Post on 25-Dec-2015
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BLOOD COAGULATION,BLOOD COAGULATION,ANTICOAGULANT, ANTICOAGULANT,
THROMBOLYTICS & THROMBOLYTICS & ANTIPLATELET DRUGSANTIPLATELET DRUGS..
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Physiology and Pathophysiology of Coagulation
• Hemostasis– Stage 1—formation of platelet
plug• Platelet aggregation
– Stage 2—coagulation• Intrinsic coagulation pathway• Extrinsic coagulation pathway
– Keeping hemostasis under control– Physiologic removal of clots
• Thrombosis– Arterial thrombosis– Venous thrombosis
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A Blood Clot
• Consists of platelets meshed into fibrin
• A web-like accumulation of strands with RBCs
• There are two major facets of the clotting mechanism – the platelets, and the thrombin system
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Anticoagulants – General Overview
• Drugs that help prevent the clotting (coagulation) of blood
• Coagulation will occur instantaneously once a blood vessel has been hurt.
• Blood begins to solidify to prevent excessive blood loss and to prevent invasive substances from entering the bloodstream
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Anticoagulant Use
• Anticoagulant drugs help prevent the development of harmful clots in the blood vessels by lessening the blood's ability to cluster together
• The function of these drugs is often misunderstood because they are sometimes referred to as blood thinners; they do not in fact thin the blood
• These drugs will not dissolve clots that already have formed, but it will stop an existing clot from becoming worse and prevent future clots
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1-Anticoagulant Drugs• Heparin and warfarin are the two traditional
anticoagulants• Anticoagulants are used for acute coronary
syndromes, deep-vein thrombosis (DVT), pulmonary embolism (PE), and heart surgery
• Thrombus - A blood clot that forms abnormally within the blood vessels
• Embolus - When a blood clot becomes dislodged from the vessel wall and travels through the bloodstream
• It is also given to certain people at risk for forming blood clots, such as those with artificial heart valves or who have atrial fibrillation (AF)
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A-Parenteral Anticoagulants 1-Heparin and Related Drugs
1-Heparin (unfractionated)• Sources
– Lungs of cattle– Intestines of pigs
• Rapid-acting anticoagulant• Uses
– Pulmonary embolism (PE)– Stroke evolving– Massive deep venous thrombosis (DVT)
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A-Parenteral Anticoagulants I:1-Heparin and Related Drugs
(cont’d)
• Adverse effects
– Hemorrhage
– Heparin-induced thrombocytopenia
– Hypersensitivity reactions
• Protamine Sulfate[ antidote]
• Activated partial thromboplastin time (APTT) for monitoring.
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2-Low-Molecular-Weight Heparins
• Heparin preparations composed of molecules that are shorter than those found in unfractionated heparin as ENOXAPARIN.
• Therapeutic use– Prevention of DVT following surgery– Treatment of established DVT– Prevention of ischemic complications
• Adverse effects and interactions– Bleeding– Immune-mediated thrombocytopenia– Cost
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3-Fondaparinux [Arixtra]
• Synthetic anticoagulant• Selective inhibition• Therapeutic use
– Prevention of DVT following surgery– Treatment of acute PE (in conjunction with
warfarin)– Treatment of acute DVT (in conjunction with
warfarin)• Adverse effects
– Bleeding– Patients weighting less than 50 kg– Thrombocytopenia– Spinal or epidural hematoma
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4-Direct Thrombin Inhibitors• Bivalirudin [Angiomax], Lepirudin
• Argatroban
• Desirudin
• Therapeutic use
– Prevent clot formation (combined with aspirin)
• Mechanism of action
– Facilitates the actions of antithrombin
– Prevents the conversion of fibrinogen into fibrin
– Prevents the activation of factor XIIIa
• Adverse effects
– Back pain
– Nausea
– Headache
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B-Oral Anticoagulant1-WARFARIN• Oral anticoagulant
• Antagonist to vitamin K• Blocks the biosynthesis of factors VII, IX, X, and
prothrombin• Therapeutic uses
– Long-term prophylaxis of thrombosis• Prevention of venous thrombosis and
associated pulmonary embolism• Prevention of thromboembolism (in patients
with prosthetic heart valves)• Prevention of thrombosis during atrial
fibrillation
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Warfarin, an Oral Anticoagulant (cont’d)
• Adverse effects– Hemorrhage– Fetal hemorrhage and teratogenesis from
use during pregnancy– Not to be Used during lactation WARNING?
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Warfarin, an Oral Anticoagulant (cont’d)
• Drug interactions
– Drugs that increase anticoagulant effects[ CYT P450 inhibitors as cimetidine]
– Drugs that promote bleeding
– Drugs that decrease anticoagulant effects[CYT P 450 INDUCERS AS PHENYTOIN]
– Heparin
– Aspirin
– Acetaminophen
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2-Dabigatran etexilate
•Dabigatran etexilate is a new oral direct thrombin inhibitor and the prodrug of dabigatran
•Dabigatran is a small molecule that reversibly inhibits both free and clot-bound thrombin by binding to exosite 1 and/or the active site of thrombin
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The future for anticoagulants
• Molecular targets are factor IIa (thrombin) and factor Xa
• The two candidate compounds, one direct thrombin inhibitor (dabigatran etexilate) and one direct factor Xa inhibitor (rivaroxaban) are hoping to be approved as new oral anticoagulants in the near future
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2-Antiplatelet Drugs
• Aspirin (ASA)
– Inhibition of cyclooxygenase
– Adverse effect
• Increase risk of GI bleeding
• Ticlopidine [Ticlid]
– Inhibits ADP-mediated aggregation
– Adverse effects
• Hematologic effects
• Clopidogrel [Plavix]
– ADP receptor antagonist
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Antiplatelet Drugs (cont’d)
• Glycoprotein (GP) IIb/IIIa receptor antagonists
– Most effective antiplatelet drugs esp. in acute coronary syndromes.
– Reversible blockade of platelet GP IIb/IIIa receptors
– EXAMPLE: ABCIXIMAB
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3-Thrombolytic Drugs
• Drugs that break down, or lyse, preformed clots
• Older drugs– streptokinase and urokinase
• Newer drugs– Tissue plasminogen activator (t-PA)– Anisoylated plasminogen-streptokinase
activator complex (APSAC)
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Thrombolytic Drugs (cont’d)
• Streptokinase– Binds plasminogen
• Uses – Myocardial infarction– Deep vein thrombosis– Massive pulmonary emboli
• Adverse effects– Bleeding
– Antibody production– Hypotension– Fever
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Thrombolytic Drugs (cont’d)NEW COMPOUNDS
• anistreplase (Eminase)
• alteplase (t-PA, Activase)
• reteplase (Retavase)
• tenecteplase (TNKase)
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Thrombolytic Drugs Indications
• Acute MI
• Arterial thrombolysis
• DVT
• Occlusion of shunts or catheters
• Pulmonary embolus
• Acute ischemic stroke
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Thrombolytic Drugs: Adverse Effects
• BleedingInternalIntracranialSuperficial
• Other effectsNausea, vomiting, hypotension, anaphylactic
reactionsCardiac dysrrhythmias; can be dangerous