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Pharmacology > Pharm 13-Direct/Indirect Thrombin Inhibitors > Flashcards

Pharm 13-Direct/Indirect Thrombin Inhibitors Flashcards

1
Q

How are anticoagulants classified?

A

Direct or indirect thrombin inhibitors

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2
Q

What drugs are indirect thrombin inhibitors? (Anticoagulants)

A

Warfarin (Coumadin)
Unfractionated Heparin/LMWH (Lovenox)
Fondaparinux (Arixtra)

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3
Q

What drugs are direct thrombin inhibitors? (Anticoagulants)

A

Lepirudin (Refludon)
Argatroban (No brand name)
Bivalirudin (Angiomax)

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4
Q

How do anticoagulants work?

A

Inhibit one or more steps in the clotting cascade that lead to fibrin formation; they do not dissolve clots

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5
Q

What is the single most important drug you will use as a perfusionist?

A

Heparin

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6
Q

What is heparin made out of?

A

Mix of straight-chain polymers consisting of extremely anionic repeating dissacharide units

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7
Q

Why is heparin so acidic?

A

So many carboxyl and sulfate groups attached

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8
Q

Which critters produce heparin?

A

virtually all critters, even ones lacking traditional blood so its an ancient molecule on the evolutionary tree

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9
Q

What are circulating mast cells?

A

basophils

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10
Q

Where does heparin “live”?

A

Mast cells

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11
Q

What do mast cells produce?

A

Histamine

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12
Q

What is the kind of heparin that is used the most?

A

Unfractionated heparin

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13
Q

How big is unfractionated heparin?

A

5000-30,000 Daltons

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14
Q

How many daltons is water?

A

Daltons

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15
Q

What is a Dalton?

A

a unit used in expressing the molecular weight of proteins, equivalent to atomic mass unit.

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16
Q

What is heparin measured in?

A

Units

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17
Q

What is 1 unit of heparin?

A

The quantity of heparin required to keep 1 mL of cat’s blood fluid for 24 hours at 0 degrees C

0.002 mg of heparin/ unit

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18
Q

What are the two main sources of heparin?

A
  1. Porcine intestinal-derived heparin

2. Bovine lung

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19
Q

Which source of heparin may be better in preventing some complications (such as HIT)?

A

Porcine intestinal-derived heparin

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20
Q

How is heparin administered?

A

Parenterally

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21
Q

Unfractionated heparin

A

High molecular weight heparin (HMWH)

5,000- 30,000 Daltons

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22
Q

Fractionated heparin

A

Low molecular weight heparin (LMWH)

5500 Daltons

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23
Q

Which type of heparin is much more uniform, contains less contaminants and inactive forms of heparin?

A

Fractionated heparin

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24
Q

What does heparin do?

A

Isn’t an anticoagulant by itself

Acts on AT-III

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25
Q

Heparin + ATIII is how many more x active than ATIII by itself?

A

> 1000x

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26
Q

IV Half Life: Heparin vs. LMWH

A

Heparin: 2 hours
LMWH: 4 hours

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27
Q

Anticoagulant Response: Heparin vs LMWH

A

Heparin: Variable
LMWH: Predictable

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28
Q

Bioavailability: Heparin vs LMWH

A

Heparin 20 %

LMWH: 90%

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29
Q

Major adverse effect: Heparin vs. LMWH

A

Heparin: Frequent bleeding
LMWH: Less frequent bleeding

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30
Q

Setting for therapy: Heparin vs LMWH

A

Heparin: Hospital
LMWH: Hospital and outpatient

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31
Q

Heparin Time to Effect: IV vs SQ

A

IV: a few minutes
SQ: 1-2 hours

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32
Q

How is heparin cleared?

A

Binding to macrophages and being depolymerized and desulfonated in the liver

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33
Q

How are heparin metabolites excreted?

A

Urine

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34
Q

What happens to heparin’s half-life with renal and/or liver dysfunction?

A

Half-life is prolonged

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35
Q

What is unfractionated heparin’s half-life?

A

1-2 hours

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36
Q

What is fractionated heparin’s half-life?

A

3-7 hours

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37
Q

How do different doses of heparin change clearance rate?

A

Lower doses of heparin are cleared at a faster rate than higher doses; implying the process is saturable

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38
Q

How does temperature affect heparin’s metabolic process?

A

Heparin clearance is naturally slow at lower temps and accelerated at higher temps (metabolic process)

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39
Q

How is heparin chemically reversed?

A

Protamine

40
Q

What are some major side effects of heparin?

A

Excessive bleeding

HIT I and II

41
Q

What is an example of a synthetic LMWH (a pentasaccharide?

A

Fondaparinux (Arixtra)

42
Q

What is the half-life of Fondaparinux (Arixtra)?

A

20 hours

43
Q

How is Fondaparinux (Arixtra) eliminated?

A

Unchanged in the urine

44
Q

What is the major advantage of Fondaparinux (Arixtra)?

A

Elimination of the risk of bad (Type II) HIT

45
Q

Who is warfarin (coumadin) sponsored by?

A

Wisconsin Alumni Research Foundation

46
Q

How does Warfarin (Coumadin) work?

A

Inhibiting Vitamin K (phytonadione/Mephyton)

Blocks an enzyme (Vitamin K epoxide reductase)

47
Q

What are the Vitamin K meds

A

Phytonadione/Mephyton

48
Q

What is Vitamin K epoxide reductase required for?

A

Allow the liver to recycle spent (oxidized) Vitamin K so eventually stores of Vitamin K are simply depleted

49
Q

What readily reverses the effects of Warfarin (Coumadin)?

A

Vitamin K

50
Q

The liver requires vitamin K to produce what factors?

A

II: Prothrombin
VII: Proconvertin
IX: Plasma Thromboplastin Component
X: Stuart-Prower Factor

51
Q

Warfarin (Coumadin) blocks carboxylation sites of what factors and proteins?

A

Factors II, VII, IX, X

Proteins C and S

52
Q

Why are Proteins C and S anticoagulants?

A

Ability to block factors Va and VIIIa

53
Q

Administering Warfarin (Coumadin) causes the liver to produce what?

A

Incomplete, biologically inactive molecules instead of functioning clotting factors

54
Q

How long does it take for Warfarin (Coumadin) to exert its clinical effect? Why?

A

8-24 hours; since those Vitamin K stores have to be depleted

55
Q

When is the peak effect of Warfarin (Coumadin)

A

2-4 days (once those stores are completely empty)

56
Q

What effects how long warfarin (coumadin) lasts?

A

Drugs, genetics, foods, spices

57
Q

What is warfarin (coumadin)’s half life and duration of action?

A

Insanely variable; normally 40 hours

58
Q

Warfarm (Coumadin) side effects

A

Bleeding
Birth/fetal deformities
Death
necrosis

59
Q

What is the warfarin (coumadin) loading dose?

A

Humans >/= 10mg; but this greatly incresaes the risk of side effects

60
Q

What is the typical dose of warfarin (coumadin)?

A

5-7 mg/day with adjustments made after one week

61
Q

How is warfarin (coumadin) typically monitored?

A

Prothrombin Time (PT)

62
Q

PT measures the activity of which factors?

A

X/V?

63
Q

Why do PTs vary from lab to lab?

A

Reagent variability

64
Q

What is added to the critter’s plasma in order to perform a PT test?

A 
Tissue Factor (Factor III)
Calcium (Factor IV)
65
Q

How long is a normal PT time?

A

12-13 seconds; time required for a clot to form to a standardized level

66
Q

If a lab determines the “normal” PT time to be 12.5 seconds, what will it set its normal PT range to?

A

80-120% of that (10-15 seconds)

67
Q

What is INR?

A

International Normalizing Ratio; it’s a way for controlling variability

68
Q

How do you calculate INR?

A

Critter’s PT/ lab “normal” PT mean

69
Q

How do direct thrombin inhibitors work?

A

All bind directly to thrombin; vary in their affinities for thrombin, half-lives and how they are cleared from the body

70
Q

Hirudin

A

First iteration of “leech spit”

Irreversibly binds to and deactivates thrombin; contains many contaminants and hard to produce

71
Q

What is Lepirudin (Refludan) and how does it work?

A

Synthetic purified form of hirudin
Bivalently and irreversibly binds to thrombin
No dependent on interactions with ATIII for its function

72
Q

One molecule of Lepirudin (Refludan) binds with how many molecules of thrombin?

A

One

73
Q

How is Lepirudin (Refludan) administered?

A

Parenterally

74
Q

How is Lepirudin (Refludan) cleared?

A

Kidneys

75
Q

What is the half-life of Lepirudin (Refludan)

A

1 hour; but can increase to several days in renal insufficiency/failure patients

76
Q

What percent of patients who receive Lepirudin (Refludan) get antibodies to the lepirudin-thrombin complex?

A

Very antigenic, 50%

77
Q

What do Lepirudin-Thrombin Complex antibodies do?

A

Prevent Lepirudin’s clearance by the kidneys and increase its anticoagulant effect and or can cause an anaphylactic reaction

78
Q

Those on Lepirudin (Refludan) must have what monitored?

A

aPTTs

Renal Functions

79
Q

What is Lepirudin (Refludan) used as a therapy for?

A

HIT or as an alternative anticoagulant (in place of heparin) in patients with HIT

80
Q

What is the reversal agent for Lepirudin (Refludan)?

A

None exists; make sure the surgeon understands this

81
Q

What is Bivalirudin (angiomax)?

A

Completely synthetic yet chemically smaller cousin of hirudin
Bivalent direct thrombin inhibitor; operates independently of ATIII and is given parenterally
Expensve

82
Q

Bivalirudin (Angiomax) Clearance

A

Less renal clearance (20%) tahn lepirudin (Refludan); the remainder being metabolized

83
Q

What is the half life of Bivalirudin (Angiomax)?

A

Short 20-25 minutes that is somewhat affected by renal Fx:
Mod renal dysfunction: 35 minutes
Severe dysfunction: 1 hour
Dialysis patient: 3.5 hours

84
Q

How can bivalirudin (Angiomax) be removed?

A

Hemoconcentrators

85
Q

When is Bivalirudin (Angiomax) commonly used?

A

PTCA to prevent platelet activation

Anticoagulation for patients with HIT

86
Q

How is Bivalirudin (Angiomax) monitored?

A

Anticoagulation is measured with Ecarin Clotting Time (ECT); practically monitored with ACTs

87
Q

What is Argatroban and how is it administered?

A

parenterally-administered small molecule direct thrombin inhibitor

88
Q

What is the half-life of argatroban?

A

40-50 minutes

89
Q

How is argatroban monitored?

A

aPTTs

90
Q

How is argatroban cleared?

A

Eliminated by hepatic clearance

91
Q

How do decide between Bivalirudin (Angiomax) and Argatroban?

A

Choice is made by whether the patient has intact renal or hepatic function and ease of monitoring anticoagulation

92
Q

What are some oral anticoagulants?

A 
Dabigatran etexilate (Pradaxa)
Apixiban (Eliquis)
Rivaroxaban (Xarelto)
93
Q

What is Dabigatran etexilate (Pradaxa) and how is it cleared?

A

Oral anticoagulant
Cleared by kidneys
direct thrombin inhibitor

94
Q

What is a possible future replacement for oral warfarin (coumadin)? Why?

A

Dabigatran etexilate (Pradaxa); dont need to test INRs fewer drug interactions, less variable half life

95
Q

What is Dabigatran etexilate (pradaxa) currently used for the tx of ?

A

A-fib

96
Q

What do Apixiban (Eliquis) and Rivaroxaban (Xarelto) inhibit? How are they cleared? What do they treat?

A

Factor Xa; cleared renally, used for a-fib

Pharmacology (23 decks)

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