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
What are the clinical uses of heparin?
Treatment of DVT, pulmonary embolism, acute MI
Used in conjunction with thrombolytics for revascularization and in combination with GPIIB/IIIA receptor inhibitors during angioplasty and coronary stent placements
Used when an anticoagulant is needed during pregnancy
Can anticoagulants directly reduce existing thrombi/clots?
No! Must be used with thrombolytics
How is heparin administered?
IV or subcutaneously, cannot give IM as it will cause hematomas
What are the adverse effects of heparin?
Hemorrhage (stop heparin, give protamin sulfate which binds to and stops heparin)
Thrombosis and thrombocytopenia
What is the significance of Vitamin K in clotting?
Reduced Vitamin K is an essential cofactor in formation of clotting factors II, VII, IX and X
Therefore vitamin K reductase is important to convert oxidized vitamin K back to reduced vitamin K for further gamma carboxylation
How do drugs reducing fat absorption affect clotting?
Less fat absorption = less absorption of fat-soluble vitamin K, reducing clotting
Can you give vitamin K epoxide with vitamin K reductase deficiency to increase clotting?
No, vitamin K epoxide is oxidized vitamin K, without reductase you can’t convert to reduced vitamin K for gamma carboxylation
What are the clinical uses of vitamin K?
Treatment and/or prevention of bleeding, counteracting oral anticoagulant drugs like warfarin or preventing hemorrhagic disease of the newborn
Treating vitamin K deficiencies in adults
What is warfarin?
An oral anticoagulant drug, acting as a vitamin K reductase inhibitor, small distribution volume and elimination dependent on hepatic CYP450
Contraindicated in pregnant women, can cause bleeding disorder in fetus
What are the clinical uses of warfarin?
Treatment of DVT, pulmonary embolism, acute MI
Used in conjunction with thrombolytics for revascularization and in combination with GPIIB/IIIA receptor inhibitors during angioplasty and coronary stent placements
Basically heparin but contraindicated in pregnant women
What are the adverse effects of warfarin?
Bleeding
Hemorrhagic disorder in fetus
Affecting fetal proteins with gamma-carboxyglutamate residues in bones and blood
What are 4 thrombolytic agents?
Alteplase (tissue plasminogen activator)
Urokinase
Streptokinase
Anistreplase
What are the thrombolytic agents’ clinical uses?
Emergency treatment of coronary artery thrombosis
Treatment of peripheral arterial thrombosis and emboli
Treating ischaemic stroke
How are thrombolytic agents administered?
Intracoronary injection, IV
What are the adverse effects of thrombolytic agents?
Bleeding
Contraindicated in pre-existing wounds and pregnancy
