Drugs Used in Disorders of Coagulation Flashcards
What are the 4 phases of hemostasis?
- Vascular spasm
- Platelet plug formation (primary hemostasis)
- Blood coagulation (secondary hemostasis)
- Dissolution of the fibrin clot (tertiary hemostasis)
What chemical mediators released by the healthy endothelium act as inhibitors of platelet aggregation?
Prostacyclin and nitric oxide
Binding of _____ and ___ to their platelet receptors results in ____ ______, leading to the relase of contents of cells’ granules: ___, ___, ___, ____, ___, and ___ are secreted from platelet granules
Binding of collagen and vWF to their platelet receptors results in platelet activation, leading to the realse of the contents of the cells’ granules: ADP, Ca2+, ATP, serotonin, vWF, and platelet factor 4
Explain the result of ADP release and mechanism?
Platelet aggregation through action on 2 G-protein-coupled recptors
- P2Y1 > couples Gq and mobilzed intracellular Ca2+
- P2Y12 > coupled to Gi inhibition of adenylyl cyclase
What is the function of thromboxane A2 (TXA2)
- Potent platelet aggregating agonist and vasoconstrictor
- TXA2 receptor couples to Gq and leads to mobilization of intracellular Ca2+
Explain the mechanism of thrombin during primary hemostasis?
Binds thrombin receptors which are protease-activated G protein receptors results in activation of PLC and inhibition of adenylyl cyclase
What is the function of fibrinogen in primary hemostasis?
Binds GPIIb/GPIIIa receptors on two seperate activated platelets (activated display high-affinity receptor)
What is the function of thrombin in secondary hemostasis?
Thrombine is a serine protease catalyzes the conversion of fibrinogen to fibrin which crosslink forming hemostatic plug
What is the role of vitamin K?
- Cofactors of gamma-gutamyl carboxylase which is needed for activation of clotting factors II, VII, IX, and X along with proteins C and S
- Vitamin K is regenerated by vitamin K epoxide reductase (warfarin)
What re the main anticoagulant factors that regulate hemostasis and their function?
- PGI2: increased cAMP levels within platelets to inhibit activation
- Antithrombin III: inactivates thrombin and Factors IXa, Xa, XIa, and XIIA by forming complex with them
- Protein C: serine proteins activated by thrombin that degrades Factors Va and VIIIa
- Tissue Factor Pathway Inhibitor: limits action of TF-mediated activation of Factors IX and X
- Plasmin: proteolytically degrades fibrin
Differentiate venous thrombosis vs arterial thrombosis?
- Venous Thrombosis: triggered by inappropriate activation of coagulation cascade or blood stasis and is rich in fibrin.
- Arterial Thrombosis: surface lesions of endothelial cells caused by atherosclerosis and platelet rich clot
What are the 3 types of drugs used to reduce clotting?
- Platelet aggregation inhibitors
- Anticoagulants
- Thrombolytics
What are the 4 types of drugs used to treat bleeding?
- Plasminogen activiation inhibitors
- Protamine sulfate
- Vitamin K
- Plasma fractions
What are the types of platelet aggregation inhibitors?
- Cyclooxygenase Inhibitors
- ADP Receptor Blockers
- Phosphodiester Inhibitors
- Blockers of Platelet GP IIb/IIIa Receptors
Aspirin (MOA, Uses, HL)
MOA: irreversible acetylation of COX which inhibits TXA2 synthesis
Uses: prophylactic treatment of TIA, reduce incidence of recurrent MI, and decrease mortality in post MI pts
HL: other salicyclates and other NSAIDs are reversible
Clopidogrel and Ticlipidine (MOA, Uses, AE, HL)
MOA: irreversibly inhibits P2Y12 which is on of two subtypes of ADP receptors on platelet surface
Uses: prevent cerebrovascular, cardiovascular, and peripheral vascular disease
AE: thrombocytopenic purpura, neutropenia for ticlopidine which is why clopidogrel is most commonly used
HL: clopidogrel is prodrug metabolized by CYP2C19 which is not to have poor metabolizers and is inhibited by Omeprazole
What are the phosphodiester inhibitor drugs?
Dipyridamole and Cilostazol
Dipyridamole (MOA, Uses, HL)
MOA: increased cAMP levels by inhibiting phosphodiesterase and/or blocking uptake of adenosine (activate adenylyl cyclase)
Uses: adjunct to warfarin p/o to prevent thromboembolic events or combined with aspirin for prophylaxis of CVD
HL: little to no beneficial effect alone
Cilostazol (MOA, Uses)
MOA: phosphodiesterase inhibitor that promotes vasodilation and inhibitor of platelet aggregation
Uses: treat intermittent claudication
What the drugs for blockers of platelet GP IIb/IIIa receptors their function and uses?
- Abciximab: chimeric mouse-human monoclonal antibody that irreversibly inhibits
- Eptifibatide: cyclic peptide reversible antagonist
- Tirofiban: nonpeptide tyrosine analogue reversible antagonist
Uses: prevent thromoblytic cardiovascular events in pts with NSTE-ACS and adjuncts to percutaneous coronary intervention
What is Glanzmann’s thrombasthenia?
Person lacking GPIIb/IIIa receptors
Name the 4 groups of anticoagulants?
- Indirect Thrombin and Factor X inhibitors
- Direct Thrombin Inhibitors
- Vitamin K antagonists
- Direct Factor Xa inhibitors
Heparin (MOA, Uses, AS, HL)
MOA: binding antithrombin III making it a better protease to inhibit thrombin, IXa, and Xa.
Uses: injectable anticoagulant to acutely interfere with formation of thrombi
AE: bleeding, hypersensitivity reactions, and Heparin Induced Thrombocytopenia (platelet factor 4)
HL: monitored by aPTT, reversed by protamine sulfate
Fondaparinux (MOA)
MOA: binding to antithrombin III to act as selective, indirect, inhibitor of factor Xa
