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Pharmo for medic school > Anticoag, antiplate, thrombolytic textbook > Flashcards

Anticoag, antiplate, thrombolytic textbook Flashcards

1
Q

Stage one of hemostasis; formation of a platelet plug

A

Platelets are activated by interaction with collagen. The GP IIb/IIIa receptors must then undergo activation (a change in shape to allow fibrinogen binding) for aggregation
This plug is unstable and requires coagulation

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2
Q

How can GP IIb/IIIa receptors become activated

A 
Thromboxane A2
Thrombin
Collagen
Platelet activation factor
ADP
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3
Q

Stage two of hemostasis; coagulation

A

Production of fibrin (a thread like protein to reinforce the platelet plug) activated through intrinsic (contact activation) or extrinsic (tissue factor) pathways
Both converge at Xa

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4
Q

Extrinsic pathway

A

Vascular wall trauma triggers release of tissue factor AKA thromboplastin (a complex of several compounds) and then:
Activates VII which activates X
X catalyzes conversion of II to IIa (prothrombin to thrombin)
Thrombin does three things:
Catalyzes conversion of fibrinogen into fibrin
Catalyzes V into Va (increases Xa)
Catalyzes VIII into VIIIa which increases activity of IXa

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5
Q

Factors affected by warfarin

A

II (prothrombin), VII, IX, X,

VII is extrinsic

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6
Q

Factors affected by heparin

A

IXa, Xa, XIa, XIIa and thrombin (IIa)

XIIa, XIa, IXa are unique to intrinsic (doesn’t hit any extrinsic until Xa)

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7
Q

Contact activation (intrinsic) pathway

A

Activated when blood makes contact with collagen that has been exposed as a result of trauma
Collagen activates XII to XIIa
XIIa activates XI to XIa
XIa activates IX which activates X
Xa catalyzes conversion of II to IIa (prothrombin to thrombin)
Thrombin does three things:
Catalyzes conversion of fibrinogen into fibrin
Catalyzes V into Va (increases Xa)
Catalyzes VIII into VIIIa which increases activity of IXa

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8
Q

Which factors require vitamin K for synthesis

A

VII, IX, X and II(prothrombin)

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9
Q

Antithrombin

A

Inactivates clotting factors that stray from site of vessel injury. XIIa, XIa, IXa (intrinsic) and Xa, IIa (thrombin)
Antithrombin involved with heparin

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10
Q

Physiologic removal of clots

A

Plasmin degrades fibrin meshwork of the clot.
Produced through activation of plasminogen
Fibrinolytic drugs act by promoting conversion of plasminogen into plasmin

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11
Q

Arterial thrombosis

A

Adhesion of platelets from damage to wall or rupture of plaque causes platelets to release ADP and TXA2 which attract additional platelets to the evolving thrombus. The rest of the clotting cascade is then activated

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12
Q

Venous thrombosis

A

Stagnation of blood initiates coagulation cascade resulting in fibrin which enmeshes RBCs and platelets to form a thrombus
Typical venous thombus has a long tail which can produce an embolus, which can travel through the venous system and then become lodged.
Arterial is local venous can be distant from origin

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13
Q

Overview of three main drugs

A

Anticoagulants (heparin, warfarin, dabigatran) disrupt coagulation cascade and therefore suppress fibrin
Antiplatelet drugs (aspirin, clopidogrel) inhibit platelet aggregation
Thrombolytic drugs promote lysis of fibrin

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14
Q

Antiplatelet drugs most effective against

A

Preventing arterial thrombosis

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15
Q

Anticoagulants are most effected against

A

Venous thrombosis

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16
Q

Warfarin vs other anticoagulants

A

Warfarin inhibits synthesis of clotting factors including X and thrombin
All others inhibit activity of clotting factors, either Xa, thrombin or both

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17
Q

Heparin and its derivatives

A

Enhance antithrombin, which inactivates thrombin and Xa, therefore fibrin production is reduced and clotting is suppressed.
Heparin reduces activity of thrombin and Xa equally
LMW heparins reduce activity of Xa more than thrombin
Fondaparinux is selective to Xa and doesn’t touch thrombin

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18
Q

Heparin distribution

A

Has many negatively charged groups making it highly polar, and hence cannot readily cross membranes

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19
Q

Heparin MOA

A

Helps antithrombin inactivate clotting factors IIa and Xa
Binding of heparin to antithrombin enhances its ability to inactivate thrombin and Xa
Heparin itself does not bind with Xa
Great for prophylaxis of venous thrombosis
Effects seen within a minute IV

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20
Q

Heparin pharmacokinetics

A

Polarity and large size means it can’t be taken orally and it can’t cross into placenta or breast milk
Hepatic and renal metabolism, normal half life is 1.5 hours and extended with hepatic/renal failure
Highly variable plasma levels as it binds nonselectively

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21
Q

Uses of heparin

A

Pregnancy, pulmonary embolism, DVT, open heart surg and renal dialysis and low dose for postop prevention of thrombosis. DIC and MI

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22
Q

Adverse effects of heparin

A

Bleeding (10%)

Shock, bruises, petechiae, hematomas, discoloured poo, headache or faintness (cerebral) lumbar pain (adrenal hemorrhage)

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23
Q

Heparin induced thrombocytopenia (HIT)

A

Potentially fatal. Development of antibodies against heparin-platelet complexes activate plateletes and damage vascular endothelium, promoting thrombosis and loss of platelets. DVT, PE, stroke and MI risk.
Consider if platelet count falls or thrombosis forms despite adequate anticoagulation
Discontinue and switch

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24
Q

Heparin interaction

A

Platelet aggregation is the major remaining defence against hemorrhage. Aspirin and other drugs that depress platelet function will weaken this defence.

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25
Q

Heparin OD

A

Protamine sulfate. Small molecule with positively charged groups which bond ionically with heparin forming a heparin-protamine complex devoid of anticoagulant activity.
Occurs immediately and lasts 2 hours
1mg to 100 units of heparin

26
Q

Lab monitoring for heparin

A

Activated partial thromboplastin time (aPTT)
Normal value is 40 seconds. Should increase 1.5-2 folx so 60-80 seconds on heparin.
Should be measured every 4-6 hours

27
Q

Heparin routes

A

IV or subq. IM causes hematoma

28
Q

LMW heparins

A

As effective as unfractionated.
Don’t require aPTT monitoring, can be used at home.
First line therapy for DVT
Enoxaparin (lovenox) and dalteparin (fragmin)

29
Q

LMW heparins MOA

A

Preferentially inactivate Xa, and are much less active on thrombin.
They are too short to provide a binding site for thrombin

30
Q

Pharmacokinetics of LMW heparins

A

Higher bioavailability and longer half-lives than heparin.
Up to 6x longer half life.
More specific binding means more predictable plasma levels and slower clearance

31
Q

Adverse effects of LMW heparin

A

Bleeding, but less risky than heparin.
Can also cause immune-mediated thrombocytopenia
OD can be treated with protamine sulfate as well
Cost is $63 a day compared to $8 for heparin but don’t require aPTT monitoring
1mg of protamine per mg of enoxaparin

32
Q

Warfarin, a vitamin K antagonist

A

Prevents thrombosis like heparin, but has delayed onset so not used in emergency

33
Q

Warfarin MOA

A

Decreases 4 clotting factors, VII, IX, X and prothrombin (vit k dependent clotting factors)
Warfarin inhibits Vit K epoxide reductase complex I (VKORC1) which converts K to the active form
Reduces Vit K clotting factors by 30-50%

34
Q

Pharmacokinetis of warfarin

A

99% binds to albumin
Unbound can cross membranes readily (placenta and milk)
Inactivated by CYP2C9
Acts quickly to inhibit synthesis of clotting factors, anticoag effects are delayed since those in circulation are not affected.
8-12 hours after first dose, peak effects take days.
After DC, effects last 2-5 days
Half life 1.5-2 days

35
Q

Warfarin uses

A

Prevention of PE, thromboembolism with heart valves, prevention of thrombosis with a-fib
Three other options for a-fib now
Dabigatran (pradaxa, pradax) epixaban (eliquis) and rivaroxaban (xarelto) which are easier to use

36
Q

Monitoring TX with warfarin

A

Prothrombin time (PT) which is sensitive to Vit K alterations in coagulation
Average PT is 12 seconds.
INR (international normalized ratio) is determined by multiplying PT ratio by a correction factor specific to particular thromboplastin prep used
INR of 2-3 appropriate for most pts (sometimes 2.5-3.5)
May take a week to reach desired INR after adjusting dosage

37
Q

INR timing

A

Daily for 5 days
2X a week for 1-2 weeks
Once a week for 1-2 months
1-2X a month after

38
Q

INR AND aPTT numbers

A

2-3 for INR sometimes 2.5-3.5

60-80 seconds for aPTT (partial thromboplastin time)

39
Q

Warfarin hemorrhage

A

Same signs as heparin
Apixaban, rivaroxaban, and dabigatran pose significantly lower bleeding risks
Soft toothbrush and electric razor for lowering bleeding risk
Class X for preggos

40
Q

Warfarin interactions

A

Lots, must avoid all drugs not prescribed.
Remember warfarin is 99% bound to albumin and something that unbinds could cause elevated plasma levels
Acetaminophen was used, but 2g a day increases high INR risk 10fold by preventing degradation of warfarin

41
Q

Vitamin K1, for warfarin OD

A

2.5mg PO or 0.5 to 1mg IV.

IV can cause anaphylatic like reactions, give it slow and dilute it.

42
Q

Dabigatran (pradax) vs warfarin

A 
5 advantages to pradax
Rapid onset
No need to monitor INR
Fewer interactions
Lower risk of major bleed
Predictable dose responses
43
Q

MOA dabigatran

A

Reversible inhibitor of thrombin
Binds and inhibits thrombin that is free as well as thrombin bound to clots (heparin only inhibits free thrombin)
It prevents conversion of fibrinogen to fibrin and prevents activation of XIII thereby preventing conversion of soluble fibrin to insoluble fibrin
No specific antidote to reverse bleeding. Recombinant VIIa or IX may be tried.
Dialysis can remove 60% in 2-3 hours.

44
Q

Rivaroxaban (xarelto)

A

Selective inhibition of factor Xa, inhibits production of thrombin
Rapid onset, fixed dose, lower bleed risk, less interactions, no INR monitoring

45
Q

Pharmacokinetics of rivaroxaban (xarelto)

A 
80-90% bioavailability
Peaks 2-4 hours
Undergoes partial metabolism by CYP3A4
Half life 5-9 hours
No antidoite, but can prevent further absorption with activated charcoal. 
Unsafe in pregnancy (class C)
46
Q

Apixaban

A

Selectively inhibits Xa and prothrombinase activity.

47
Q

Three major classes of antiplatelet drugs

A

Aspirin, P2Y12ADP receptor antagonists, GP IIb/IIIa receptor antagonists (strongest effects)

48
Q

Aspirin MOA

A

Irreversible inhibition of cyclooxygenase which is required to synthesize TXA2.
TXA2 can promote platelet activation, it also promotes vasoconstriction. Both o which promote hemostasis
Lasts 7-10 days.
Prostacyclin inhibition happens over 325mg and CAUSES platelet aggregation and vasoconstriction (81mg appears as effective as higher dose)

49
Q

Aspirin risks

A

GI bleeding in 2-4 per 1000 pts and hemorrhagic stroke 0-2 in 1000 pts in middle aged people taking it for 5 years

50
Q

P2Y12ADP receptor antagonists

A

Block P2Y12ADP receptors on platelet surface, preventing ADP-stimulated aggregation.
Clopidogrel, prasugrel, ticlopidine cause irreversible blockade and ticagrelor causes reversible blockade.

51
Q

Clopidogrel (plavix)

A

Oral antiplatelet similar to aspirin
Irreversible P2Y12ADP block. Effects begin 2 hours after first dose.
Inhibits platelets 40-60%
Prodrug that activates from CYP2C19
Same adverse effects aspirin
Less GI bleeding and stroke risk than aspirin

52
Q

Thrombotic thrombocytopenic purpura (TTP) in clopidogrel

A

Rare, potentially fatal
Thrombocytopenia, hemolytic anemia, neuro symptoms, renal dysfunction and fever.
Urgent tx including plasmapheresis

53
Q

Clopidogrel PPIs

A

Often given to prevent GI bleeding but they may inhibit CYP2C19 making clopidogrel (plavix) less active

54
Q

Ticagrelor (brilinta)

A

P2Y12ADP receptor antagonist. It is reversible.
Better results than clopidogrel (both were given with ASA) but higher risk of hemorrhage
Not a prodrug like plavix, metabolized by CYP3A4
Dyspnea in 13.8% of pts
Can give ventricular pauses

55
Q

Glycoprotein IIb/IIIa receptor antagonists

A

Abciximab, tirofiban, eptifibatide.
All 3 given IV with ASA and low dose hpearin, tx is $1000 or more per course
SUPER ASPIRIN

56
Q

GP IIb/IIIa receptor antagonists MOA

A

Reversible blockade of GP IIb/IIIa receptors thereby inhibiting the final step in aggregation. Prevent aggregation by all factors, TXA2, ADP, thrombin, platelet activation factor

57
Q

Thrombolytic (fibrinolytic) drugs

A

To remove thrombi which have formed.

Alteplase, reteplase, tenecteplase (VHR).

58
Q

Alteplase (tPA)

A

Tissue plasminogen activator. Identical to natural human tPA.
Binds with plasminogen to form active complex. The complex then catalyzes conversion of other plasminogen molecules into plasmin, an enzyme that digests the fibrin meshwork of clots.
It also degrades fibrinogen and other clotting factors (which don’t lyse the thrombi but do increase bleeding risk)

59
Q

Therapeutic uses tPA

A

MI, stroke, massive PE

60
Q

Pharmacokinetics tPA

A

Large molecule must be given parenterally, 5 minute half life from hepatic inactivation. 50% cleared in 5 minutes, 80% in ten

61
Q

Fixing tPA

A

Blood products usually. If not aminocaproic acid prevents activation of plasminogen and directly inhibits plasmin

62
Q

Tenecteplase (TNKase)

A

Varient of human tPA for MI.
80X more resistant than tPA to circulating inhibitors. 20-24 minute half life.
Converts plasminogen to plasmin to digest fibrin
Single bolus instead of infusion.
Same risks mostly as tPA but lower major hemorrhage (other than intracranial)

Pharmo for medic school (26 decks)

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