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The Cardiovascular System > Pharmacology 5 - Anti-platelet, Anticoagulant and Thrombolytic Drugs > Flashcards

Pharmacology 5 - Anti-platelet, Anticoagulant and Thrombolytic Drugs Flashcards

1
Q

What is the process of haemostasis?

A

A series of mechanisms by which a damaged blood vessel will limit blood loss

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2
Q

What are the three main stages in the haemostasis sequence?

A
  1. Vascular wall damage - exposes collagen, von Willebrand factor and tissue factor within the subendothelial matrix
  2. Primary haemostasis - local vasoconstriction occurs immediately, platelets adhere forming a soft plug, fibrinogen allows for activation and aggregation of platelets
  3. Activation of clotting mechnisms - fibrinogen is converted to fibrin due to thrombin producing a solid clot
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3
Q

What are the three key events in primary haemostasis?

A
  1. Adhesion
  2. Activation
  3. Aggregation
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4
Q

How do platelets adhere to the subendothelial matrix?

A

Platelets bind to collagen in the subendothelial matrix via von Willebrand factor - to which they bind by GPIb receptors

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5
Q

During the activation step in primary haemostasis, how can platelets bind to the subendothelial matrix more strongly?

A

Utilising their integrin (α2β1) anf GPVI receptors for a direct bind to collagen

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6
Q

How do platelets become activated? (2)

A
  • By binding directly to collagen via integrin and GPVI
  • Action of thrombin
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7
Q

What morphological change do platelets undergo during activation?

A

Disc shaped to star-like with many projections

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8
Q

What are the projections from activated platelets called, and what is their function?

A

Pseudopodia

(allows connections between platelets)

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9
Q

What do platelets do once activated, and what is the outcome of this?

A

Produce thromboxane A2 from arachidonic acid due to enzyme action of COX-1

Thromboxane A2 acts on adjacent platelets causing activation

Platelets release 5-HT and ADP from dense granules

von Willebrand factor and factor V are released from α-granules

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10
Q

What is 5-HT?

A

5-hydroxytryptamine

(serotonin)

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11
Q

Why is ADP released from activated platelets useful to coagulation?

A

ADP binds to GPCR P2Y12 receptors on platelets allowing for:

  • Activation of more platelets
  • Increased expression of platelet GP IIb/IIIa receptors to bind to fibrinogen
  • Exposure of more acidic phospholipids on the surface of platelets for clot formation
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12
Q

In the final stage of primary haemostasis, aggregation, what are the three sub-stages?

A
  1. Initiation
  2. Propagation
  3. Amplification
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13
Q

What is the overarching aim of the three stages of aggregation?

A

Form a tight mesh of fibrin stands

This is acieved by creating large amounts of thrombin which allows fibrin strands to be formed

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14
Q

What does the initiation phase require and why?

A

Cells associted with tissue factor such as:

  • Fibroblasts
  • Monocytes
  • Damaged epithelial cells
  • Cell fragments associated with TF

These cells are present in the subendothelial matric and are exposed to factor VIIa forming a complex TF:VIIa with tissue factor

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15
Q

What does the TF:VIIa complex proceed to do after its formation?

A

Activate factor X to Xa

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16
Q

How is prothrombin converted to thrombin?

A

Factor Xa, in combination with Va (cofactor) convertes prothrombin to thrombin

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17
Q

The activation of which factors requires calcium?

A

Factor X and prothrombin

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18
Q

After the initial production of thrombin via this extrinsic pathway, why is only a small amount of thrombin produced?

A

Producing large amounts of thrombin at this stage is not the goal

The aim is to produce enough to allow for amplification of the process to occur

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19
Q

How is clot formation usually supressed?

A

Tissue factor pathway inhibitor (TFPI)

This inhibts factor Xa by forming a complex with it

This complex subsequently blocks TF:VIIa preventing the extrinsic coagulation pathway completely

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20
Q

How is the tissue factor pathway inhibitor counteracted when a clot if formed?

A

The action of this inhibitor is overwhelmed when the influx of plasma factors and endothelial damage is too great

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21
Q

Where does the process of amplification occur?

A

On the surface of platelets

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22
Q

How does thrombin produced during the initiation phase aid in the amplification phase?

A

Thrombin activates more platelets and factor V which is released from α-granules upon activation

Upon binding to the platelet membrane, thrombin cleaves factor VIII from vWF which normally keeps the factor from degrading

Factor VIIIa is now active

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23
Q

In the propagation phase, how can factor IX become activated? (2)

A
  1. Factor XIa (which is itself activated by thrombin)
  2. Via TF:VIIa
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24
Q

When activated, what happens to factor IXa?

A

It will complex with factor VIIIa produced in the amplification phase

This complex is called tenase

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25
Q

What is the function of tenase?

A

Activate factor X

It is better at this than TF:VIIa meaning more factor Xa is produced

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26
Q

What happens after more factor Xa has been produced in the propagation phase?

A

Like before, factors Xa and cofactor Va are produced and bind to form prothrombinase on the platelet membrane

This difference now, is that this happens on a much larger scale due to increases factor Xa production because of the action of tenase

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27
Q

During the propagation phase, how much larger is the prothrombinase mediated production of thrombin than in the initiation phase?

A

1000 times

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28
Q

After thrombin is produced what effect does it have?

A

It can cleave small fibrinopeptides from fibrinogen which creates small fibrin monomers

These monomers will form polymers - strands of fibrin

These strands are crosslinked with factor XIIIa which is a factor activated in the presence of thrombin and calcium

This allows a stable clot to be formed

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29
Q

How is the stable clot compressed and made tougher/denser?

A

Platelets trapped in the fibrin mesh will retract

This aids in toughening up the clot and bringing the edges of the wound together

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30
Q

What is Virchow’s triad?

A
  1. Injury to the vessel wall
  2. Abnormal blood flow (stasis)
  3. Increased coaguability of blood

Describes the factors likely to contribute to thrombus formation

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31
Q

What are the two types of thrombus?

A
  1. Red thrombi
  2. White thrombi
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32
Q

Describe white thrombi

A

They are formed primarily of platelets and a few red blood cells

A fibrin mesh holds this together

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33
Q

Where are white thrombi likely to develop?

A

In the coronary circulation

They can detach forming emboli affecting the brain or another organ

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34
Q

Which drug class is utilised to treat white thrombi?

A

Antiplatelet drugs

(white thrombi contain mostly platelets)

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35
Q

Describe red thrombi

A

Red thrombi have a higher concentration of red blood cells than white thrombi

They also have less platelets and fibrin and are more jelly-like

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36
Q

Where are red thrombi likely to originate from?

A

Deep veins such as those in the lower limbs

Upon forming emboli they will tend to lodge in the lungs

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37
Q

Which drug class is used to treat red thrombi?

A

Anticoagulants

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38
Q

Upon activation, factor X will associate with what?

A

Cofactor Va

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39
Q

Where does cofactor Va originate and how is it activated?

A

α-granules from platelets

Activated by thrombin

40
Q

Together, what are factor Xa and Va called?

A

Prothrombinase

41
Q

Which drugs can act on the production or action of prothrombinase thereby preventing conversion of prothrombin to thrombin?

A
  • Warfarin
  • Rivaroxiban
  • Heparin
  • Dabigatran
42
Q

What does the drug warfarin do?

A

Block modifications of factors X and II preventing activation

This is called gamma carboxylation

43
Q

What does the drug rivaroxiban do?

A

Direct inhibition of factor Xa causing its inactivation

44
Q

What does the drug heparin do?

A

Heparin, LMWH and fondaparinux can directly inhibit factor Xa via antithrombin III

Heparin also acts on thrombin (factor IIa) via antithrombin II to inactive thrombin

45
Q

What does the drug dabigatran do?

A

Directly inhibits thrombin

46
Q

After roughly how many half lives is a drug considered eliminated from the body?

A

5

47
Q

What must happen to clotting factors II, VII, IX and X before they can be activated?

A

They require a specific conformational change to allow them to become available for activation

This change is γ carboxylation of glutamate residues which involves the addition of oxygen and carbon dioxide to allow for glutamic acid residues to be carboxylated

48
Q

What acts as a cofactor in the γ carboxylation of glutamate residues?

A

Vitamin K in its reduced form - hydroquinone

Vitamin K reductase provides a constant supply

49
Q

How does warfarin affect vitamin K reductase?

A

It inhibits it

This prevents the clotting factors II, VII, IX and X from being made available for activation because γ carboxylation of glutamate residues cannot occur without hydroquinone, which now cannot be reduced

50
Q

Why does wafarin take a while to work?

A

γ carboxylated factors must be cleared from the body

51
Q

Which drug is used for a quick anticoagulant effect?

A

Heparin

52
Q

In which instances would an anticoagulant be used?

A
  • DVT
  • PE
  • AF
  • MI
  • Congestive heart failure
  • Thromboembolic stroke
53
Q

When warfarin is used what is mandatory?

A

Regular labratory monitoring

(pro-thrombin time)

54
Q

Which factors will potentiate the action of warfarin?

A
  • Liver disease (less clotting factors produced)
  • High metabolic rate
  • Drug interactions - drugs that inhibit vitamin K reduction, platelet activation
  • Drug interactions - drugs that inhibit hepatic metabolism of warfarin
55
Q

Which factors lessen warfarin action?

A
  • Physiological state - pregancy (increased clotting factor synthesis)
  • Vitamin K consumption
  • Drug interactions - agents that increase hepatic metabolism of warfarin
56
Q

How is warfarin overdose treated?

A
  • Vitamin K administration (an antidote)
  • Withdrawal of warfarin
  • Blood transfusion of clotting factors
57
Q

Where is heparin naturally extracted from?

A

Beef lung or hog intestine

58
Q

Why is heparin measured in units of activity?

A

Due to the non-synthetic origin of heparin, there is significant variation found between batches

Hence, a certain weight is not guranteed a uniform efficacy between batches

59
Q

In every case except what are LMWH preferred over heparins and why?

A

Renal failure

LMWHs require renal excretion, heparins do not

60
Q

How does heparin work?

A

Speeds up the process at which antithrombin III functions by binding to the antithrombin/factor complex

61
Q

Give two examples of LMWHs

A
  1. Enoxaparin
  2. Dalteparin
62
Q

How do LMWHs function?

A

They inhibit factor X but not factor II (prothrombin)

(this is due to their low molecular weight, but this is all that is required to inhibit the active factor)

63
Q

Which drugs are related to LMWHs, yet act in a simpler fashion?

A
  • Fondaparinux
  • Idrabiotaparinux
64
Q

How do fondaparinux and idrabiotaparinux differ?

A

Idrabiotaparinux - longer duration of action (does not need to be administer subcutaneously very frequently)

Idrabiotaparinux has an antedote

65
Q

How are:

a) Heparins administered
b) LMWHs administered

A

a) IV or SC
b) SC

66
Q

By which order of kinetics are heparins and LMWHs processed?

A

Heparins - zero order kinetics

LMWHs - first order (more predictable)

67
Q

Why is something such as protamine sulfate an effective antidote against heparin?

A

Heparin is highly charged, so molecules with opposing charges can act to inhibit heparin

68
Q

What is the main downside to LMWHs?

A

They have no antidote

69
Q

What are the adverse effects of heparin and LMWHs?

A
  • Haemorrhage
  • Osteoporosis
  • Hypoaldosteronism
  • Hypersensitivity reactions
  • Thrombocytopenia - depleted platelet count (caused primarily by heparins vs LMWHs
70
Q

Dabigatran etexilate is a prodrug of dabigatran. Once metabolised to dabigatran, what is the function of this oral drug?

A

Direct inhibition of thrombin

71
Q

Molecularly, what is significant about dabigatran that allows it to avoid absorption by the small intestine?

A

It is a zwitterion

It has both positive and negative charges meaning it is not absorbed.

72
Q

Rivaroxiban can directly inhibits what?

A

Factor Xa

73
Q

Do orally active inhibitors of coagulation have an antidote?

A

No

74
Q

When thromboxane is produced during the activation of platelets, what does it do?

A

Acts on G protein coupled thromboaxane A2 receptors

75
Q

When ADP s produced by activated platelets, what does it then do?

A

Binds to P2Y12 receptors

76
Q

What happens when P2Y12​ and thromboxane A2 receptors are bound?

A

Intracellular calcium is increased

This increases expression of GP IIb and IIIa receptors on platelet surfaces

This allows for the binding of fibrinogenwhich brings the platelets together and under the action of thrombinthe fibrin is converted to fibrinogen

77
Q

How is the process of increasing intracellular calcium in platelets inhibited?

A
  1. Blocking P2Y12​ receptors - Clopidogrel
  2. Block the binding of fibrinogen to GP IIb and IIIa receptors preventing platelet aggregation - Tirofiban
  3. Block cyclooxygenase 1 preventing synthesis of thromboxane A2 hindering fibriongen binding - Aspirin
78
Q

What are anti-platelet drugs primarily used for?

A

Arterial thrombi

79
Q

What are anticoagulant drugs primarily used for?

A

Venous thrombi

80
Q

How does aspirin work?

A

Irreversibly blocks COX-1 in platelets

This prevents synthesis of thromboxane A2

(also, COX in endothelial cells is blocked so the production of antithrombotic prostaglandin I2 is inhibited - this is not useful, but the overall effect is the desired effect)

81
Q

Why is the effect of aspirin on platelets relatively long lasting?

A

Platelets do not have a nucleus so cannot synthesise new enzyme

82
Q

What are the main adverse effects of aspirin?

A

GI bleeding

Ulceration

83
Q

In order to function what does clopidogrel require?

A

Hepatic metabolism

84
Q

How does clopidogrel function?

A

Links to P2Y12​ receptors on platelets by disulphide bonds

This produces irrevrsible inhibition

This means ADP cannot bind and intracellular calcium cannot be raised - so GP IIb/IIIa do not incease in expression and fibrinogen cannot bind as easily

85
Q

When would clopidogrel be administered?

A

In patients intolerant to aspirin

86
Q

When _________ is administed with aspirin, there is a synergistic effect

A

Clopidogrel

87
Q

When would tirofiban be administered?

A

Alongside aspirin and heparin to prevent MI in high risk patients with unstable angina

88
Q

How do fibrinolytic drugs work?

A

They activate tissue plasminogen which can produce plasmin

Plasmin dissolves clots

89
Q

How can plasminogen be activated endogenously?

A
  • Tissue plasminogen activators (tPA)
  • Plasminogen is converted to plasmin
  • Plasmin acts on fibrin to break it into fragments
90
Q

What is the purpose of fibrinolytic drugs?

A

To reopen occuluded arteries in acute MI or stroke

(also potentially in life threatening venous thrombosis or PE)

91
Q

What is the treatment of choice for acute MI?

A

Primary percutaneous coronary intervention (PCI)

This involves using catherisation to visulaise the occulsed artery and reopen it via balloon catheterisation

92
Q

Fibrinolytics have a synergistic effect when used with what other drug?

A

Aspirin

93
Q

What is streptokinase and what is its origin?

A

Fibrinolytic drug

It is extracted from streptococci cultures so the body produces antibodies against it after 4 days

It should not be used if the patietn has recently had a streptococcal infection

94
Q

What are alteplase and duteplase?

A

Tissue plasminogen activators

95
Q

Alteplase and duteplase are more effective where?

A

Fibrin bound plasminogen - they show selectivity for clots

96
Q

How can fibrinolytics be controlled?

A

Oral tranexamic acid

Can inhibit plasminogen activation

The Cardiovascular System (24 decks)

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