Treatment of Thrombolytic Disorders Flashcards
Vascular Injury: Arteries vs. Veins
Vascular injury = exposes collagen and vWF causing platelet release, adhesion, recruitment, activation, and aggregation to form a thrombus; tissue factor exposure causes activation of coagulation cascade, thrombin generation, fibrin formation, and thrombus formation
Venous thrombosis will be clotting activation and arterial thrombosis will mostly be platelet aggregation
Coumadin/Warfarin
Coumadin/warfarin = inhibits actions of VIIa, X, IX, II
Warfarin/Coumadin mechanism: does not directly work on clotting protein, but interferes so you don’t get proteins 7, 9, and 10
Inhibits synthesis, so if have already formed then won’t work as well to cause immediate effects
Warfarin Antidote: fresh frozen plasma
Heparin
Heparin products (fondaparinux, danaparoid, LMWH, and UFH) = fewer drug interactions
LMWH is more effective on Xa, but also works on IIa (thrombin)
Fondaparinux only works on Xa, no action on thrombin
Heparin: doesn’t do anything by itself; with antithrombin, will neutralize thrombin or factor X aka increases rate of anti-thrombin
Heparin has an antidote
DTIs
DTIs: directly bind to thrombin (IIa) and inhibit activation; direct thrombin inhibitors
DTIs: lepirudin, bivalirudin, argatroban, and dabigatran
DTI: no antidote
Heparin vs. Warfarin
Heparin (often as LMWH) is used acutely and Warfarin for prolonged therapy
Mechanism of Thrombus Formation
Plaque disruption causing platelet activation and adhesion with release of thromboxane A2 and ADP to cause conformational activation of GPIIb/IIIa receptors thus causing platelet aggregation
Aspirin
Cyclooxygenase (COX-1)
Irreversible inhibition of COX-1 blocks TXA2 mediated platelet activation
At higher doses aspirin inhibits COX-2 in endothelial cells and thereby blocks synthesis of PGI2, a potent inhibitor of platelet aggregation, by elevating platelet cyclic AMP levels
NSAIDs + aspirin = drug interaction and aspirin will not work; if need to take both, take aspirin 8 hours before or after
Side Effects: Bleeding, Gastro-Intestinal complications including Gastric ulcers
Clopidogrel
ADP (P2Y12)-receptor
Irreversible antagonism of P2Y12 blocks platelet aggregation
Irreversible and prodrug (must be metabolized to become active); patients may not respond
Side Effects: Bleeding; Rash; Neutrocytopenia; Thrombocytopenia; TTP
Prasugrel
ADP (P2Y12)-receptor
Irreversible antagonism of P2Y12 blocks platelet aggregation
Irreversible and prodrug (must be metabolized to become active); patients may not respond
Side Effect: Bleeding
Ticlopidine
ADP (P2Y12)-receptor
Irreversible antagonism of P2Y12 blocks platelet aggregation
Irreversible and prodrug (must be metabolized to become active); patients may not respond
Side Effects: Bleeding; Gastro-Intestinal complications; Rash; TTP Neutrocytopenia; Thrombocytopenia
Ticagrelor
ADP (P2Y12)-receptor
Reversible antagonism of P2Y12 blocks platelet aggregation
Direct acting and reversible
Side Effects: Bleeding, Dyspnea, and Bradyarrhythmia
Dipyridamole
Cyclic nucleotide phosphodiesterase (PDE)
Adenosine uptake
Inhibition of PDE and adenosine uptake prevents platelet activation by increasing cyclic AMP levels
Side Effects: Bleeding, Headache; Dizziness; Dizziness; Rash; Pancytopenia
Cilostazol
Cyclic nucleotide phosphodiesterase 3 (PDE3)
Inhibition of PDE 3 prevents platelet activation by increasing cyclic AMP levels in vascular tissue thus causing vasodilation
Side Effects: Bleeding; Headache; Diarrhea Dizziness; Rash; Pancytopenia
Abciximab
Integrin aIIbb3-receptor
Inhibition of fibrinogen binding to integrin aIIbb3 prevents platelet aggregation
Do not give patients for prevention of MI or stroke, and only given intravenously during surgery or in hospital
Side Effects: Bleeding and thrombocytopenia
Eptifibatide
Integrin aIIbb3-receptor
Inhibition of fibrinogen binding to integrin aIIbb3 prevents platelet aggregation
Do not give patients for prevention of MI or stroke, and only given intravenously during surgery or in hospital
Side Effects: bleeding and thrombocytopenia
Tirofiban
Integrin aIIbb3-receptor
Inhibition of fibrinogen binding to integrin aIIbb3 prevents platelet aggregation
Do not give patients for prevention of MI or stroke, and only given intravenously during surgery or in hospital
Side Effects: bleeding and thombocytopenia
Adenosine and PGI2
Adenosine: works on A2 receptor; increase cAMP
PGI2: works on AC receptor; increase cAMP
Clinical Use of Antiplatelet Drugs
Patients with acute myocardial infarction
Patients who have recovered from myocardial infarction
Patients with symptoms from atherosclerosis, including angina, transient cerebral ischemic attacks, intermittent claudication
Following coronary artery bypass grafting
Following coronary artery angioplasty and stenting
Acute thrombotic stroke
Atrial fibrillation in patients who have a contraindication to oral anticoagulation
Fibrinolytic Drugs
Streptokinase Urokinase Tissue plasminogen activators (t-PA) Reteplase Tenecteplase
All convert plasminogen to plasmin to cause breakdown of fibrin
More specific for fibrin where clot is: t-PA
Streptokinase is cheaper but not as specific – so effective everywhere; from bacterium so higher risk of reactions
Urokinase: like streptokinase
Clinical Use of Fibrinolytic Drugs
Acute myocardial infarction, within 12 hours of onset
Acute thrombotic stroke within 3 hours of onset
Deep vein thrombosis, pulmonary embolus, clearing thrombosed shunts and cannulae, acute arterial thromboembolism
Treatment of Peripheral Arterial Disease
Antiplatelet drugs ACE inhibitors β-blockers Statins Cilostazol
Class of Evidence for Claudication Therapies
Class I: Evidence and general agreement or both that treatment is beneficial, useful and effective
Class IIb: Conflicting evidence or divergence of opinion about efficacy or usefulness
Class III: Evidence and general agreement or both that treatment is not beneficial, useful and effective
Level of Evidence for Claudication Therapies
Level A: Data derived from multiple trial or meta analysis
Level B: Single randomized trial or non-randomized studies
Level C: Consensus opinion of experts, case studies or the standard of care
Class I
Cilostazol
Class A
Contraindicated in heart failure; headache, diarrhea, palpitations, dizziness
