Wk 8 Anticoagulation1 PDF

Anticoagulation CRD 203 Cardiovascular Pharmacology  Lecture Outline Background information Coagulation cascade Intrinsic Extrinsic Platelet activation Aggregation Steps and stages Receptor function  Lecture Outline Pharma...

Anticoagulation CRD 203 Cardiovascular Pharmacology  Lecture Outline Background information Coagulation cascade Intrinsic Extrinsic Platelet activation Aggregation Steps and stages Receptor function  Lecture Outline Pharmacological Classes Aspirin ADP inhibitors GP IIb/IIIa Inhibitors Heparin and low molecular weight heparins Thrombin inhibitors Warfarin Novel oral anticoagulants Fibrinolytics  Lecture Outline Cholesterol and other lipids Dietary recommendations Medication classes Statins Bile acid sequestrants Niacin Fibrates Ezetimbe  Opposing Forces Anti-aggregation Protein C Pro-aggregation Platelet adhesion Coagulation cascade Both necessary for hemostasis Must be balanced  Endothelial Early Warning Normal blood flow platelets remain inactive Rupture or damage to vascular tissue Exposes collagen layer Platelets activate Adhere to collagen and each other  Plaque Rupture Plaque rupture causes endothelial injury Platelets begin to adhere Coagulation cascade initiates locally to strengthen initial platelet plug Test question now the two pathways like name them that’s it Coagulation Cascade Two pathways Extrinsic Tissue factor activates factor VII Thrombin Intrinsic Positive feed back to activate intrinsic pathway More thrombin generation thru common pathway  Platelet Clot Formation Adhesion Platelet attaches to sub endothelium TF is released Activation Thrombin causes platelet activation and shape change Aggregation Further receptor activation Platelet Inhibition  Platelet Receptor Targets Platelets have multiple receptors and metabolic processes that serve as drug targets ADP GpIIb/IIIa TXA2 synthesis Different drugs target each of these sites  Aspirin Inhibitor of COX-1 Irreversible Inhibits production of Thromboxane A2 Inhibits activity for whole lifespan of platelet (8-10 days) Only blocks activation related to Thromboxane  Aspirin Indication Dose Concerns Primary Prevention 81mg Bleeding, Resistance***, Risk greater than reward Secondary in some patients 81mg Prevention Some patients use 325mg strength Covered by ODB - Ontario Drug Benefits  ADP Inhibitors Inhibitor of ADP action at receptor P2Y12 Prevents activation of GpIIb/IIIa receptor Prevents platelet aggregation Older agents are irreversible newer ones reversible  Adp inhibitors would have what side affect Ticlopidine Test question Indication Dose Concerns Repeat stroke prevention 250 mg Neutropenia, Bleeding BID PCI x 30days Need CBC before initiation and q2weeks until 3 months Not used frequently  MOST USED Clopidogrel =PLAVIX NEED TO KNOW FOR TEST Indication Dose Concerns 600/300 Loading Dose Bleeding (less GI mg bleeding than ASA), 75 mg resistance*** All others daily Variable length of treatment based on indication PCI with DES one year Hold x 5days before CABG  GpIIb/IIIa Receptor Antagonists Inhibitor of final step in platelet aggregation Prevent cross link of GpIIb/IIIa receptor with fibrinogen and/or VWf May be used in combo with clopidogrel and ASA especially in high risk PCI  DONT NEED TO KNOW Abciximab Indication Concerns PCI upstream with in high risk patients clopidogrel watch for thrombocytopenia Monoclonal Antibody Monitor platelet counts Acute Anticoagulation  Heparin and LMWH Heparin Indirect Inhibitor of thrombin Must be closely monitored (unpredictable dose /effect) Must be given IV Titrate to aPTT LMWH = LOW MOLECULAR WEIGHT HEPARIN Subcutaneous More predictable dose response Monitor kidney function  Heparin and LMWH Major side effects: Bleeding Heparin Induced Thrombocytopenia (HIT) About 3-5% of all patients Platelet count falls but patient needs more Anticoagulation Too much thrombin Thrombin storm Treat with direct thrombin inhibitor  LMWH Examples: Dalteparin Enoxaparin Tinzaparin Much less Heparin Induced Thrombocytopenia 1% of patients  Direct Thrombin Inhibitors Useful in cases of HIT Also licensed for use in PCI Better at clot bound thrombin inhibition Heparin 20-40% DTI ~70% Bivalrudin Lepirudin Oral Anticoagulation  Vitamin K - Antagonists Warfarin = COUMIDONE Inhibition of hepatic microsome vitamin k activity Inhibits vitamin k dependent clotting favors Response takes 2-7 days Long half life  Warfarin HIGHER INR =LONGER TIME BLOOD TAKES TO CLOT Dosing Must be individualized Starting dose 5mg is common Monitored by INR blood test Specific ranges for various indications Typically INR 2-3 for most  Warfarin Drug-Drug interactions Pharmacodynamic Care must be taken when combined with other drugs that cause bleeding Pharmacokinetic Many CYP 450 interactions Amiodarone BAD COMBINATION WITH WARFARIN  Warfarin Drug-Food interactions Vitamin K Green leafy vegetables Must ensure consistent and constant intake of some foods Avoidance not best strategy  Warfarin Cautions: Bruising Bleeding Care must be taken Antidote Vitamin K administration Route Depends on severity Oral IV  Warfarin Cautions: Warfarin induced skin necrosis Usually Early Depletion of natural anticoagulants Protein C  Novel Oral Anticoagulants New agents recently developed First alternatives to warfarin for long term Anticoagulation No monitoring Predictable dose response curve No readily available antidote Limited indications to date but has been increasing  Novel Oral Anticoagulants Indications: Stroke prevention in Atrial Fibrillation VTE prevention after hip and knee replacement Treatment of DVT in legs Duration of therapy based on indication Must adjust for renal unction and age  3 REASONS WHY YOU WOULD GIVE Dabigatran= PRADAXA PRADAXA OVER COUMADINE Indication Dose Concerns Stroke prevention Bleeding 150mg BID Atrial Fibrillation Liver dysfunction VTE prevention in Kidney disease 110mg BID orthopedic surgery RE-LY: In AF 150mg dose less embolism ****Evidence bleeding but more dyspepsia and GI based medicine bleed less severe bleeds than warfarin Rivaroxaban Indication Dose Concerns Stroke prevention 20 mg daily Atrial Fibrillation with food VTE prevention in Bleeding 10 mg daily Liver dysfunction orthopedic surgery 15 mg bid x 3 Kidney disease weeks then Treatment of DVT 20mg daily with food  Rivaroxaban Evidence based medicine ROCKET-AF Non inferior to warfarin Less severe bleeding but more minor bleeding (ex. epistaxis, GI bleed and Hg drops requiring transfusion)  Apixaban Indication Dose Concerns Stroke prevention 5 mg twice Atrial Fibrillation daily with food Bleeding Liver dysfunction Kidney disease VTE prevention in 2.5 mg twice orthopedic surgery daily  Apixaban= ELIQUIS Evidence based medicine ARISTOTLE Superior to warfarin in stroke and embolism prevention Less bleeding major and minor The evolution of oral anticoagulants - 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