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Renal, Hematological, and Cardiovascular Organ Systems > Pharmacology-Anticoagulants and antiplatelet drugs and thrombolitics > Flashcards

Pharmacology-Anticoagulants and antiplatelet drugs and thrombolitics Flashcards

1
Q

What is hemostasis?

A

includes mechanisms which inhibits the loss of blood from damaged vessels

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2
Q

what are the physiological consequences of coagulation?

A

wound repair and healing, integrity of hte circulatory system, and prevention of exsanguination ((blood loss)

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3
Q

what are the pathological consequences?

A

cardiovascular disease, vascular injury and tissue trauma

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4
Q

this pathway is rapid and massive in response due to?

A
  • proteolytic positive feedback that enhances factor activation
  • normally high plasma concentration of prothrombin and fibrinogen
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5
Q

what is fibrinolysis modulated by?

A

plasminogen activatior inhibiotr-1 which inhibits t-PA, and by a2-antiplasmin

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6
Q

what are the therapeutic options?

A

prevent the formation of pathologic thromubs

-destroy formed pathological thrombus

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7
Q

How do you prevent the formation of pathologic thrombi?

A
  • traditional approach– anticoagulant drugs (heparin and warfarin)
  • newer approach– prevention of arterial damage, and inhibiton of platelet aggregation (asprin or ticlopidine)
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8
Q

How do you destroy formed pathological thrombi?

A

dissoling preformed closts is difficult to achieve w/o causing bellding but fibrinolytic drugs like sreptokinase, rtPA, retalplase adn ASPAC can be used in emergency

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9
Q

What is the mechanism of heparin?

A

binds to antithrombin III and increases its affinity for its clotting factors, that are serine proteases, X, Thrombin

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10
Q

what is the pathophys of HIT?

A

platelet factor 4 binds to heparin and when a patient is no heparin for 5-10 days
Abs can form against the complex of heparin-PF4 and can :
-activate platelts to form clots in arteries,
-release more PF4 from their alpha granules which cross react with heparin-PF4 complex on endothelial cells and destroys the endothelial cells

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11
Q

What is the clinically useful coumarins?

A

warfarin

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12
Q

what is the molecular action of warfarin?

A

binds to the vit k epoxide reductase and block its activity

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13
Q

what are warfarin’s pharmacokinetics?

A

-oneset, considerably delayed (36-72 hrs)
(due to long t1/2 of warfarin adn the fact htat pre-existing clotting factors are slowly cleared from the blood)
-duration: prolonged (proportional to the elimination T1/2 (25-60Hs)

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14
Q

When is warfarin used?

A
  • over lap with heparin therapy to avoid long delay in onset of action
  • DVT
  • PE
  • Arterial fib
  • Rheumatic hrt disese
  • Mechanical and prosthetic hrt valves
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15
Q

What is warfarin’s therapeutic window?

A

narrow

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16
Q

is there a variablility in dose of warfarin?

A

considerable inter-indicidaul and intra-indivdual variability

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17
Q

Is monitoring required for warfarin?

A

yes,

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18
Q

what is the saftey profile for warfarin?

A

difficut in maintaining pts within therapeutic w/in the target theraptuitc range (INR 2-3)
-contributes to and increased risk of bleeding

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19
Q

What are the low molecular weight heparins?

A

Enoxaparin, Danaproid

  • smaller, active pieces of regular heparin
  • greater anti-Xa activity, less antiplatelet activity
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20
Q

What are LMWH used for?

A

prophylaxis of DVT associated with hip and abdominal surger

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21
Q

What is the differnce b/t LMWH versus Heperain?

A

longer duration, simpler kinetis, clotting test not usally required

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22
Q

Is there cross reaction with HIT with use of LMWH?

A

yes!!!

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23
Q

what are the limitation of heparins?

A

parenteral administration only
risk of heparin-induced thrombocytopenia
need for lab monitoring (platelet cound)

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24
Q

what are the limitations of Warfarin?

A

narrow therapeutic window
significant interaction with food and other drugs
need for frequent lab monitoring and dose adjustment

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25
Q

What are the direct thrombin inhibitors?

A

hirudin
leprirudin
Argatroban
Dabigatran

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26
Q

what is hirudin?

A
  • found in slaivary glands of medicinal leech
  • direct thrombin inhibitor (doesn’t require ATIII
  • can be used in pts with heparin-induced thrombocytopenia
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27
Q

What is lepirudin?

A

A recombinant derivative of hirudin

  • shorter half life (80min)
  • renal elimination
  • HIT approved
  • IV
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28
Q

what is the mechanism of DTIs?

A

-Block both circulating and clot-bound thrombin!!!!
the bind directly to thrombin and inhibit the active site
-have potential for greater anticoagulant action than heparin. further, the direct throbin inhibitors that bind reversibly may also avoid any increase in bleeding risk

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29
Q

Which DTIs inhibit thrombin reversible and which are irreversible?

A

hirudin, lepirudin is irreversible at the active site

argatroban and dabigatran bind reversibly at active site

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30
Q

what are the characteristics of DTIs?

A
  • specific adn potent direct inhibiton of thrombin, independent of antithrombin III
  • inhibit thrombin-mediated activation of clotting factors (V,VIII,XI,XIII,) and platetlets
  • action against free (soluble) and clot-bound thrombin
  • unaffected by factors that neutralize heparin
  • don not induce immune-mediated thrombocytopenia
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31
Q

What are the PK charcteristics of dabigatran?

A

oral
t1/2- 12 hrs
renal elimination

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32
Q

What are the PK charcteristics of argatroban?

A

iv
t1/2- 45min
liver elimination

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33
Q

What are the PK charcteristics of hirudins?

A

iv and subcu
t1/2 iv-60 min subcu- 120 min
renal elimination

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34
Q

what is the problem with dabagatran if od?

A

no antidote

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35
Q

venous thrombosis

A

acute: heparin
Chronic: warfarin

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36
Q

TIA, thrombotic strok

A

acute: heparin, aspirin
chronic: aspirin, clopidogrel

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37
Q

Unstable angina

A

acute; heparin, aspirin, GpIIb/IIIa inhib

chronic: aspirin, clopidigrel

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38
Q

MI

A

acute: thrombolytic, heparin, aspirin,
chronic: aspirin

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39
Q

atrial fib

A

acute: heparin
Chronic: warfarin (aspirin)

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40
Q

Angioplasty/ stent

A

acute: heparin, GpIIb/IIIa inhib
Chronic: aspirin, clopidigrel

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41
Q

what are arterial thromboisis?

A

stroke
MI
peripheral artery occlusion
Endothelium (damaged- atherosclerosis, HTN, homocystine etc)
Platelets (adhere to vessel wall and to each other)

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42
Q

what are venous thromboisis?

A

DVT
PE
other sites (intracrania, intra-abdominal/ plevic upper extremities)

43
Q

What are arterial clots?

A

white thrombi, pale on one end
cause death in 40% of events
cause maj disability in 20%

44
Q

What are venous clots?

A

red chrombus
-cause death in 6% of events
after effects (post phlotic sysntrome, veins are dammaged by the clots, edema, breakdown of tissue ets)

45
Q

What are the consequences of arterial thrombosis>

A

ischemic injury/ death of tissue (infarcation)

46
Q

what are the actue management of arterial thrombi?

A

thrombectomy, mechanical removeal of clot
stent placement (make vessle wider)_
-thrombolysis
-follow with anti-platelet adn anticoagulant drugs

47
Q

How do platelets reduce reactivity?

A
  • block thromboxane production (ASA)
  • Block IIb IIIa receptors (abciximab, eptifibatide)
  • reduce thrombin production (heparin)
  • Block receptors for ADP (clopidogrel)
48
Q

What favor venous thromboemoblic disease?

A 
immobility- DVT in 10-40% hospital admissions 
-DVTs in 40-60% orthopedic admission 
thrombophilia 
-deficiency of PC, PS, AT, V liden etc
procoagulant states
-acquired (CA, prg, trauma, etc)
-congential (high VIII, abnormal I, etc)
49
Q

What are the symptoms of DVT?

A 
pain in calf
swelling calf/ entire leg
homans sing (pull up on toes-- pain)
none of the above
sudden death
50
Q

What are the symptomps of PE?

A 
SOB
pleuritic chest pain 
hemoptysis 
shock 
none of the above
sudden death
51
Q

What is the txment of PE?

A

anticoagulation

thrombolysis

52
Q

what are the reasons for antivoagulation?

A

prevent extension of clot form calf into thigh
prevent PE
prevent recurrence
prevent post-phlebitic syndrom
-precent emboli form atrial fib and mechanical hrt valves

53
Q

What are the drugs we use to try and dissovel clots (thrombolytics)

A

tissue plaminogen activator (t-PA)
urokinase
thrombectomy

54
Q

what are the drugs we use to anticoagulate?

A 
heparin 
LMWH
warfarin 
Lepirudin 
aragatroban 
dabigatran 
fondaparinus
rivaroxban
55
Q

what determines if heparin dose needs to be changed?

A

the PTT

56
Q

how can the effect of heparin be reversed?

A

UFH- protamine sulfate (IV)

LMWH - protamine sulface only partially effective)

57
Q

what is the desired INR for warfarin?

A

for txment and prophylaxis DVT ~ 2.5

-for protectiono f mechanical hrt valves ~3.0

58
Q

What reversed the effect of warfarin?

A

vit K
prothombin comple concentrate
FFP

59
Q

What occur with an IM injection during warfarin toxicity?

A

hematomas!!!!!!! have to give antidote by mouth, or subcu!

60
Q

what are the side effects of anticoagulants?

A

bleeding
coumarin necrosis (big blisters, swelling and necrosis)
HIT syndrome (can cause gangrenous fingers and other appendices)
osteopenia
brusing, intracranial bleeding w/o head bump

61
Q

what are most effective at preventing arterial thrombosis?

A

antiplatelet drugs (asprin and clopidogrel)

62
Q

antiplatelet drugs (asprin and clopidogrel) an less effective at preventing what?

A

venous thrombosis

63
Q

what to thrombolytic drugs lyse?

A

arterial and venous thrombi

64
Q

what is asprin?

A

a cox inhibitor (1 and 2)

65
Q

what is dypyridaole?

A

a PEI

66
Q

what is clopidogrel and prasugrel?

A

platelet receptory inhibiotrs (ADP r antagonists)

67
Q

what are eptifibidate adn abciximab?

A

glycoprotein IIb/IIIa receptor antagonists

68
Q

Whata are streptokinase, urokinase, TPA, and reteplase?

A

thrombolytic drugs

69
Q

what does the inhibition of COX1 prevent?

A

synthesis of pro-aggregatory prostaglandin and thrombozane (TBX)

70
Q

what is the half-life of aspirin?

A

4-7 days

71
Q

what are the adverse effects of aspirin?

A

GI bleeding
hemorrhagic stroke
asthma (leukotrines)

72
Q

what is contraindicated with aspirin?

A 
coumarin anticoagulants (increases risk of bleeding)
peptic ulcer disease, 
aspirin hypersensitivity (asthma)
73
Q

What is prostacyclin?

A

IDK!

74
Q

how does aspirin bind and what about the other cox inhibitors?

A

asprin acetylates cox, and the other NSAIDS do not! not hey are reversible

75
Q

What should you use for antiplatelet effect?

A

asprinin or clopidogret

76
Q

what is the mechanism of action for PDIs?

A

inhibit enxyme that degrades cAMP in cells, –> ^ platelte cAMP in response to prostacyclin inhibits aggregation. also activates platelet adenylate cyclase by inhibiting adensonine uptake

77
Q

what are the properties of dpyridamole?

A

-weak antiplatelet effect used alone
-evidance of added benefit in combo with asprin in pts with cerebrovascular disease
-reduces thromboembolic events combined with warfarin in pts with prosthetic hrt valves
-potent vasodilator, used IV to induce coronary steal in cardiac studies
(inhibits PD and reuptake of adenosine)

78
Q

what are the adverse effects of dipyridamole?

A

headache
dizziness
GI upset

79
Q

What is the efficacy of combo asprin with dypyridamole in cerebrovascular disease?

A

additon of extened release dypyridamole ot asprinin prvides added benifit in pts with cerebrovascular disease
-blocking more than one effect

80
Q

what are the properties of clopidogrel?

A
  • a produrg! metabolized by Cype2C19 to become biologically acitve
  • higher dose needed in poor metabolizers (2-14% of population)
  • CYP2C19 inhibiotrs (omeprazole) may interfere with formation active metabolite of clopidogretl and reduce efficay
81
Q

what are the propterites of prasugrel?

A

prodrug, but activeated by CYP3A4 adn CYP2B6

-consider in ptns with CYP2C19 gene polymorphisms

82
Q

what is prasugrel more at risk for than clopidogrel?

A

slightly higher bleeding risk

83
Q

is clopidogrel offer additional benefit over asprin alone?

A

not siginifcatly in gerneral population

if had periferal vascular disease saw an improvment so in the pts yes…

84
Q

what are the benifits of clopidogrel + aspirin?

A

with pts unstable angiina - saw and inreask bleeding complication whith CABG

  • in percutaneous coronary intervention - reduced cardiovascular endpoints
  • no evidance of benifit = ^ bleeding risk
85
Q

what is the mechanism of eptifibidate

?

A 
synthetic polypeptide (6aa)
-prevents binding of fibrinogen, vWF to GpIIb/IIIa-R
86
Q

What is the mechanism of abciximab?

A

rab fragment of chimeric human-murine monoclonal antibody 7E3
-blocks Gp IIb/IIIa receptor, vitronnectin R

87
Q

What are the benifit of admistering glycoprotein IIb/IIIa recetpor inhibitor prior to cardiac catherization oand angioplasty?

A

prevent in-stent thrombosis/stenosis

88
Q

what is the drug that can rescue failed angioplasty?

A

abciximab!

89
Q

what is the mechanism of ation for fibrinolytic drugs?

A

promote firbrinolysis by convesion of incative plasma zymogen, plasminogen to active fibrinolytic enzyme plasmin

  • plasmin degrades fibrin in thromus
  • plasmin also degrades fibrinogen in plasma and can induce sysytemic lytic state which may increase risk of bleeding
90
Q

what are the therapeutic uses of fibrinolytic drugs?

A

MI, PE, DVT, other arterial or venous thrombosis, thrombotic stroke

91
Q

what is systemic lytic state and how does it occur>

A

when plasmin degrades fibrinogen in plasma, and casues and increased risk for bleeding

92
Q

what are the maj toxicity for throbolytic therpy?

A

systemic lytic state
serious hemorrhage occur in 2-4%
most serious side effect is intracranial hemorrhage

93
Q

what occured when strptokinase and asprine were given together?

A

additive effect

94
Q

what are the first generation thrombolytics?

A

streptokinase

urokinase

95
Q

what are the properties of strptokinase?

A
  • isolated from strptococci
  • unique mehcanism – forms activator comples with plasminogen (in intrisnis protease activety)
  • activates circulating and fibrin-bound plasminogen indiscriminantly, producing systemic lytic state
96
Q

what is the problem of streptokinase?

A

can only be give once!!

stronly immunogenic, due to antistreptokinase anibodies adn causes serum sickness etc

97
Q

What are the properties of urokinase?

A

-produced from human fetal kindey cells
-trypsin-like serine protease, directly cleaves plasminogen to plasmin
-nonspecific degradation of fibrin, fibrinogen and other plasma proteins (systemic lytic state)
-not antigenic - no allergic response!!!
indicated for txmetn of acute massive or hemodynamically usntable pulmonary embolism

98
Q

what are the second generation thrombolyics?

A

tissue-type plasminogen activator (t-PA)

99
Q

what are the properties of (t-PA)?

A
  • naturally-occuring protein relesaed by vascular endothelial cells (serine protease)
  • produced by recombinant technology
  • relatiely firin specific
  • -t-PA fibrin, and plasminogen form a ternary complex, localizes plasminogen activation to fibrin clot
100
Q

waht is t-PA indicated for?

A

acute MI
pe
acute ischemic stroke

101
Q

what are the thrid generation thrombolytics?

A

reteplase r-PA

102
Q

what are theproperties of reteplase?

A

deletion variant of t-PA contianing only the kringle-2 and serine protease domains
prolonged 1/2 life, can be admisiter by bolus injection rather than bolus/infusion
shrot-term mortality comparable to that with strptokinase (^iincidence of hemorrhagic stroke)

103
Q

what is aminocaproic acid?

A

A fibrinolytic inhibitor
inhibits plasmin, and analogue of lysine,
treats excessive bleeding from systemic hyperfibrinolysys and urinary fibrinolysys

Renal, Hematological, and Cardiovascular Organ Systems (9 decks)

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