Anticoagulants

Anticoagulants prevent the development of the coagulation process of blood. Therapy using anticoagulants is first and foremost directed at preventing the formation of clots in blood vessels, which are the main cause of death in thromboembolic diseases. Anticoagulants are subdivided into direct-acting coagulants, i.e. those that have an effect on coagulation factors directly in the blood, and indirect-acting coagulants, i.e. those that have an effect on factors of synthesis or blood coagulation in the liver. On the other hand, anticoagulants are classified as parenteral and oral drugs. Heparin is the only representative of parenteral anticoagulants. Oral coagulants are made up of a number of coumarin derivatives (dicumarol, ethylbiscumacetate, warfarin, phenprocumon, and acenocumarol), and indanone (fenidion, anisindion).

24.1.1 Direct-acting coagulants or parenteral anticoagulants

Heparin is one of the first types of direct-acting anticoagulants.

Heparin: Heparin, a natural anticoagulant, is formed in the body. The source of commercial heparin is the mucous membranes of pig intestine and ox lungs [1-5]. Heparin is a mixture of natural sulfated mucopolysaccharides, which are generally found in granules of mast cells. A lot of heparin is found especially in the liver and lungs. Lysosomes of mast cells contain proteases and glycosidases that evidently destroy heparin-proteoglucan that is contained in them, forming various sulfated oligosaccharides, of which heparin is one; it is present in extracellular fluid, and cleansed samples are used in clinics. Heparin is active only upon parenteral introduction. It is frequently used intravenously.

Heparin is a heterogenic mixture of sulfonated polysaccharides made from a repeating units of D-glucosamine, D-glucoronic, and L-iduronic acid. Commercial heparin is essentially a mixture of a number of compounds with various chain lengths and of molecular masses between 5000 and 30,000. Monosaccharides that form heparin are modified by either N-acetyl, or N- or 0-sulfate groups, and are joined by glucoside bonds, thus forming polymers like 24.1.6 with different chain lengths. The main monosaccharides that form heparin are 6-sulfate-2-desoxy-2-sulfamino-a-D-glucose (24.1.1), 2-sulfate a-L-iduronic acid (24.1.2), 2-acetamido-2-desoxy a-D-glucose (23.1.3), /-D-glucoronic acid (24.1.4), and a-L-iduronic acid (24.1.5). These sugars are present in commercial heparin in descending order: (24.1.1) > (24.1.2) > (24.1.3) > (24.1.4) > (24.1.5). Because of the presence of sulfonate and carboxyl groups in the molecules, heparin is a strongly acidic compound that is partially neutralized in the body by substituting acidic hydrogen atoms in sulfate groups with sodium ions.

It is believed that heparin acts by neutralizing a number of active blood coagulation factors, thus disrupting the transformation of prothrombin into thrombin. Heparin is used to prevent thrombo-formation in myocardial infarctions, thrombosis, and embolism, for maintaining liquid conditions in the blood in artificial blood circulation and hemodialysis. Synonyms of this drug are arteven, hepalen, leparan, liquemin, panheprin, vetren, and many others.

Heparin antagonist: A heparin antagonist used for heparin overdose is protamin, a mixture of proteins that are isolated from fish sperm. Upon reaction, it inactivates heparin by forming an insoluble complex. Direct-acting coagulants include sodium citrate, which is used for stabilizing blood during its conservation. It is believed that its anticoagulant action consists of binding calcium ions necessary for preventing prothrombin from turning into thrombin.

24.1.2 Direct-acting coagulants, or enteral anticoagulants

The most widely used enteral anticoagulants in medicine are structural derivatives of 4-hydroxycoumarin, a compound that is isolated from sweet clover, and that was a cause of fatal hemorrhagic diathesis in flocks in the 1920s—the so-called 'sweet clover disease.' After discovering that coumarin is able to suppress prothrombin synthesis, intense studies in the area of coumarinic derivative synthesis occurred, and as a result drugs, such as dicoumarol (bishydroxycoumarin), ethyl biscoumacetate, warfarin, phenprocoumon, and acenocumarol were introduced into medicine. Their therapeutic action depends on the ability to suppress formation of a number of functional factors of blood coagulation in the liver. These factors are described as vitamin K-dependent factors since their biosynthesis by hepatocytes is partially linked with hepatic vitamin K metabolism. Oral anticoagulants are effective only in vivo because their principal effect is suppression of synthesis of pro-thrombin, proconvertin, and other blood coagulation factors in the liver. They are sometimes conventionally called vitamin K antagonists.

Dicoumarol: Dicoumarol, 3,3'-methylene-bis(4-hydroxycoumarin) (24.1.8), is synthesized from 4-hydroxycoumarine (24.1.7), which is in turn synthesized from salicylic acid methyl ester by cyclization to a chromone derivative using sodium or sodium methoxide; or from o-oxyacetophenone by reacting it with diethylcarbonate in the presence of sodium ethoxide. Condensation of the resulting 4-hydroxycoumarin with formaldehyde as a phenol component gives dicoumarol [6-9].

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