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Pharmacology: Exam 2 > Lecture 7: Anticoagulants > Flashcards

Lecture 7: Anticoagulants Flashcards

1
Q

Explain critical components of the vascular system

A
  • Blood is free flowing and does not coagulate naturally
  • Endothelial cells express inhibition factors of coagulation
  • This prevents platelets from activating
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2
Q

What is the major function of endothelium in the vascular system?

A

Anti-coagulant system

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3
Q

1 of 2 anti-coagulation mechanism

Explain the Endothelial Anti-coagulation mechanism: Thrombin

Anti-coagulattion: to stop blood clotting

A
  1. Thrombin binds to thrombomodulin (on cell surface)
  2. Thrombin cleaves Protein C to activate it
  3. Activated Protein C forms a complex with Protein S
  4. Complex leads to inactivation of coagulation factors Va and VIIIa
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4
Q

2 of 2 anti-coagulation mechanism

Explain the Endothelial Anti-coagulation mechanism: Heparan

Anti-coagulattion: to stop blood clotting

A
  • Heparan sulfate proteoglycans (on endothelium) binds to anti-thrombin III to activate it
  • Anti-thrombin III strongly inhibits thrombin and other key coagulation factors
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5
Q

Tissue factor pathway inhibitor requires ____________ to inhibit tissue factor/factor VIIa complexes

A

Protein S

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6
Q

List the 3 major mechanisms that allow endothelial cells to block hemostasis

Hemostasis: Stop bleeding

A
  1. Platelet inhibitory effects
  2. Anti-coagulant effects
  3. Fibrinolytic effects
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7
Q

1 of 3 mechanism to block hemostasis

Explain the Platelet Inhibitory Effects

A
  • Endothelial cells makes PGI2, NO and degrade ADP through cell surface-expressed adenosine diphosphatases
  • Which together block platelet activation

PGI2: Prostaglandin I2
NO: Nitric oxide

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8
Q

2 of 3 mechanism to block hemostasis

Explain the Anti-coagulant effects

A

Endothelial cells normally control through their expression of:

  • Thrombomodulin
  • Protein C receptor
  • Cell surface heparan sulfate
  • Tissue factor pathway inhibitor
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9
Q

3 of 3 mechanism to block hemostasis

Explain the Fibrinolytic Effects

A
  • Endothelial cells make tissue plasminogen activator (tPA)
  • tPA converts plasminogen to plasmin
  • Plasmin degrades fibrin clots
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10
Q

Define Hemostasis

A

The functional ability to stop bleeding invloves platelets, coagulation factors, endothelial cells and subendothelial extracellular matrix

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11
Q

What are the two key items that allow our bodies to perform Hemostasis?

A
  1. Function and appropriate number of platelets
  2. Normal levels of coagulation factors
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12
Q

List the 5 key steps in Hemostasis

A
  1. Arteriolar Vasoconstricton
  2. Primary hemostasis
  3. Secondary hemostasis
  4. Clot stabilization
  5. Resortion/Resolution of clot
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13
Q

Step 1 of 5: Hemostasis

What occurs during Arteriolar vasconstriction?

A

Reduces blood flow to injured area

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14
Q

Step 2 of 5: Hemostasis

What occurs during Primary hemostasis?

A

Formation of platelet plug

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15
Q

Step 3 of 5: Hemostasis

What occurs during Secondary hemostasis?

A

Formation of fibrin clot

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16
Q

Step 4 of 5: Hemostasis

What occurs during Clot stabilization?

A

Platelet aggregation and cell-mediated clot contraction and stabilization

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17
Q

Step 5 of 5: Hemostasis

What occurs during Resorption/Resolution of clot?

A

Fibrinolysis (breakdown of fibrin in blood clot)

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18
Q

Define Thrombosis

A

Coagulation or clotting of the blood in the vessels or heart

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19
Q

What causes Thrombosis

HIGH Yield

A

Vicrhow Triad

  • Endothelial injury (e.g. hypercholesterolemia, inflammation)
  • Abnormal blood flow (e.g. afib, stasis, turbulence)
  • Hypercoagulabilty (e.g. Inherited or Acquired diseases)
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20
Q

What is an acute myocardial infarction?

A

Thrombosis of the coronary vasculature

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21
Q

What causes Pulmonary Embolism?

A
  • Deep venous thrombosis (in lungs)
  • A cause of sudden death
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22
Q

What organ does a red infract occur in?

A

Lungs

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23
Q

What organ does a white infarct occur in?

A

Spleen

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24
Q

What occurs in a renal infarct?

A

Necrotic tissue replaced by fibrotic scar

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25
Q

List pharmacological regulators of hemostasis

A
  • Platelets inhibitors
  • Anticoagulants
  • Thrombolytic agents
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26
Q

List the drugs that are Platelets inhibitors (3)

A
  • Abciximab-(Inhibit GP IIb/IIa receptors of platelets)
  • Aspirin-(COX 1/2 inhibitor=No thromboxane A2)
  • Clopidogrel-(P2y12 receptor antagonist=blocks ADP receptors)
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27
Q

List the drugs that are Anticoagulants (3)

A
  • Heparin-(Increase antithrombin activity)
  • Rivaroxaban- (Direct inhibitor of Xa)
  • Warfarin- (Vit K analog=inactive clotting factors)

Coagulation casacade needs vitamin K

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28
Q

List the drugs that are Thrombolytic agents (1)

A
  • Alteplase (tPA)- (Converts plasminogen to plasmin→Degrades fibrin)
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29
Q

Using the image below explain the coagulation cascade pathway thats Vitamin K dependent

Major pathway affecting coagulation in humans
A
  1. Stimuated by Tissue factor (TF) that activates Factor VIIa
  2. Factor VIia activated IXa
  3. Factor IXa and VIIIIa wok together to activated Factior Xa
  4. Xa turns pro-thrombin to thormbin
  5. Thrombin is going to turn fibronogen to fibrin

Circulating vWF stabilizes Factor VIII

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30
Q

Where is the location of the coagulation cascade?

A

On the activated platelet cell surfaces

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31
Q

What is required for the coagulation factors (and Ca2+ ions) on the platelet surface?

A

𝛾-carboxylation which is Vitamin K dependent

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32
Q

What does the drug Warfarin block in the coagulation cascade?

A

Vitamin K-dependent process (𝛾-carboxylation)

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33
Q

Explain the mechanism(s) of a Resting platelet

A
  1. On a resting platelet, the GP IIb/IIIa receptors are inactive
  2. The endothelial cells release Prostacyclin into the plasma
  3. Prostacyclin binds to platelet membrane receptors, causing the increase in cAMP
  4. cAMP (1) stabilizes the GP IIb/IIIa receptors to keep them inactive and (2) decreases Ca2+ and inhibit release of granules containing platelet aggregation agents
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34
Q

What are the steps of platelet activation?

What happens after a wound?

A
  1. Platelet adhesion
  2. Platele activation
  3. Platelet aggregation
  4. Formation of platelet fibrin plug
  5. Fibrinolysis
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35
Q

Explain the mechanism(s) of platelet adhesion

A
  1. Wound occurs, GP IIb/IIIa receptors are activated
  2. Activated platelets cover and adhere to collagen at the exposed subendothelial surface of damaged epithelium
  3. cAMP is decreased
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36
Q

Explain the mechanism(s) of platelet activation

A
  1. Activated platelets release chemical mediators
  2. Chemical Mediators include: Thromboxane A2, ADP, Thrombin, Serotonin and PAF
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37
Q

Explain the mechanism(s) of platelet aggregation

A

1.More platelets are recriuted to form a platelet plug
2.Thrombin, thromboxane A2, ADP cause an increase in Ca2+ levels

38
Q

What does elevated Ca2+ levels cause during platelet activation?

A
  • Release of platelet granules
  • Activation of thromboxane A2 synthesis
  • Activation of the GP IIb/IIIa receptors
39
Q

Explain the mechanism(s) of the formation of platelet-fibrin plug

A
  1. Activation of cogulation factors in plasma
  2. (Coagulation casade) Prothrombin→Thrombin→Fibrinogen→Fibrin
  3. Platelet fibrin plug forms
40
Q

Explain the mechanism(s) of Fibrolysis

A
  1. Plaminogen forms Plasmin activated by tissue plasminogen activator (tpa)
  2. Plasmin breaks down fibrin plug
41
Q

What is the von Willebrand Factor (vWF)?

HIGH yield

A

Factor that helps platelets adhere to collagen when endothelium is damaged

42
Q

What is GpIb factor?

LOW yield

A

Factor that binds platelet to vWF on endothelim

43
Q

What is GpIIb-IIIa factor?

A

Factor that binds platelet to fibrnogen

44
Q

List examples of human genetic diseases with platelet adhesion defects and the factors that are affected

A

Platelet adhesion defects-cannot form clots

  • von Willebrand diease-vWF
  • Bernard-Soulier Syndrome-Gplb
  • Glanzmann thrombasthenia-GpIIb-IIIa
45
Q

What is required for activation of platelet integrin (⍺IIbβ3)?

Low yield

A

Talin and Kindlin

46
Q

What inhibits Thrombin?

A

PGI2

47
Q

Anti-platelet drug

What does the drug Aspirin target?

A
  • Blocks COX-1 which inhibits the creation of Thromboxane A2 (TxA2)
  • This STOPS platelet recruitment and activation
48
Q

Anti-Platelet drug

What does the drug Clopidrogel target?

A

Blocks ADP which STOPS platelet recruiment and activation

FYI Other drugs with similar mechanism:
Ticlopidine, Prasugrel, Cangrelor, Ticagrelor

49
Q

Anti-platelet drug

What does the drug Vorapaxar target?

A

Blocks Thrombin which STOPS platelet recruitment and activation

50
Q

Anti-platelet drug

What does the drug Abciximab target?

A

Blocks GPIIb/IIIa activation which STOPS platele aggregation

FYI Other drugs with similar mechanism:
Eptifibatide, Tirofiban

51
Q

What is the mechanism of action of Asprin?

A
  • Inhibits the synthesis of thromboxane A2 (TXA2) d/t the irreversible acetylation of Cyclooygenase-1 (COX-1)
  • Can NOT synthesise more COX during its 10-day lifespan (why we take low doses)
  • (TXA2 function: platelets Δc shape, releases granules & aggregation)
52
Q

What are the therapeutic use(s) and side effects of Asprin?

A
  • Therapeutic Use: 1° prohylaxis of Myocardial Infarction (MI) and Transcient Ischaemic Attack (TIA)
  • Side Effects: Bleeding, GI Ulcers

Prohpylaxis: action take to prevent disease (taken before(
TIA: “mini stroke”

53
Q

Asprin

  • Type (class)
  • Mechanism
  • Therapetic Use
  • Side Effects
A
  • Type (class): Anti-platelet drug
  • Mechanism: Inhibit TXA2 by blocking COX-1 (stop platelet recruiment and activation)
  • Therapetic Use: 1° prohylaxis of MI and TI
  • Side Effects: Bleeding. GI ulcers
54
Q

What is the mechanism of action of Clopidogrel?

A
  • Inhibits ADP-induced platelet-fibrinogen binding & subsequent platelet-platelet interaction (Stops primary platelet plug)
  • A P2Y12 receptor antagonist (ADP receptor)
55
Q

What are the therapeutic use(s) and side effects of Clopidogrel?

A
  • Therapeutic use: Aterial thromboembolism prophylaxis: Prevent myocardial infarction (MI), stroke
  • Side effects: Thrombocytopenia, Leukopenia, Thrombotic Throbocytopenic Purpura
56
Q

Clopidogrel

  • Type (class)
  • Mechanism
  • Therapetic Use
  • Side Effects
A
  • Type (class): Anti-platelet drug
  • Mechanism: Inhibits ADP-induced platelet-fibrinogen binding (stop platelet recruiment and activation)
  • Therapetic Use: Prevent MI & stroke
  • Side Effects: Thrombocytopenia, Leukopenia, Thrombotic Throbocytopenic Purpura
57
Q

What is the mechanism of action of Vorapaxar?

A
  • Inhibits thrombin mediated activation of platelets
  • A protease-activated receptor-1 (PAR-1) antagonist [thrombin receptor]
58
Q

What are the therapeutic use(s) and side effects Vorapaxar?

A
  • Therapeutic use: MI, Peripheral artery disease, ↓ thrombotic cardiovascular events w/ aspirin (ASA) and Clopidogrel
  • Side Effects: Hemorrhage: contraindicated in patients with
    1. active bleeding conditions
    2. history of TIA (“mini stroke”)
    3. Stroke
  1. Inntercranial bleeding, Anemia, Retinopathy (diplopia)
59
Q

Vorapaxar

  • Type (class)
  • Mechanism
  • Therapetic Use
  • Side Effects
A
  • Type (class): Anti-Platelet Drugs
  • Mechanism: Inhibits thrombin mediated activation of platelets
  • Therapetic Use: MI, Peripheral artery disease
  • Side Effects: Hemorrhage
60
Q

Which drugs can be combined to decrease thrombotic cardiovascular events?

A

Vorapaxar, Aspirin (ASA), and Clopidogrel

61
Q

What drug is a Fab fragment of chimeric human and mouse monoclonal Ab?

A

Abciximab

62
Q

What is the mechanism of action of Abcixmab?

A
  • Inhibits the glycoprotein IIb/IIIa receptors of platelets→decreases platelet aggregation w/ fibrinogen and vWF
63
Q

What are the therapeutic use(s) and side effects of Abciximab?

A
  • Therapeutic use: Acute coronary syndrome: percutaneous coronary intervention (PCI) used with asprin &/or heparin
  • Side Effects: Thrombocytopenia
64
Q

Abciximab

  • Type (class)
  • Mechanism
  • Therapetic Use
  • Side Effects
A
  • Type (class): Anti-platelet drug
  • Mechanism: GP IIb/IIIa inhibitor (stops platelet aggregation)
  • Therapetic Use: Acute coronary syndrome: PCI w/ aspirin &/or heparin
  • Side Effects: Thrombocytopenia
65
Q

Which drugs are used for percutaneous coronary intervention (PCI)?

A

Abciximab, Aspirin &/or Heparin

66
Q

What is the mechanism of action of Heparin?

A
  • Increase the rate of activity of antithrombin (Heparin binds to antithrombin III which inhibits serine protease clotting enzymes by forming a stable 1:1 molecular complex by association between an arginine-reactive site on antithrombin & active site of serine protease.)
  • Inhibits clotting factors IIa (thrombin) & Xa, (IXa, XIa & XIIa)
67
Q

What are the therapeutic use(s) of Heparin?

A
  • Thrombosis/Embolism: Prohylaxis (e.g. after major surgery & active Treatment (e.g. PE, DVT)
  • Disseminated Intravascular Coagulation (DIC)
68
Q

What are the side effects of Heparin?

A
  • Hemorrhage (<10%) anywhere in the body (e.g. GI)
  • Allergy (chills, fever, urticaria)
  • Thrombocytopenia (HIT) {<100,000/mm3)
    Heparin induces autoantibodies which destroy platelets and attack the lining of blood vessels which can trigger a coagulation cascade
    HIT can cause stroke & other thrombotic complications which can be life threatening
69
Q

What is the duration of usage for Heparin?

A

Used for the first 5 days to avoid the side effect thrombocytopenia

70
Q

Heparin

  • Type (class)
  • Mechanism
  • Therapetic Use
  • Side Effects
A
  • Type (class): Anti-coagulant drug
  • Mechanism: ↑ rate of activitiy of antithrombin III, Inhibit clottng factors IIa (thrombin) and Xa
  • Therapetic Use: Thrombosis/Embolism, DIC
  • Side Effects: Thrombocytopenia
71
Q

What is the mechanism of action for Enoxaprin?

A
  • Inhibits Xa via antithrombin III
  • Targets Xa more than IIa so there is less side effects (3-4:1)
  • Enoxaprin is a low molecular weight heparin (2-9 kDa, depolymerization of unfractionated porcine heparin)
72
Q

What are the therapeutic use(s) and side effects of Enoxaparin?

A
  • Therapeutic use: DVT prophylaxis, DVT Tx (+/- PE), Unstable angina/Non-Q-wave MI
  • Side Effects: Less than Heparin
73
Q

Enoxaparin

  • Type (class)
  • Mechanism
  • Therapetic Use
  • Side Effects
A
  • Type (class): Anti-coagulant
  • Mechanism: Inhibit factor Xa (via antithrombin III)
  • Therapetic Use: DVT prohylaxis
  • Side Effects: less than heparin
74
Q

What is the mechanism of action of Rivaroxaban?

A
  • Direct Xa inhibitor
  • Best for chronic therapy (10 days+)
75
Q

What are the therapeutic use(s) and side effects of Rivaroxaban?

A
  • Therapeutic uses: Atrial fibrilation: Prevent→Stroke, Systemic embolism, Prophylaxis of DVT: Knee, hip replacement
  • Side Effects: Hemorrhage: Spinal or epidural anesthesia or puncture
76
Q

Rivaroxaban

  • Type (class)
  • Mechanism
  • Therapetic Use
  • Side Effects
A
  • Type (class): Anti-coagulant drug
  • Mechanism: Inhibits Xa factor
  • Therapetic Use: Afib, Prophylaxis of DVT
  • Side Effects: Hemorrhage
77
Q

What is the mechanism of action of Warfarin?

A
  • Is a Vitamin K analog which blocks the 𝛾-carboxylation of several glutamate resides in clotting factors (II,VII,IX & X)
  • A racemic mixture, S-enantiomer 4x more potent than R-enantiomer
78
Q

What are the therapeutic use(s) of Warfarin?

A
  • MI, DVT, PE: prophylaxis & treatment
  • Atrial fibrilation: prevent embolization
79
Q

Whare are the side effects of Warfarin?

A
  • Hemorrhage
  • Necrosis (gangrene of the skin)
  • Hypercoagulation (transient)
    Warfarin blocks the biosynthesis of protein C which inactivates clotting factors Va, VIIa (via proteolysis), Because the slow onset of anticoagulation with warfarin therapy, Heparin tx is used for the 1st 5 days
  • Birth defects (facial, CNS)
80
Q

Why is Warfarin not used often as treatment? and what can be used if a pt acquires Warfarin toxicity?

A
  • Not used d/t MANY side effects (life-threatening)
  • Vitamin K is used when Warfarin toxicity occurs
81
Q

Warafin

  • Type (class)
  • Mechanism
  • Therapetic Use
  • Side Effects
A
  • Type (class): Anti-coagulation drug
  • Mechanism: Vit. K analog, blocks 𝛾-carboxylation in clotting factors
  • Therapetic Use: DVT, Afib
  • Side Effects: Hypercoagulation
82
Q

What is the mechanism of action of Altplase?

A
  • Converts plasminogen to plasmin which degrades fibrin & fibrinogen
  • Is a recombinant tissue plaminogen activator (tPA)
83
Q

What are the therapeutic use(s) of Atleplase?

A
  • Acute myocardial infraction
  • Pulmonary embolism
  • Acute ischemic stroke
  • Must be admistered ASAP
84
Q

Altepase

  • Type (class)
  • Mechanism
  • Therapetic Use
  • Side Effects
A
  • Type (class): Fibrinolytics
  • Mechanism: Degrades fibrin and fibrinogen (by activating plasminogen→plasmin)
  • Therapetic Use: Acute MI, pulmonary embolism, Acute ischemic stroke
  • Side Effects:N/A
85
Q

What is an important therapeutic in the treament of acute ischemic stroke?

A

Tissue plasminogen activator (tPA): Altepase

86
Q
  1. A subject arrives to screen for a new research trial. Upon reviewing their concomitant medications, you noticed he is on Rivaroxaban. What is the Mechanism of action for this drug?
    a. Increases Antithrombin III
    b. Vitamin K analog
    c. Inhibits GPIIb/GPIIIa
    d. Direct Xa inhibitor
A

d. Direct Xa inhibitor

87
Q
  1. Thrombocytopenia is a major side effect for what type of drug?
    a. P2Y12 Antagonist
    b. Anticoagulant that increases Antithrombin III
    c. Recombinant tpa
    d. PAR-1 Antagonist
A

b. Anticoagulant that increases Antithrombin III

88
Q
  1. You are volunteering at an emergency department and hear the doctor state a patient possibly having an acute ischemic stroke. What drug must be administered immediately?
    a. Alteplase
    b. Warfarin
    c. Heparin
    d. Vorapaxar
A

a. Alteplase

89
Q
  1. Which of the following drug is used for DVT prophylaxis and inhibits Xa?
    a. Warfarin
    b. Abciximab
    c. Clopidogrel
    d. Enoxaparin
A

d. Enoxaparin

90
Q
  1. Warfarin blocks:
    a. β-Carboxylation
    b. 𝛾-Carboxylation
    c. ADP
    d. Thromboxane a2
A

b. 𝛾-Carboxylation

Pharmacology: Exam 2 (10 decks)

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