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Pharmacology III (PHL 418). Drugs to Reduce Blood Clotting ( تخثر الدم ). Dr. Mohammad Nazam Ansari. Drugs used to reduce clotting. DVT: Deep venous thrombosis. Thrombus Formation. Arterial formation:
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Pharmacology III (PHL 418) Drugs to Reduce Blood Clotting (تخثر الدم) Dr. Mohammad Nazam Ansari
Drugs used to reduce clotting DVT: Deep venous thrombosis
Thrombus Formation • Arterial formation: Begins with platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation Blood flow inhibited fibrin, platelets & RBC’s surround clot build up of size structure occludes blood vessels tissue ischemia • The result of Arterial Thrombus is localized tissue injury from lack of perfusion
Thrombus Formation • Venous Formation: Usually from slow blood flow Can occur rapidly Stagnation of the blood flow initiate the coagulation cascade production of fibrin enmeshes RBC’s & platelets to form the thrombus. Venous thrombus has a long tail that can break off to produce an embolus. These travel to faraway sites then lodge in lung (capillary level) inadequate O2 & CO2 exchange occur (i.e. pulmonary embolism & cerebral embolism) • Oral & parenteral anticoagulants (Heparin/Warfarin) primarily act by preventing venous thrombosis • Antiplatelet drugs primarily act by preventing arterial thrombosis
Hemostasis • Involves formation of blood clots to stop bleeding from damaged vessels, and activation of natural anticoagulation and fibrinolytic systems to limit clot formation to sites of injury • Bleeding disorders are due to defects in clot formation or overactive fibrinolytic systems • Hypercoagulability disorders are due to defects in anticoagulant system or underactive fibrinolytic systems
Normal hemostasis • Initial step is formation of platelet plug to stop bleeding from damaged vessel • Then, platelet plug is reinforced by fibrin clot • Then, fibrin clot is stabilized by activated factor XIII (Fibrin stabilizing factor), which cross-links fibrin strands • Fibrin clot may occur via either intrinsic or extrinsic pathway (or both), • Coagulation factors in intrinsic or extrinsic pathway assemble on surface of activated platelets, which are usually at site of vascular injury • Many coagulation reactions also require calcium as a cofactor
The coagulation factors (proteins) are manufactured by the liver. • The liver must be able to use Vitamin K to produce Factors II, VII, IX, and X. • Dietary vitamin K is widely available from plant and animal sources.
Clotting Factor • Factor I: fibrinogen • Factor II: prothrombin • Factor III: tissue thromboplastin(tissue factor and phospholipid) • Factor IV: ionized calcium • Factor V: occasionally called labile factor or proaccelerin • Factor VI: unassigned • Factor VII: occasionally called stable factor or proconvertin • Factor VIII: antihemophilic factor or von Willebrand factor • Factor IX: plasma thromboplastin component, Christmas factor • Factor X: occasionally called Stuart-Prower factor • Factor XI: occasionally called plasma thromboplastin antecedent • Factor XII: Hageman factor • Factor XIII: fibrin-stabilizing factor
Coagulation cascade Extrinsic Pathway • Initiating factor is outside the blood vessels: tissue factor • Clotting: faster in Seconds Intrinsic Pathway • All clotting factors are within the blood vessels • Clotting: slower
Intrinsic pathway • Involves factors VIII, IX, XI, XII, prekallikrein, high molecular weight kininogen • Merges with extrinsic pathway into common pathway • Activated when factor XII binds to negatively charged “foreign” surface exposed to blood • Then sequentially activates factors XI, IX, X, then factor II (prothrombin to thrombin), which converts fibrinogen to fibrin • Once extrinsic pathway is inhibited by TFPI-Xa complex, factor VIIIa / IXa complex becomes dominant generator of factor Xa, thrombin and fibrin • Factor XIIa also converts prekallikrein to kallikrein, which activates more factor XIIa; both require high molecular weight kininogen as cofactors
Schematic showing the intrinsic and extrinsic pathways of the coagulation cascade leading to fibrin formation. Factor III - tissue thromboplastin (tissue factor) Factor IV – ionized Ca++ (Factor I)
Extrinsic pathway • Involves tissue factor (TF), originally considered “extrinsic” to blood since it is present on cell surfaces not normally in contact with (i.e. extrinsic to) the circulatory system • The primary mechanism of the coagulation pathway in vivo is tissue factor binding to activated factor VII (factor VIIa) • TF-Factor VIIa complex activates factors X and IX • Activated factor IX activates more factor X, • Activated factor X converts prothrombin to thrombin, with activated factor V, anionic phospholipids and calcium as cofactors • After initial activation, pathway is inhibited by the binding of tissue factor pathway inhibitor (TFPI) to factor Xa, which inhibits TF-VIIa complex, and further coagulation is dependent on the intrinsic pathway
Common pathway • Involves fibrinogen (factor I), factors II (prothrombin), V, X • Thrombin converts soluble fibrinogen to insoluble fibrin; remaining fibrin monomers polymerize to form fibrin; thrombin also binds to antithrombin, which inhibits thrombin to prevent excessive clotting • Factor XIII cross links fibrin to increase stability of fibrin clot
Drugs used to reduce clotting DVT: Deep venous thrombosis
Intrinsic Pathway Extrinsic Pathway Tissue Injury Blood Vessel Injury Tissue Factor XIIa XII Thromboplastin XIa XI IXa IX VIIa VII Xa X X Prothrombin Thrombin Factors affected By Heparin Fribrin monomer Fibrinogen Vit. K dependent Factors Affected by Oral Anticoagulants Fibrin polymer XIII
Definition of Anticoagulation • Therapeutic interference ("blood-thinning") with the clotting mechanism of the blood to prevent or treat thrombosis and embolism.
Indications of Anticoagulant Therapy • Treatment and Prevention of Deep Venous Thrombosis • Pulmonary Emboli • Prevention of stroke in patients with atrial fibrillation, artificial heart valves, cardiac thrombus. • Ischemic heart disease • During procedures such as cardiac catheterisation and apheresis.
1. Standard Heparin • Heterogenous mixture of polysaccharide chains • MW 3,000 to 30,000 • Administration • Parenteral: only IV or deep s.c. • Do not inject IM (danger of hematoma formation)- • Metabolism • Partially in the liver by heparinase to uroheparin, which has only slight antithrombin activity. • Adverse effect • haemorrhage - antidote - protaminesulphate
Mechanism of action: • Primarily: interaction with antithrombin III: alters the molecular configuration of antithrombin III, making it 1,000 to 4,000 times more potent as an inhibitor of thrombin formation: limits conversion of fibrinogen to fibrin: prolongs aPTT (activated partial thromboplastin time) • Also inhibits the effects of factor Xa on the coagulation cascade & limits platelet aggregation.
Heparin mechanism of action Heparin Antithrombin III Thrombin
Complications of Heparin • Haemorrhage(bleeding from ruptured blood vessels) • Heparin-induced thrombocytopenia (HIT) [an abnormally low amount of platelets] • Most significant adverse effect of heparin after haemorrhage • Begins 3 - 15 days after start of heparin • Treatment • Stop heparin immediately: Platelet count returns 4 days after stopping heparin • Use other drugs for anticoagulation • Osteoporosis (long-term only) [thinning of bone tissue and loss of bone density ]
Low Molecular Weight Heparin • Advantages • Standard (Unfractionated) heparin 3k to 30k • LMWH contains polysaccharide chains MW 5k • Same incidence of bleeding • Lower incidence of thrombocytopenia • Lower incidence of bone loss • Safe for use during pregnancy {does not cross the placenta} • Higher Bioavailability: 90% Vs 30% • Longer Plasma Half life: 4-6 h Vs 0.5-1 h • Renal (Slower) Vs Hepatic clearance
LMWH Administration • Subcutaneous injection • Once every 12 or 24 hours • Outpatient • Patients that need monitoring • Pregnant • Pediatric • Renal • Prolonged therapy • Those at risk for bleeding • Mechanism of action • Primarily by inhibiting factor Xa, which is higher in the coagulation cascade than antithrombin: LMWH is more efficient than UFH (Un-fractionated). • {the molecular configuration of antithrombin III is not altered by LMWH}
2. Oral anticoagulantsVitamin K-Dependent Clotting Factors Vitamin K VII Synthesis of Functional Coagulation Factors IX X II
Warfarin Mechanism of Action Vitamin K Antagonism of Vitamin K VII Synthesis of Non Functional Coagulation Factors IX X II Warfarin
Warfarin Enhances Antithrombin Activity PT: Prothrombin time aPTT: Activated partial thromboplastin time
Warfarin: Major Adverse Effect—Haemorrhage • Factors that may influence bleeding risk: • Intensity of anticoagulation • Concomitant clinical disorders • Concomitant use of other medications • Quality of management Warfarin-induced Skin Necrosis
Warfarin Dosing & Monitoring • Start low • Initiate 5 mg daily • Educate patient • Stabilize • Titrate to appropriate INR (International normalized ratio) • Monitor INR frequently (daily then weekly) • Adjust as necessary Relative Contraindications • Pregnancy • Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy • Uncontrolled alcohol/drug abuse • Unsupervised dementia/psychosis
Signs of Warfarin Over dosage • Any unusual bleeding: • Blood in stools or urine • Excessive menstrual bleeding • Bruising (Minor hematoma) • Excessive nose bleeds/bleeding gums • Persistent oozing from superficial injuries • Bleeding from tumor, ulcer, or other lesion
Why do we need new anticoagulation drugs? • Heparin-induced thrombocytopenia • Heparin prophylaxis is imperfect • Heparin-associated osteoporosis • Warfarin takes several days for its effect • Warfarin interacts with many other drugs • Warfarin is dangerous if not monitored
New Anticoagulation Drugs • Direct Thrombin Inhibitors • Synthetic pentasaccharide • Enhanced Protein C pathway • Tissue Factor Pathway Inhibitor (TFPI) • Thrombolytic Drugs • Antiplatelet Drugs
Direct Thrombin Inhibitors • Advantages • Bound thrombin readily inhibited • More predictable patient response • Not neutralized by PF4 (Platelet factor 4) • Disadvantages • Higher cost of the drugs Ximelagatran • Promising oral direct thrombin inhibitor • Converted to the active form melagatran in vivo • No dosing problems • No monitoring needed. • Recent atrial fibrillation study showed it to possibly be superior to warfarin.
Ximelagatran Enhances Antithrombin Activity
Dabigatranetexilate • Oral dosing • Absorbed from GI tract • Transforms to active dabigatran • Future – replace warfarin • Wider therapeutic range • Acceptable bleeding risk • Little or no lab monitoring Argatroban • Small molecule • A synthetic derivative of L-arginine with antithrombotic activity • univalent and direct inhibitor of fibrin-bound thrombin • Used to treat HIT
Hirudin and Derivatives • Hirudin is a naturally occurring peptide in the salivary glands of medicinal leeches (such as Hirudomedicinalis) • has a blood anticoagulant property • Thrombin is produced from prothrombin. • A key event in the final stages of blood coagulation is the conversion of fibrinogen into fibrin by the thrombin. • Fibrin is then cross linked by factor XIII to form a blood clot. • The principal inhibitor of thrombin in normal blood circulation is antithrombin III. • Similar to antithrombin III, the anticoagulatant activity of hirudin is based on its ability to inhibit the procoagulant activity of thrombin.
Hirudin is the most potent natural inhibitor of thrombin. • Therefore, hirudin has therapeutic value in blood coagulation disorders, in the treatment of skin hematomas, either as an injectable or a topical application cream. • It is difficult to extract large amounts of hirudin from natural sources, so a method for producing and purifying this protein using recombinant biotechnology has been developed. This has led to the development and marketing of a number of hirudin-based anticoagulant pharmaceutical products, such as lepirudin (Refludan), and desirudin (Revasc/Iprivask). • Several other direct thrombin inhibitors are derived chemically from hirudin.
Hirudin and Derivatives 1. Lepirudin (Refludan) • It is almost identical to hirudin extracted from Leech saliva of Hirudomedicinalis • Cleared by kidneys • Inhibits clot bound thrombin • Clot associated Xa will trigger generation of more thrombin once treatment stops
Hirudin and Derivatives 2. Bivalirudin (Angiomax) • Semisynthetic • Cleared by liver • Half-life • Shorter than lepirudin • Safer drug • No risk of HIT
Hirudin and Derivatives • Indications: • HIT (heparin-induced thrombocytopenia ) • Cardiopulmonary bypass • Hip replacement surgery • Unstable angina
New Anticoagulation Drugs • Direct Thrombin Inhibitors • Synthetic pentasaccharide • Enhanced Protein C pathway • Tissue Factor Pathway Inhibitor (TFPI) • Thrombolytic Drugs • Antiplatelet Drugs
Synthetic Pentasaccharide E.g. Fonaparinux (Arixtra) • Synthetic, single molecular entity • Targets Factor Xa • Does not cause thrombocytopenia • Shown promise in DVT prevention during orthopedic procedures. • Also being examined in ischaemic heart disease • Approved for surgery prophylaxis • General • Total hip replacement • Total knee replacement
New Anticoagulation Drugs • Direct Thrombin Inhibitors • Synthetic pentasaccharide • Enhanced Protein C pathway • Tissue Factor Pathway Inhibitor (TFPI) • Thrombolytic Drugs • Antiplatelet Drugs
The protein C/protein S anticoagulant pathway Thrombin-thrombomodulin (TM) complex activates protein C. Activated protein C with its cofactor, free protein S, degrades factors Va and VIIIa. In addition, when thrombin binds thrombomodulin, thrombin loses its procoagulant functions.
New Anticoagulation Drugs • Direct Thrombin Inhibitors • Synthetic pentasaccharide • Enhanced Protein C pathway • Tissue Factor Pathway Inhibitor (TFPI) • Thrombolytic Drugs • Antiplatelet Drugs
Inhibition of VIIa/TF • TFPI – tissue factor pathway inhibitor