Topic 13 Flashcards
1
Q
Anticoagulants: Indirect thrombin inhibitors=
A
Warfarin (Coumadin)
Unfractionated heparin
Low-MW heparin (Lovenox)
Fondaparinux (Arixtra)
2
Q
Anticoagulants: Direct thrombin inhibitors=
A
Lepirudin (Refludon)
Argatroban
Bivalirudin (Angiomax)
3
Q
Warfarin
A
(Coumadin)
4
Q
Low-MW heparin
A
(Lovenox)
5
Q
Fondaparinux
A
(Arixtra)
6
Q
Lepirudin
A
(Refludon)
7
Q
Bivalirudin
A
(Angiomax)
8
Q
Anticoagulants inhibit
A
one or more steps in the clotting cascade that lead to fibrin formation
9
Q
Anticoagulants do NOT
A
dissolve clots
10
Q
Heparin is a mix of
A
straight-chain polymers consisting of extremely anionic repeating dissacharide units.
11
Q
Heparin is one of the most acidic molecules in a critter’s body because so many
A
carboxyl and sulfate groups are attached
(and virtually all critters produce heparin, even ones lacking “traditional blood”, so it’s an ancient molecule
on the evolutionary tree.)
12
Q
Heparin lives in
A
mast and basophils
13
Q
Unfractionated heparin (the kind that’s used the most) is a mixture of molecules ranging from
A
5000-30,000 Daltons
14
Q
heparin is measured in
A
units (not by weight)
15
Q
What’s One (1) Unit of Heparin?
A
“The quantity of heparin required to keep 1 milliliter of blood fluid for 24 hours at 0°C”
This is ~~0.002 mg of heparin/unit
16
Q
Two Main Sources of Heparin
A
- Insteninal
- Lung
- Porcine intestinal -derived heparin may be better in preventing some complications (such as heparin-induced thrombocytopenia)
17
Q
Heparin is always given
A
parenterally
18
Q
“Fractionated heparin” = “Low molecular weight heparin” (LMWH): how many daltons?
A
5500
19
Q
LMWH is much more….
A
uniform, contains less “contaminants” and inactive forms of heparin
20
Q
Heparin performs a lot of poorly-described functions in critters, but isn’t really
A
an anticoagulant all by itself.
21
Q
Heparin + AT-III =
A
> 1000X more active anticoagulant activity than AT-III by itself
22
Q
Interaction of antithrombin with heparin and LMWH is mediated by a
A
pentasaccharide sequence
23
Q
Unfractionated heparin accelerates interaction of
A
antithrombin with both thrombin and factor Xa
24
Q
LMWH selectively accelerates interaction of
A
antithrombin and Factor Xa
25
IV half life: Heparin and LMWH
Heparin: 2 hours
LMWH: 4 hours
26
Anticoagulant response: Heparin and LMWH
Heparin: Variable
LMWH: Predictable
27
Bioavailability:Heparin and LMWH
Heparin: 20%
LMWH: 90%
28
Major adverse effect: Heparin and LMWH
Heparin: Frequent bleeding
LMWH: Less frequent bleeding
29
Setting for therapy:Heparin and LMWH
Heparin: Hospital
LMWH: Hospital and out patient
30
Heparin time to effect
Intravenous (IV): a few minutes
| Subcutaneous (SQ): 1-2 hours
31
Heparin is cleared by
binding to macrophages and being depolymerized and
| desulfonated in the liver...and the metabolites are excreted in the urine
32
heparin’s half-life is prolonged by either
renal &/or liver dysfunction.
33
Unfractionated heparin’s half-life is
~1-2 hours
34
Fractionated (LMWH) has a much longer half-life
3-7 hours
35
Lower doses of heparin are cleared at a
faster rate than higher doses
| implying that the process is saturable
36
Since it’s a metabolic process, heparin clearance is (naturally) slower
at lower temps and accelerated at higher temps
37
Heparin is chemically reversed with
Protamine
38
Heparin side effects
Excessive bleeding
| Heparin-Induced Thrombocytopenia (HIT) I & II
39
A synthetic LMWH (a pentasaccharide) (name the drug)
Fondaparinux
40
Fondaparinux: half life? Eliminated how?
~20 hours and eliminated unchanged in the urine
41
Fondaparinux major advantage
is the elimination of the risk of “bad” (Type II) HIT.
42
Warfarin is a widely prescribed
orally administered anticoagulant
43
Warfarin works by inhibiting
Vitamin K
44
Other names for vitamin K
(phytonadione / Mephyton)
45
Warfarin blocks an enzyme called
Vitamin K epoxide reductase
46
Vitamin K epoxide reductase is required to allow the
liver to “recycle” spent (oxidized) Vitamin K so eventually stores of Vitamin K are simply depleted.
47
Warfarin is NOT a Vitamin K
antagonist
(it doesn’t have antagonist kinetics)
...so giving the critter Vitamin K readily reverses the effects of warfarin.
48
Liver requires Vitamin K to produce what factors
```
II: Prothrombin
VII: Proconvertin
IX: Plasm Thromboplastin Component
X: Stuart-Power Factor
2 7 9 10
```
49
Warfarin Blocks the γ-carboxylation sites of factors II, VII, IX, & X as well as
Proteins C and S
| --Consequently, the liver produces incomplete, biologically inactive molecules instead of functioning clotting factors
50
Proteins C and S are also anticoagulants via their
| ability to block factors
Va and VIIIa
51
Takes a while for Warfarin to exert its clinical
| effect (____ hours) since those Vitamin K stores have to be depleted
8-24 hours
52
Warfarin peak effects occur
~2-4 days (once those stores are completely empty).
53
Warfarin’s half-life and duration of action are insanely variable because
1. it’s highly protein-bound
| 2. Drugs, genetics, foods, spices (!), etc. all effect how long it lasts
54
Warfarins normal half life is
~ 40 hours
55
Warfarin Side Effects
Bleeding
Birth/fetal deformities &/or death.
Warfarin necrosis
56
Warfarin dose
5-7mg/day with adjustments made after ∽ one week
57
Warfarin typically monitored via the ______. Normal time? Normal value?
prothrombin time (PT)
Typically this is 12-13 seconds
“normal” PTs is 12.5 seconds
58
PT measures the activity of which factors
VII, X, V, II, I (7, 10, 5, 2, 1)
59
What is added to the critter’s plasma before an optical measurement is made of the subsequent clot formation
```
Tissue Factor (Factor III)
Calcium (Factor IV)
```
60
INR stands for
“International Normalized Ratio”
61
INR= [formula]
Critters PT / Labs normal PT mean
62
Direct Thrombin Inhibitors All bind directly to
thrombin
63
Direct Thrombin Inhibitors Vary in their
affinities for thrombin, half-lives, and how they are cleared from the body.
64
What Irreversibly binds to and deactivates thrombin, Contains many contaminants and is hard to produce
Hirudin
65
What is a synthetic, purified form of hirudin that Bivalently and irreversibly binds to thrombin
Lepirudin (Refludan)
66
Lepirudin
(Refludan)
67
Unlike heparin, lepirudin is not
dependent on interactions with AT III for its function
68
One molecule of lepirudin binds to
one molecule of thrombin
69
how is Lepirudin given
parenterally
70
Lepirudin is Cleared by the
kidneys
71
Lepirudin half life
1 hour, but can increase to several days in renal insufficiency/failure patients!
72
what drug is Very antigenic
Lepirudin
73
~50% of patients who receive Refludan courses of therapy develop
antibodies to the lepirudin-thrombin complex
74
the lepirudin-thrombin complex prevent Lepirudin’s
clearance by the kidneys and increases its anticoagulant effect &/or can cause an anaphylactic reaction.
75
Critters on Lepirudin must there have BOTH their ___ and ___ monitored.
aPTTs and renal functions
76
Lepirudin is used as a therapy for HIT and/or as an
alternative anticoagulant (in place of heparin)in patients with HIT
77
Lepirudin: Unlike heparin, NO ...
REVERSAL AGENT EXISTS!!!
78
What is a completely synthetic yet chemically smaller
| “cousin” of hirudin
Bivalirudin (Angiomax)
79
Bivalirudin
(Angiomax)
80
Bivalirudin Like hirudin, it’s also a
- bivalent direct thrombin inhibitor
- operates independent of AT III
- Is given parenterally
81
Bivalirudin Less renal clearance (___%) than lepirudin (the remainder being metabolized)
~20%
82
```
Bivalirudin half life
Normal?
Mod. renal dysfunction?
Severe renal dysfunction?
Dialysis patient?
```
Normal= 20-25 minutes
Mod. renal dysfunction= 35 minutes
Severe renal dysfunction= 1 hour
Dialysis patient= 3.5 hours
83
Bivalirudin Can be removed by
hemoconcentrators
84
Bivalirudin: Very commonly used during
- -PTCAs to prevent platelet activation
| - -anticoagulation for patients with HIT
85
Bivalirudin Monitoring:
* Ideally , anticoagulation (as on bypass) is measured with the ______.
* Practically monitored with _____.
```
Ideally= “ecarin clotting time” (ECT)
Practically= ACT’s
```
86
what is a parenterally-administered small molecule direct thrombin inhibitor.
Argatroban
87
Argatroban half life
~40-50 minutes
88
Argatroban: Clinical use similar to Angiomax but monitored with
aPTTs
89
Argatroban is eliminated by
hepatic clearance
90
Angiomax vs. Argatroban
| •Essentially, the choice is made by whether the patient has
intact renal or hepatic function
| ...and ease of monitoring the anticoagulation
91
Oral Anticoagulants: drug names
```
Dabigatran etexilate (Pradaxa)
Apixiban (Eliquis)
Rivaroxaban (Xarelto)
```
92
Dabigatran etexilate
(Pradaxa)
93
Apixiban
(Eliquis)
94
Rivaroxaban
(Xarelto)
95
Dabigatran etexilate (Pradaxa) =
An oral anticoagulant cleared by the kidneys that also acts as a direct thrombin inhibitor
96
what drug is a possible future replacement for oral warfarin (don’t need to test INRs, fewer drug interactions, less variable half-life)
Dabigatran etexilate (Pradaxa)
97
Dabigatran etexilate (Pradaxa) is currently used for
A-Fib
98
Apixiban (Eliquis) and Rivaroxaban (Xarelto) are both...
oral anticoagulants that directly inhibit Factor Xa
| –Both are cleared renally and used for a-fib
