Anticoagulants And Other Drugs Used In Thromboembolic Disorders

Front 1

Describe the mechanism of action of heparin.

Back 1

Heparin -- with antithrombin -- inhibits proteolytic activity of many coagulation cascade proteolytic enzymes. The inhibition of IIa and Xa is most important.

Heparin binds to antithrombin, causes a conformational change and accelerates antithrombin interaction with Xa.

Heparin also enhances TFPI activity.

Front 2

How does heparin affect the following coagulation players:

1) IIa
2) Xa
3) TFPI

Back 2

Heparin...

1) inhibits IIa
2) inhibits Xa
3) enhances TFPI

Front 3

Compare the following in terms of structure

1) Unfractionated Heparin (UFH)

2) Low MW Heparin (LMWH)

3) Fondaparinux

Back 3

1) UFH: avg MW = 15 kDa; 1/3 of molecule has necessary pentasaccharide sequence for activity

2) LMWH: avg MW = 5kDa; 20% of moleculae has necessary pentasaccharide sequence for activity

3) Fondaparinux: is a synthetic pentasaccharide binding sequence

Front 4

TRUE OR FALSE

Heparin arrests thromboiss and prevent embolizaton, especially on the arterial side of circulation.

Back 4

FALSE

This is the true statement:

Heparin arrests thromboiss and prevent embolizaton, especially on the **venous** side of circulation

Front 5

Describe the administration and elimination for the following:

1) Unfractionated Heparin (UFH)

2) Low MW Heparin (LMWH)

3) Fondaparinux

Back 5

) Unfractionated Heparin (UFH): IV, SubQ // rapid and saturable clearance by endothelial cells and macrophages; once saturated, cleared slowly by kidneys

2) Low MW Heparin (LMWH): SubQ // excreted by kidneys

3) Fondaparinux: SubQ // excreted by kidneys

Front 6

Why do LMWH and fondaparinux have a more predictable anti-coagulant response compared to UFH?

Back 6

LMWH and fondaparinux have a more predictable anti-coag response because they

1) have better bioavailability vs. UFH
2) have longer half-lives vs. UFH
3) have dose-INdependent clearance

Front 7

Describe the pathogenesis of heparin-induced thrombocytopenia (HIT).

What drugs can be given to a patient if HIT develops?

Back 7

HIT is caused by IgG antibodies directed against (UFH + platelet factor 4) complexes. These complexes form on platelet surfaces.

HIT is diagnoses when the platelet count falls by 50% or more. HIT is signficant because it is associated with thromboembolic disorders that can produce severe morbidity and mortality - like DVT, DIC, PE, and MI.

Fondaparinux, lepirudin, and argatroban can be given to patients with HIT.

Neither LMWH or warfarin are substituted for UFH in HIT.

Front 8

What are the indications for the use of protamine?

How does protamine work?

Back 8

Protamine is the antidote for UFH overdose.

Protamine is a chemical antagonist and combines with UFH to form a stable salt.

Protamine can neutralize anti-IIa activity of LMWH and cannot reverse fondaparinux.

Front 9

What is the most commonly used LMWH?

What are the indications for its use?

Back 9

The most commonly used LMWH is enoxaparin.

It is used as prophylaxis in moderate-risk patients. It can also treat venous thromboembolism or unstable angina.

Front 10

What is the most common test used to assess UFH effect?

What test is used to measure warfarin effect?

Back 10

Assess UFH: activated partial thromboplastin time (aPTT)

Assess warfarin: prothrombin time (PT)

Front 11

TRUE or FALSE

Heparin acts in vivo and in vitro, while warfarin acts only in vivo.

Back 11

TRUE

Front 12

Name 2 examples of oral anticoagulants.

Back 12

1) bishydroxycoumarin
2) warfarin

Front 13

Describe the importance of vitamin K in the coagulation cascade.

What is warfarin's mechanism of action?

Back 13

Pre-state II, VII, IX, and X have glutamic acid, which needs to be carboxylated by vitamin K-dependent enzyme. In this reaction, vit K becomes oxidized and is rendered inactive.

Oxidized vit K is then reduced back to its active form by vit K oxide reductase enzyme so that it can continue to modify precursor coagulant factors.

Warfarin blocks the enzymatic reduction of vitamin K. Without reduced vitamin K, precursor factors cannot be modified.

Front 14

Describe the signifcance of S-warfarin compared to R-warfarin.

Back 14

S-warfarin is 5x more potent compared to R-warfarin. This is especially important when you consider that S-warfarin is metabolized by different CYPs than R-warfarin.

S-warfarin is metabolized by CYP2C9 system, wherease R-warfarin is metabolized by CYP1A2 system. Thus, a slow CYP1A2 metabolizer is of less clinical significance than a CYP2C9 slow metabolizer.

Front 15

Describe the administration and elimination of warfarin.

Back 15

Warfarin is given orally. It is well absorbed and 99% is bound to albumin.

Warfarin is eliminated via first order kinetics by stereoselective P450 metabolism.

CYP2C9 metabolizes S-warfarin, while CYP1A2 metabolizes R-warfarin.

Front 16

Why is warfarin challenging to use in clinical practice?

Back 16

Warfarin is a challenge because..

1) narrow therapeutic window
2) dose response variability due to genetics
3) drug interactions
4) lab standardization
5) metabolism and genetic differences make maintenance of therapeutic levels difficult

Front 17

Describe warfarin toxicity.

Back 17

Warfarin toxic effects:

1) bleeding: often GI bleeding

2) recurrent skin necrosis: can occur if warfarin given too quickly or if patients Protein C levels are too low

Front 18

What drugs are likely to potentiate the effects of warfarin?

What drugs are likely to inhibit the effects of warfarin?

Back 18

Likely to potentiate warfarin: fluconazole, amiodarone, omeprazole

Likely to inhibit warfarin: cholestyramine, barbiturates, foods with high vitamin K content

Front 19

How would you treat a heparin overdose?

How would you treat a warfarin overdose?

Back 19

Treat heparin OD: withdrawal UFH and give protamine

Treat warfarin OD: give prothrombin complexes and vitamin K

Front 20

TRUE or FALSE

While heparin and warfarin are used prophylactically, they can also be used to alter pre-formed clots.

Back 20

FALSE

Both heparin and warfarin are used for prophylaxis but they do NOT alter preformed clots.

Front 21

In general, what is the recommended INR range for oral anticoagulant therapy?

In what clinical scenario would a higher range be recommended?

Back 21

For prophylaxis, PE treatment, venous thrombosis treatment, the recommended INR range is 2-3.


For pts with mechanical prosthetic heart valves, recommended INR range is 2.5-3.5.

Front 22

Outline a typical scenario for DVT treatment.

Back 22

You must confirm the patient has a DVT.
Give the patient heparins (because they work quickly) and warfarin.
Do not discontinue heparin until INR indicates that warfarin is effective.

Front 23

List 4 examples of fibrinolytic agents.

Back 23

1) streptokinase
2) alteplase
3) reteplase
4) tenecteplase

Front 24

Which fibrinolytic agent is approved for use in acute ischemic stroke?

Back 24

Alteplase (tPA) is approved for use in acute ischemic stroke.

Give tPA after excluding intracranial hemorrhage and within 4h of syptom onset.

Front 25

What is the therapeutic use of fibrinolytics?

How are they administered?

Back 25

Fibrinolytics are used to treat acute MI's when angioplasty is not an available option.

They are given IV and preferrably shortly after thrombus formation since recently formed thrombi are easier to lyse.

Front 26

Describe the mechanism of action of aminocaproic acid.

What is a major contraindication of aminocaproic acid?

Back 26

Aminocaproic acid binds to plasminogen and blocks the binding of plasminogen to fibrin. Thus, plasminogen cannot become plasmin.

It is contraindicated in patients with DIC.

Front 27

List the 3 major antiplatelet agents.

Back 27

1) Aspirin (COX inhibitor)
2) Clopidogrel (ADP pathway inhibitor)
3) Abciximab, eptifibatide (GPIIb/IIIa antag)

Front 28

Describe the different effects of low dose and high dose aspirin.

Back 28

Low dose aspirin: inhibits thromboxane A2 formation, thereby inhibiting platelet aggregation.

High dose aspirin: inhibits prostacyclin, thereby blocking prostacyclin's anti-aggregation effect

Front 29

What is the mechanism of action of clopidogrel?

What are the indications for clopidogrel use?

Back 29

Clopidogrel is a ADP pathway inhbitor.

Clopidogrel blocks platelet ADP receptor so that ADP cannot bind, which indirectly inhibits binding of fibrinogen to GIIb/IIIa.

Clopidogrel is used with aspirin as prophylaxis before angioplasty. It is also used in acute coronary syndrome, and as stroke prevention in pts with TIA's.

Front 30

Describe the importance of pharmacogenetics in the use of clopidogrel .

Back 30

Clopidogrel is a prodrug and must be oxidized by CYP enzymes to its active form. If a patient has a polymorphism that intereferes with this conversion, clopidogrel will be ineffective.

Front 31

What is the mechanism of action of abciximab and eptifibatide?

What are the indications for their use?

Back 31

Abciximab and eptifibatide are GIIb/IIIa antag's.

THey prevent platelet aggregation by binding to GIIb/IIIa receptor. This binding prevents fibrinogen, vWF (and other adhesive proteins) from binding to GIIb/IIIa.

Without adhesive proteins binding to GIIb/IIIa, platelet aggregation does not occur.

GIIb/IIIa antag's are used as adjuncts in pts with IHD who are about to undergo angioplasty.

Front 32

Describe the mechanism of action of bivalirudin.

What are the indications for its use?

Back 32

Bivaliruin is a direct, reversible thrombin inhibitor.

It inactivates platelet bound Xa and clot bound heparin.

It is used instead of heparin in pts with unstable angina undergoing PCI.

Front 33

Describe the mechanism of action of dipyridamole.

What are the indications for its use?

Back 33

Dipyridamole inhibits phosphodiesterase and blocks adenosine uptake.

It is used as stroke prevention.