ANTICOAGULANT DRUGS Dr.V.V.Gouripur

Clotting Process Formation of a blood clot (thrombus) in blood vessels or the heart. may be life saving (when it plugs a severed vessel) or life-threatening if it occludes a vessel supplying a vital structure. may break loose to create an embolus that flows downstream to lodge at a distant site. The potential consequence is ischemic necrosis of cells and tissues known as infarction. Cerebral vascular accidents (stroke), myocardial infarction and pulmonary embolisms are examples of disorders resulting from thrombosis or embolism.

Thrombophlebitis is the term used for a venous thrombosis with associated inflammation. 1. Arterial thrombosis—Result is localized tissue injury owing to lack of perfusion 2. Venous thrombosis—Usually develops when blood flow is slow; this initiates coagulation cascade; part can become embolus

Hemostasis Physiologic process by which bleeding is stopped Stage 1: formation of a platelet plug—Begins when platelets come in contact with collagen on exposed surface of damaged vessel, adhere to area, release adenosine diphosphate (ADP) and thromboxane A2 platelet plug and bleeding stopped. Platelet aggregation ends with fibrinogen bridges

Stage 2: coagulation (reinforcement of platelet plug with fibrin)—Occurs in series of cascading reactions from extrinsic and/or intrinsic systems. Four of the coagulation factors (VII, IX, X and prothrombin) require vitamin K for synthesis Stage 3. Keeping hemostasis under control—Antithrombin III prevents widespread coagulation Stage 4. Physiologic removal of clots—Essential in healing process using plasmin

Physical Process of Clotting

Chemical Process of Clotting

IXa and VIIIa work together to convert X into Xa. Xa and Va work together to convert II into IIa. IIa works on a number of steps. HMWK and TF are initiation points CLOT is the end point

Anti-coagulants Anti-coagulants are molecules that prevent blood from clotting. They inhibit the chemical process of proteolytic formation of the three-dimensional fibrin polymer. These include heparin, low molecular weight heparin, coumarins, and 1,3-indanediones.

anti-platelet agents. Molecules that do not allow platelets to aggregrate and thus prevent clotting, especially in the arteries, are called anti-platelet agents These include aspirin, sulfinpyrazone, dipyridamole, and ticlopidine.

Fibrinolytic agents. Molecules that disintegrate a pre-formed clot are called fibrinolytic agents. Some examples are -streptokinase -Altaplase -Tenactaplase

Coagulation factors Factor Name I Fibrinogen II Prothrombin III Tissue Factor or thromboplastin IV Ca++ V Proaccelerin VII Proconvertin VIII Antihemophilic A factor IX Christmas factor or Stuart-Prower factor XI Plasma thomboplastin antecedent XII Hageman factor XIII Fibrin stabilizing factor HMWK- High molecular weight kininogen

Endogenous Inhibitors of Clotting  Thrombin plays a pivotal role in blood coagulation and Nature has designed several serine protease inhibitors (SERPINS) to regulate the its activity. These include - antithrombin (major), -Protein C -Thrombomodulin       

Antithrombin Antithrombin is present in the plasma ,primarily neutralizes factor Xa and thrombin, in addition to inhibiting most active serine proteases of the clotting system..)  Protein C is another plasma protein that limits clotting by being activated by thrombin to proteolytically inactivate proaccelerin (V) and antihemophilic factor (VIII). Thrombomodulin, a cell membrane bound glycoprotein lining the vascular endothelium, specifically binds thrombin so as to convert it to a form with decreased ability to catalyze clot formation but with a >1,000-fold increased capacity to activate protein C.       

Heparin Heparin is a naturally occurring, strongly acidic mucopolysaccharide found in granules of mast cells and basophils. These polysaccharides possess a wide range of molecular weights (3000 to 30,000) and are negatively charged making them highly polar and unable to readily cross membranes. The dosage is measured in units of activity determined by its ability to prevent clotting of plasma standards. In contrast to coumarin derivatives, it is only administered parenterally.

Mechanism of action Acts by combining with an antithrombin III. Heparin-antithrombin complex combines with, and neutralizes, thrombin within seconds. This complex also inhibits the action of activated factors XIIA, IXa, VIIA, and Xa. Action - prolongs clotting time in vivo and in vitro. Monitoring is via the activated partial thromboplastin time (APTT) Duration of action <4hrs

Low-Molecular-Weight (LMW) Heparins Enoxaparin (Lovenox Lepirudin (Refludan) These are heparins with shorter molecules than those found in standard (unfractionated) heparin. They are as effective as standard heparin and do not require APTT monitoring Only for prophylaxis of DVT after hip or abdominal surgery

Adverse Reactions Hemorrhage Thrombocytopenia Chemical antagonism occurs with protamine sulfate, a strongly basic protein that neutralizes heparin.

Coumarin Derivatives    Warfarin    Dicoumarol Coumarin    4-Hydroxycoumarin

Coumarin Derivatives (Warfarin [Coumadin®]) Mechanism Vitamin K antagonist Inhibit formation of prothrombin (factor II) and factors VII, IX and X, which are synthesized in the liver, and the synthesis, is dependent upon vitamin K. Action Absorbed rapidly from GI tract Lowering of prothrombin occurs slowly. Monitoring is via the prothrombin time (PT) or the international normalized ratio (INR) Duration of action – 2-3 days Other Agents-Anisindione—Like warfarin but greater side effects

Biochemical Mechanism of Action Coumarins are competitive inhibitors of vitamin K in the biosynthesis of prothrombin.         The coagulation cascade relies on the conversion of prothrombin to thrombin in a very important step. However, this conversion depends on the presence of 10 g-carboxyglutamic acid (GLA) residues in the N-terminus of prothrombin. The multiple Gla residues form a binding site for Ca+2. Under normal circumstances 10 glutamic acid (Glu) residues of prothrombin are converted to Gla residues in a  post-translational modification.        

Biochemical Mechanism of Action This post-translation modification is catalyzed by an enzymes vitamin K reductase and vitamin K epoxide reductase. Vitamin K is a co-factor in this conversion reaction. Thus it cycles between a reduced form and an epoxide form. Because of their structural similarity with vitamin K coumarins are thought to bind the enzymes, vitamin K reductase and vitamin K epoxide reductase, without facilitating the conversion of Glu residues of prothrombin to Gla. Thus prothrombin cannot be acted upon by factor Xa.

Adverse Reactions mild diarrhea, soft stools Hemorrhage Treatment of overdose Vitamin K1 is the antagonist to the coumarins, and administration of phytonadione (emulsion of vitamin K1) will restore prothrombin level after period of hours When an immediate effect is desired, prothrombin is given (fresh blood, freeze dried plasma). Possible risk of "rebound" with abrupt cessation of therapy,

Bleeding or hematological diseases Drug Interactions Contraindications Bleeding or hematological diseases Drug Interactions Stimulation of coumarin metabolism by administration of drugs that induce microsomnzymes (barbiturates, meprobamate and other sedative-hypnotic drugs; griseofulvin). Inhibition of metabolism (e.g., allopurinol [Zyloprim®]); disulfiram (Antabuse®). Displaced from binding sites by phenylbutazone, phenytoin, sulfinpyrazone, clofibrate and other drugs. Others Salicylates, indomethacin Oral Contraceptives Acetaminophen (Tylenol)inhibits warfarin degradation Effect of anticoagulants on other drugs Coumarin agents prolong and intensify action of chlorpropamide, tolbutamide, phenytoin and phenobarbital.

Comparison of Heparin and warfarin Heparin warfarin Onset of action Immediate Gradual to peak at 48hrs Duration < 4 hours 2 – 5 days Route of adm. Parenteral Oral Lab.control of dose- [APTT] Prothrombintime[PT]/INR Antidote Protamine/Fresh blood Vitamin K1 Cost Expensive Inexpensive Active in vitro Yes No

The end