Anticoagulants Flashcards
TxA2
a platelet activator & vasoconstrictor synthesized from arachidonic acid
ADP
induces platelet aggregation; makes platelets sticky
5HT
stimulates platelet aggregation and vasoconstriction
What are the granules released from platelets?
- TxA2
- ADP
- 5HT
- PAF
- thrombin
How does increase in intracell. Ca induce platelet aggregation?
Increase in intracellular Ca -> granule release -> TxA2 synthesis & activation of GPIIb/IIIa receptors -> expressed on surface of platelets which bind to circulating fibrinogen in blood -> further platelet aggregation
GPIIb/IIIa receptors
- activated by intracell. Ca and reduced cAMP
- expressed on surface of platelets to activate other platelets
- activated GPIIb/IIIa receptors bind to circulating fibrinogen in blood to cause further platelet aggregation
What are the 3 categories that regulate platelet function?
- Agents generated outside the platelet that interact with platelet membrane receptors
- Agents generated within the platelet that interact with membrane receptors
- Agents generated within the platelet that act within the platelet
Agents generated outside the platelet that interact with platelet membrane receptors
- catecholamines
- collagen
- thrombin
- prostacyclin
Agents generated within the platelet that interact with membrane receptors
- ADP
- prostaglandin D2
- prostaglandin E2
- serotonin
Agents generated within the platelet that act within the platelet
- prostaglandin endoperoxidases
- thromboxane A2
- cyclic nusleotides cAMP and cGMP
- calcium ion
What are the 5 mechanisms of action of antiplatelets?
- Inhibition of PG (TxA2 precursor) synthesis
- Inhibition of ADP-induced platelet aggregation
- Protease activated receptor -1 inhibitor
- Blockade of glycoprotein IIb/IIIa receptors
- Phosphodiesterase inhibitors / vasodilators
ASA
irreversible acetylation of the COX1 enzyme
Inhibition of ADP-induced platelet aggregation
Irreversibly block ADP receptors -> decreased intracellular Ca and increased intracellular cAMP
Glanzmann’s thrombasthenia
when pts do not have the glycoprotein IIb/IIIa receptors complex and cannot aggregate
Clopidogrel
- Inhibition of ADP-induced platelet aggregation
- thrombotic thrombocytopenic purpura
Cangrelor
- Kengreal
- Inhibition of ADP-induced platelet aggregation
- acts on allosteric site (doesn’t compete with ADP for binding) -> reversible in its action
Vorapaxar
- Zontivity
- Protease activated receptor -1 inhibitor
- Inhibits thrombin receptor on platelets
- leads to decreased Ca and increased cAMP -> reduced platelet activation and aggregation
Abciximab
- Reopro
- inhibit GP IIb/IIIa complex -> decreased platelet aggregation
- Can bind to fibrinogen receptor or the vitronectin receptor
Dipyridamole
- Persantine
- Phosphodiesterase inhibitors / vasodilators
- decreases Ca -> decreased muscle contraction | also inhibits phosphodiesterase enzyme (PDE) -> increased cAMP -> decrease TxA2 synthesis -> decreased platelet aggregation
- Not very useful alone -> Given in combination with aspirin to prevent cerebrovascular ischemia
mechanisms of action for anticoagulants
- Indirect thrombin inhibitors
- Direct thrombin inhibitors
- Direct inhibitors of Factor Xa
- Vitamin K antagonists
Indirect thrombin inhibitors
- UFH
- LMWH
UFH
- works with antithrombin to prevent activation of coagulation factors; helps AT work much faster
- Is allergenic, impure (only 1/3 have potential activity), binds to a lot of proteins which pts can develop resistance and unpredictable PK
- Can develop Heparin-induced thrombocytopenia and thrombosis (HITT) in which they become hyper-coagulable; body develops antibodies that attacks the body’s platelets and makes the body more prone to having clots (mainly veins)
- Heparin is acidic and negative; if overdose, administer protamine which is basic and positive charge but excess protamine can cause anticoagulation
LMWH
- made from unfractionated heparin by various methods of depolymerization: works with thrombin in the activation of factor X to Xa
- Enoxaparin, Dalteparin, Tinzaparin
Direct thrombin inhibitors
- Desirudin
- Bivalirudin
- Dabigatran etexilate mesylate
Desirudin
- Iprivask
- irreversible thrombin inhibitor
- Binds to catalytic sites of thrombin as well as the substrate recognition site
- Excreted by kidney; careful with renal patients
- Pts can develop antibody against the complex that forms when this drug binds to thrombin -> anaphylaxis
Bivalirudin
- Angiomax
- Reversible bivalent inhibitor of free & clot-bound thrombin
- Inhibits platelet activation
- Bivalirudin ↑ protein C activity vs Lepirudin ↓activity
Dabigatran etexilate mesylate
- Pradaxa
- Prodrug
- Bioavailability: 6-7%
- Prodrug requires acidic environment for absorption (do not take PPI while on this drug)
Direct inhibitors of Factor Xa
- Fondaparinux
- Rivoraxaban
- Apixaban
- Edoxaban
Fondaparinux
- Arixtra
- allows Xa to bind to AT by binding to Xa
- More predictable PK -> less monitoring
- Does not cross react with pathologic HIT antibodies
Rivoraxaban
- Xarelto
- Drug-Drug interactions: Interactions with CYP3A4 and for P-glycoprotein
- No antidote for overdose
Apixaban
- Eliquis
- Drug-Drug interactions: Interactions with CYP3A4 and for P-glycoprotein
- No antidote for overdose
Warfarin
- Coumadin
- Can cross placental barrier; could cause hemorrhage in fetus and/or abortion; teratogenic, birth defects; contraindicated in pregnancy; give LMWH instead
SNPs’ impact on warfarin
- Genetic polymorphisms (SNPs) in VKOR complex subunit (VKORC1) higher risk of bleeding due to reduced Vitamin K dependent coagulation factors.
- Because of this SNP, there is 30% patient variability
Differentiate between the mechanisms of unfractionated heparin and low molecular weight heparins
- Unfractionated heparin: works on both AT and thrombin
- Low molecular weight heparins: only works on thrombin
tPA
- Alteplase, Reteplase, Tenecteplase
- prefer plasminogen bound to fibrin -> fibrinolysis will only occur in the formed thrombus and avoids activation in the systemic flow
- converts plasminogen to plasmin; plasmin works on fibrin to break down the clot
hemostatic agents
- Aminocaproic acid
- tranexamic acid
- Protamine sulfate
- Vitamin K
Aminocaproic acid
- inhibitor of fibrinolysis
- competitively inhibits plasminogen activation
tranexamic acid
- analog of aminocaproic acid
- same properties; 10 times more potent
Protamine sulfate
- antagonizes effect of heparin
- positive charge of protamine interacts with negative charge of heparin and forms a sable complex that has no activity
Positive regulators of the fibrinolytic process
- Damaged endothelium releases tissue Plasminogen Activator (tPA)
- tPA binds plasminogen bound to fibrin rather than circulating plasminogen
- tPA cleaves (activates) plasminogen into plasmin
Negative regulators of the fibrinolytic process
- tPA inhibitors (PAI-1, PAI-2) inhibit tPA
- Circulating antiplasmin (AP) inhibits plasmin that is not bound to a clot
- AP is also found covalently bound to clot, protects the clot from premature lysis
Alteplase
- Activase
- fibrin selective; will only work on fibrin in those clots
- more efficient in dissolving older clots (than streptokinase)
- glycosylated human tPA
- efficient in dissolving older clots
Reteplase
- Retavase
- non-glycosylated recombinant human tPA
- Longer half life
- lower affinity for fibrin vs. alteplase
- improved ability to penetrate into clots
Tenecteplase
- TNKase
- recombinant protein with substitutions of amino acids
- Binds to the fibrin component of the thrombus and selectively converts thrombus-bound plasminogen to plasmin, which degrades the fibrin matrix of the thrombus
- Higher fibrin specificity and greater resistance to inactivation
risks of tPA
Increased chance to cause local thrombi as clot dissolves and parts come loose -> used in conjunction with aspirin (antiplatelet agent) or heparin (antithrombotic agent)
