Antiplatelets, Anticoagulants and Thrombolytic Drugs: Mechanisms and Uses Flashcards Preview

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Flashcards in Antiplatelets, Anticoagulants and Thrombolytic Drugs: Mechanisms and Uses Deck (27):
1

Describe the events in haemostasis

Vessel damage exposes collagen to which platelets bind and become activated

2

Describe the effect of activated platelets

extend pseudopodia

synthesise and release thromboxane A2 (TXA2)

3

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

4

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

5

What converts inactive factor X to Xa

Tenase

6

What converts factor II into IIa

Prothrombinase

7

What converts fibrinogen to fibrin?

thrombin

8

What is the treatment for arterial thrombi?

Antiplatelet

9

What is the treatment for venous thrombi?

Anticoagulants

10

How does rivaroxiban work?

Inhibits factor Xa

11

Which drugs inactivate factor Xa via antithrombin III

Heparin, LMWHs and fondaparinux

12

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

13

How does dabigatran work?

inhibits factor IIa

14

How does hepatic work?

inactivates factor IIa via antithrombin III

15

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

16

How is warfarin overdose treated?

administration of vitamin K1 (as phytomenadione)*, or concentrate of plasma clotting factors (IV)

17

What potentiates warfarin action?

Hyperthyroidism

18

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

19

LMWHs?

enoxaparin and dalteparin

inhibit factor Xa, but not thrombin (IIa)

20

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

21

When are orally active inhibitors used?

to prevent venous thrombosis in patients undergoing hip and knee replacements

22

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)

23

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

24

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)

25

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

26

How do fibrinolytics work?

activate plasminogen

27

Three stages in coagulation?

Initial phase
Amplification phase
Propagation phase