Antithrombotics

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Aspirin

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- Oral antiplatelet
- Low dose is antithrombotic → prevent MI
- High dose is used for angina, AMI, TIA, and to prevent post-carotid surgery CVA
- Irreversibly acetylates COX-1/2 → inhibit platelet TXA2 (beneficial) and PGI2 (not-beneficial) production
- Platelets cannot make new COX, but endothelial cells can → endothelial cells will produce new COX-2 to produce PGI2
- Inhibition lasts for life-span of platelet (~10 days)
- Can cause GI discomfort, peptic ulcer disease, and GI/systemic bleeding

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Dipyridamole

Back 2

- Oral antiplatelet
- Used for prosthetic heart valve thromboemboli prophylaxis and post-stroke prophylaxis
- Increases cAMP/cGMP by blocking uptake of adenosine and inhibiting PDE
- Adenosine binds GPCRs on platelets to increase cAMP
- Usually combined with aspirin (aggrenox) or warfarin

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Clopidogrel

Back 3

- Oral antiplatelet
- Used for recent ACS/CVA, PAD, or post-PCI
- Irreversibly inhibits ADP receptors → takes 4-7 days to achieve full platelet inhibition
- Often used in combination with aspirin or alone in aspirin-intolerant patients
- Can cause nausea, dyspepisa and diarrhea
- Rare TTP, hemorrhage, and neutropenia (reason it is reaplacing ticlopidine)
- CI in active bleeding

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Abciximab

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- IV monoclonal GP IIb/IIIa inhibitor (antiplatelet)
- Used as adjunct for PCI and refractory UA angina
- Blocks GP IIb/IIIA inhibition to prevent platelet aggregation
- Fc portion is cleaved to reduce thrombocytopenia due to splenic uptake
- 0.5 - 2 hour half-life
- Cleared by kidney
- Can cause bleeding and thrombocytopenia

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Eptifibatide

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- IV synthetic GP IIb/IIIa inhibitor (antiplatelet)
- Used in ACS and PCI
- Hepapeptide that binds to GP IIb/IIIa RGD sequence receptor to prevent platelets from binding fibrinogen
- 0.5 - 2 hour half-life
- Cleared by kidney

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Tirofiban

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- IV synthetic GP IIb/IIIa inhibitor (antiplatelet)
- Used in ACS and PCI
- Non-peptide that binds GP IIb/IIIa receptor to prevent platelets from binding fibrinogen
- Often used with heparin and aspirin
- 0.5 - 2 hour half-life
- Cleared by kidney

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Heparin

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- IV/SC anticoagulant
- Used for DVT, PE, post-MI, UA, non-Q-wave MI, and to coat stents
- Contains 3 pentasaccharide binding domains that catalyze ATIII's anti-serine protease activity against FIIa/IXa/Xa/XIa
- Heparin can be reversed by protamine sulfate
- Resistance occurs do to non-specific binding to cells/acute phase reactants or elevated FVIII
- Cleared renally
- Important to monitor platelet levels and PTT
- Can cause heparin-induced thrombocytopenia (HIT) → allergy-like reaction that causes widespread arterial and venous thromboembolism (20-30% mortality)
- CI in allergic patients, active bleeding, hemophiliacs, thrombocytopenia, hepatic/renal disease, or compromised BBB (brain/eye surgery or LP)

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Enoxaparin

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- IV/SC LMWH (anticoagulant)
- Used for DVT, PE, post-MI, UA, non-Q-wave MI, and to coat stents
- Contains 1 binding domain that is more selective for FXa
- Superior bioavailability, limited resistance, and non-dose dependent half-life → once or twice daily dosing with minimal need for laboratory monitoring
- Lower incidence of HIT, less bleeding and lower risk of thrombocytopenia than heparin
- Cleared renally
- Only partially reversed by protamine sulfate

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Dalteparin

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- IV/SC LMWH (anticoagulant)
- Used for DVT, PE, post-MI, UA, non-Q-wave MI, and to coat stents
- Contains 1 binding domain that is more selective for FXa
- Superior bioavailability, limited resistance, and non-dose dependent half-life → once or twice daily dosing with minimal need for laboratory monitoring
- Lower incidence of HIT, less bleeding and lower risk of thrombocytopenia than heparin
- Cleared renally
- Only partially reversed by protamine sulfate

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Lepirudin

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- IV thrombin inhibitor (anticoagulant)
- Used as anticoagulant in patient that develop HIT
- Inhibits thrombin independent of ATIII
- Originally isolated as hirudin from leech saliva
- Patients may develp anti-hirudin antibodies → decreased renal clearance, which increases anticoagulant effect

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Bivalirudin

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- IV thrombin inhibitor (anticoagulant)
- Used as anticoagulant in patient with UA undergoing PCTA
- Synthetic analog of carboxyterminus of hirudin → reversible inhibition of thrombin independent of ATIII
- 25 minute half-life
- 300 times more expensive than heparin → restricted to patients with HIT at UVA
- May cause bleeding and hypersensitivity

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Argatroban

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- IV thrombin inhibitor (anticoagulant)
- Used for prophylaxis/treatment of thrombosis in patients with HIT, especially when undergoing PCI
- Tripeptide that directly inhibits free and fibrin bound thrombin independent of ATIII

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Warfarin

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- Oral anticoagulant
- Used for prevention of thromboembolism, DVT, systemic arterial embolism due to AF/prosthetic heart valves, and MI
- Vitamin K analog that prevents gamma-carboxylation (synthesis) of FII/VII/IX/X/proteinC
- Since it decreases synthesis of clotting factors, 4-5 days are required for before it takes effect → start patient with heparin
- 100% oral bioavailability and 99% bound to albumin
- Start with a low dosage, stabilize drug level, monitor with PT and INR, and then adjust
- Metabolized by CYP450 → many drug interactions and requires close monitoring
- Bleeding is major complications → monitor for GI tract, subdural, and intracerebral bleeds and give vitamin K to reverse effects
- History of bleeding, cigarette smoking, renal insufficiency, anemia, and hypertension increase bleeding risks
- Rarely, skin necrosis develops 3-8 days after initiation of therapy
- Purple toe syndrome → patient with atherosclerotic disease can develop atheroembolic ischemia
- CI in pregnancy → crosses placenta to cause hemorrhagic disorder and possible birth defects

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Streptokinase

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- IV fibrinolytic
- Was used to treat DVT/MI but has been replaced by safer fibrinolytics
- Binds to plasminogen to causeauto-catalytic reaction
- Not selective for fibrin and resistant to alpha-antiplasmin → creates massive formation of plasmin and systemic lytic state
- Allergic reactions in 6% of patients due to previous streptococcal infection
- Main side effect is bleeding

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Reteplase

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- IV fibrinolytic
- Used for multiple PEs, DVT, AMI, and CVA
- Recombinant non-glycosylated form of tPA that has lower fibrin binding affinity, longer half-life (15 minutes), and greater specificity for coronary thrombi
- Delivered as two IV boluses rather than continuous infusion like alteplase
- Can cause bleeding, systemic plasmin production, and allergic reactions

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Tenecteplase

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- IV fibrinolytic
- Used for AMI
- Recombinant human tPA with 3 sets of mutations that make it more resistant to PAI-1
- Longer half-life, single bolus dosing, and 14 fold greater specificity for fibrin are all advantages over alteplase

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Alteplase

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- IV fibrinolytic
- Used for multiple PEs, DVT, and AMI
- Recombinant tPA → trypsin-like serine protease that activates plasminogen to plasmin
- Specificity for clots is created by using fibrin as a co-factor and the presence of plasminogen activator inhibitor (PAI-1) in blood to prevent widespread plasminogen activation
- Can cause lytic state if therapeutic levels overwhelm PAI-1
- 3 minute half-life → rapidly cleared by liver
- Can cause hemorrhage and allergic reactions (less immunogenic than streptokinase)