Antiplatelets, Anticoagulants and Thrombolytic Drugs: Mechanisms and Uses

Question 1

Describe the events in haemostasis

Answer 1

Vessel damage exposes collagen to which platelets bind and become activated

Question 2

Describe the effect of activated platelets

Answer 2

extend pseudopodia

synthesise and release thromboxane A2 (TXA2)

Question 3

What does TXA2 bind to?

Answer 3

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

Question 4

What i the role of ADP in primary haemostasis?

Answer 4

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

Question 5

What converts inactive factor X to Xa

Answer 5

Tenase

Question 6

What converts factor II into IIa

Answer 6

Prothrombinase

Question 7

What converts fibrinogen to fibrin?

Answer 7

thrombin

Question 8

What is the treatment for arterial thrombi?

Answer 8

Antiplatelet

Question 9

What is the treatment for venous thrombi?

Answer 9

Anticoagulants

Question 10

How does rivaroxiban work?

Answer 10

Inhibits factor Xa

Question 11

Which drugs inactivate factor Xa via antithrombin III

Answer 11

Heparin, LMWHs and fondaparinux

Question 12

How does warfarin work?

Answer 12

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

Question 13

How does dabigatran work?

Answer 13

inhibits factor IIa

Question 14

How does hepatic work?

Answer 14

inactivates factor IIa via antithrombin III

Question 15

How are clotting factor precursors activated and what does this require?

Answer 15

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

Question 16

How is warfarin overdose treated?

Answer 16

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

Question 17

What potentiates warfarin action?

Answer 17

Hyperthyroidism

Question 18

How does heparin work?

Answer 18

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

Question 19

LMWHs?

Answer 19

enoxaparin and dalteparin

inhibit factor Xa, but not thrombin (IIa)

Question 20

Orally active inhibitors are?

Answer 20

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

Question 21

When are orally active inhibitors used?

Answer 21

to prevent venous thrombosis in patients undergoing hip and knee replacements

Question 22

How does aspirin work?

Answer 22

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)

Question 23

How does clopidogrel work?

Answer 23

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

Question 24

When is tirofiban used?

Answer 24

Given IV in short term treatment to prevent myocardial infarction in high risk patients with unstable angina (with aspirin and heparin)

Question 25

When are fibrinolytics used?

Answer 25

principally to reopen occluded arteries in acute myocardial infarction (M.I.), or stroke – less frequently life-threatening venous thrombosis or pulmonary embolism

Question 26

How do fibrinolytics work?

Answer 26

activate plasminogen

Question 27

Three stages in coagulation?

Answer 27

Initial phase
Amplification phase
Propagation phase