Coagulants

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Chapter: Medicinal Chemistry : Coagulants

Homeostasis is the cessation of blood loss from damaged vessels. Platelets first adhere to macromolecules in the subendothelial regions of injured blood vessels; they aggregate to form the primary haemostatic plug.


DRUGS ACTING ON BLOOD AND BLOOD FORMING ORGANS

Coagulants

INTRODUCTION

Homeostasis is the cessation of blood loss from damaged vessels. Platelets first adhere to macromolecules in the subendothelial regions of injured blood vessels; they aggregate to form the primary haemostatic plug. Platelets stimulate the local activation of plasma coagulation factors, leading to generation of a fibrin clot that reinforces the platelet aggregate. Later, as wound healing occurs, the platelet aggregates and fibrin clots are degraded. Thrombosis is a pathological process in which a platelet aggregates and a fibrin clot occludes blood vessels. Arterial thrombosis may result in ischaemic necrosis of tissues supplied by the artery (e.g. myocardial infarction due to thrombosis of coronary artery). Venous thrombosis may cause tissue drain by the vein to become edematous and inflamed.

Coagulation of blood comprises the formation of fibrin by a series of interactions among a large number of protein factors and other substances. Blood coagulation process requires coagulation factors, calcium, and phospholipids.

·The coagulation factors (proteins) are manufactured by the liver.

·Ionized calcium (Ca++) is available in the blood and from intracellular sources.

·Phospholipids are prominent components of the cellular and platelet membranes. They provide a surface on which the chemical reactions of coagulation can take place. The coagulation factors are numbered in the order of their discovery.

Factor I—Fibrinogen

Factor II—Prothrombin

Factor III—Tissue thromboplastin (tissue factor)

Factor IV—Ionized calcium (Ca++)

Factor V—Labile factor or proaccelerin

Factor VI—Unassigned

Factor VII—Stable factor or proconvertin

Factor VIII—Antihaemophilic factor

Factor IX—Plasma thromboplastin component, Christmas factor

Factor X—Stuart–Prower factor

Factor XI—Plasma thromboplastin antecedent

Factor XII—Hageman factor

Factor XIII—Fibrin stabilizing factor

 

Mechanism of Blood Clotting

Coagulation can be initiated by either of the two distinct pathways (Fig. 1.1):

1.           The intrinsic pathway can be initiated by events that take place within the lumen of blood vessels. This requires only elements (clotting factors, Ca++ platelet surface, etc) found within or intrinsic to the vascular system.

2.           The extrinsic pathway is the other route to coagulation. It requires tissue factor (tissue thromboplastin), a substance that is extrinsic to or not normally cumulating in the vessel. Tissue factor is released when the vessel wall is ruptured.


 

2. Calcium salts: Calcium salts, especially Ca++ intravenous injections, are very popular, but it does not help much unless there is deficiency of Ca++ in the blood.

 

2 .Vitamin K (Synonym: Vitamin K1-Phytomenadione)


Properties and uses: Phytomenadione is a clear intense yellow viscous oily liquid, practically insoluble in water, sparingly soluble in ethanol, and miscible with fatty oils. Vitamin K is essential to keep up the prothrombin level in blood by forming prothrombin in the liver. Hence, it is used orally and intramuscular (IM), now water-soluble vitamin K is available for intravenous (IV) administration. This is called methyl naphthaquinone and is very useful in emergency.

Assay: It is assayed by adopting liquid chromatography technique.

Dosage forms: Phytomenadione injection B.P., Phytomenadione tablets B.P.

 

3. Vitamin K3 (Menadione)


Properties and uses: Menadione is a pale-yellow crystalline powder, practically insoluble in water, soluble in toluene, sparingly soluble in alcohol and methanol. Used as source of vitamin K and has prothrombogenic property.

Assay: Dissolve the sample in glacial acetic acid and add dilute hydrochloric acid and zinc powder. Allow the mixture to stand and titrate against 0.1 M ammonium cerric nitrate using ferroin as indicator.

 

Anticoagulants

Anticoagulants are drugs that prevent the clotting of blood. Heparin is a glucosaminoglycan found in the secretory granules of mast cells. It is synthesized from uridine diphosphate sugar precursor as a polymer of alternating D-gluconic acid and N-acetyl-D-glucosamine residue. About 10–15 glucosaminoglycan chains, each containing 200–300 monosaccharide units, are attached to a core protein and yield a proteoglycan with a molecular mass of 750,000–1,000,000 daltons. The glucosaminoglycan then undergoes a series modification, which includes n-acetylation and n-sulphonation of glucosamine, epimerization of D-gluconic acid to L-iduronic acid, O-sulphation of iduronic and glucoronic acid residues at the C2 position, and O-sulphation of glucosamine residue at C3 and C6 position. Each of these modification reactions is incomplete, yielding variety of oligosaccharide structures. After the heparin proteoglycan has been transported to the mast cell granule, an endo-β-D-glucuronidase degrades the glycosamionoglycan chains to 5000–30,000 dalton fragments over a period of hours.

 

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