Flashcards in Antiplatelets, Anticoagulants and Thrombolytic Drugs: Mechanisms and Uses Deck (27):
Describe the events in haemostasis
Vessel damage exposes collagen to which platelets bind and become activated
Describe the effect of activated platelets
synthesise and release thromboxane A2 (TXA2)
What does TXA2 bind to?
1. platelet GPCR TXA2 receptors (aka TP receptors) causing mediator release [5-hydroxytryptamine (5-HT – aka serotonin) and adenosine diphosphate (ADP)]
2. vascular smooth muscle cell TXA2 receptors causing vasoconstriction that is augmented by mediator 5-HT binding to smooth muscle GPCR 5-HT receptors
What i the role of ADP in primary haemostasis?
binds to platelet GPCR purine receptors (P2Y12) that:
act locally to activate further platelets
aggregate platelets into a ‘soft plug’ act the site of injury [via increased expression of platelet glycoprotein (GP) receptors that bind fibrinogen]. TXA2 acts similarly
expose acidic phospholipids on the platelet surface that initiate coagulation of blood and solid clot formation
What converts inactive factor X to Xa
What converts factor II into IIa
What converts fibrinogen to fibrin?
What is the treatment for arterial thrombi?
What is the treatment for venous thrombi?
How does rivaroxiban work?
Inhibits factor Xa
Which drugs inactivate factor Xa via antithrombin III
Heparin, LMWHs and fondaparinux
How does warfarin work?
Structurally related to vitamin K with which it competes for binding to hepatic vitamin K reductase preventing production of the active hydroquinone
renders factors II, VII, IX and X inactive
How does dabigatran work?
inhibits factor IIa
How does hepatic work?
inactivates factor IIa via antithrombin III
How are clotting factor precursors activated and what does this require?
gamma-carboxylation of glutamate residue
requires vitamin K [Koagulation in German - from diet (K1) and intestinal flora (K2)] in its reduced form as an essential cofactor
How is warfarin overdose treated?
administration of vitamin K1 (as phytomenadione)*, or concentrate of plasma clotting factors (IV)
What potentiates warfarin action?
How does heparin work?
Heparin binds to antithrombin III, increasing its affinity for serine protease clotting factors [particularly Xa and IIa (thrombin)] to greatly increase their rate of their inactivation
enoxaparin and dalteparin
inhibit factor Xa, but not thrombin (IIa)
Orally active inhibitors are?
direct inhibitors of thrombin (e.g. dabigatran etexilate, a prodrug to dabigatran) or factor Xa (e.g. rivaroxaban) have the advantages of:
convenience of administration
predictable degree of anticoagulation, but no specific agent is available to reduce haemorrhage in overdose which is a major disadvantage
When are orally active inhibitors used?
to prevent venous thrombosis in patients undergoing hip and knee replacements
How does aspirin work?
Main antiplatelet agent – irreversibly blocks cycloxygenase (COX) in platelets, preventing TXA2 synthesis, but also COX in endothelial cells inhibiting production of antithrombotic prostaglandin I2 (PGI2)
balance is shifted in favour of an antithrombotic effect because endothelial cells can synthesise new COX enzyme whereas enucleate platelets cannot. TXA2 synthesis does not recover until affected platelets are replaced (7-10 days)
How does clopidogrel work?
Links to P2Y12 receptor by a disulphide bond producing irreversible inhibition
Most often used in patients intolerant to aspirin (cost is an issue)
Administered orally, when combined with aspirin has a synergistic action
When is tirofiban used?
Given IV in short term treatment to prevent myocardial infarction in high risk patients with unstable angina (with aspirin and heparin)
When are fibrinolytics used?
principally to reopen occluded arteries in acute myocardial infarction (M.I.), or stroke – less frequently life-threatening venous thrombosis or pulmonary embolism
How do fibrinolytics work?