抗凝和溶栓.ppt
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Anticoagulants and Thrombolytics
S. Ramakrishnan
Objectives
*To learn 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
* Blood clots - Thrombus
* Thrombus dislodge from arteries and veins and become an embolus.
* Venous emboli can block arterioles in the lung and pulmonary circulation
* Thromboembolism
*
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
*Non-nucleated - arise from magakaryocytes
*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
Platelets and Thromboemolism
* Arteries : White Thrombus
* Platelets adhere
* Release ADP
* More adhesion/ aggregation
* Reduced blood flow (stasis)
* Fibrin clot
* Veins low pressure : Red thrombus is formed
* Especially in valve pockets
* Contains a long tail of fibrin
* Can detach and form emboli
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
*Most of these factors are proteases
*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)
Prothrombin time (PT)
Activated partial thromboplastin time (APTT)
Diagnosis of coagulation defects
Activation
Thrombosis
* Arterial Thrombosis :
* Adherence of platelets to arterial walls - White in color - Often associated with MI, stroke and ischemia
*Venous Thrombosis :
* Develops in areas of stagnated blood flow (deep vein thrombosis), Red in color- Associated withCongestive Heart Failure, Cancer,Surgery.
Anticoagulant drugs to treat thromboembolism
Heparin
* Sulphated carbohydrate
* Purified from bovine lungs
* Differentsize
* Active in vitro and in vivo
* Administration - parenteral- Do not inject IM - only IV or deep s.c.
* Half-life 1 - 5 hrs - monitor aPTT
* Adverse effect - hemorrhage - antidote - protamine sulphate
Heparin mechanism of action
Oral anticoagulants : warfarin, dicumarol
* Coumarins - warfarin, dicumarol
* Isolated from clover leaves
* Structurally related to vitamin K
* Inhibits production of active clotting factors
* Absorption rapid - binds to albumin
* Clearance is slow - 36 hrs
* Delayed onset 8 - 12 hrs
* Overdose - reversed by vitamin K infusion
* Can cross placenta - do not use during late pregnancies
Mechanism of action
Antiplatelet drugs
* Aspirin
* Prevents platelet aggregation /adhesion
* Clinical use - prevents arterial thrombus
* Myocardial infarction (MI), stroke, heart valve replacement and shunts
*Other antiplatelet drugs are - Dipyridamole, sulfinpyrazone and Ticlopidine
Mechanism of action
* Aspirin inhibits cyclooxygenase (COX)
* COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins)
* Inhibits platelet aggregation
Prophylactic use of Aspirin
* Low dose daily ( 180 mg/day)
* Prevents ischemic attack (ministroke) and MI
* 335 mg/dayreduced the risk of heart attack in patients over 50
* More than 1000 mg/day NO EFFECT
* High dose inhibits prostacyclin synthesis in cells surrounding vessels. PS normally prevents platelet aggregation.Therefore, inhibition of PS leads to abrogation of the prophylactic benefit of Aspirin
*Contraindication - DO NOT give to patients with glucose 6-PO4 dehydrogenase deficiency
*
Drug interaction- prototype Warfarin
Drug interaction- prototype Warfarin
Fibrinolysis
*Enhance degradation of clots
* Activation of endogenous protease
* Plasminogen (inactive form) is converted to Plasmin (active form)
* Plasmin breaks down fibrin clots
Fibrinolysis
* Exogenously administered drugs
* Streptokinase -bacterial product - continuous use - immune reaction
* Urokinase - human tissue derived - no immune response
* Tissue plasminogen activator (tPA) - genetically cloned - no immune reaction - EXPENSIVE
*Inhibitors of fibrinolysis - aminocaproic acid
* Lysine analog- inhibits proteases
Drug preparations : To reduce clotting
* Heparin(generic, Liquaemin sodium)
* Parenteral - 1000 - 40,000 U/ml
*Warfarin (generic , Coumadin)
* Oral : 2 - 20 mg tablets
*Dipyridamole (Persantine)
* Oral : 25,50,75 mg tablets
Drug preparations :
to lyse clots
* Alteplase recombinant (tPA, Activase)
*20, 50 mg Lyophilized powder - reconstitute for iv
*streptokinase (Kabikinase, streptase)
* Parenteral : 250000 - 1.5 million units per vial . Lyophilized powder. Reconstitute for iv
*Urokinase ( Abbokinase)
* Parenteral : 250000 units per vial. Powder to reconstitute to 5000 u/ml for injection
Drug preparations
: clotting deficiencies
* Vitamin K ( Phytonadione (K1), Mephyton
* Oral : 5 mg tablets
*Plasma fractions - for hemophilia
* Antihemophilic factor ( VIII, AHF)
* Parenteral
*Factor IX complex(konyne HT, proplex T)
* Parenteral : in vials
*Due to HIV risks in blood products recombinant proteins of the factors are made.
* E.g. transgenic goats secreting factors into milk
Drug preparations : to stop bleeding
* Systemic use : aminocaproic acid (Amicar); Tranexamic acid (cyclokapron),Vitamin K
*Local adsorbable drugs
* Gelatin sponge (Gelfoam)
* Gelatin film
* Oxidized cellulose ( Oxycel)
* Microfibrillar collagen (Avitene)
* Thrombin
Anticoagulants and Thrombolytics
S. Ramakrishnan
Objectives
*To learn 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
* Blood clots - Thrombus
* Thrombus dislodge from arteries and veins and become an embolus.
* Venous emboli can block arterioles in the lung and pulmonary circulation
* Thromboembolism
*
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
*Non-nucleated - arise from magakaryocytes
*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
Platelets and Thromboemolism
* Arteries : White Thrombus
* Platelets adhere
* Release ADP
* More adhesion/ aggregation
* Reduced blood flow (stasis)
* Fibrin clot
* Veins low pressure : Red thrombus is formed
* Especially in valve pockets
* Contains a long tail of fibrin
* Can detach and form emboli
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
*Most of these factors are proteases
*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)
Prothrombin time (PT)
Activated partial thromboplastin time (APTT)
Diagnosis of coagulation defects
Activation
Thrombosis
* Arterial Thrombosis :
* Adherence of platelets to arterial walls - White in color - Often associated with MI, stroke and ischemia
*Venous Thrombosis :
* Develops in areas of stagnated blood flow (deep vein thrombosis), Red in color- Associated withCongestive Heart Failure, Cancer,Surgery.
Anticoagulant drugs to treat thromboembolism
Heparin
* Sulphated carbohydrate
* Purified from bovine lungs
* Differentsize
* Active in vitro and in vivo
* Administration - parenteral- Do not inject IM - only IV or deep s.c.
* Half-life 1 - 5 hrs - monitor aPTT
* Adverse effect - hemorrhage - antidote - protamine sulphate
Heparin mechanism of action
Oral anticoagulants : warfarin, dicumarol
* Coumarins - warfarin, dicumarol
* Isolated from clover leaves
* Structurally related to vitamin K
* Inhibits production of active clotting factors
* Absorption rapid - binds to albumin
* Clearance is slow - 36 hrs
* Delayed onset 8 - 12 hrs
* Overdose - reversed by vitamin K infusion
* Can cross placenta - do not use during late pregnancies
Mechanism of action
Antiplatelet drugs
* Aspirin
* Prevents platelet aggregation /adhesion
* Clinical use - prevents arterial thrombus
* Myocardial infarction (MI), stroke, heart valve replacement and shunts
*Other antiplatelet drugs are - Dipyridamole, sulfinpyrazone and Ticlopidine
Mechanism of action
* Aspirin inhibits cyclooxygenase (COX)
* COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins)
* Inhibits platelet aggregation
Prophylactic use of Aspirin
* Low dose daily ( 180 mg/day)
* Prevents ischemic attack (ministroke) and MI
* 335 mg/dayreduced the risk of heart attack in patients over 50
* More than 1000 mg/day NO EFFECT
* High dose inhibits prostacyclin synthesis in cells surrounding vessels. PS normally prevents platelet aggregation.Therefore, inhibition of PS leads to abrogation of the prophylactic benefit of Aspirin
*Contraindication - DO NOT give to patients with glucose 6-PO4 dehydrogenase deficiency
*
Drug interaction- prototype Warfarin
Drug interaction- prototype Warfarin
Fibrinolysis
*Enhance degradation of clots
* Activation of endogenous protease
* Plasminogen (inactive form) is converted to Plasmin (active form)
* Plasmin breaks down fibrin clots
Fibrinolysis
* Exogenously administered drugs
* Streptokinase -bacterial product - continuous use - immune reaction
* Urokinase - human tissue derived - no immune response
* Tissue plasminogen activator (tPA) - genetically cloned - no immune reaction - EXPENSIVE
*Inhibitors of fibrinolysis - aminocaproic acid
* Lysine analog- inhibits proteases
Drug preparations : To reduce clotting
* Heparin(generic, Liquaemin sodium)
* Parenteral - 1000 - 40,000 U/ml
*Warfarin (generic , Coumadin)
* Oral : 2 - 20 mg tablets
*Dipyridamole (Persantine)
* Oral : 25,50,75 mg tablets
Drug preparations :
to lyse clots
* Alteplase recombinant (tPA, Activase)
*20, 50 mg Lyophilized powder - reconstitute for iv
*streptokinase (Kabikinase, streptase)
* Parenteral : 250000 - 1.5 million units per vial . Lyophilized powder. Reconstitute for iv
*Urokinase ( Abbokinase)
* Parenteral : 250000 units per vial. Powder to reconstitute to 5000 u/ml for injection
Drug preparations
: clotting deficiencies
* Vitamin K ( Phytonadione (K1), Mephyton
* Oral : 5 mg tablets
*Plasma fractions - for hemophilia
* Antihemophilic factor ( VIII, AHF)
* Parenteral
*Factor IX complex(konyne HT, proplex T)
* Parenteral : in vials
*Due to HIV risks in blood products recombinant proteins of the factors are made.
* E.g. transgenic goats secreting factors into milk
Drug preparations : to stop bleeding
* Systemic use : aminocaproic acid (Amicar); Tranexamic acid (cyclokapron),Vitamin K
*Local adsorbable drugs
* Gelatin sponge (Gelfoam)
* Gelatin film
* Oxidized cellulose ( Oxycel)
* Microfibrillar collagen (Avitene)
* Thrombin
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