Anti-platelets and anti-thrombotics Flashcards
Process of haemostasis?
- Vasoconstriction
- Platelet plug formation (adhesion, activation and aggregation)
- Coagulation cascade
- Fibrin mesh to stabilise platelet plug
Types of anti-clotting drugs
- Anti-platelets
- Anti-coagulants
- Thrombolytics
4 main classes of anti-platelets
- NSAIDs (e.g. aspirin)
- Platelet GP IIB/IIIA receptor blockers
- ADP receptor blockers
- PDE inhibitor
Role of prostacyclin in inhibiting platelet aggregation?
- Prostacyclin (PGI2) binds to platelet membrane receptors causing synthesis of cAMP from ATP
-cAMP inhibits release of granules containing platelet aggregating agents
Role of thromboxane A2 in activating platelet aggregation?
-Thromboxane A2 causes release of arachidonic acid from the platelet membrane
-Increased synthesis of TXA2
-Binds to receptors on neighbouring platelets, initiating release of aggregating agents
Mechanism of action of aspirin in inhibiting platelet aggregation
-Irreversible COX inhibitor that decreases the synthesis of TXA2 from arachidonic acid
How long does the effect of aspirin last?
-Lifespan of the platelet as it is an irreversible COX inhibitor (7-10 days)
Clinical uses of aspirin
- Prophylactic treatment of transient cerebral ischaemia
- Reduce incidence of recurrent myocardial infarction
- Decrease mortality in post myocardial infarction in patients
Adverse effects of aspirin
- Bleeding (PGI2)
- Gastric upset and ulcers / GI bleeding (PGE2)
What 4 molecules do GPIIB/IIIA bind to activate platelet aggregation?
- Fibronectin
- Fibrinogen
- Vitronectin
- von Willebrand factor
MOA of GP IIB/IIIA blockers?
-Bind to GPIIB/IIIA, preventing the binding of fibrinogen and other ligands that promote platelet aggregation
Name the 3 GPIIB/IIIA blockers.
- Abciximab (monoclonal antibody; reversible inhibitor)
- Eptifibatide (analogue of the sequence at the carboxyl terminal of the delta chain of fibrinogen)
- Tirofiban (small molecule blocker)
2 clinical uses of GP IIB/IIIA blockers
- Prevent restenosis after coronary angioplasty
- Acute coronary syndromes
Name the 2 ADP receptor blockers that inhibit platelet activation
- Clopidogrel
- Ticlopidine
Name the phosphodiesterase inhibitor.
Dipyridamole (increases cAMP which inhibits granule release)
Name the 4 types of anticoagulants.
- Heparin derivatives
- Warfarin
- Lepirudin, hirudin
- Antithrombin III
Describe 4 actions of thrombin
- Further thrombin generation by activating FV, VIII and IX
- Cleaves fibrinogen, forming fragments that polymerise to fibrin
- Activates FXIII, a fibrinoligase that forms fibrin-fibrin links, stabilising coagulum
- Platelet aggregation, smooth muscle cell proliferation and contraction
Function of antithrombin III
Irreversibly inactivates IIa, IXa and Xa by forming equilimolar stable complexes with them
What are heparins?
Sulfated glycosaminoglycans (mucopolysaccharides)
Do LMWHs or unfractionated heparins have a longer duration of action?
LMWHs
MOA of heparin
-Binds to ATIII, induces a conformational change that exposes its active site for more rapid interaction with clotting factor proteases
-To inactivate IIa, needs to bind to IIa and ATIII
-To inactivate Xa, only needs to bind to ATIII
MOA of LMWHs
-Increases action of ATIII on Xa but not IIa
Clinical uses of heparin
- DVT, PE and AMI (Prevents worsening and spread of thrombus)
- Combined with thrombolytics for revascularisation
- Combined with GP IIa/IIIb inhibitors for angioplasty and placement of coronary stents
- Anticoagulant of choice in pregnancy
How is heparin administered?
IV or subcutaneously (NO IM as it predisposes to haematoma formation)
Two adverse effects of heparin
- Haemorrhage (Stop heparin and administer protamine sulfate)
- Thrombosis and thrombocytopaenia (Ig M and Ig G mediated)
What is Vitamin K used for in the body?
Reduced vitamin K is an essential cofactor in the carboxylation (post-translational modification) of glutamate residues (FII, VII, IX and X)
Two clinical uses of Vitamin K?
- Treatment and/or prevention of bleeding resulting from use of oral anticoagulants (e.g. warfarin) and prevention of haemorrhagic disease of the newborn; give reduced Vit K
- Vitamin K deficiencies in adults
MOA of warfarin
Inhibits Vit K reductase, preventing the formation of reduced Vitamin K and thus the post-translational modification of FII, VII, IX and X
Clinical uses of warfarin
Same as heparin but MUST NOT be used in pregnancy
PK factors of warfarin
- Small and lipid-soluble, good oral bioavailbility
- Small Vd, >99% bound to plasma albumin
- Elimination by CYP450
Three adverse effects of warfarin
- Bleeding
- Contraindicated in pregnancy due to fetal haemorrhagic disorder and effects on fetal proteins with gamma carboxyglutamate residues in bone and blood
- DDIs (CYP450)
Name the 4 thrombolytic agents
- t-PA (alteplase)
- Urokinase
- Streptokinase
- Anistreplase
MOA of thrombolytic agents
Activate plasminogen, forming plasmin which degrades fibrin to form fibrin degradation products
Three clinical uses of thrombolytics
- Emergency treatment of coronary artery thrombosis
- Peripheral arterial thrombosis and emboli (e.g. PE)
- Ischaemic stroke (<4.5h)
How are thrombolytic agents administered?
Intracoronary or IV injection
Two adverse effects of thrombolytic agents?
- Bleeding
- CI: healing wound, pregnancy
