Drugs Used In Coagulations Disorders II: Anticoagulant Drugs Flashcards
1
Q
What are the endogenous inhibitors of coagulation?
A
Protein C
Protein S
Antithrombin III
Tissue factors pathway inhibitor (TFPI)
2
Q
What type of enzyme is Antithrombin III?
A
Serine protease inhibitor
3
Q
What is the mechanism of action of ATIII?
A
It inactivated Thrombin and Xa
4
Q
What is the mechanism of action of Heparin?
A
Heparin forms a complex with ATIII, thereby inactivating thrombin and factor Xa
5
Q
Where is heparin produced?
A
Mast cells
6
Q
What is the chemical nature of heparin?
A
Large polysaccharide
Water soluble
7
Q
What is the clinical indication of UFH and LMWH?
A
The prevention of fibrin formation
- Acute thromboembolism (DVT, PE and arterial emboli)
- Prophylaxis of post-op VT and recurrent TE
- ACS (MI, unstable angina)
- Anticoagulant therapy during pregnancy
8
Q
What is the dosage of UFH in prophylactic use?
A
Prophylactic use: 2-3 x 5000-7500 IU or 5-7 IU/kg/h (IV infusion)
9
Q
What is the dosage of UFH in acute therapy?
A
Starts with 5000 IU bolus — later 1000-15000 IU/h (IV infusion)
10
Q
What is the dosage of LMWH in prophylactic use?
A
2500-5000 IU 1/day
11
Q
What is the dosage of LMWH in acute treatment?
A
175-200 IU/Kg S.C. 1 or 2/day
12
Q
What is the half life of UFH?
A
60-90 min half life
13
Q
What is the half life of LMWH?
A
2-4h half life (longer in kidney insufficiency)
14
Q
Does UFH and LMWH have good or bad absorption?
A
Bad
15
Q
How are UFH and LMWH administered?
A
Only parenteral: IV or SC
16
Q
What is the bioavailability of UFH after SC administration?
A
30%
17
Q
What is the bioavailability of LMWH after SC administration?
A
90%
18
Q
Do LMWH and UFH cross the placenta?
A
No
19
Q
What anticoagulant drug should be used in pregnancy?
Why?
A
UFH and LMWH
Because both are large, water soluble polysaccharides that are unable to cross the placenta.
20
Q
What does UFH bind to?
A
Binds to endothelium, macrophages, plasma proteins. These sites must be saturated 1st - this complicates elimination
21
Q
What does LMWH bind to?
A
Limited binding to endothelium, macrophages and plasma proteins. Therefore there is a more predictable dose effect relationship and elimination.
22
Q
How do we monitor UFH?
What is the control value
A
- aPTT
- 1.5-2.5
23
Q
Does UFH or LMWH have more predictable pharmacokinetics?
A
LMWH
24
Q
Is heparin used for rapid or long term anticoagulation?
A
Rapid
25
What is the antagonist of heparin?
What type of antagonism is this?
Protamine sulfate
Chemical antagonism (no receptor required)
26
In which are side effects less frequent?
LMWH
27
What are the severe adverse affects of UFH and LMWH?
Bleeding
HIT
Osteoporosis
Hypersensitivity
28
What are the rare adverse affects of UFH and LMWH use?
```
Hair loss
Hypersensitivity
Mild transaminase elevation
Hypoaldosterone (at high doses)
Hyperkalemia
```
29
Bleeding as a side effect of UFH or LMWH use is associated with what?
IV therapy
30
What is the clinical indication of Fondaparinux?
DVT
PE
Prophylaxis of VTE in orthopaedic surgery
31
What is the half life of Fondaparinux?
15-17h
32
How is Fondaparinux administered?
Parenteral (S.C)
33
What is the bioavailability of Fondaparinux when administered SC?
100%
34
What are the side effects of Fondaparinux?
Bleeding
| Not HITII, thus no reversal by protamine sulphate
35
What is HIT type 1?
Reversible
Transient
5-10%
36
What is HIT type 2?
0.5-3% occurrence
Very dangerous 20-30% lethality
Ab mediated thrombocyte aggregation - paradoxically thromboembolic complications
37
What is the treatment of HIT type 2?
Protamine sulfate
38
What is the mechanism of action of Fondaparinux?
It is an analogue of the heparin binding site on antithrombin III
Selective inhibition of factors Xa by binding and potentiating antithrombin III
- higher specificity than LMWH
39
What is the mechanism of action of Danaparoid?
Inactivates factor Xa by accelerating antithrombin III
40
What is the half life of Danaparoid?
25h
41
How is Danaparoid administered?
Parenteral (SC)
42
What is the bioavailability of Danaparoid when administered SC?
100%
43
What is the side effect of Danaparoid?
Bleeding (not antagonised by protamine sulphate)
44
What is the side effect of Hirudin?
Bleeding
45
What is the side effect of Bivalirudin?
Bleeding
46
What is the side effect of Argatroban?
Bleeding
47
What is the side effect of Dabigatran etexilate?
```
Bleeding
GI discomfort (abdominal pain, esophagus is, GI bleeding)
```
48
What is the mechanism of action of Hirudin?
Direct thrombin inhibitor
49
How is Hirudin eliminated?
Through the kidney
50
What is the half life of Hirudin?
1-1.5h
51
How is Hirudin eliminated?
Through the kidney
52
How is Hirudin administered?
Parenteral use (SC)
53
What is the bioavailability of Hirudin when administered SC?
100%
54
How is Hirudin monitored?
- aPTT
| - Should be 1.5-3 x higher than control
55
What is the mechanism of action of Bivalirudin?
Direct thrombin inhibitor
56
What is the clinical indication of Bivalirudin?
Used during PCR in patients having or at risk of having HIT
57
How is Bivalirudin administered?
IV
58
How is Bivalirudin monitored?
- aPTT
- Hemoglobin
- Hematocrit
59
How is Bivalirudin eliminated?
Elimination is mostly independent from the kidney
60
What is the onset and duration of action of Bivalirudin?
Faster onset and shorter duration of action than Hirudin
61
What is the mechanism of action of Argatroban?
Direct thrombin inhibitor
62
What is the clinical indication of Argatroban?
HIT type II
Prophylaxis of treatment of VTE in patients with HIT
Used during PCI in patients having or at risk of having HIT
63
What is the half life of Argatroban?
Short half life
64
What is the administration of Argatroban?
IV
65
How is Argatroban eliminated?
Elimination is independent from the kidney (influenced by liver disease)
66
What is the mechanism of action of Dabigatran etexilate?
Direct thrombin inhibitor
| Direct oral anticoagulant prodrug
67
What are the clinical indications of Dabigatran etexilate?
Prophylaxis of stroke and systemic embolism in patients with non-valvular atrial fibrillation
68
How is Dabigatran etexilate administered?
Oral
| 1-2 x day
69
What is the antidote for Dabigatran etexilate?
Idarucizumab (Ab)
70
How is Dabigatran etexilate activated?
After absorption, conversion to dabigatran and activation
71
What is the mechanism of action of Rivaroxaban and Apixaban?
Direct Xa inhibitors
| Direct oral anticoagulant (DOA)
72
What is the antidote for Rivaroxaban and Apixaban?
Idarucizumab
73
How are Rivaroxaban and Apixaban administered?
Oral 2x/day
74
What is the clinical use of Rivaroxaban and Apixaban?
Prophylaxis and treatment of DVT and PE in patients having knee or hip replacement surgery
Prophylaxis of systemic embolism with non-valvular A fib
75
Name the Coumarin drugs
Acenocoumarol
Warfarin
Phenprocoumon
76
What is the half life of warfarin?
25-60h
77
What is the half life of Acenocoumarol?
9-24h
78
What is the half life of Phenprocoumon?
130-160h
79
What are the clinical indications of coumarin like drugs?
Continuation of heparin therapy
| Prophylaxis for TE (in long term treatment: A-fib and DVT)
80
What is the dose of Warfarin?
2-10mg
81
What is the dose of Acenocoumarol?
1-12mg
82
What is the dose of Phenprocoumon?
0.75-6mg
83
What is the mechanism of action of Coumarin type drugs?
They block vitamin K epoxide reductase resulting in functionally inactive clotting factors II, VII, IX, X protein S and Protein C.
Synthesis of these clotting factors requires a gamma carboxylation on glutamate residues necessary for Calcium binding and thus binding to phospholipids.
Gamma carboxylation is coupled with oxidation of reduced vitamin K to epoxide form
84
How are the Coumarin type of drugs administered?
Orally
85
What is the cause of Coumarin sensitivity?
Genetic polymorphism of the Coumarin metabolising enzyme CYP2C9 resulting in its decreased activity
86
What is the coumarin metabolising enzyme?
CYP2C9
87
How are the Coumarin type drugs eliminated?
Through the urine and bile
88
Where are the Coumarin type drugs metabolised?
Liver (glucuronidation)
89
What is the absorption of coumarin type drugs?
Good absorption - almost 100%
90
What is the antidote for Coumarin type drugs?
Rapid antidote - fresh frozen plasma (as it contains the active coagulant factors)
Delayed antidote - antagonised effect by vitamin K1 administration
91
What is the normal INR?
0.8-1.2
92
How is Coumarin monitored?
INR
| and PT
93
What is the therapeutic INR goal in Coumarin use?
1.5-3
94
What is the INR goal in prophylactic use of coumarin?
1-2
95
When are Coumarin type drugs contraindicated?
Pregnancy
Nursing women
Active bleeding
Increased risk of dangerous bleeding
96
Is there a possibility to develop a resistance to coumarin?
Yes
97
Why is it possible to develop a resistance to coumarin?
Due to a mutation of Vit K epoxide reducatase
98
When is there a strong risk of bleeding in Coumarin administration?
If the INR >4
99
What are the side effects of Coumarin?
Bleeding (minor: 10-20%, major: 5%, lethal: 1%)
Teratogenic malformations, death of Fetus
Necrosis of subcutaneous tissue and skin (rare)
100
What is the cause of the necrosis of subcutaneous tissue and skin in coumarin use?
Protein C is also Vit K dependent. Protein C is an endogenous anti-coagulant and has a short half life (the shortest after factor 7) - therefore there is a prominent inhibition of protein C in the 1st week which results in a hypercoaguable state the increased risk of TE.
101
What are the rare side effects of coumarin administration?
Allergic reactions
GI symptoms
Alone is
Purple toe syndrome
102
What does vitamin K concentration in the blood depend on?
Diet and intestinal bacterial flora
103
At absorbtion, what are Coumarin type drugs inhibited by?
Antacids
| Cholestyramine
104
What CYP450 enzyme inhibitors?
```
Phenylbutazone
Sulfinpyrazone
Metronidazole
Fluconazole
Sulphonamides
Amiodarone
Disulfiram
Citemidine
```
105
What are CYP450 enzyme inducers?
```
Barbiturates
Rifampin
Carbamazepine
Phenytoin
Griesofulvin
```
106
What will warfarin administration do to the INR?
Increased INR
107
What will the use of CYP450 inhibitors do to the INR when warfarin is also administered?
INR increased
108
What will CYP450 inducers do to the INR if administered with warfarin?
INR will decreases
109
What is the mechanism of thrombin?
It converts soluble fibrinogen to insoluble fibrin (clot)
110
Why does HIT result in a hyper coagulable state?
Because the damaged platelets result factors that activate thrombin
111
What is the pathomechanism of HIT?
Abs are generated against heparin and platelet factor 4
112
What is the mechanism of Xa?
It converts prothrombin to thrombin
113
When should LMWH be avoided?
In renal insufficiency. LMWH is eliminated in the kidney so renal insufficiency can lead to high plasma levels of LMWH that are hard to monitor.
114
What does aPTT measure?
The common and intrinsic pathway
115
When is heparin administered IV?
In acute cases:
DVT
PE
MI
116
When is Heparin administered SC?
```
In prophylactic cases:
Pregnancy
Surgery
Malignancy
Immobilisation
History of oral contraceptive use
```
117
Why is hyperkalemia a side effect of UFH use?
UFH can lead to hypoaldosteremia leading to hyperkalemia
118
What is the antidote of UFH?
Protamine sulfate (+)
119
What is the mechanism of action of LMWH?
Forms a complex with ATIII and inactivates Xa
120
What drugs is protamine sulphate less effective against?
LMWH
121
Does LMWH have a short or prolonged half life compared to UFH?
Prolonged
122
Does LMWH require continuous and strict monitoring?
Not as much as UFH
123
How is UFH eliminated?
The liver
124
Is heparin safe in pregnancy?
Yes
125
Which anti-coagulant infers the lowest risk of HIT?
Fondaparinux
126
What are the indirect anticoagulants?
UFH
LMWH
Fondaparinux
127
What are the direct thrombin inhibitors?
- Bivalirudin
- Argatroban
- Dabigatran
128
What are the direct factor Xa inhibitors?
Rivaroxaban
| Apixaban
129
How are Rivaroxaban and Apixaban administered?
Orally
130
Is there need to monitor Rivaroxaban and Apixaban?
Not so much
131
What are the Vitamin K dependent coagulation factors?
Factor 2, 7 9 and 10
| Protein S and Protein C
132
What does warfarin block?
Vit K epoxide reductase
133
Which coagulation factor has the shortest half life? What is that half life
Factor VII
6 hours
134
What is the serum half life of warfarin?
36-42 hours
135
What does PT measure?
The function of the extrinsic pathway
136
What is the extrinsic pathway dependent on?
Factor VII
137
What is the clinical indication of warfarin?
- A fib
| - Tx and prophylaxis of DVT and PE.
138
Why does warfarin have a delayed onset of action?
Because it works at the level of transcription. So you have to wait for circulating activated factors to be eliminated before it works.
139
Can warfarin be used in pregnancy?
NO
140
When is warfarin induced tissue necrosis most likely?
In Protein C deficiency
141
How can you reverse warfarin anticoagulation?
Vit K - but the response is delayed
142
What enzyme metabolises warfarin?
CYP450
143
Which anti-coagulant drugs are part of an inactivation complex?
Heparin
LMWH
Danaparoid
Fondaparinux
144
What anti-coagulants are direct thrombin inhibitors?
Hirudin
Bivalirudin
Argatroban
Dabigatran
145
What are the direct factor Xa inhibitors?
Rivaroxaban
Apixaban
Endoxaban
Betrixaban
