Drugs Used In Coagulations Disorders II: Anticoagulant Drugs Flashcards
What are the endogenous inhibitors of coagulation?
Protein C
Protein S
Antithrombin III
Tissue factors pathway inhibitor (TFPI)
What type of enzyme is Antithrombin III?
Serine protease inhibitor
What is the mechanism of action of ATIII?
It inactivated Thrombin and Xa
What is the mechanism of action of Heparin?
Heparin forms a complex with ATIII, thereby inactivating thrombin and factor Xa
Where is heparin produced?
Mast cells
What is the chemical nature of heparin?
Large polysaccharide
Water soluble
What is the clinical indication of UFH and LMWH?
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
What is the dosage of UFH in prophylactic use?
Prophylactic use: 2-3 x 5000-7500 IU or 5-7 IU/kg/h (IV infusion)
What is the dosage of UFH in acute therapy?
Starts with 5000 IU bolus — later 1000-15000 IU/h (IV infusion)
What is the dosage of LMWH in prophylactic use?
2500-5000 IU 1/day
What is the dosage of LMWH in acute treatment?
175-200 IU/Kg S.C. 1 or 2/day
What is the half life of UFH?
60-90 min half life
What is the half life of LMWH?
2-4h half life (longer in kidney insufficiency)
Does UFH and LMWH have good or bad absorption?
Bad
How are UFH and LMWH administered?
Only parenteral: IV or SC
What is the bioavailability of UFH after SC administration?
30%
What is the bioavailability of LMWH after SC administration?
90%
Do LMWH and UFH cross the placenta?
No
What anticoagulant drug should be used in pregnancy?
Why?
UFH and LMWH
Because both are large, water soluble polysaccharides that are unable to cross the placenta.
What does UFH bind to?
Binds to endothelium, macrophages, plasma proteins. These sites must be saturated 1st - this complicates elimination
What does LMWH bind to?
Limited binding to endothelium, macrophages and plasma proteins. Therefore there is a more predictable dose effect relationship and elimination.
How do we monitor UFH?
What is the control value
- aPTT
- 1.5-2.5
Does UFH or LMWH have more predictable pharmacokinetics?
LMWH
Is heparin used for rapid or long term anticoagulation?
Rapid
What is the antagonist of heparin?
What type of antagonism is this?
Protamine sulfate
Chemical antagonism (no receptor required)
In which are side effects less frequent?
LMWH
What are the severe adverse affects of UFH and LMWH?
Bleeding
HIT
Osteoporosis
Hypersensitivity
What are the rare adverse affects of UFH and LMWH use?
Hair loss Hypersensitivity Mild transaminase elevation Hypoaldosterone (at high doses) Hyperkalemia
Bleeding as a side effect of UFH or LMWH use is associated with what?
IV therapy
What is the clinical indication of Fondaparinux?
DVT
PE
Prophylaxis of VTE in orthopaedic surgery
What is the half life of Fondaparinux?
15-17h
How is Fondaparinux administered?
Parenteral (S.C)
What is the bioavailability of Fondaparinux when administered SC?
100%
What are the side effects of Fondaparinux?
Bleeding
Not HITII, thus no reversal by protamine sulphate
What is HIT type 1?
Reversible
Transient
5-10%
What is HIT type 2?
0.5-3% occurrence
Very dangerous 20-30% lethality
Ab mediated thrombocyte aggregation - paradoxically thromboembolic complications
What is the treatment of HIT type 2?
Protamine sulfate
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
What is the mechanism of action of Danaparoid?
Inactivates factor Xa by accelerating antithrombin III
What is the half life of Danaparoid?
25h
How is Danaparoid administered?
Parenteral (SC)
What is the bioavailability of Danaparoid when administered SC?
100%
What is the side effect of Danaparoid?
Bleeding (not antagonised by protamine sulphate)
What is the side effect of Hirudin?
Bleeding
What is the side effect of Bivalirudin?
Bleeding
What is the side effect of Argatroban?
Bleeding
What is the side effect of Dabigatran etexilate?
Bleeding GI discomfort (abdominal pain, esophagus is, GI bleeding)
What is the mechanism of action of Hirudin?
Direct thrombin inhibitor
How is Hirudin eliminated?
Through the kidney
What is the half life of Hirudin?
1-1.5h
How is Hirudin eliminated?
Through the kidney
How is Hirudin administered?
Parenteral use (SC)
What is the bioavailability of Hirudin when administered SC?
100%
How is Hirudin monitored?
- aPTT
- Should be 1.5-3 x higher than control
What is the mechanism of action of Bivalirudin?
Direct thrombin inhibitor
What is the clinical indication of Bivalirudin?
Used during PCR in patients having or at risk of having HIT
How is Bivalirudin administered?
IV
How is Bivalirudin monitored?
- aPTT
- Hemoglobin
- Hematocrit