ANTITHROMBOTIC AGENTS Flashcards
What activates the intrinsic and extrinsic pathways of coagulation
The extrinsic pathway is initiated by damage to a blood vessel which releases tissue factor
while the intrinsic pathway is initiated by binding of Factor XII to a negatively-charged foreign surface on the blood vessel. The extrinsic
pathway is more important for coagulation
4 general steps in Thrombogenesis
● platelets adhere to site of blood vessel damage
● platelets aggregate
● formation of hemostatic plug
● fibrin strands strengthen plug and form stable clot
How are the extrinsic and intrinsic pathways analyzed
The extrinsic plus common pathway is analyzed using the prothrombintime (PT) while the intrinsic plus common pathway is analyzed using the activated partial thromboplastin time (aPTT).
What are the two mechanisms of regulation of the coagulation cascade
(1) inhibition of fibrin formation via protease inhibitors (e.g., antithrombin III) ➡blocks 3a, 4a, 5a and 2a
(2) fibrinolysis via plasmin
HEPARIN - MOA
a heterogeneous mixture of sulfated mucopolysaccharides with molecular weights ranging from 5,000 to 30,000.
● binds to antithrombin III (ATIII), which accelerates inhibition of clotting factorsby ATIII, also has some direct inhibitory activity on activated Factor X
Heparin- toxicity
major adverse effect is bleeding, which is more common in elderly females and patients with impaired renal function
● thrombocytopenia (~3-5% of patients)
● long-term treatment can lead to osteoporosis and spontaneous fractures
Heparin- administration
- either IV or SC
● must monitor efficacy using activated partial thromboplastin time (aPTT) to maintain anticoagulant activity within a safe range
● can be reversed by stopping treatment and infusion with protamine sulfate,which combines with heparin.
Heparin - use
prevention or treatment of deep vein thrombosis
● Acute MI: used in conjunction with thrombolysis or PCI
● anticoagulation in pregnant women
Low molecular weight heparin -vs heparin and why is it preferred
(Enoxaparin, Dalteparin)
● fewer bleeding side effects than standard heparin
- has a weaker activity on ATIII than heparin, but still inhibit Factor Xa activity
LMW heparins are generally preferred over heparin due to the fact that it is more convenient, eliminates need for aPTT monitoring, and reduces the risk of infection associated with IV injection. Although more expensive than heparin perdose, studies suggest that use of LMW heparins are more cost-effective when
outcomes are included in the analysis.
FACTOR X INHIBITORS- which drugs and what are they used for
Fondaparinux is a synthetic pentasaccharide that is an indirect inhibitor of Factor Xa without a direct effect on thrombin. It is delivered subcutaneously. It is licensed for preventing deep venous thrombosis and acute pulmonary embolism.
Apixaban and rivaroxaban are small-molecule orally-active inhibitors of Factor Xa.
Rivaroxaban is approved for prophylaxis against venous thromboembolism associated with knee and hip replacement surgery
apixaban is approved for non-valvular atrial fibrillation.
DIRECT THROMBIN INHIBITORS (3)
- Hirudin, the protein in leech saliva responsible for keeping blood flowing during feeding has potent antiacoagulant properties.
- Desirudin is a derivative of hirudinused in the prevention of post-operative development of venous thromboembolism, and some studies have demonstrated its superiority to low MW heparins. It is delivered subcutaneously.
- Bivalirudin, is a synthetic peptide analog of hirudin delivered IV, and is used as an anticoagulant during percutaneous coronary interventions.
Oral thrombin inhibitors
Dabigatran-etexilate is a prodrug which is metabolizedto the active form (dabigatran) in a P450-independent fashion. Its efficacy is equivalent to warfarin, and there may be a reduced risk of bleeding compared to warfarin. It has great potential to replace warfarin as the oral anticoagulant of choice. Additional compounds are under development.
Used for prevention of stroke in patients with atrial fibrillation
WARFARIN AND COUMARIN ANTICOAGULANTS - MOA, time to be effective
analogs of Vitamin K
● block γ-carboxylation of glutamate residues in a number of members of the coagulation cascade by interfering with the conversion of Vitamin K to its active form. Results in proteins that are inactive in the coagulation cascade.
● 8-12 hour delay in the onset of effects, and 1-3 day delay in the appearance of peak effects
Treatment with warfarin
- threatment should start with a small daily dose to obtain optimal adjustment of prothrombin time
- effects can be reversed by stopping administration and treating with Vitamin K and/or Factor IX concentrates (Proplex, Konyne 80)
Uses and drug interactions
Indications
- atrial fibrillation
- prosthetic heart valves
Note: warfarin is teratogenic, so its use is contraindicated in women who are
pregnant or contemplating pregnancy. If an anticoagulant is needed, LMW
heparin should be used
Warfarin: Drug Interactions
● a number of agents affect the activity of oral anticoagulants
● particular attention must be paid to those agents that increase the anticoagulant effects of oral anticoagulants
● effects can be via pharmacokinetic mechanisms (i.e., altering metabolism ofthe anticoagulant) or pharmcodynamic mechanisms (i.e., altering activity)
