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Pharmacology B > Lecture 16 - Anticoagulants > Flashcards

Lecture 16 - Anticoagulants Flashcards

1
Q

Antithrombotics

A

drugs that interfere with the platelet function

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2
Q

Anticoagulants

A

drugs which interfere with the coagulate cascade

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3
Q

Thrombolytics

A

drugs which dissolve the clot

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4
Q

asprin

A

COX 1 and 2 inhibitor

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5
Q

clopidogrel

A

ADP receptor antagonist

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6
Q

abciximab

A

GP IIb/IIIa antagonist

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7
Q

heparin

A

antithrombin III activator

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8
Q

LMW heparin

A

antithrombin III activator

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9
Q

protamine sulfate

A

binds heparin and LMW heparin

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10
Q

warfarin

A

vitamin K antagonist

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11
Q

vitamin K

A

needed to activate coagulation factors

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12
Q

dabigatran

A

direct thrombin inhibitor

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13
Q

idarucizumab

A

binds direct thrombin inhibitors

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14
Q

rivaroxaban

A

direct factor Xa inhibitor

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15
Q

andexanet alfa

A

binds direct factor Xa inhibitors

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16
Q

tissue plasminogen activator

A

activates plasminogen

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17
Q

List some drugs which prevent the formation of a platelet plug (anti platelet drugs)

A

asprin
clopidogrel
abciximab

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18
Q

List some anticoagulants

A 
heparin
LMW heparin
warfarin
dabigatran
rivaroxaban
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19
Q

List some antidotes

A

protamine (for heparin)
vitamin K (for warfarin)
idarucizumab (for dabigatran)
andexanet alfa (for rivaroxaban)

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20
Q

List a fibrinolytic agent

A

tissue plasminogen activator (t-PA)

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21
Q

Hemostasis

A

the process of arresting the loss of blood from injured vessels

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22
Q

Hemostatic plug

A
  • first step after injury, makes platelets stick to each other
  • formed by aggregated platelets and then stabilized by cross-linked fibrin fibers
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23
Q

Thrombosis

A

unwanted formation of a hemostatic plug or clot inside a blood vessel or heart chamber

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24
Q

Thrombus

A
  • blood clot attached to a blood vessel
  • may obstruct flow (harmful)
  • pieces may break off which then “plug” capillaries
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25
Q

Emboli

A
  • portion of thrombus that breaks away
  • clot floating in the blood
  • if “mobilized” will get stuck in capillaries
  • damage depends on where it lodges (heart, brain, lung)
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26
Q

An _____ clot is platelet rich

A

arterial

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27
Q

A ____ clot is red blood cell rich

A

venous

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28
Q

Describe Atherosclerosis

A
  • atherosclerosis (build up of cholesterol) may partially obstruct flow in artery
  • eventually the plaque damages the endothelium - thrombus forms
  • blood flow is blocked by the atherosclerosis and the thrombus
  • if thrombus ruptures - emboli lodge in capillary and block flow
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29
Q

How do thrombotic disorders involve arteries?

A
  • damaged endothelial layer stimulates thrombus formation
  • atherosclerosis damages endothelial layer of arteries
  • physical damage caused by: balloon angioplasty, stenting
  • if artery perfuses the brain:
  • emboli lodge in cerebral capillary
  • acute ischemic stroke
  • if artery perfuses the heart muscle:
  • emboli lodge in coronary artery
  • acute myocardial infarction
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30
Q

How do thrombotic disorders involve veins?

A
  • involves red blood cells and less platelets
  • so anti platelet drugs less effective in veins
  • more related to “stagnant flow” in veins and/or atria
  • problem post surgery, long term bed rest or just sitting (long plane rides)
  • clots form and if dislodge (emboli) - flow to capillaries in the lungs - known as pulmonary embolism
  • two major sites where venous clots form:

1) lower leg veins (DVT)
2) right atria (if atria not contracting properly)

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31
Q

Hemostasis involves 3 steps:

Describe them

A

1) Formation of a platelet plug
a) platelet adhesion
b) platelet activation
c) platelet aggregation

2) Coagulation - clot formation
- stabilizes clot (platelet plug)
- thrombin increases fibrin formation (re-enforces platelet plug)

3) Fibrinolysis - clot dissolving (as wound heals - removes clot)

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32
Q

Describe the drugs that affect hemostasis (they affect the 3 steps)

A

1) Platelet inhibitors:
a) COX inhibition - aspirin
b) ADP receptor block - clopidogrel
c) GP IIb/IIIa block - abciximab

2) Anticoagulants
a) thrombin inhibition - heparin
b) vitamin K antagonist - warfarin
c) thrombin antagonist - dabigatran
d) factor Xa inhibitor - rivaroxaban

3) Thrombolytic Agents
a) fibrin breakdown - tPA (tissue plasminogen activator)

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33
Q

Intact endothelium would normally release to ____ to stabilize the platelet - inhibit mediator release and prevent GPIIb/IIIa receptor activation on platelets

A

PGI2

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34
Q

Damage to the endothelium exposes ______. Platelets adhere to this collagen which results in a change in platelet shape and the release a number of mediators (ADP, TxA2, serotonin, etc). These mediators activate and attract other platelets and activate GPIIb/IIIa receptors.

A

collagen

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35
Q

_____ crosslinks platelets and holds them together

A

fibrin

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36
Q

List the 3 steps of a clot

A

1) formation of platelet plug
2) formation of clot
3) breakdown of clot (if no longer needed)

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37
Q

Describe step 1 (formation of platelet plug)

A
  • damaged endothelium: collagen exposed
  • platelets stick to exposed collagen
  • platelets activated: release mediators (TxA2, ADP, serotonin) to excite other platelets
  • released mediators activate resting platelets and recruit to the platelet plug
  • activation of GPIIb/IIIa receptors binds fibrin linking platelets
  • avalanche of platelet aggregation
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38
Q

How do you prevent plug formation?

A

1) selective change in prostaglandin levels (possible?)
- increase/maintain endothelial prostacyclin
- decrease thromboxane A2 levels in platelets
ex. COX inhibitor (aspirin)

2) block effects of released mediators
- block ADP receptor
ex. clopidogrel

3) prevent GPIIb/IIIa receptor coupling
- block GPIIb/IIIa receptor
ex. abciximab

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39
Q

NSAIDs are _____ ______

A

platelet inhibitors (prevent formation of platelet plugs)

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40
Q

Where do NSAIDs act?

A

inhibit COX enzymes

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41
Q

MOA of asprin

A
  • aspirin blocks COX irreversibly (it never lets go)

* once blocked, a cell would need to produce new COX to be able to synthesize prostaglandins

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42
Q

What do COX enzymes do?

A
  • COX is the enzyme necessary for the formation of PGs
  • PGs are ubiquitous and do many things
  • in platelets, COX produces TxA2 which promotes aggregation
  • in vascular endothelium, COX produces PGI2 which acts on platelets to increase stability (less likely to aggregate)
  • a balance between TxA2 and PGI2 determines how “sticky” the platelets will be
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43
Q

Platelets lack a _____ and cannot generate new COX.

  • life span of a platelet is 7-10 days
  • so for the life of the platelet (up to 10 days) - no COX, no TxA2
A

nucleus

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44
Q

____ endothelial cells do have a nucleus - produce more COX and therefore PGI2. This shifts the balance to PGI2 thus impeding aggregation

A

vascular

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45
Q

Aspirin can be used as a ______ Tx

A

prophylactic

  • baby aspirin 81 mg daily
  • following MI - start w higher dose
  • used to prevent cerebral schema and MI (both caused by emboli lodging in these capillary beds)
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46
Q

Aspirin may produce problems associated with increased _______

A

bleeding

  • hemorrhagic stroke (stroke due to bleeding into brain)
  • GI bleeding
  • easy bruising
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47
Q

Clopidogrel MOA

A
  • prevents ADP from binding to platelets
  • this prevents activation of the GP IIb/IIIa receptor on platelets
  • fibrinogen is now unable to link platelets
  • aggregation is significantly decreased
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48
Q

What is clopidogrel used for?

A
  • effective in preventing ischemic stroke and MI
  • given routinely during stent insertion during a MI
  • bleeding may be prolonged and hard to stop
  • easy bruising (bleeding)
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49
Q

Clopidogrel is a _______

A

pro-drug

hepatic conversion to active form

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50
Q

Clopidogrel:

genetic variation of CYP2C19 causes a ______ effect

A

decreased

51
Q

Clopidogrel:

_______ ADP receptor antagonist

A

irreversible

52
Q

Clopidogrel:

prolongs bleeding for ____ days

A

7-10

53
Q

Clopidogrel:

AE?

A
  • neutropenia
  • thrombotic thrombocytopenia purport (TTP)
  • hemorrhage (increased by the co-administraton of ASA)
    • GI hemorrhage (2% per year)
    • Cerebral hemorrhage (0.1-0.4 per year)
    • Co-use of NSAIDs discouraged
54
Q

Clopidogrel:

Minor adverse effects?

A
  • rash

- respiratory (upper respiratory infections, rhinitis, shortness of breath, cough)

55
Q

Abciximab:

MOA

A
  • the activated GP IIb/IIIa receptor is important to “aggregate” platelets
  • abciximab is a monoclonal antibody against this receptor
  • this prevents fibrinogen from binding and joining platelets
  • aggregation of platelets can not occur, prevents forming a plug
  • Potential problems for bleeding/bruising
  • Given IV
56
Q

What is coagulation?

A

stabilizing the clot (platelet/fibrin plug)

57
Q

What are coagulation/clotting factors?

A

proteins in the blood

58
Q

Describe the coagulation process

A
  • part of complex cascade to ultimately form fibrin strands

- fibrin strands strengthen/stabilize the platelet plug

59
Q

There are two pathways involved in the coagulation process: Describe them

A

Two pathways result in thrombin and ultimately fibrin formation:

1) Intrinsic pathway - factors released from site of damage
2) Extrinsic pathway - tissue factors released from elsewhere

60
Q

What is the purpose of the pathways?

A

Both pathways are complicated and involve a number of coagulation factors.

Purpose of pathways: conversion of prothrombin to thrombin

61
Q

What does thrombin do?

A

converts fibrinogen to fibrin (the threads to hold and strengthen the clot)

62
Q

Without fibrin, the platelet plug _____

A

dissolves

63
Q

Thrombin generation is essential for the conversion of ???

A

fibrinogen to fibrin (stabilizes clot)

64
Q

What does vitamin K do?

A

Vit K is an important cofactor in the synthesis of many of the coagulation factors (Factors 2, 7, 9, 10).

65
Q

Low vitamin K is associated with ??

A

bleeding disorders

66
Q

__________ naturally inactivates thrombin and factor Xa (decreasing fibrin formation)

A

Antithrombin 3

67
Q

see diagram on slide 27

extrinsic & intrinsic pathway

A

okay

68
Q

Describe the interactions between platelet activation and coagulation cascade (4)

A

1) Platelet-derived polyphosphates activate intrinsic pathway
2) Activated platelets present a pro-coagulant surface (phophatidylserine rich) for Factors X and II activation
3) Thrombin (Factor IIa) is a platelet agonist
4) Thrombin converts fibrinogen to fibrin which binds to platelet and stabilizes the clot

69
Q

Where does heparin work?

A

Heparin works to prevent coagulation (stabilization of the clot)

70
Q

Where is heparin normally found?

A

in mast cells

71
Q

What forms is heparin given as?

A

unfractionated heparin and low molecular weight heparin (LMWH)

72
Q

What does heparin lead to?

A
  • heparin (via antithrombin) leads to thrombin inactivation
  • heparin increases the inactivation of coagulation factors (thrombin)
  • heparin binds to antithrombin and increases its activity, thereby increasing thrombin inactivation
73
Q

What does antithrombin III do?

A

antithrombin III naturally degrades thrombin and a number of other coagulation factors (it slowly inactivates these clotting factors)

74
Q

_____ increases the rate at which antithrombin inactivates these factors

A

heparin

*as a result, thrombin is degraded faster.

75
Q

With less _____, there is less conversion of fibrinogen to fibrin, less fibrin is formed, this prevents the expansion of the thrombi

A

thrombin

*see diagram on slide 30

76
Q

Heparin:

Prevents the expansion of the thrombi by blocking ____ formation

A

fibrin

77
Q

Heparin:

What is used for?

A

used in prevention of arterial and venous thrombosis

78
Q

Heparin and LMWH are anticoagulant of choice for use in ______

A

pregnancy

79
Q

Heparin does not cross the ______

A

placenta (safe for the fetus)

80
Q

What is the antidote for excessive bleeding caused by heparin?

A

protamine sulfate (given IV)

81
Q

What is the main difference between heparin and LMWH?

A

heparin is has a variable anticoagulant response

LMWH has a predictable anticoagulant response

*read chart on slide 32

82
Q

What does warfarin do?

A
  • It is a coumarin
  • Prevents coagulation
  • Vitamin K antagonist
83
Q

What does vitamin K do?

A

is a cofactor for activation of many coagulation factors

84
Q

What is a downside of using warfarin?

A
  • Requires constant monitoring (INT measured)
  • Anticoagulation effects take 8-12 hours to be effective (slow to act)
  • *if immediate effect needed - have to start with heparin and then switch to warfarin
85
Q

What is the antidote for excessive bleeding caused by warfarin?

A

vitamin K

86
Q

What is Enoxaparin?

A

a form of LMWH

87
Q

What does Enoxaparin do?

A

accelerates (1000x) effects of anti-thrombin III

*higher specificity for factor X over factor II

88
Q

Enoxaparin is not _____ active

A

orally

89
Q

Uses of Enoxaparin?

A
  • prevents post-op DVT/pulmonary embolism
  • maintains extracorporeal circulation (surgery/dialysis)
  • unstable angina
  • ischaemic stroke
90
Q

______:

  • prevents the reactivation of vitamin K
  • prevents activation of many coagulation factors
A

Warfarin

91
Q

Warfarin:

Adverse effects?

A
  • effects variable - too little or too much, must monitor constantly
  • dietary vitamin K may alter bleeding/effects of warfarin
  • bleeding disorders - major problem, have to monitor closely
  • many drug interactions - increase or decrease metabolism
  • dietary interactions - vitamin K
  • avoid during pregnancy - teratogenic and may cause abortion
92
Q

Is warfarin safe in pregnancy?

A

No - it is a teratogenic and may cause abortion !!!

Heparin is safe during pregnancy

93
Q

What is INR?

A

International normalized ratio:
-In general this is a ratio of the patient’s (with warfarin) pro-thrombin time to that of a control subject (with no warfarin)

94
Q

What is pro-thrombin time?

A

is a measurement (in seconds) of the extrinsic pathway

95
Q

Target INR = ?

A

2.0 - 3.0

96
Q

INR < 2 = ?

A

may lead to thrombotic complications

97
Q

INR > 3 = ?

A

may lead to bleeding

98
Q

Dabigatran is a ?

A

direct thrombin inhibitor

99
Q

Rivaroxaban is a ?

A

direct factor Xa inhibitor

100
Q

Compare Dabigatran and Rivaroxaban to Warfarin

A

D & R: orally active and more predictable than with warfarin - increasing in popularity

101
Q

Heparin and warfarin have _____ therapeutic windows

A

narrow

102
Q

Is there an antidote for Dabigatran and Rivaroxaban?

A

yes

103
Q

Dabigatran:

direct orally active, irreversible, _____ inhibitor

A

thrombin

104
Q

Dabigatran:

Does it require INR measurements?

A

No

105
Q

Dabigatran:

Primary adverse effect?

A

bleeding, particularly if co-administered with an NSAID

106
Q 
Dabigatran:
What drugs (other than NSAIDs) enhance bleeding?
A

SSRI/SNRI anti-depressants

107
Q

Dabigatran:

Antidote for excessive bleeding?

A

idarucizumab

108
Q

What is Idarucizumab?

A
  • monoclonal antibody fragment that binds dabigatran

- binding affinity 350 times greater than seen with thrombin

109
Q

Rivaroxaban:

Orally active, irreversible, direct ______ inhibitor

A

factor Xa

110
Q

Rivaroxaban:

MOA?

A
  • factor Xa inhibitor, prevents prothrombin conversion to thrombin, which prevents fibrinogen to fibrin
  • prevents clot stabilization
  • allows clot to be dissolved naturally
111
Q

Rivaroxaban:

Does it require INR measurements?

A

No

112
Q

Rivaroxaban:

Major adverse effect ?

A

enhanced bleeding with NSAIDs

113
Q

Rivaroxaban:

Antidote for excessive bleeding?

A

andexanet alfa

  • a modified factor Xa molecule that binds direct factor Xa inhibitors
  • only molecule thus far to reverse direct factor Xa inhibitors
114
Q

Fibrinolytic drugs are ??

A

clot busters

115
Q

Describe the role of plasminogen

A

Plasminogen is converted to plasmin which breaks down fibrin, which breaks down the clot (busts the clot LOL)

116
Q

What does increased plasmin mean?

A

increased fibrin breakdown and clot dissolution

117
Q

Give an example of a thrombolytic drug (clot buster)

A

tissue plasminogen activator (tPA)

118
Q

tPA:

MOA

A

activates plasminogen which gets converted to plasmin and then breaks down fibrin which breaks down the clot

119
Q

tPA:

_____ the treatment the better

A

earlier

*at greater than 4.5 hour after symptom onset - benefit is uncertain

120
Q

tPA:

Adverse effect ?

A
  • these drugs do not distinguish between fibrin of a beneficial hemostatic plug and unwanted thrombi
  • will decrease thrombi, but may cause bleeding in an unknown lesion (ex. peptic ulcer)
121
Q

List 2 fibrinolytic inhibitors

A

Tranexamic acid

Aminocaproic acid

122
Q

Describe the 2 fibrinolytic inhibitors:
Tranexamic acid
Aminocaproic acid

A
  • lysine analogues
  • bind to and inhibit plasmin and plasminogen
  • stabilize clots
  • used to reduce peri and post operative bleeding especially in patients with bleeding disorders
  • used mouthwash, cream
123
Q

go over review slide - slide 49

A

okay

Pharmacology B (21 decks)

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