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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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MECHANISM OF PLATELET AGGREGPATION

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Mechanism of platelet aggregation and actions of antiplatelet drugs.

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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

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