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CVB by Minnie (Madeleine) > SM 124a - Pharmacology of Anticoagulants > Flashcards

SM 124a - Pharmacology of Anticoagulants Flashcards

Some anti-platelet info from SM 121a

1
Q

What is the goal INR for Warfarin therapy?

A

2-3

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2
Q

How is dabigatran reversed?

A

Idarucizumab (a monoclonal antibody to the drug)

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3
Q

Why is warfarin monitoring difficult in patients who are taking direct thrombin inhibitors concurrently?

A

Direct thrombin inhibitors prolong PT time

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4
Q

Which anti-platelet agent inhibits cyclooxygenase 1?

Why does this work?

A

Aspirin (irreversible)

NSAIDS (reversible)

Inhibiting cyclooxygenase 1 inhibits the production of thromboxane A2, which normally plays a role in platelet activation and aggregation

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5
Q

Describe the structure of low molecular weight heparin (LMWH)

A
  • Glycosaminoglycan
  • <20 saccharides
    • Thrombin has a hard time binding because few molecules have a 5-saccharide binding site with at least 12 saccharides for a tail
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6
Q

What are the clinical indications for heparin prescription?

A

Cardiovascular intervention

  • Surgery
  • Cardiac assist devices
  • Acute arterial or venous thrombosis
  • ECMO
  • Dialysis
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7
Q

How is LMWH reversed?

A

Protamine sulfate

(But reversal is less effective for LMWH than heparin)

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8
Q

What are the advantages of fondaparinux?

What are the disadvantages?

A
  • Advantages
    • Well absorbed
    • Long 1/2 life
    • No monitoring required
    • Minimal platelet interactions
  • Disadvantages
    • Unsafe in pregnancy
    • Cannot use in renal failure
    • Expensive
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9
Q

What factors affect a person’s response to Warfarin?

A
  • Genetic polymorphism
    • VKORC1 mutation = resistance to warfarin
    • CYP2C9 mutation = inhibited clearance
  • Dietary vitamin K levels
    • Low vitamin K = very sensitive to warfarin
  • Liver disease
  • Some drugs affect clearance
    • Erythromycin, fluconazol, anti-inflammatory agents, H2 blockers
  • Antibiotics and other medications
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10
Q

List some relevant thienopyridines

Which would you give to somebody with a CYP2C19 mutation?

A
  • Clopidogrel
  • Prasugrel
  • Ticagrelor

Give Prasugrel or Ticagrelor to patients with CYP2C19 mutations; Clopidogrel is a pro drug that must be converted to its active form by CYP2C19

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11
Q

How is heparin-induced thrombocytopenia (HIT) reversed?

A
  • Stop drug administration
  • Give agratroban

Then, use fondaparinux or DOACs instead of heparin

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12
Q

What is the significance of gamma carboxyglutamic acid in the clotting cascade?

What inhibits gamma carboxylation of clotting factors?

A

The conversion of glutamic acid to gamma carboxyglutamic acid is necessary for clotting factors to bind to the phospholipid membrane

Reduced vitamin K is a cofactor in this reaction

Warfarin inhibits epoxide reductase, the enzyme that the reduces vitamin K. Without reduced vitamin K, gamma carboxylation cannot proceed

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13
Q

How does antithrombin affect the function of unfractionated heparin?

A

Antithrombin binds to heparin’s 5-saccharide binding site, which initiates a change in antithrombin

  • Increases antithrombin’s ability to inhibit thrombin, FXa, and other clotting facotrs
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14
Q

What are some possible adverse responses to warfarin?

A
  • Birth defects
    • Warfarin is teratogenic
  • Warfarin necrosis/gangrene
    • In patients with low Protein C or S due to…
      • Vitamin K deficiency
      • Inherited
      • Heparin-induced
    • Causes massive skin and subcutaneous fat necrosis if proteins C or S are <10%
    • Induces widespread thrombosis of post-capillary venules in skin and muscle
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15
Q

What clotting factors does LMWH inhibit?

A

Thrombin (weakly) and FXa in a 1:3 ratio

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16
Q

Describe the structure of unfractionated heparin

A
  • Negatively charged glycosaminoglycan
  • Polymeric chains containing 30-50 heavily sulfated saccharide units
    • Alternating iduronic acid and glucosamine
  • 1/3 of chains have a 5-saccharide biding site for antithrombin
    • At least 12 saccharides must be adjacent to the 5-saccharide binding site for antithrombin to bind
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17
Q

Which anticoagulant is most commonly prescribed for long-term use?

A

Warfarin

(DOACs are better, but expensive)

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18
Q

What is the mechanism of action of NSAIDs in preventing thrombosis?

A

NSAIDs reversibley inhibit cyclooxygenase 1

*Note: Possible drug interactions with aspirin, which also inhibits cyclooxygenase 1 (and cyclooxygenase 2 if levels are too high)

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19
Q

Which anti-platelet agent acts by inhibiting adenosine uptake, acting on PLA2, and increaseing platelet cAMP?

A

Dipyridamole (persantidine)

Inhibits platelet function, promotes quiescence

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20
Q

What are the clinical indications for DOAC prescription?

A
  • Prevent thromboembolism in atrial fibrillation patients
    • Except betrixaban
  • Thromboprophylaxis
    • Medical and surgical patients
    • DVT
    • PE
    • VTE
  • Treatment of acute venous thrombosis
  • Prevent major CV events in at risk patients
    • Especially rivaroxaban combined w/ aspirin

Note: not indicated for patients with prosthetic heart valves

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21
Q

What is the mechanism of action of Aspirin in preventing thrombosis?

A

Aspirin inhibits the production of thromboxane A2, which plays a role in clot formation

  • Acetylates cyclooxygenase 1 (aka prostaglandin H-synthase 1) to irreversibly inhibit it

Note: doses that are too high will also inhibit cyclooxygenase 2 (aka prostaglandin H-synthase 2); this inhibits the production of prostacyclin c, which has a role in quescence

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22
Q

What is INR?

What is it used for?

A

INR = International Normalized Ratio
= (Patient’s PT)/(control PT)

It is used to standardize PT across labs that use different protocols for measuring PT

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23
Q

What are the vitamin-K dependent hemostatic factors?

What do they have in common?

A
  • FVII, FIX, FX, FII (Prothrombin)
  • Proteins C, S, Z

All must be gamma carboxylated at their glutamic acid residues in order to function

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24
Q

How are the FXa inhibitors (Rivaroxaban, Apixaban, Edoxaban, Betrixaban) reversed?

A

Andexanet (modified FXa) binds and inhibits the drug

It also inhibits TFPI and stimulates FXa

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25
Q

Which anticoagulant is most commonly given to prevent thrombosis in prosthetic devices?

A

Heparin (IV)

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26
Q

What are the clinical indications for Bivalirudin?

A

Treatment of coronary artery angioplsasty

Thromboprophylaxis in coronary interventions

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27
Q

Which DOAC is processed mostly by the liver?

A

Betrixaban (85% liver - think B for Bile)

Apixaban (75% Bile)

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28
Q

What are the possible adverse effects of DOACs?

A
  • Bleeding
    • ​Potentiated by dual inhibitors of P-glycoprotein and CYP3A4
  • Birth Defects
    • The DOACs are teratogenic
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29
Q

Which anticoagulant is most commonly used for thromboprophylaxis in patinets who are hospitalized for medical and surgical procedures?

A

LMWHs

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30
Q

How is fondaparinux reversed?

A

Reversal with protamine sulfate is not effective

Bleeding can be stopped with 4-factor prothrombin complex concentrate

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31
Q

What are the clinical indications for fondaparinux prescription?

A
  • Prophylaxis for acute venous thromboembolism
  • Not effective for prevention of thrombosis in prosthetic devices
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32
Q

What is the mechanism of action of Argatroban?

A

Argatroban is an IV-administered direct thrombin inhibitor

It binds to thrombin’s active site, preventing the conversion of fibrinogen to fibrin

33
Q

Which indirect anticoagulants can be reversed with protamine sulfate?

A

Unfractionated heparin

LMWH

34
Q

What will happen if cyclooxygenase 2 is inhibited?

What agent would do this?

A

If cyclooxygenase 2 is inhibited, the production of prostacyclin C is inhibited

Prostacyclin C normally maintains quiescence, so inhibiting its production would promote clot formation

Too much aspirin will inhibit cyclooxygenase 2, in addition to cyclooxygenase 1 (its target)

35
Q

What is heparin-induced thrombocytopenia (HIT)

A

The negatively charged drug forms a complex with positively charged platelet factor-4

  • Induces the formation of antibodies that agglutinate platelets
    • Sequesters platelets, resulting in thrombocytopenia (low platelets in circulating blood)
    • Also triggers thrombosis, due to platelet activation by the antibodies

Note: Risk is lower with LMWH

36
Q

What is the mechanism of action of Apixaban?

A

Apixaban is a direct inhibitor of FXa

It does not require antithrombin

(DOAC)

37
Q

Are the effects of aspirin reversible or irreversible?

How does this affect treatment?

A

Aspirin irreversibly inhibits cyclooxygenase 1 via acetylation

This means that platelet function is inhibited for its lifetime. Function will return to normal 7-10 days after treatment has stopped, as enough new platelets appear

38
Q

What is the mechanism of action of Rivaroxaban?

A

Rivaroxaban is a direct inhibitor of FXa

It does not require antithrombin

(DOAC)

39
Q

What is the mechanism of action of Edoxaban?

A

Edoxaban is a direct inhibitor of FXa

It does not require antithrombin

(DOAC)

40
Q

Why might diarrhea increase INR in patients who are taking warfarin?

A

Diarrhea decreases the absorption of vitamin K, thus making the patient more sensitive to warfarin

41
Q

What clotting factors does fondaparinux inhibit?

A

FXa only

(Not thrombin)

42
Q

Which DOAC is processed mostly by the kidney?

A

Dabigatran (80% kidney)

Rivaroxaban (66% kidney)

43
Q

List the direct thrombin inhibitors

A
  • Dabigatran (DOAC)
  • Bivalirudin (IV)
  • Argatroban (IV)
44
Q

How is warfarin reversed?

A
  • Stop warfarin
  • Give plasma vitamin K
  • If pt is bleeding, give clotting factors with IV 4-factor prothrombin complex concentrate
    • Pt will be refractory to warfarin for several days
45
Q

What is the consequence of a dose of aspirin that is too high?

A

Normally, aspirin inhibits cyclooxygenase 1 to inhibit the production of thromboxane A2 (which normally activates new platelets and promotes aggregation)

Too much aspirin will also inhibit cyclooxygenase 2, inhibiting the production of prostacyclin C, which normally plays a role in maintaining quiescence

46
Q

What is warfarin necrosis/gangrene?

How is it treated?

A

Warfarin necrosis/gangrene is a possible adverse effect of warfarin that…

  • Occurs in patients with low Protein C or S due to…
    • Vitamin K deficiency
    • Inherited
    • Heparin-induced
  • Causes massive skin and subcutaneous fat necrosis if proteins C or S are <10%
  • Induces widespread thrombosis of post-capillary venules in skin and muscle
  • Treatment
    • ​Stop warfarin
    • Give plasma vitamin K
    • If pt is bleeding, give clotting factors with IV 4-factor prothrombin complex concentrate
47
Q

What are the advantages of warfarin?

What are the disadvantages?

A
  • Advantages
    • Good GI absorption
    • Long 1/2 life
    • Inexpensive reversal agent (Vitamin K)
  • Disadvantages
    • Slow onset of action (3-5 days)
    • Must be monitored by PT
    • Has a narrow therapeutic index
48
Q

What are the clinical indications for Warfarin prescription?

A

Warfarin prevents thromboembolism in patients with…

  • Atrial fibrillation
  • Prosthetic heart valves
  • Anti-phospholipid antibody syndrome
    • Warfarin is an anticoagulant used in lupus pts
  • Recurrent VTE
49
Q

What is the mechanism of action of Bivalirudin?

A

Bivalirudin is an IV-administered direct thrombin inhibitor that binds thrombin’s catalytic site and exosite

This prevents the binding of fibrinogen and its conversion to fibrin

50
Q

What are the clinical indications for LMWH prescription?

A

Better than heparin for prevention and treatment of acute venous thromboembolism (acute VTE)

  • ​DVT
  • PE
51
Q

Why are DOACs replacing warfarin?

A
  • Monitoring is not required
  • Dietary restrictions are not required
  • They can be administered orally

(However, they are expensive - this makes long-term use difficult)

52
Q

What is the mechanism of Abciximab in preventing thrombus formation?

A

Abciximab (Reopro) is a humanized murine monoclonal Fab antibody that binds and inhibits Gp IIb/IIIa

This prevents Gp IIb/IIIa from binding fibrinogen, thus preventing platelet aggregation and plug formation

53
Q

What is the mechanism of action of Dabigatran?

A

Dabigatran is a DOAC that is a small molecule inhibitor of thrombin

It binds to thrombin’s active site; fibrinogen cannot be converted to fibrin

54
Q

Which direct thrombin inhibitor requires monitoring?

A

Argatroban

55
Q

Describe the structure of fondaparinux

A
  • Synthetic 5-saccharide antithrombin binding site only
    • Can only inhibit FXa (not thrombin)
56
Q

Why isn’t Warfarin used alone to treate acute venous thrombosis?

A

Warfarin is a slow-onset anticoagulant

If venous thrombosis is acute, rapid anticoagulation is required

57
Q

What is the mechanism of action of warfarin?

A

Warfarin inhibits the reduction of vitamin K epoxide (by inhibiting expoxide reductase)

  • Normally, reduced vitamin K epoxide acts as a cofactor for gamma carboxylation of FVII, FIX, FX, prothrombin, and proteins C, S, and Z.
  • The conversion of glutamic acid to gamma carboxyglutamic acide is necessary for clotting factors to bind to the phospholipid membrane
58
Q

What is the mechanism of action of Betrixaban?

A

Betrixaban is a direct inhibitor of FXa

It does not require antithrombin

(DOAC)

59
Q

Which anti-platelet agent is a humanized murine monoclonal Fab antibody that binds and inhibits Gp IIb/IIIa?

A

Abciximab (Reopro)

Eptifibatide

Tirofiban

60
Q

Which DOACs are direct inhibitors of FXa?

A

Rivaroxaban

Apixaban

Edoxaban

Betrixaban

61
Q

What is the mechanism of action of Thienopyridines in preventing thrombosis?

A

Thienopyridines irreversibly block the P2Y12 ADP receptor

This inhibits platelet aggregation

62
Q

Which class of anti-platelet agents block the P2Y12 ADP receptor?

A

Thienopyridines (like clopidogrel, prasugrel, ticagrelor)

63
Q

Why does warfarin have a slow onset of action?

A
  • Warfarin inhibits coagulation factors FVII, FIX, FX, and FII, by inhibiting the production of reduced vitamin K
    • Reduced vitamin K is necessary to gamma-carboxylate these clotting factors
  • After warfarin is administered…
    • The functional gamma-carboxylated FIX and FX take 3-5 days to leave the blood
      • When they leave, clotting is inhibited
    • The functional, gamma-carboxylated FVII leaves the blood quickly, inhibiting the extrinisc pathway
      • But this does not inhibit coagulation; the alternative (FXII) pathway can still activate the intrinsic pathway
64
Q

What are the clinical indications for argatroban?

A

Treatment of heparin-induced thrombocytopenia

65
Q

What is the mechanism of action of unfractionated heparin?

A

Unfractionated heparin binds to antithrombin, increasing the effects of antithrombin

(It acts as a scaffold that holds antithrombin and thrombin close together)

66
Q

Which drug family does clopidogrel come from?

What is the mechanism of action?

A

Thienopyridines

Irreversibly inhibit the P2Y12 ADP receptor to inhibit platelet aggregation

67
Q

Which DOAC is a small molecule inhibitor of thrombin?

A

Dibagatran

68
Q

What clotting factors does unfractionated heparin inhibit?

A

Thrombin and FXa in a 1:1 ratio

Other clotting factors too (IXa, Xa, XIIa, VIIa, Tissue factor complex)

69
Q

What is the bioavailability of LMWH?

How does this compare to unfractionated heparin?

A

LMWH has 90% bioavailability

Unfractionated heparin has lower and more variable bioavailability; it needs to be monitored, while LMWH usually does not

70
Q

How is unfractionated heparin reversed?

A

Protamine sulfate

71
Q

What kinds of patients are most likely to receive Abciximab to prevent thrombosis?

A

Patients with cardiovascular catheter interventions

72
Q

Which DOAC has the best bioavailability?

A

Rivaroxaban (60-80%, increased with food intake)

Apixaban (80%)

73
Q

What is the mechanism of action of Dipyridamole in preventing thrombosis?

A

Dipyridamole (persantidine)…

  • Inhibits adenosine uptake
  • Act on PLA2
  • This increases platelet cAMP (promotes quiescence)

To inhibit platelet function

74
Q

Why have LMWHs replaced unfractionated heparin for the treatment of venous thrombosis?

A

They do not require IV infusion or laboratory monitoring

They are less likely to cause heparin-induced thrombocytopenia and osteoporosis

75
Q

Which anticoagulants are safe to use in patients with renal failure?

A

Warfarin

Argatroban (but this is used against HIT, not typically as a first-line anticoagulant)

76
Q

Which genetic polymorphisms affect warfarin response?

A
  • VKORC1 mutation = resistance to warfarin
  • CYP2C9 mutation = inhibited clearance
77
Q

List some examples of LMWH drugs

A

-parins

Dalteparin

Enoxaparin

Nadroparin

Parnaparin

Reviparin

Tinzaparin

78
Q

What kind of drugs end in -parin?

A

Low molecular weight heparins (LMWHs)

These are anticoagulants that inhibit Factor Xa

CVB by Minnie (Madeleine) (43 decks)

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