ANTICOAGULATION LEARNING OBJECTIVES• At the end of lecture students should be able to know,• How Blood Clots are formed.• How the blood clots are broken down ?• What drugs can be used to regulate clotting ?• How to rectify clotting deficiencies Coagulation Factors• Factor Name• I Fibrinogen• II Prothrombin• III Tissue Factor or thromboplastin• IV Ca++• V Proaccelerin• VII Proconvertin• VIII Antihemophilic A factor• IX Antihemophilic B factor or Christmas factor Classes of Drugs• Prevent coagulation• Dissolve clots• Prevent bleeding and hemorrhage - Hemostatic• Overcome clotting deficiencies (replacement therapies) Blood Clotting• Vascular Phase• Platelet Phase
• Coagulation Phase• Fibrinolytic Phase Vascular Phase• Vasoconstriction• Exposure to tissues activate Tissue factor and initiate coagulation• Platelet phase• blood vessel wall (endothelial cells) prevent platelet adhesion and aggregation• platelets contain receptors for fibrinogen and von Willebrand factor• after vessel injury Platelets adhere and aggregate.• Release permeability increasing factors (e.g. vascular permeability factor, VPF)• Loose their membrane and form a viscous plug• Coagulation Phase• Two major pathways• Intrinsic pathway• Extrinsic pathway• Both converge at a common point• 13 soluble factors are involved in clotting• Biosynthesis of these factors are dependent on Vitamin K1 and K2• Normally inactive and sequentially activated
• Hereditary lack of clotting factors lead to hemophilia -A• Intrinsic Pathway• All clotting factors are within the blood vessels• Clotting slower• Activated partial thromboplastin test (aPTT)• Extrinsic Pathway• Initiating factor is outside the blood vessels - tissue factor• Clotting - faster - in Seconds• Prothrombin test (PT)• COAGULATION DISORDERS• THROMBOSIS• BLEEDING• CLOTTING MECHANISM• Physical trauma to vascular system causes:• Vasoconstriction• Platelet aggregation• Formation of fibrin meshwork and clot• Initially platelets adhere to the blood vessel at the site of injury and adhered platelets release chemicals that cause aggregation of platelets thus a plug is formed.• Platelet activation and aggregation is promoted by exposure to collagen, thromboxane A2 (powerful stimulator), decreased prostacyclins and ADP.• Platelet aggregation is essential for the clot formation.
• Factors released by injured tissues and platelets stimulate the intrinsic and extrinsic pathways of clotting cascade that lead to the formation of fibrin that forms meshwork with aggregated platelets and strengthen the plug.• Intrinsic system takes several minutes for formation of activated factor X, in extrinsic system activated factor X is produced very rapidly within seconds.• As wound heals fibrinolytic pathway is activated in that plasminogen is converted to plasmin (fibrinolysin) that interferes with clot propagation and dissolves fibrin network.• Clotting mechanism may be pathologically activated resulting in thrombosis and embolism that produce ischemia of various organs.• PLATELET AGGREGATION• Platelet activation and aggregation is promoted by:• Exposure to collagen• Thromboxane A2 (powerful stimulator)• Decreased prostacyclins• ADP
ANTICOAGULANTS• Parenteral: o HEPARIN o HIRUDIN• Oral:• Coumarin Derivatives: o WARFARIN o DICOUMAROL o ACENOCOUMAROL ANTICOAGULANTS• Indanedione Derivatives:• PHENINDIONE• DIPHENADIONE• BROMINDONE• Out of all these orally effective drugs• warfarin is the most important and most• widely used.
o HEPARIN• WARFARIN• DICOUMAROL• PHENINDIONE o SODIUM CITRATE o SODIUM OXALATE o EDTA HEPARIN:• Heparin is highly acidic drug and is mixture of mucopolysaccharides.• It occurs in mast cells, richest source being lungs, liver and intestine.• It is obtained from bovine lung and porcine intestine for commercial use.• Commercial preparations of heparin available in un- fractionated form (UFH) are composed of high molecular weight heparin and low molecular weight heparin fractions. MECHANISM OF ACTION:• Antithrombin III a naturally occurring anticoagulant, normally prevents the coagulation by blocking the activated factors II, IX, & X.• Normally the activity of antithrombin III is very slow, heparin accelerates the activity of antithrombin III 1000 fold.
• Antithrombin III acts as heparin cofactor and inhibits activated factors of clotting; factor IIa and factor Xa are most sensitive to inhibition. MECHANISM OF ACTION: o Heparin blocks antithrombin III without being consumed itself. Once antithrombin binds with activated clotting factors, heparin detaches from antithrombin III intact and binds with other molecules of antithrombin III. o HMW heparin has high affinity for antithrombin III and markedly blocks blood coagulation. o LMW fraction inhibits activated factor X but has less effect on antithrombin III and on coagulation. ACTIONS OF HEPARIN• Heparin prevents blood coagulation within body and outside the body, it decreases thrombus formation.• It does not act as thrombolytic agent i.e. it does not dissolve already formed thrombus.• Heparin also decreases the platelets by increasing the platelet aggregation that may lead to paradoxical thromboembolism and by the formation of antibodies against platelets. Unfractionated heparin (UFH)• Advantage:• A short half-life(60 minutes)• easily reversed (by protamine sulfate)• Disadvantage:
• Intravenous administration necessitates hospitalization before surgery,• Inconvenient and expensive. Low-molecular-weight-heparin (LMWH)• Allowed bridging therapy to be administered to outpatients.• Doses of LMWH that are recommended for treatment of venous thromboembolism are administered once or twice daily, generally for 3 days before surgery.• Required to determine whether the benefit of bridging therapy outweighs the associated risks of bleeding. Low-molecular weight heparin• Low-molecular weight heparin is gradually replacing heparin for treatment of most patients with venous thromboembolism and acute coronary syndromes because it has more convenient and cost-effective• It has similar results to heparin• Administered by subcutaneous• injection• LOVENOX® is an example• PHARMACOKINETICS:• Heparin does not cross cell membrane and is not absorbed from gut. It is given subcutaneously or intravenously.
• Heparin should not be given intramuscularly as it produces hematoma.• Heparinase present in liver degrades heparin.• Some of the parent drug and inactive metabolites are excreted in urine; half-life of heparin is 80 minutes.• Heparin does not cross placenta but should be used carefully during pregnancy as it can produce maternal bleeding. SIDE EFFECTS:• Main problem with heparin therapy is hemorrhage, careful monitoring of APTT (Activated Partial Thromboplastin Time) is essential to prevent bleeding.• Dose of heparin is so adjusted that APTT is raised to 2–2½ times to that of control value. (Normal 30 seconds).• Patients with hepatic and renal impairment are more prone to develop hemorrhage.• Risk of hemorrhage is less with LMW heparin than with HMW heparin.
• SIDE EFFECTS:• As heparin for commercial use is of animal origin it may produce hypersensitivity reactions. Chills fever, urticaria, itching and anaphylactic shock may occur.• On prolonged use heparin may produce osteoporosis, spontaneous fractures of bones and alopecia.• Heparin also produces thrombocytopenia that is either mild or transient due to platelet aggregation or severe due to platelet antibodies. SIDE EFFECTS• Bleeding• Hypersensitivity reactions• Osteoporosis• Spontaneous fractures of bones• Alopecia• Thrombocytopenia TREATMENT OF HEPARIN OVERDOSE• Protamine sulfate is antidote of heparin• It binds with heparin• 1 mg of protamine sulfate neutralizes 100 units of heparin CONTRA-INDICATIONS• Hypersensitivity INDICATIONS• Prevention of thromboembolism in:• Deep vein thrombosis• Prolonged immobilization
• Myocardial infarction• In vitro:• To prevent blood coagulation during blood sampling• Hemodialysis DEEP VEIN THROMBOSIS• BOLUS 5000–10000 IU I/V M.DOSE 5000 IU 2–3 TIMES DAILY S/C
HIRUDIN:• Hirudin is powerful and specific thrombin inhibitor• Its action is independent of antithrombin III.• It can inactivate the fibrin bound thrombin in thrombi.• ORAL ANTICOGULATS• Oral anticoagulants are chemically related to vitamin K;• They prevent coagulation within body and are not effective outside the body (In vitro)• Warfarin• Warfarin is an oral medication• It is a synthetic derivative of coumarin, a chemical found naturally in many plants -- it decreases blood coagulation by interfering with vitamin K metabolism• It stops the blood from clotting within the blood vessels and is used to stop existing clots from getting bigger (as in DVT) and to stop parts of clots breaking off and forming emboli (as in PE)• Dicumarol
• It is a potent oral anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent clotting factors (prothrombin and factors VII, IX and X) in the liver; it is starting to largely replace warfarin• Dicumarol is produced naturally by conversion of nontoxic coumarin in moldy sweet clover hay, lespepeza hay or sweet vernal hay• It is used especially in preventing and treating thromboembolic disease• Formerly called bishydroxycoumarin MECHANISM OF ACTION:• Warfarin and other anticoagulants resemble vitamin K and vitamin K is essential for the formation of activated clotting factors II, VII, IX and X by the liver. Only reduced form of vitamin K is effective for this purpose.• Reduced form of vitamin K is oxidized to vitamin K epoxide during the activation of clotting factors. MECHANISM OF ACTION:• Vitamin K epoxide is reduced back by vitamin K epoxide reductase and is used for the formation of clotting factors.• Oral anticoagulants inhibit the enzyme vitamin K epoxide reductase competitively thus they prevent the formation of active form of vitamin K and its action.• Unlike the heparin, their peak effect appears after 36– 48 hours, and they have long duration of action (4–7 days).• PHARMACOKINETICS
• They are well absorbed from gut; food delays their absorption, are highly bound to plasma proteins (99%) and are mainly concentrated in liver, which is the main site of their action.• They do not cross blood brain barrier but cross placenta and predispose fetal and neonatal bleeding.• Drugs have high affinity for protein binding like sulfonamides can displace oral anticoagulants and increase their effects.• Oral anticoagulants are metabolized in liver and their metabolites are excreted in urine. DRUGS INCREASING WARFARIN ACTION DRUGS DECREASING WARFARIN ACTION
SIDE EFFECTS OF ORAL ANTICOAGULANTS• Bleeding• Phenindione can produce skin rashes, blood dyscrasias, jaundice, fever, nausea, vomiting and red discoloration of urine. Warfarin-induced Skin Necrosis• CONTRAINDICATIONS
• Pregnancy & lactation• Bleeding disorders• Thrombocytopenia• Uncontrolled hypertension• Gastrointestinal ulcers• CONTRAINDICATIONS• Tuberculosis• With aspirin• With tetracyclines and other broad spectrum antibiotics• Vitamin K deficiency• INDICATIONS• To prevent thrombus formation in:• Acute myocardial infarction• Deep vein thrombosis• Pulmonary embolism• Cerebrovascular accident (Stroke)• Atrial fibrillation• Prosthetic heart valves• Thromboembolic Risk When Discontinuing Warfarin• Venous thromboembolism (VTE):• The absence of OAC during the first month of an acute VTE event－Recurrence 40%/month• During the second and third month－ Recurrence 10%/2month• After the 3 month treatment－15%/year
• Surgery should be deferred following an acute episode of venous thromboembolism until patients have received at least 1 month, and preferably 3 months, of anticoagulation.• REFERENCES
• BASIC AND CLINICAL PHARMACOLOGY,KATZUNG,11th EDITION.• THANKYOU