Unit 2 - Antithrombotic Drugs Flashcards Preview

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Flashcards in Unit 2 - Antithrombotic Drugs Deck (55):

what are the 3 types of antithrombotic drugs? when are they used?

1. anticoagulants - venous thrombosis
2. fibrinolytic drugs - acute thrombosis
3. antiplatelet drugs - arterial thrombosis


what are 4 types of anticoagulants?

1. heparins (unfractionated, low-molecular weight, fondaparinux)
2. vitamin K antagonists (oral warfarin)
3. direct thrombin (IIa) inhibitors (oral dabigatran, bivalirudin, argatroban)
4. direct Xa inhibitor (oral rivaroxaban, oral apixaban)


what are the types of fibrinolytic drugs?

tissue plasminogen activator (tPA)
-reteplase, alteplase, tenecteplase


what are the 4 types of antiplatelet drugs?

1. COX inhibitor
2. P2Y12 (ADP receptor) inhibitor (clopidogrel, prasugrel, ticagrelor)
3. GPIIbIIIa (fibrinogen receptor) inhibitor (abciximab, epifibatide, tirofiban)
4. phosphodiesterase inhibitor (dipyridamole)


what is the general use of anticoagulants?

prophylaxis and treatment of venous thrombosis
-do not lyse already formed clots, but prevent their further propagation
-in the low shear environment (venous system, heart)
--atrial fibrilation
--valvular disease
--valve replacement


what is the classical anticoagulation paradigm?

1. heparin used initially (immediate-acting, short half-life, parenteral
2. warfarin for long-term therapy (slow-acting, long half=life, oral)
3. paradoxical thrombotic complications
-heparin --> HIT
-warfarin --> skin necrosis
-thus dosing is difficult and requires constant monitoring
-antidotes can quickly reverse effect


explain what heparins are and their mechanism?

anticoagulant indirect thrombin inhibitors similar to heparan sulfate of endothelial cells
-bind to and activate antithrombin (AT)
-heparin-AT complex inactivates IIa, Xa, IXa, XIa, and XIIa
-immediate-acting and given parenterally

however, switch to oral warfarin after 2 days


what does standard (unfractionated) heparin do? side effects?

inhibits both Xa and thrombin
-ASE: bleeding, heparin-induced-thrombocytopenia (HIT), thrombosis (5% patients), osteoporosis in long-term use
-can be reversed with antidote protamine sulfate


explain the structure of standard (unfractionated) heparin

-heterogeneous mixture of acidic mucopolysaccharides from porcine intestine or bovine lung
-anticoagulatn activity due to pentasaccharide sequence that binds antithrombin and longer (>18) polysaccharide sequences that bind thrombin


explain the dosage of standard (unfractionated) heparin

measured in activity units (U), and given sc or iv
-short half-life (1hr), and dosing is unpredictable due to binding of cell to surface GP, vitronecctin, PF4, etc.
-therapeutic effectiveness is monitored by using PTT (should be 2-2.5x normal), but unpredictable pharmacokinetics


what are indications for unfractionated heparin?

1. maintain patency in dialysis, bypass surgery, venous lines
2. prevent thrombosis in major surgical procedures
3. treatment of acute venous thromboembolism
4. unstable angina, MI, angioplasty, stent


what are advantages and disadvantages to giving unfractionated heparin?

pro: rapid turn-on and turn-off, and often more effective in cancer patients
con: requires hospitalization due to continuous infusion


what is the antithrombotic drug of choice in pregnant women?

unfractionated heparin (doesn't cross placenta)


explain heparin-induced thrombocytopenia

heparin-antithrombin complex is attached by IgG
-this immune complex binds to platelets
--destroyed in spleen by macrophages --> thrombocytopenia
--but in some population, these platelets become activated, released, and aggregated, and release procoagulant microparticles --> thrombosis --< ischemic death --> amputation


what is the "optimal" aPTT one should see while using heparin?

50-70 seconds
-repeat test every 6 hours to confirm changes


explain the dosage and monitoring of LMWH?

shorter chain heparin modified from standard heparin
-longer half-life, so can be given once or twice daily
-dose response curve is predictable, thus requires less laboratory monitoring (when needed, use heparin (anti-factor Xa) assay


explain how LMWH works, and side effects

anticoagulants inhibits Xa, instead of thrombin
-ASE: accumulates in renal impairment, but doesn't have thrombocytopenia and osteoporosis of normal heparin


what are indications for LMWH?

-replaces unfractionated heparin in many indications
-can be used in outpatient setting
-unstable angina
-pregnancy (like heparin)


what are 4 LMWH?

1. dalteparin
2. enoxaparin
3. tinzaparin
4. danaparoid


explain what fondaparinux (Arixtra) is? side effects? indications? use?

anticoagulants LMWH pentasaccharide
-binds to activation site of antithrombin, to inhibit factor Xa (ineffective against thrombin)
-used in moderate VTE risk in hospitalized patients as an alternative to LMWH
-used if patient develops HIT
-17-21 hour half-life, but NO antidote, so if patient begins to bleed, there's nothing you can do


explain what idraparinux is

anticoagulants similar to fondaparinux, with 5-6 day half-life
-but also doesn't have an antidote, so considered too risky


explain what warfarin is? structure? mechanism?

only oral anticoagulant coumarin derivative
-fat-soluble vit K antagonist that blocks vit K-dependent carboxylation of factors II, VII, IX, and X to prevent activity (intrinsic pathway)


explain dosages of warfarin?

slow onset (up to 1 week b/c need to wait until pre-made factors run out)
-long-half life (36 hours), oral, chronic, often life-long treatment
-always preceded by another anticoagulant, as it has a slow onset, and to avoid warfarin-induced thrombosis


explain warfarin metabolism?

rapidly absorbed from the gut and extensively bound to albumin
-laxatives and mineral oil may reduce absorption
-displacement of albumin-bound warfarin by other medications increases free warfarin concentration and anticoagulant activity
-increasing vit K consumption will decrease anticoagulant activity, and vice-versa
-metabolized by P560


what is INR?

international normalized ratio = PT patient / PT control


what are adverse effects of warfarin?

1. bleeding
2. thrombosis at beginning of treatment
-due to rapid decrease in anticoagulants protein C and S
-due to short half-life, a rapid drug-induced decrease in PRO C activity may temporarily shift balance toward coagulation, resulting in vascular thrombosis and skin/fat necrosis
3. teratogen


what can warfarin therapy be reversed by?

1. stop warfarin (takes 1-2 days)
2. give vitamin K (reverses effect in 10 hours)
3. give protrhombin factor concentrate (II, VII, IX, X, PRO C/S)
4. give fresh frozen plasma (FFP) for immediate effect (but Kcentra above is preferred)


what is the "therapeutic window" of warfarin compared to heparin?

warfarin has narrow therapeutic window between hemorrhage and thrombosis, while heparin has wider window


what is the mechanism of direct thrombin inhibitors

1. directly bind to catalytic site of thrombin
2. immediate onset of action
3. no antidote (under development)
4. direct thrombin inhibitors also active in clots


explain bivalirudin

anticoagulant direct thrombin inhibitor
-synthetic polypeptide derivative of leech Hiruden
-specific, irreversible thrombin inhibitor that binds to catalytic site
--inactivates both fibrinogen-bound and free thrombin
-approved for PCI, and has very short half-lfie
-administered parenterally with rapid on/offset of action, monitored by PTT, but NO antidote


what is argatroban?

anticoagulant direct thrombin inhibitor
-synthetic analog of arginine, that inhibits catalytic site of thrombin


what is dabigatran?

anticoagulant direct thrombin inhibitor
-oral serine protease inhibitor, and competitive inhibitor of thrombin cleared by kidney, and used for nonvalvular atrail fibrilation
-administered as predrug (dabigatran etexilate)
-few drug interactions
-safe over large range of doses (don't need monitoring, standard dose once/twice daily)
-half-life 8 hours after single dose, 17 after multiple
-currently no antidote, thus mortality with hemorrhages; but performs better than warfarin and Lovenox


what are direct Xa inhibitors?

oral anticoagulants that are small molecules that reversibly block active site


what is rivaroxaban?

direct Xa inhibitor anticoagulant
-used in postoperative DVT prophylaxis, AFib, DVT, PE


what is apixaban?

direct Xa inhibitor anticoagulant
-used in postoperative DVT prophylaxis, AFib, but NOT DVT/PE


what is betrixaban?

direct Xa inhibitor anticoagulant in phase 3 trials
-not dependent on renal or hepatic clearance, with minimal drug interaction, long-half life
-antidote is being made


what is the key thing to know about direct inhibitors of Xa and IIa?

no methods to assess levels, thus no specific antidotes


how do fibrinolytic (thrombolytic) drugs work?

in acute venous and arterial thrombosis
-effective when started within 3-12 hours of thrombosis, and given for 1-2 days
-activate plasminogen to plasmin, including free and bound
--free plasmin cuts and depletes coagulation factors and fibrinogen to induce hemorrhage


when are fibrinolytic drugs used?

used in all STEMI (ST elevation MI)


what is alteplase?

recombinant tPA fibrinolytic drug used in ischemic stroke, massive PE
-not entirely clot specific


what is reteplase?

recombinant tPA fibrinolytic drug
-lacks fibrin-binding domain, and goes deeper into clot
-more rapid effect, but less thrombus-selective


what is tenecteplase?

recombinant tPA fibrinolytic drug that is clot-specific, with long half-life


what is streptokinase?

fibrinolytic bacterial protein that activates plasminogen in circulation and at the clot
-not thrombus-selective, and not used in US


what are antiplatelet drugs used for?

prevention and treatment of
-peripheral artery disease
-percutaneous coronary intervention
-usually several drugs used in combination


what is aspirin?

antiplatelet drug that at low doses is weak, but effective
-irreversibly binds COX-1 and inhibits platelets (no turnover)
--in endothelium, effect is transient, as new COX-1 is made; effect increases with higher doses, causing PGI2 to become more significant, and become ineffective at thrombosis


what is dipyridamole?

antiplatelet phosphodiesterase inhibitor
-used alone or with aspirin parenterally
-secondary stroke prevention due to weak antiplatelet effect


what is cilostazol?

antiplatelet phosphodiesterase inhibitor
-used in peripheral arterial disease
-also reduces smooth muscle proliferation and intimal hyperplasia


how do antiplatelet phosphodiesterase inhibitors work?

increase cAMP and cGMP
-marginally effective


how does clopidogrel work?

antiplatelet P2Y12 (ADP receptor) blocker
-reduces platelet aggregation
-antithrombotic effect is dose-dependent and within 5 hours, 80% of platelets are irreversibly inhibited for up to 10 days
-TTP is rare side effect, but antithrombotic effect can be reversed by platelet infusion
-so slow onset and slow offset; activated by P450 enzymes in liver


what is prasugrel?

antiplatelet P2Y12 (ADP receptor) blocker
-activation by different P450 enzyme than clopidogrel
--effective in patients with clopidogrel resistance
-more potent, but also causes more bleeding


what is ticagrelor?

antiplatelet P2Y12 (ADP receptor) blocker
-adlosterone analog
-allosteric, reversible inhibitor
-used in ACS and PCI


what is Abciximab?

antiplatelet GPIIb-IIIa antagonist
-monoclonal Ab that may elicit immune response (limits repeated use)
-fragment of chimeric mouse/human
-effective for 24-48 hours


what is eptifibatide?

antiplatelet GPIIb-IIIa antagonist
-from rattlesnake venom peptide fibrinogen analog
-rapid onset, short half-life, and reversible action
-compete with endogenous fibrinogen and vWF binding to IIb/IIIa


what is tirofiban?

antiplatelet GPIIb-IIIa antagonist
=tyrosine derivative fibrinogen analog


what must you know about antiplatelet GPIIb-IIIa antagonist?

parenteral drugs that are fast acting
-cause paradoxical thrombosis, platelet activation