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N929 Pharmacology > Anticoagulants, Antiplatelets and thrombolytics > Flashcards

Anticoagulants, Antiplatelets and thrombolytics Flashcards

1
Q

What do Anticoagulants do?

A

prevent clot formation or extension of existing clot

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2
Q

What do Antiplatelet agents do?

A

reduce platelet aggregation on the surface of the plateelt

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3
Q

What do thrombolytics do?

A

convert endogenous plasminogen to the fibrinolytic enzyme plasmin to dissolve newly formed clots

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4
Q

What are the four major counter-regulatory pathways of the intrinsic anticoagulant system?

A

fibrinolysis
tissue factor plasminogen inhibitor (TFPI)
protein C system
serine protease inhibitors (SERPINs)

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5
Q

What is the main source of anticoagulation factors?

A

capillary endothelium

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6
Q

How is prevention of blood coagulation outside the body maintained?

A

silionized containers
heparin in CPB or artifical kidney machines
citrate ion

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7
Q

Tissue Factor Plasminogen Inhibitor

A

polypeptide produced by endothelial cells

acts as a natural inhibitor of the extrinsic pathway by inhibiting TF-VIIa complex

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8
Q

What are the four key elements of the Protein C pathway?

A

protein C
thrombomodulin
endothelial protein C receptor
protein S

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9
Q

How does protein C contribute to the APC?

A

enzyme with potent anticoagulant, profibrinolytic and anti-inflammatory properties. It is activated by thrombin to form activated protein C (APC) and acts by inhibiting activated factors V and VIII (with protein S and phospholipids acting as cofactors

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10
Q

How does thrombomodulin contribute to the APC?

A

a transmembrane receptor on the endothelial cells, it prevents the formation of the clot in the undamaged endothelium by binding to the thrombin

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11
Q

How does endothelial protein receptor C contribute to the APC?

A

another transmembrane receptor that helps in the activation of Protein C

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12
Q

How does Protein C contribute to the APC?

A

vitamin K dependent glycoprotein, synthesized by endothelial cells and hepatocytes. Activity can be free or bound. When bound it acts as an inhibitor to the complement system and is up regulated in the inflammatory states, which reduce the Protein S level thus resulting in a procoagulant state
It functions as a cofactor to APC in the inactivation of FVa and FVIIIa

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13
Q

Antithrombin

A

previously known as AT III
it is the main inhibitor of thrombin
Binds and inactivates thrombin, factor 2a, IXa, Xa, XIa and XIIa

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14
Q

When is the enzymatic activity of antithrombin (AT) enhanced?

A

In the presence of heparin

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15
Q

Deficiency in Antithrombin

A 
hereditary AT deficiency is estimated to be 1 in 2000-5000
acquired deficiency 
(prolonged heparin infusions >4-5 days decreased plasma AT activity by 50-60% of normal
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16
Q

Antithrombin inhibits

A

Xa and IIa but also inhibits VIIa, IXa and XIIa

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17
Q

Citrate Ion

A

any substance that deionizes the blood calcium will prevent coagulation

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18
Q

How is an un-ionized calcium compound formed?

A

negatively charged citrate ion combines with positively charged calcium in the blood to cause un-ionized calcium compound

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19
Q

What occurs with liver dysfunction or massive transfusion and citrate ion,

A

the citrate ion may not be removed quickly enough, and this can greatly depress the level of calcium in the blood

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20
Q

Anticoagulants

A 
vitamin K antagonist
unfractionated heparin
low molecular weight heparin and Fondaprinux
direct thrombin inhibitors
direct oral anticoagulants
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21
Q

Coumadins are

A

vitamin K antagonist

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22
Q

Coumarin

A

precursor reagent in the synthesis of a number of synthetic anticoagulants, warfarin

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23
Q

Mechanism of action of Warfarin (Coumadins)

A

inhibit vitamin K which results in the hemostatically defective vitamin K dependent coagulation proteins (II,VII, IX, and X)

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24
Q

MOA of Warfarin

A

competition of vitamin K for reactive sites (antagonism) in the enzymatic processes for formation of prothrombin and other clotting factors, producing the blocking action of vitamin K

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25
Q

Is platelet activity altered with warfarin adiministration?

A

no

Its effects the coagulation cascade

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26
Q

Pharmacokinetics of Coumadin

A

rapidly and completely absorbed
97% protein bound
long elimination half time of 24-36 hours after oral administration
not suitable for pregnancy
metabolized to inactive metabolites that are conjugated and excreted in bile and urine

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27
Q

Why is coumadin unsafe for pregnancy?

A

it crosses the placenta and severely teratogenic

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28
Q

What is coumadin effective for?

A

prevention of thromboembolisms

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29
Q

What is the dose of coumadin?

A

2.5mg-10mg, dose varies

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30
Q

Onset of coumadin

A

3-4 days

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31
Q

Duration of single dose of coumadin

A

2-4 days

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32
Q

How are the effects of coumadin best tested?

A

PT/INR

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33
Q

INR Goals and Coumadin 2-3

A

Afib
Treatment of VTE, PE
prevention of VTE in high risk surgery
tissue heart valves

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34
Q

INR Goals of Coumadin (2.5-3.5)

A

Mechanical heart valve
prevention of recurrent MI
History of VTE with INR 2-3

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35
Q

Coumadin Management before surgery (minor surgery)

A

check PT/INR
d/c 1-5 days preoperative for PT 20% within baseline
restart 1-7 days postop

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36
Q

Coumadin Management before surgery (Immediate surgery)

A

24-48 hours prior or active bleeding
Vitamin K
2.5mg-20mg PO or 1-5 mg IV @ 1mg/min
PT to normal range within 4-24 hours

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37
Q

Coumadin Management before surgery (emergency)

A

FFP or 4 factor concentrate (Kcentra)

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38
Q

What is heparin

A

a naturally occurring polysaccharide that inhibits coagulation
released endogenously by mast cells and basophils and used widely as an anticoagulation drug

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39
Q

Which heparin is more unpredictable?

A

Unfractionated Heparin

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40
Q

Unfractionated Heparin

A

binds to anti-thrombin (antithrombin III)
which enhances the ability of antithrombin to further inactivate thrombin IIa, Factors Xa,XII,XI and IX
Functions as an anticoagulant by accelerating the normally occuring anti-thrombin induced neutralization of activated protein factors
neutralized thrombin prevents the conversion of fibrinogen to fibrin

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41
Q

Preparation of Unfractionated Heparin Preparation

A

large molecular weight
only about 1/3 of the administered heparin binds to antithrombin and this fraction is responsible for its anticoagulant effect
Must contain atleast 120 UPS Units/ml
Prescribed in units

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42
Q

Pharmacokinetics of Unfractionated Heparin

A

poor lipid solubility (large molecule)
cannot cross lipid barriers in significant amounts
does not cross placenta (safe in obstetrics)
once injected it circulates bound to plasma proteins
most commonly monitored by biologic activity
dose-response relationship
Decreaes in body temp prolongs elimination

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43
Q

Clinical Monitoring of Unfractionated Heparin

A

aPTT
ACT
HEPTEM

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44
Q

aPTT for monitoring Unfractionated heparin

A

1.5-2.5 times pre-drug value (30-35 seconds)

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45
Q

ACT for Unfractionated Heparin

A

baseline
3-5 min post administration
30 mins to 1 hour intervals post administration

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46
Q

Clinical Uses of Heparin

A

SQ VTE and PE prophylaxis
Warfarin bridge
vascular or non CPB cases vary ACT >200-300 seconds
interventional aneurysm clipping/coiling >250seconds
CPB: ACT >400-480 seconds (inadequate <180seconds)

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47
Q

Prophylaxis again Thromboembolism Dose of Unfractionated Heparin

A

5000units SC Q8-12 hours

48
Q

Treatment of thromboemobolism Dose of Unfractionated Heparin

A

5000units IV following by continuous infusion for goal Ptt 1.5-2.5 times control value

49
Q

Cardiopulmonary Bypass Dose of Unfractionated Heparin

A

400units/kg IV

50
Q

Vascular Interventions Dose of Unfractionated Heparin

A

100-150units/kg IV

51
Q

Side effects of Heparin

A 
hemorrhage/hematomas
thrombocytopenia (HIT)
allergic reaction
hypotension with large doses 
altered protein binding
chronic exposure cna progress to reduction of antithrombin activity
52
Q

Heparin Induced Thrombocytopenia

A

heparin dependent antibodies that aggregate platelets and leads to consumption which produces thrombocytopenia

53
Q

Mild or Type 1 HIT

A

30-40% of heparin treated patients
nonimmune mediated
PLT count < 100,000 cells/mm3
typically presents 3-15 days after initiation of therapy starts

54
Q

Severe or Type 2 HIT

A

immune mediated
plt count < 50,000
typically presents after 6-10 days after initation therapy
0.5-6% of treated pts

55
Q

How do you confirm HIT?

A

laboratory tests for antibodies

56
Q

Allergic reactions to Heparin

A

fever, urticaria and hemodynamic changes

57
Q

Heparin Reversal

A

Protamine for heparin neutralizaion (100%)

FFP

58
Q

What is the dose of protamine for heparin reversal?

A

1-1.5mg for each 100 units of heparin administered

59
Q

Low Molecular Weight Heparins

A

are derived from standard commerical grade unfractionated heparin by chemical depolymerization to yield fragments approximately 1/3 the size of heparin

60
Q

What is the difference in the anti-activated factor ten to anti-activated factor 2 in LMWH vs unfractionated heparin?

A

LMWH - antiactivated factor X to antiactivated factor 2 activity is 4:1 to 2:1
UH- antiactivated factor X to anti-activated factor 2 activity is 1:1

61
Q

Compare the protein binding of LMWH vs UH

A

LMWH less protein bound

UH strongly protein bound

62
Q

Compare dosing between LMWH and UH

A

LMWH- elimination 1/2 life 24 hours, once daily dosing

UH- elimination 1/2 life 2-3 hours, repeat dosing every 8-12 hours

63
Q

Advantages of LMWH

A

reduced dosing frequency and the lack of need for monitoring
more predictable pharmacokinetic response
fewer effects on platelet function
reduced risk for heparin induced thrombocytopenia

64
Q

Disadvantages of LMWH

A

more expensive
surgery must be delayed 12 hours after last dose
protamine only neutralizes 65% of anti-factor X activity of LMWH a more complete reversal of LMWH must be wuth FFP

65
Q

Enoxaparin

A

binds to and accelerates anti-thrombin

inhibits factors Xa nad IIa

66
Q

What does factor Xa in enoxaparin do?

A

catalyzes the conversion of prothrombin to thrombin, so enoxaparin’s inhibition of this process results in decreased thrombin activity and prevention of fibrin clot formation

67
Q

Direct Oral Anticoagulants are

A

alternatives to warfarin

68
Q

Direct oral anticoagulants indications

A

treatment of VTE
prevention of embolic stroke
prophylaxis in patients undergoing surgery

69
Q

Advantages of Direct Oral Anticoagulants

A

rapid onset with peak effect in 2-4 hours
predictable pharmacodynamics
minimal drug interactions
no required routine laboratory monitoring

70
Q

Direct thrombin IIa inhibitor

A

dabigatran (pradaxa)

71
Q

Dabigatran

A

renally eliminated (reduce dose)
1/2 life 12 hours
Reversal- idarucizumab (praxbind)

72
Q

Monitoring of Dabigatran (Pradaxa)

A

coagulation assay
dilute thrombin time (more reliable and precise measurement)
aPTT (however, a normal aPTT does not exclude residual anticoagulant effect)

73
Q

Idarucizumab

A

specific antidote for dabigatran
binds to dabigatran with 350 fold higher than thrombin
1/2 life is 45 mins

74
Q

Direct Factor Xa inhibitors

A

rivaroxaban (xarelto)
apixaban (Eliquis)
Edoxaban (Savaysa)

75
Q

Edoxaban (Savaysa)

A

Direct Factor Xa inhibitor

MOA hepatic metabolism

76
Q

Monitoring of Edoxaban (Savaysa)

A

coagulation assay - anti Xa
ROTEM is not sensitive
PT can be helpful indicator for rivaroxaban only

77
Q

DOAC treated Patients undergoing Surgery (minimal bleeding)

A

likely safe to undergo with no DOAC interruptions (minor dental procedures, cataracts, skin biopsies)

78
Q

DOAC treated Patients undergoing Surgery (low bleeding risk)

A

hernia repair

generally recommended stopping DOCAs for 24 hours prior to elective surgery

79
Q

DOAC treated Patients undergoing Surgery (high risk)

A

cardiac, intracranial
generally recommend interruption of DOAC therapy prior to 48 hours to surgery
* longer needed for renal patients taking dabigatran

80
Q

Categories of Antiplatelet Agents

A

cyclooxygenase inhibitors
P2Y12 Receptor antagonist
Glycoprotein IIB/IIIA inhibitors

81
Q

Antiplatelets

A

suppress platelet function (inhibit platelet aggregation) for prevention of thrombosis

82
Q

Aspirin

A

exerts antithrombic effects by inhibiiting platelet aggregation
inhibits thromboxane A2 synthesis by interfering wiht the activity of cyclogenase 1 and 2 enzymes and the subsequent release of ADP by platelets and their aggregation
effects are irreversible and last the life of the platelet

83
Q

Dose of aspirin

A

81-325mg

84
Q

NSAIDs

A

ketorolac, naprosyn, ibuprofen

85
Q

MOA of NSAIDs

A 
same mechanism of action as aspirin (nonselective cox inhibitors) but they are reversibly depress thromboxane A2 production by platelets
more temporary (24-48 hours) and are often held prior to surgery
86
Q

Primary prophylaxis in the management of ASA in the perioperative period

A

hyperlipidemia in the absence of established CV disease
ASA should be continued in the perioperative period up to and including the day of the procedure
ASA may be held for a few days at the discretion of the surgeon or procedural physician due to possible heightened risk for perioperative bleeding

87
Q

Secondary prophylaxis in the management of ASA in the perioperative period

A

A fib, previous MI, stent

ASA should be continued in the perioperative period up to and including the day of the procedure

88
Q

What specific circumstances do you hold ASA?

A

intracranial, middle ear, posterior eye or intramedullary spine surgery; possibly in prostate surgery

89
Q

P2Y12 receptor antagonist

A

clopidogrel (plavix) and ticagrelor (brillinta)

must be discontinued 7 days prior to elective surgery

90
Q

Clopidogrel and ticagrelor are

A

inhibitors of platelet activation and aggregation through irreversible binding of its active metabolite to the P2Y12 class of ADP receptors in platelets

91
Q

What is Clopidogrel metabolized by and what is its effect?

A

prodrug
metabolized by CYP450 enzymes to produce the active metabolites that inhibits platelet aggregation for the the life of the platelet

92
Q

What is best to restore hemostasis for emergent surgery with a patient taking P2Y21 receptor antagonist or Platelet Glycoprotein IIB/IIIa antagonist ?

A

platelet transfusion

93
Q

Indications for P2Y12 receptor antagonist

A 
secondary prevention of MI, CVA
coronary artery stenting
acute coronary syndrome
peripheral artery disease
as a general approach, elective surgical procedures should be delayed by at least 6 weeks after BMS and ideally 6 months after DESd
94
Q

ASA and P2Y12 receptor antagonists work

A

synergistically

95
Q

Withdrawl of ASA in patients with CAD is associated with a

A

2-4 fold increase in death/MI

96
Q

Platelet Glycoprotein IIB/IIIa antagonist act at teh

A

corresponding fibrinogen receptor that is important for platelet aggregation
blocks fibrinogen which is the final common pathway of platelet aggregation

97
Q

What are Platelet Glycoprotein IIB/IIIa antagonist used for?

A

ACS, angioplasty failure, stent thrombosis

98
Q

Platelet Glycoprotein IIB/IIIa antagonist are

A

abciximab (reopro)
tirofiban (aggrastat)
epitifibatide (integrilin)

99
Q

Platelet Glycoprotein IIB/IIIa antagonist Monitoring

A

their effects can be monitoring with ACTs and reversible with the clearance of the drug
most of these agents are renally excreted and have half-lives around 2.5 hours except abciximab

100
Q

Garlic

A

inhibits platelet aggregation d/c for 7 days

101
Q

Gingko

A

inhibits platelet aggregation factor discontinue for 36 hours

102
Q

Ginseng

A

inhibits platelet aggregation and lowers BG

check pt/ptt and glucose d/c for 24 hours (preferably 7 days)

103
Q

Black Cohosh

A

includes small amounts of anti-inflammatory compounds, including salicylic acid

104
Q

Feverfew

A

prevents migraines
increases risk of bleeding because it individually inhibits platelet aggregation, has additive effects with other antiplatelet drugs

105
Q

Feverfew has additive effects with

A

warfarin

106
Q

Plasminogen

A

is a serum protein that is absorbed into the clot at its formation

107
Q

Plasmin

A

breaks down fibrin and fibrinogen

is cleaved from plasminogen

108
Q

Where is tissue pasminogen activator and urokinase-type plasminogen activators released from

A

capillary endothelium

109
Q

Fibrin specific agents (thrombolytics)

A

alteplase
reteplase
tenecteplase

110
Q

Non-fibrin specific agents

A

streptokinase

111
Q

Thrombolytics

A

possess inherent fibrinolytic effects or enhances the body’s fibrinolytic system by converting endogenous pre-enzyme plasminogen to the fibrinolytic enzyme plasmin

112
Q

Thrombolytics (contd)

A

convert plasminogen to the active form, plasmin

plasmin breaks down fibrin

113
Q

Alteplase

A

recombinant tissue plasminogen activator
fibrin specific thrombolytic drug synthesized by endothelial cells
limited to use to the first 3-6 hours of ischemic stroke
can be administered systemically or directly into embolism (place of invasive lines before administration)
short 1/2 life (about 5 mins) usually administered as bolus then infusion

114
Q

Streptokinase

A

protein produced by beta hemolytic streptococci
not an enzyme, noncovalently binds to plasminogen and converts it to a plasminogen-activator complex that acts on other plasminogen molecules to generate plasmin
elimination half time is 20 minutes
bacterial product is may stimulate antibody production and subsequent allergic reactions (even if years later)
it is least expensive of thrombolytic drugs

115
Q

Adverse effects of Thrombolytics

A

bleeding
re-thrombosis
efficiacy depends on clot

116
Q

Thrombolytics possess

A

inherent fibrinolytic effects

117
Q

Antithrombotic drugs influence

A

the formation of clot by inhibiting platelet activity

N929 Pharmacology (16 decks)

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