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.Pharmacology > Part 27: Hemostasis & Anticoagulants > Flashcards

Part 27: Hemostasis & Anticoagulants Flashcards

1
Q

what is hemostasis in a general sense?

A

the process by which our body keeps our blood through our body and contained in the vascular system

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2
Q

thombrosis is related to ____ (excessive or impaired) clotting

A

excessive

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3
Q

the immediate reaction of BV that have been damaged is to ____ (dilate/constrict). Why?

A

constrict to prevent excess blood loss

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4
Q

when a breach in the endothelial lining of blood vessel is detected by circulating ____ and they become activated and they clump together to “plug the hole” in the bleeding vessel

A

platelets

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5
Q

when a bv is cut, in parallel to the activation of platelets, the _____ cascade is started to form a strong ____ clot to seal the hole until repair can be made

A

coagulation; fibrin polymer

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6
Q

the healing process for a minor cut may take ____ (time) and more major cuts may take ____ (time)

A

a few days; several weeks

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7
Q

when the injury is repaired and the fibrin clot is no longer needed, it will be broken down by ___ and the clot will be removed

A

plasmin

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8
Q

___ makes ___ which makes ____ which makes fibrin

A

prothrombrin, thrombin, fibrinogen

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9
Q

when a BV is injured, ___ and ___ become exposed, allowing platelets to bind to them and become activated

A

collagen; von Willebrand factor

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10
Q

activated platelets secrete ___, ___, & ___ to cause the initial vasoconstriction and to recruit and activate other platelets to the injury site

A

ADP; thromboxane and serotonin

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11
Q

activated platelets cross-link to form the ____, while the fibrin clot begins to form

A

platelet plug

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12
Q

____ and ____ are key mediators of fibrin formation within the coagulation cascade, making them important pharm targets when modulating hemostasis

A

factor X and thrombin (factor 2A)

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13
Q

another important mediator is ___, which regulates clot size and extent of spread within the vessel

A

prostacyclin (PGI2)

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14
Q

prostacyclin is secreted by ____ cells and acts like a traffic controller to keep the clot containe dto the injury site so it doesnt overgrow and occlude bloodflow completely

A

neighbouring

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15
Q

as the injured vessel is repaired, ____ breaks down the clot upon activation of plasmin

A

fibrinolysis

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16
Q

thrombosis can be pathologic when ___

A

a clot is made unnecessarily or when the clot becomes mobile

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17
Q

when a blood clot becomes mobile it is called a ____

A

embolus

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18
Q

an embolus can cause what kinds of bad things?

A

stroke, MI, pulmonary embolism

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19
Q

what patient populations are likely to be on antiplatelet drug?

A

those at increased risk for blood clots (ex: past MI, certain arrhythmias like A fib) or after a surgery

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20
Q

if someone is bedridden, the are ___ (more/less) likely to develop a blood clot. why?

A

more; bc blood tends to pool in the lower extremeties and not circulate well

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21
Q

antiplatelets are typically used ___ (chronically/acutely)

A

chronically

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22
Q

fibrinolytic drugs are typically used ___ (chronically/acutely)

A

acutely (when a clot as already formed), must be given as quickly as possible to reduce risk of downstream effects of obstructed blood flow (like cardiac ischemia caused by an MI)

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23
Q

what is a slang term for fibronolytic agents?

A

clot busters

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24
Q

ASA, clopidogrel and tirofiban are all examples of ___ type drugs

A

antiplatelts

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25
Q

when platelets are activated, they release ___, ___ and ___ that contrubute to early vasoconstriction of the injured vessel and initiate a cascade of activating and aggregating additional platelets

A

thromboxane A2, ADP and serotonin

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26
Q

____ is one of the many mediators produced in the arachidonic acid pathway where COX is a central enzyme and pharm target

A

thromboxane A2

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27
Q

reducing thromoxane production by inhibiting ____ enzymes will reduce the activation and aggregation signals

A

COX

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28
Q

platelets express ADP P2Y receptors, which are activated by the ____ released from activated platelets

A

ADP

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29
Q

blocking ADP P2Y receptors reduces the intracellular signal to secrete ____ and ____

A

mediator granules and aggregate

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30
Q

the ADP P2Y signalling pathway is involved in the ____ (increased/decreased) expression of glycoprotein receptors which are involved in platelet adhesion and aggregation

A

increased

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31
Q

one glycoprotein activated by the ADP P2Y signalling pathway that acts to increase platelet adhesion and aggregation is the ____ complex

A

glycoprotein 2b/3a (GP 2b/3a)

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32
Q

the GP2b/3a complex acts as a receptor for ____ to link platelets togther, forming the platelet plug

A

fibrinogen

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33
Q

blocking the CP2b/3a receptors leads to decreased platelet ____ (aggregation/dissociation)

A

aggregation

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34
Q

____ is the most commonly recognized antiplatelet agent used clinically

A

ASA (asprin)

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35
Q

ASA’s inhibition of COX-1 is ____ (reversible or irreversible)

A

irreversible (covalent)

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36
Q

ASA ____ (increases/decreased) the thromboxane A2 (TXA2) production

A

decreases

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37
Q

prostaglandins are important to inflammatory reponse and pain signalling, but they are also importnat to ____

A

hemostasis

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38
Q

in the arachidonic acid pathway, membrane lipids are used to produce inflammatory mediators along with thromboxane in ___ and prostacyclin in ___

A

platelets; endothelial cells

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39
Q

prostaglandins are pro-____ and cyto____

A

inflammatory; protective

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40
Q

thromboaxane and prostacyclin regulate platelet ___

A

aggregation

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41
Q

platelets express COX-1 to produce ___

A

thromboxane A2

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42
Q

what is the MOA of ASA?

A

bind covalently to COX 1 to inhibit enzymatic activity and reduce platelet activation & aggregation

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43
Q

the dose of ASA needed to have antiplatelet effects is much ____ (higher/lower) than the dose needed for pain/inflammation

A

lower

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44
Q

why is ASA blocking COX1 permanent?

A

platelets are anuclear so they cant make new proteins like the COX receptors

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45
Q

what is the typical dose of ASA used for anti-platelet?

A

81-325mg

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46
Q

what is the typical dose of ASA used for anti-inflammatory?

A

600mg+

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47
Q

what is the MOA of clopidogrel

A

irreversibly inhibits the ADP P2Y receptor on platelets, which acts to reduce platelet aggregation

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48
Q

t/f clopidogrel is a prodrug

A

t

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49
Q

clopidogrel is activated by ____ enzyme in the liver prior to having any anti-platelet effects

A

CYP2C19

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50
Q

what is a downside of clopidogrel being a pro-drug?

A

may be subject to genetic variation and or drug-drug interactions related to the CYP2C19 enzyme that metabolizes it

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51
Q

what is a clinically relevant drug-drug interaction with clopidogrel?

A

omeprazole will result in sub-therapeutic levels of clopidogrel

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52
Q

t/f there are now ADP-P2Y inhibitors that are not pro-drugs, so clopidogrel is not used as much anymore

A

t

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53
Q

clopidogrel can be used as a monotherapy or in combo with ____

A

ASA

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54
Q

what is the moa of tirofiban?

A

binds to the glycoprotein 2b/3a receptor to prevent fibrinogen from binding and causing the cross-linking of platelets (decreases platelet aggregation by blocking this)

55
Q

Tirofiban is only available as a _____ formulation and is most often used in the ____ setting for ____(long/short) term treatment

A

IV; hospital; short (usually post-op)

56
Q

can a patient be switched back to their regular clopidogrel/ASA treatment after post-op treatment with tirofiban?

A

yes

57
Q

antiplatelet agents are typically used in ____(lower/higher) risk and agents that modulate the coagulation cascade are used in ____ (lower/higher) risk pts

A

lower; higher

58
Q

anticoagulants are classed based on ___ and ____

A

where they interact within the coagulation cascade and whether they have direct intercation with a target or an action that has indirect reduction in thrombin production

59
Q

t/f the coagulation cascade actually exists as many processes occuring in parallel and can feed back onto each other to potentiate clotting

A

t

60
Q

in the coagulation cascade, the ___ clotting factors are produced an circulating at all times

A

inactive

61
Q

when a circulating inactive clotting factor interacts with ___ on the exposed endothelium, factor ___ is activated and the coagulation cascade begins, causing the activation of factor ____, which catalyzes the formation of _____ which then catalyzes the reactions of converting ____ to ___ to form the blood clot

A

tissue factor (TF); factor 7; factor ten (AKA 10A); thrombin (AKA factor 2A); soluble fibringogen to insoluble fibrin

62
Q

____ is one of the oldest clinically used anticoagulants

A

warfarin

63
Q

warfarin is classed as a ____ acting anticoagulant. Why?

A

indirect; bc its MOA does not involve physically interacting with any component of the coagulation cascade itself, but rather by influencing the synthesis of several clotting factors

64
Q

warfarin is a synthetic ____ compound, which were originally isolated from natural products after discovery of their anticoagulation properties

A

coumarin

65
Q

what was the original use of warfarin and other related compounds?

A

pest control (causes rats to hemorrhage and die)

66
Q

use of warfarin in small doses for anticoagulation began in the ____ (timeframe)

A

1950’s

67
Q

warfarin is a competitive inhibitor of vitamin ___ epoxide

A

K

68
Q

the enzyme ___ is required to reactivate vitamin K

A

vitamin K epoxide

69
Q

vitamin K is a cofactor in the biosynthesis of several ____

A

clotting factors

70
Q

the vitamin K dependent clotting factors are __, __, __ and ___

A

7,9,10 & 2

71
Q

clotting factor 2 is also called ___

A

prothrombin

72
Q

t/f in the presence of warfarin, vitamin K cannot be reactivated and the production of clotting factors

A

t

73
Q

why does coagulation become impaired in the presence of warfarin?

A

reduced formation of fibrin at the end of the coagulation cascade

74
Q

warfarin inhihitis vitamin K epoxide ____ (competitively/non-competiticely)

A

competively

75
Q

t/f if the presence of vitamin K is high, it can out-compete warfarin

A

t (pts need to be conscious of their K levels/intake)

76
Q

an important consideration with the initiation of warfarin is that there is a delay in the onset of therapeutic effect that is related to the ___ of the circulating clotting factor

A

half lives

77
Q

why does it take a while for the therapeutic effects of warfarin to kick in?

A

we have premade clotting factors circulating in our blood, so these must be depleted b4 the full extent of warfarin effects can be seen

78
Q

what is the onset time when targeting factor 7 with warfarin?

A

4-6 hours

79
Q

what is the onset time when targeting factor 9 with wrfarin?

A

24 hrs

80
Q

what is the onset time when targeting factor 10 with warfarin?

A

48-72 hrs

81
Q

what is the onset time when targeting factor 2 with warfarin?

A

60 hours

82
Q

t/f regular monitoring of warfarin includes measuring how long it takes for a patient’s blood to clot

A

t

83
Q

what is INR and what is it usd for?

A

international normalized ratio; used as a tool to assess the clotting time in comparision to a normal patient population

84
Q

what is the ratio used for INR?

A

patient prothrombin time / mean of normal prothrombin time

85
Q

what is the ideal INR range during warafrin treatment?

A

~2.0 – 3.0

86
Q

if the INR is less than ___, the patient is at risk of a clot

A

2.0

87
Q

if the INR is greater than ___ the patient is at risk of hemorrhage

A

3.0

88
Q

invasive surgeries are not recommended if the INR is greater than ___

A

4

89
Q

in the case of a very high INR (warfarin overdose), what can be administered?

A

vitamin K

90
Q

an INR of 2-3 means ___ when on warfarin

A

it takes 2-3 times longer for the warfarin patient to form a clot

91
Q

warfarin is metabolized by CYP enzymes, primarily ____, but also others including _____

A

CYP2C9; CYP3A4

92
Q

what are 5 examples of drug classes that can have serious drug-drug interactions with warfarin?

A
  1. some antibiotics
  2. some analgesics
  3. antidepressants, hypnotics, psychostimulants
  4. oral contraceptives
  5. natural products, food
93
Q

do heparins interact directly with the coagulation factors themselves?

A

no

94
Q

heparin interacts with ____ to enhance the inactivation of factor Xa and thrombin, thus reducing the availability of active coagulation factors and causing an anticoag effect

A

antithrombin

95
Q

heparins are ___ polymers that are produced naturally in the body as regulators of hemostasis

A

mucopolysaccharide

96
Q

_____ is a naturally sourced product that contains a mixture of heparin polymers with a wide range in sizes upto a very large MW (~30 000 daltons) to very small MW (4-5 kilodaltons)

A

unfractionated heparin

97
Q

heparin is a ____ acting anticoag

A

indirect

98
Q

give an example of a low MW heparin (LMWH)

A

enoxaparin

99
Q

all heparin polymers that contain the necessary ____ sequence to bind to the ____ enzyme have anticoag effects, regardless of their overall

A

5 sugar; antithrombin

100
Q

heparin binds to the antithrombin enzyme by the ____ sequence within the heparin polymer

A

pentasaccharide

101
Q

when heparin is bound to the antithrombin, the affinity of binding with active clotting factors is significantly ____ (increased/decreased)

A

incerased

102
Q

when factor Xa or thrombin binds to antithrombin, they become ____

A

inactive (can no longer participate in the coag cascade)

103
Q

antithrombin is active w/o heparin, but in the presence of heparin, its activity can be increased as much as ______x

A

1000

104
Q

what is an additional bonus of larger heparin polymers?

A

the long polysaccharide tails are able to bind to thrombin and antithrombin, hugging the 2 togther to further accelerate the inactivation of thrombin

105
Q

heparins bind ____ (reversibly / irrreversibly) to antithrombin

A

reversibly

106
Q

antithrombin activity by heparin causes increased ____ of clotting factors

A

inactivation

107
Q

why do UfH (large MW) have greater activity in accelerating inactivation of thrombin than LMWH?

A

the long tails of UfH reach around and hug thrombin into the active site of the antithrombin

108
Q

both UFH and LMWH are able to facilitate the inactivation of factor ____ , and LMWH only poorly inactivate ____

A

XA; thrombin

109
Q

bleeding risk of heparin can be enhanced when pts are taking other drugs than can increase bleeding, such as ____

A

NSAIDs

110
Q

t/f INR testing is not needed for heparin, but other tests are performed

A

t

111
Q

if heparin levels are too high, ___ can be administered to bind to circulating heparin molecules and prevent them from binding to antithrombin

A

protamine sulfate

112
Q

the interaction between heparin and protamine is a ____ type bond

A

ionic (positive protamine and negative heparin)

113
Q

the anticoag actions of heparin are achieved through the binding with the enzyme ____, they dont interact directley with Xa or thrombin without this enzyme

A

antithrombin

114
Q

give 2 examples of direct actiing anticoags classes

A
  1. factor Xa inhibitors

2. direct thrombin inhibitors

115
Q

give an example of a direct acting factor Xa inhibitor

A

rivaroxaban

116
Q

give an example of a direct acting thrombin inhibitor

A

dabigatran

117
Q

what is the effect of rivoroxaban on thrombin?

A

no effect; selective for Xa

118
Q

rivoroxaban binds directly to the ____ site of the Xa, preventing its activity in the coa g cascade

A

catalytic

119
Q

what is the effect of dabigatran of Xa?

A

no effect; selective for thrombin

120
Q

dabigatran binds to the catalytic site of thrombin to prevent its activation of ____

A

fibrin

121
Q

factor Xa and thrombin inhibitors are given as fixed ___ dosing regimens

A

oral

122
Q

what does it mean that Xa and thrombin inhibitors are fixed dose?

A

there is no real fine-tuning of doses like there is with warfarin, but there also is less monitoring bc the anticoag effects are more predictable

123
Q

what is the therapeutic goal of fibrinolytics?

A

breakdown clot after its formation in emergency situations like MI, stroke etc.

124
Q

give an example of a synthetic tPA fibrinolytic

A

altesplase

125
Q

what is tissue plasminogen activator (tPA)?

A

an endogenous protein that is released from endothelial cells in response to injury

126
Q

what is the normal physiologic role of tPA?

A

to regulate the extent of clot formation and also remove the clot after tissue repair

127
Q

tPA catalyzes the formation of ___- from ___, which breaks apart the fibrin polymers that make up a blood clot

A

plasmin plasminogen

128
Q

what is the timeframe of administering fibrinolytic agents like alteplase after onset of blood clot symptoms that has been shown to reduce complications associated with ischemia and loss of blood flow?

A

within the first few hours

129
Q

when thinking of giving a fibrinolytic for a stroke, it is important to determine if the stroke is a ____ type stroke before administering. why?

A

hemorrhagic; bc if it is hemorrhagic (bleeding into the brain), a fibrinolytic will make the bleeding worse

130
Q

how soon after symptoms of stroke should a fibrinolytic be given>

A

within 3 hours

131
Q

how soon after symptoms of mI should a fibrinolytic be given?

A

within 6-12 hours (sooner the better)

132
Q

why is the bleeding risk not so bad for fibrinolytics?

A

they have a short half life and used acutely for emergencies

133
Q

what is the primary fibrinolytics?

A

bleeding

.Pharmacology (55 decks)

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