by the gastrointestinal tract, is available only by injection its effect is immediate. 

De Kort, M., Buijsman, R.C., and van Boeckel, C.A. 2005. Synthetic heparin derivatives as new anticoagulant drugs. Drug Discovery Today 10(11), 769-779. 

Drugs that inhibit platelet function (e.g., aspirin) or produce thrombocytopenia increase the risk of bleeding when heparin is administered. Oral anticoagulants and heparin produce synergistic effects. Many basic drugs precipitate in the presence of the highly acidic heparin (e.g., antihistamines, quinidine, quinine, phenothiazines, tetracycline, gentamicin, neomycin). 

Regulation of the fibrinolytic system is useful in therapeutics. Increased fibrinolysis is effective therapy for thrombotic disease. Tissue plasminogen activator, urokinase, and streptokinase all activate the fibrinolytic system (Figure 34-3). Conversely, decreased fibrinolysis protects clots from lysis and reduces the bleeding of hemostatic failure. Aminocaproic acid is a clinically useful inhibitor of fibrinolysis. Heparin and the oral anticoagulant drugs do not affect the fibrinolytic mechanism. 

Editor s Note Tile following references have been selected to provide the interested reader wiLli more detail on the pharmacologic complexities of anticoagulants Tile article by Edwin W. Salzman, M.D. is a short, but excellent summary of the status of antithrombotic drugs as of early 1992. The article on heparin by Jack Hirsh, MD. and the article on warfarin by the same author proride important fundamental background information on the pharmacokinetics and pharmacodynamics of the most widely used anticoagulant drugs, Brandjes. D.P.M., et al. Acenocoumarol and Heparin Compared with Acenocoumarol. Alone in the Initial Treatment of Proximal-Vein Thrombosis," N. Eng. J. Med., 1485 (November 19, 1992). 

Normal hemostasis is a balance between excessive and inadequate blood clotting. Overactive blood clotting is harmful because of the tendency for thrombus formation and occlusion of arteries and veins. Vessels may become directly blocked by the thrombus, or a portion of the thrombus may break off and create an embolism that lodges elsewhere in the vascular system. The tendency for excessive thrombus formation in the venous system is usually treated with anticoagulant drugs such as heparin and warfarin. Platelet inhibitors such as aspirin help prevent arterial thrombogenesis. Thrombolytic drugs (streptokinase, t-PA) that facilitate the dissolution of harmful clots may successfully reopen... 

The most representative example utilizing this approach is the synthesis of the ultralow molecular weight (ULMW) heparin construct 27 (Scheme 9.2), a heptasac-charide that has a very similar structure to the FDA-approved anticoagulant drug fondaparinux. Fondaparinux is currently synthesized chemically through 50 steps... 

F-1) Heparin interferes with the activity of a number of clotting enzymes in the clotting cascade. It is a useful anticoagulant drug (see also 151). 

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