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IMED2002 UWA > Pharmacology, use and monitoring of anticoagulant, antiplatelet, and fibrinolytic agents > Flashcards

Pharmacology, use and monitoring of anticoagulant, antiplatelet, and fibrinolytic agents Flashcards

1
Q

What Kind of drugs do we often look towards for haemostasis?

A

We are mostly concerned with preventing thrombosis.

Drugs to treat or prevent this imbalance to away from clot formation:
Anticoagulant
Pro-fibrolytic
Anti-platelet

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2
Q

What pathways are manipulated for antiplatelet formation?

A

Coagulation

Fibrinolysis

Platelets

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3
Q

What are anticoagulants?

A

Warfarin (oral)

Heparin (SC / IV)

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4
Q

Where does tissue factor come from?

A

Tissue exposure to circulation

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5
Q

What are new oral anticoagulants?

A

Direct Anti-Xa

Direct Anti-IIa

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6
Q

Where is warfarin derived from?

A

Coumarin which is a toxin occurring in plants

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7
Q

What is another use for warfarin?

A

Active component in rat poisons

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8
Q

What does warfarin do?

A

Inhibits vitamin K epoxide reductase.

It inhibits formation of vitamin K

It is a Vitamin K antagonist

Leads to reduced formation of vitamin K dependent coagulation proteins (factor II, VII, IX, and X)

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9
Q

Can warfarin outside of the body? Why?

A

No, it only works in vivo. It has a delayed onset of activity and doesn’t affect coagulation factors that are already formed.

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10
Q

How is warfarin taken?

A

Orally active and rapidly absorbed. (works through the liver.

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11
Q

How fast is warfarin absorbed?

A

Rapidly absorbed

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12
Q

What is warfarin’s half like like? What does this mean?

A

Long half life because it becomes strongly bound to plasma protein so can be taken once a day

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13
Q

What must we be weary of when administering warfarin?

A

It can interact with many other drugs and is affected by diet. This means dosage is difficult as it must be monitored

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14
Q

What increases warfarin anticoagulation activity?

A

Vitamin K deficiency (already low activity down that pathway so warfarin makes things even lower)

Hepatic diseases (already impaired synthesis of coagulation factors)

Hypermetabolic states

Drug interactions with other anti-haemostatic drugs and liver enzyme medications.

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15
Q

What decreases warfarin anticoagulation activity?

A

Pregnancy

High Vit K diet (vitamin K competitively inhibited by warfarin)

Drug interactions such as alcohol which stimulates liver to increase clearance.
Vitamin K supplements

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16
Q

How is warfarin tested?

A

Prothrombin Time (PT) [time for coagulation of plasma after stimulation of extrinsic factor pathway by addition of tissue factor and calcium]

International Normalized Ratio (INR) The PT of patient divided by a normal PT adjusted for the batch of reagents

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17
Q

What are the possible adverse effects of warfarin?

A

Haemorrhage which is difficult to reverse

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18
Q

How can warfarin adverse effects be treated?

A

Oral vitamin K (takes too long)

Fresh Frozen Plasma (FFP)

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19
Q

How can adverse effects of warfarin be prevented?

A

Dosage must be carefully titrated based on INR

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20
Q

Warfarin summary:

A

Chronically used

Delayed effect

Dosing is problematic

Difficult to reverse

Orally administered

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21
Q

What is heparin?

A

Highly suflated glycosaminoglycan derived from pig or cow mucosa.

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22
Q

What is heparin’s polarity?

A

Very strong negative charge

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23
Q

What is heparin’s molecular weight?

A

Highly variable molecular weight (60 to 100 kDa)

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24
Q

What does heparin mimic?

A

Human heparin sulphate

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25
Q

What is the active part of the heparin molecule?

A

A repeating pentasaccharide unit

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26
Q

How is heparin administered?

A

IntraVenously or subcutaneously

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27
Q

How does heparin work?

A

Binds to and increases activity of endogenous antithrombin to bind to activated factor II by 1000 fold. Heparin is reusable because complex reversibly binds to AT.

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28
Q

What is heparin resistance?

A

Effectiveness tapers of due to loss of active AT molecules and this can be reversed with subsequence AT injection following heparin administration

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29
Q

How long does heparin need to take effect?

A

Works immediately

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30
Q

How is heparin activity monitored?

A

Activated Partial Thromboplastin Time (APTT)

some controversy about this method’s effectiveness

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31
Q

How is heparin activity reversed?

A

Administration of protamine sulphate

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32
Q

What are the adverse effects of using heparin?

A

Haemorrhage

Thrombocytopenia

Osteoporosis (inhibition of vitamin D in the kidneys)

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33
Q

What is low molecular weight heparin?

A

Heparin which has been treated to remove many of the non-active parts creating a more consistent sized protein of consistent molecular weight.

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34
Q

Why is consistency of the low molecular weight heparin useful?

A

Creates more predictable pharmacokinetics.(dosing is easier)

Molecule is far more active and potent

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35
Q

What is the problem with low molecular weight heparin?

A

Cannot be reversed

36
Q

What is warfarin typically used for?

A

Chronic thrombo-embolic risk

37
Q

What is heparin used for?

A

Acute anticoagulation and as a bridge to warfarin

38
Q

How useful are anticoagulants for cardiovascular disease?

A

Relatively ineffective alone for CVD

39
Q

What are the new oral anticoagulants?

A

Direct thrombin inhibitors which do not require monitoring and do not require antithrombin.

40
Q

What are the thrombin inhibitor drugs?

A

Ximelagatran (withdrawn)

Dabigatran (approved)

41
Q

What are the benefits to using direct thrombin inhibitors?

A

Overcomes dietary and drug interactions of warfarin.

42
Q

What are oral factor Xa inhibitors?

A

Inhibitors of factor Xa

Alternative to heparin for certain procedures and in Atrial Fibrillation

43
Q

Are oral factor Xa inhibitors reversible?

A

No

44
Q

Name a factor Xa inhibitor

A

Rivaroxaban

Apixaban
Edoxaban
Betrixaban

45
Q

What are the advantages of using new anticoagulants over warfarin?

A

Decreased risk of intracranial bleeding

Predictable anticoagulant effect

Quick onset and offset of action

Fewer drug and food interactions

46
Q

What are some fibrinolytics?

A

Streptokinase / Urokinase

Alteplase (hrtPA)

47
Q

Where are streptokinase and urokinase derived from?

A

Bacteria

48
Q

Why is streptokinase often used?

A

Inexpensive and very effective

49
Q

Where does alteplase come from?

A

Human recombinant protein

50
Q

What is the problem with Alteplase use?

A

Extremely expensive

Clot selective with more action on fibrin bound plasminogen

51
Q

When are antifibrinolytics taken?

A

After the thrombus has already occurred because heparin and warfarin don’t breakdown clots only stops new clots from forming.

52
Q

What is the problem with streptokinase use?

A

Antigenic and single use. Elicits an immune response which means can only work once.

53
Q

Where does streptokinase and alteplase work?

A

Plasminogen

54
Q

What are pro-fibrinolytics used for?

A

Can be used to rapidly break downa thrombus or embolism which is causing an infarct (effective treatment for myocardial infarction or stroke)

55
Q

How is the fibrinolytic pathway normally triggered?

A

Activated by the same pathway that starts the coagulation cascade (factor XIIa)

56
Q

What are the adverse effects of pro-fibrinolytic compound administration?

A

They can lead to inflammation and overdose can lead to haemorrhage.(but this can be treated by aminocaproic acid)

57
Q

What is the number of platelets we need to survive? Why do we have much more than that?

A

20x10^9/L. We have way more due to bleeding less often nowadays.

58
Q

What are you most likely to die from?

A

A platelet related disease

59
Q

What is atherothrombosis?

A

A sudden atherosclerotic plaque disruption (rupture or erosion) leading to platelet activation and thrombus formation.

60
Q

What kind of events are triggered by atherothrombosis?

A

Myocardial infarction

Ischaemic stroke

Vascular death

61
Q

How do endothelial cells actively prevent coagulation?

A

Through the production of NO and prostacyclin

62
Q

What happens when endothelial layer is removed?

A

NO and prostaglandin are no longer produced and so collagen exposed starts binding platelets and VWF through GPVI.

Bound platelets produce ADP and thromboxane which propagate further binding of platelets to the collagen resulting in a thick yellow thrombus.

63
Q

What receptor does prostaglandin bind to? What does it trigger?

A

IP which triggers cAMP activation and in turn inhibits signal transduction of P2y1 and P2y12 receptors.

NO does this as well

64
Q

What do P2y receptors do?

A

They

65
Q

What binds to P2y1 and P2y12 receptors?

A

ADP

66
Q

What inhibits ADP from binding to P2y1 and P2y12?

A

CD39

67
Q

What does collagen binding to platelet trigger?

A

GPIb-IX-V (through VWF)

GPVI

alpha2beta2

These receptors trigger signal transduction

68
Q

What is the end result of signal transduction after receptor binding?

A

Exocytosis of dense granules containing ADP (activates platelets), 5HT (serotonin) [activates platelets],

They also release alpha granules containing a receptor called p-selectin which allows platelets to bind to white blood cells forming prothrombinase complex.

Inside out signalling takes place releasing fibrinogen GPIIb/IIIa which binds fibrinogen.

Platelets mobilize arachidonic acid

69
Q

Where does aspirin work?

A

it inhibits COX1 to thromboxane irreversibly

Arachidonic acid can no longer be converted to prostaglandin and then thromboxane.

Prostaglandin ends up being inhibited in endothelial cells but this gets fixed by upregulation of COX2 which restores function because endothelial cells have a nucleus and platelets don’t.

Aspirin thus prevents one of the mechanism of platelet amplification following initial activation which tips the balance away from thrombosis.

70
Q

What are the side effects of aspirin?

71
Q

How long does the effect of aspirin last?

A

Very short half life but it irreversibly removes COX1 from platelets until the platelets are produced again.

72
Q

What are the drug interactions that aspirin can have?

A

Interacts with other NSAIDs affecting COX

73
Q

How can aspirin be monitored?

A

Monitered with arachidonic acid stimulated platelet stimulated aggregometry

74
Q

Where is resistance an issue in aspirin use in particular?

A

Diabetes

75
Q

What are fibrinogen receptor antagonists?

A

Antibodies or small molecules which bind to and block the GPIIb-IIIa integrin

76
Q

What do fibrinogen receptor inhibitors do?

A

Prevent fibrinogen from binding to fibrinogen receptor on platelets and so prevents platelet aggregation.

Platelet activation and degranulation occurs normally

77
Q

What is the problem with fibrinogen receptor inhibitors?

A

It is only effective if injected acutely. Long term receptor blockade causes more problems than it prevents.

These drugs were withdrawn from the market because of their long term problems.

Used in percutaneous coronary intervention.(PCI)

78
Q

What are thienopyradines?

A

P2Y12 receptor (ADP receptor) antagonists which inhibit platelet aggregation caused by ADP released by degranulation.

Does not affect other pathways of platelet activation.

79
Q

What are the types of thienopyridines?

A

First generation was ticlopidine

Second generation was clopidogrel

Now these drugs are widely used.

80
Q

Where are thienopyridines metabolised? What does this mean?

A

in the liver; so poor liver function would affect them.

They can interact with other liver metabolised drugs.

81
Q

Is thienopyridine activity reversible?

A

No

82
Q

How do aspirin and thienopyridines work together for CVD?

A

Very well

83
Q

What does Voloparazol do?

A

Inhibitor of thrombin receptor on platelets

84
Q

How can platelet aggregation be inhibited?

A

By using a glycoprotein IIb-IIIa antagonist

85
Q

What do Dipyridamole and Cilostazol do?

A

Dipyridamole and Cilostazol inhibit signaling pathways within the platelet

86
Q

What does atopaxar do?

A

Inhibits activation by thrombin receptor action

IMED2002 UWA (29 decks)

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