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MSII Pharmacology > Unit 2 - Antithrombotic Drugs > Flashcards

Unit 2 - Antithrombotic Drugs Flashcards

1
Q

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

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

what are 4 types of anticoagulants?

A
  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)
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3
Q

what are the types of fibrinolytic drugs?

A

tissue plasminogen activator (tPA)

-reteplase, alteplase, tenecteplase

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4
Q

what are the 4 types of antiplatelet drugs?

A
  1. COX inhibitor
  2. P2Y12 (ADP receptor) inhibitor (clopidogrel, prasugrel, ticagrelor)
  3. GPIIbIIIa (fibrinogen receptor) inhibitor (abciximab, epifibatide, tirofiban)
  4. phosphodiesterase inhibitor (dipyridamole)
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5
Q

what is the general use of anticoagulants?

A

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
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6
Q

what is the classical anticoagulation paradigm?

A
  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
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7
Q

explain what heparins are and their mechanism?

A

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

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8
Q

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

A

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
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9
Q

explain the structure of standard (unfractionated) heparin

A
  • 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
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10
Q

explain the dosage of standard (unfractionated) heparin

A

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
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11
Q

what are indications for unfractionated heparin?

A
  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
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12
Q

what are advantages and disadvantages to giving unfractionated heparin?

A

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

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13
Q

what is the antithrombotic drug of choice in pregnant women?

A

unfractionated heparin (doesn’t cross placenta)

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14
Q

explain heparin-induced thrombocytopenia

A

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
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15
Q

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

A

50-70 seconds

-repeat test every 6 hours to confirm changes

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16
Q

explain the dosage and monitoring of LMWH?

A

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
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17
Q

explain how LMWH works, and side effects

A

anticoagulants inhibits Xa, instead of thrombin

-ASE: accumulates in renal impairment, but doesn’t have thrombocytopenia and osteoporosis of normal heparin

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18
Q

what are indications for LMWH?

A
  • replaces unfractionated heparin in many indications
  • can be used in outpatient setting
  • unstable angina
  • pregnancy (like heparin)
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19
Q

what are 4 LMWH?

A
  1. dalteparin
  2. enoxaparin
  3. tinzaparin
  4. danaparoid
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20
Q

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

A

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
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21
Q

explain what idraparinux is

A

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

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22
Q

explain what warfarin is? structure? mechanism?

A

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)

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23
Q

explain dosages of warfarin?

A

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
24
Q

explain warfarin metabolism?

A

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
25
Q

what is INR?

A

international normalized ratio = PT patient / PT control

26
Q

what are adverse effects of warfarin?

A
  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
27
Q

what can warfarin therapy be reversed by?

A
  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)
28
Q

what is the “therapeutic window” of warfarin compared to heparin?

A

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

29
Q

what is the mechanism of direct thrombin inhibitors

A

anticoagulants

  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
30
Q

explain bivalirudin

A

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
31
Q

what is argatroban?

A

anticoagulant direct thrombin inhibitor

-synthetic analog of arginine, that inhibits catalytic site of thrombin

32
Q

what is dabigatran?

A

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
33
Q

what are direct Xa inhibitors?

A

oral anticoagulants that are small molecules that reversibly block active site

34
Q

what is rivaroxaban?

A

direct Xa inhibitor anticoagulant

-used in postoperative DVT prophylaxis, AFib, DVT, PE

35
Q

what is apixaban?

A

direct Xa inhibitor anticoagulant

-used in postoperative DVT prophylaxis, AFib, but NOT DVT/PE

36
Q

what is betrixaban?

A

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
37
Q

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

A

no methods to assess levels, thus no specific antidotes

38
Q

how do fibrinolytic (thrombolytic) drugs work?

A

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
39
Q

when are fibrinolytic drugs used?

A

used in all STEMI (ST elevation MI)

40
Q

what is alteplase?

A

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

41
Q

what is reteplase?

A

recombinant tPA fibrinolytic drug

  • lacks fibrin-binding domain, and goes deeper into clot
  • more rapid effect, but less thrombus-selective
42
Q

what is tenecteplase?

A

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

43
Q

what is streptokinase?

A

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

44
Q

what are antiplatelet drugs used for?

A

prevention and treatment of

  • MI
  • TIA
  • peripheral artery disease
  • percutaneous coronary intervention
  • usually several drugs used in combination
45
Q

what is aspirin?

A

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
46
Q

what is dipyridamole?

A

antiplatelet phosphodiesterase inhibitor

  • used alone or with aspirin parenterally
  • secondary stroke prevention due to weak antiplatelet effect
47
Q

what is cilostazol?

A

antiplatelet phosphodiesterase inhibitor

  • used in peripheral arterial disease
  • also reduces smooth muscle proliferation and intimal hyperplasia
48
Q

how do antiplatelet phosphodiesterase inhibitors work?

A

increase cAMP and cGMP

-marginally effective

49
Q

how does clopidogrel work?

A

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
50
Q

what is prasugrel?

A

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
51
Q

what is ticagrelor?

A

antiplatelet P2Y12 (ADP receptor) blocker

  • adlosterone analog
  • allosteric, reversible inhibitor
  • used in ACS and PCI
52
Q

what is Abciximab?

A

antiplatelet GPIIb-IIIa antagonist

  • monoclonal Ab that may elicit immune response (limits repeated use)
  • fragment of chimeric mouse/human
  • effective for 24-48 hours
53
Q

what is eptifibatide?

A

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
54
Q

what is tirofiban?

A

antiplatelet GPIIb-IIIa antagonist

=tyrosine derivative fibrinogen analog

55
Q

what must you know about antiplatelet GPIIb-IIIa antagonist?

A

parenteral drugs that are fast acting

-cause paradoxical thrombosis, platelet activation

MSII Pharmacology (43 decks)

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