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33 Cards in this Set

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  • Back
Describe the mechanism of action of heparin.
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.
How does heparin affect the following coagulation players:

1) IIa
2) Xa

1) inhibits IIa
2) inhibits Xa
3) enhances TFPI
Compare the following in terms of structure

1) Unfractionated Heparin (UFH)

2) Low MW Heparin (LMWH)

3) Fondaparinux
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

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

This is the true statement:

Heparin arrests thromboiss and prevent embolizaton, especially on the **venous** side of circulation
Describe the administration and elimination for the following:

1) Unfractionated Heparin (UFH)

2) Low MW Heparin (LMWH)

3) Fondaparinux
) 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
Why do LMWH and fondaparinux have a more predictable anti-coagulant response compared to UFH?
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
Describe the pathogenesis of heparin-induced thrombocytopenia (HIT).

What drugs can be given to a patient if HIT develops?
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.
What are the indications for the use of protamine?

How does protamine work?
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.
What is the most commonly used LMWH?

What are the indications for its use?
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.
What is the most common test used to assess UFH effect?

What test is used to measure warfarin effect?
Assess UFH: activated partial thromboplastin time (aPTT)

Assess warfarin: prothrombin time (PT)

Heparin acts in vivo and in vitro, while warfarin acts only in vivo.
Name 2 examples of oral anticoagulants.
1) bishydroxycoumarin
2) warfarin
Describe the importance of vitamin K in the coagulation cascade.

What is warfarin's mechanism of action?
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.
Describe the signifcance of S-warfarin compared to R-warfarin.
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.
Describe the administration and elimination of warfarin.
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.
Why is warfarin challenging to use in clinical practice?
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
Describe warfarin toxicity.
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
What drugs are likely to potentiate the effects of warfarin?

What drugs are likely to inhibit the effects of warfarin?
Likely to potentiate warfarin: fluconazole, amiodarone, omeprazole

Likely to inhibit warfarin: cholestyramine, barbiturates, foods with high vitamin K content
How would you treat a heparin overdose?

How would you treat a warfarin overdose?
Treat heparin OD: withdrawal UFH and give protamine

Treat warfarin OD: give prothrombin complexes and vitamin K

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

Both heparin and warfarin are used for prophylaxis but they do NOT alter preformed clots.
In general, what is the recommended INR range for oral anticoagulant therapy?

In what clinical scenario would a higher range be recommended?
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.
Outline a typical scenario for DVT treatment.
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.
List 4 examples of fibrinolytic agents.
1) streptokinase
2) alteplase
3) reteplase
4) tenecteplase
Which fibrinolytic agent is approved for use in acute ischemic stroke?
Alteplase (tPA) is approved for use in acute ischemic stroke.

Give tPA after excluding intracranial hemorrhage and within 4h of syptom onset.
What is the therapeutic use of fibrinolytics?

How are they administered?
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.
Describe the mechanism of action of aminocaproic acid.

What is a major contraindication of aminocaproic acid?
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.
List the 3 major antiplatelet agents.
1) Aspirin (COX inhibitor)
2) Clopidogrel (ADP pathway inhibitor)
3) Abciximab, eptifibatide (GPIIb/IIIa antag)
Describe the different effects of low dose and high dose aspirin.
Low dose aspirin: inhibits thromboxane A2 formation, thereby inhibiting platelet aggregation.

High dose aspirin: inhibits prostacyclin, thereby blocking prostacyclin's anti-aggregation effect
What is the mechanism of action of clopidogrel?

What are the indications for clopidogrel use?
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.
Describe the importance of pharmacogenetics in the use of clopidogrel .
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.
What is the mechanism of action of abciximab and eptifibatide?

What are the indications for their use?
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.
Describe the mechanism of action of bivalirudin.

What are the indications for its use?
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.
Describe the mechanism of action of dipyridamole.

What are the indications for its use?
Dipyridamole inhibits phosphodiesterase and blocks adenosine uptake.

It is used as stroke prevention.