Antithrombotics and antiplatelets Flashcards
What are the 4 main classes of antiplatelet drugs?
NSAIDs
Platelet GPIIB/IIIA receptor inhibitors
ADP receptor blockers
PDE inhibitors
What are the signals that prevent platelet aggregation?
When everything is normal, prostacyclin signals cause the production of cAMP from AMP, keeping platelet activation at bay by preventing the degranulation of platelets containing substances like ADP and serotonin which activate platelets and promote platelet aggregation
What are the signals that promote platelet aggregation?
Thromboxane A2 signal causes platelets to aggregate, with DAG IP3 signalling causing degranulation. TXA2 also activates a pathway via arachidonic acid –> prostaglandin H2, leading to further increased TXA2 production
This causes increased aggregation and degranulation, releasing ADP and serotonin which activate platelets and promote platelet aggregation
What happens when there is more prostacyclin than thromboxane A2?
Nothing
What happens when there is more thromboxane A2 than prostacyclin?
Degranulation, aggregation
How does aspirin work?
Irreversible inhibitor of COX
Inhibits PGH2 to limit platelet aggregation/degranulation
Reduces PGE2, causing gastric upset and ulcers due to reduction in protection and maintenance of the gastric mucosa
Reduces PGI2, causing bleeding
Reduces PGF2a, which is important for uterine contraction and hence may cause complications for pregnant women during delivery
Aspirin duration?
Rapid onset, lasting the life of the platelet (7-10 days)
What are the clinical uses of aspirin?
Prophylactic treatment of transient cerebral ischemia
Reduce incidence of recurrent MI
Decrease mortality of post-MI patients
What are GPIIB/IIIA receptors?
Platelet membrane proteins that are receptors for fibrinogen, vitronectin, fibronectin and von willebrand factor
Activation is the final common pathway for platelet aggregation
What are 3 GPIIB/IIIA receptors inhibitor drugs?
Abciximab, eptifibatide, tirofiban
How do GPIIB/IIIA receptor inhibitors work?
They stop fibrinogen binding to the receptor to inhibit formation of the fibrin mesh to stop later stages of clot formation
What are the clinical usages of GPIIB/IIIA receptor inhibitors?
Prevent restenosis after coronary angioplasty, where a balloon is used to enlarge the blocked BV, but also damages blood vessel walls which might induce clotting
Also used in acute coronary syndromes to inhibit further blockage of coronary arteries
What is abciximab?
A GPIIB/IIIA receptor inhibitor
Specifically a monoclonal antibody drug acting against the IIB/IIIA complex, reversibly inhibiting activation of the receptor
Cannot be taken orally as it is a peptide, will be digested, so taken IV instead
What is tirofiban?
A GPIIB/GPIIIA receptor inhibitor
A small organic molecule which can be taken orally, blocking the receptor to inhibit platelet aggregation
What is eptifibatide?
A GPIIB/GPIIIA receptor inhibitor
An analog of the terminal sequence of fibrinogen, can bind to GPIIB/IIIA receptors to competitively inhibit platelet aggregation
What are clopidogrel and ticlopidine?
ADP receptor inhibitors, preventing clotting activation even with ADP release upon platelet degranulation
What is dipyridamole?
PDE inhibitor, preventing degradation of cAMP to 5’-AMP, thus increasing the amount of cAMP present
cAMP, in the prostacyclin route of action, sends an “alls-good” signal that prevents platelet aggregation
What are the 4 broad categories of anticoagulants?
Heparin derivatives
Coumarin derivatives
Lepirudin/hirudin
Antithrombin III
What does thrombin do?
Thrombin (factor IIa), is the last executor in the coagulation cascade, cleaving fibrinogen to form fibrin
Also activates upstream factors V, VIII and XI to further increase thrombin generation
Activates XIII, strengthening fibrin-to-fibrin links to stabilize the coagulum
Also causes platelet aggregation, stimulates cell proliferation and modulates smooth muscle contraction
Has to be activated from prothrombin via Xa and Va
What factors do heparin inhibit?
Intrinsic pathway:
XIIa, XIa
Common pathway:
IXa, VIIa, Xa, IIa
What factors do warfarin and other oral anticoagulant drugs inhibit?
Intrinsic pathway:
IX
Extrinsic pathway:
VII
Common pathway:
X, II
What does antithrombin III do?
ATIII is an endogenous anticlotting protein, irreversibly inactivating clotting factor proteases like IIa (thrombin), IXa, Xa
How does heparin interact with ATIII?
Active heparin binds to ATIII to cause a conformation change, exposing its active site for more rapid interaction with proteases
Thrombin: Heparin must bind to thrombin AND ATIII to inhibit thrombin
Factor Xa: Heparin only needs to bind to ATIII for inhibition, where ATIII can bind directly to factor Xa
LMWHs effects on ATIII?
LWMHs can increase the action of ATIII on Xa but not action on thrombin
