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Fall 2020: Therapeutics 2 > Wendt's Antiplatelet Lectures > Flashcards

Wendt's Antiplatelet Lectures Flashcards

1
Q

Explain the role that platelets play in hemostasis.

A

Platelets are recruited to the site of vascular injury, where they are activated, and with the help of vWF and fibrinogen, form a platelet plug. This is known as primary hemostasis.

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2
Q

What are the three steps of platelet activation?

A
  1. Adhesion and shape change
  2. Secretion
  3. Aggregation
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3
Q

What molecule/chemical induces platelet aggregation and recruite more platelets to the site of injury?

A

ADP

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4
Q

Although platelets have organelles and secretory granules, they have no nucleus. Why?

A

Because they are just pieces of larger cells (megakaryocytes)

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5
Q

Platelet adhesion is mediated by what three processes?

A
  • GPIa binding to collagen
  • GPIb binding to vWF bridged to collagen
  • Shape change facilitating receptor binding
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6
Q

Fill in the blank: during platelet adhesion, intact endothelial cells secrete ________ to inhibit ___________.

A

PGI2 (prostacyclin), thrombogenesis

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7
Q

What molecules do platelet granules release during secretion?

A
  • ADP
  • TXA2
  • Serotonin (5-HT)
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8
Q

What do ADP, TXA2, and serotonin (5-HT) all have in common?

A
  • Released by platelet granules
  • Activate and recruit other platelets
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9
Q

What do TXA2 and serotonin (5-HT) have in common?

A

They are potent vasoconstrictors

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10
Q

Explain the process of platelet aggregation, step by step.

A
  1. ADP, 5-HT, and TXA2 activtation induce conformation of GPIIb/IIIa receptors to bind fibrinogen
  2. Platelets are cross-linked by fibrinogen
  3. Temporary hemostatic plug forms
  4. Platelets contract to form irreversibly-fused mass
  5. Fibrin stabilizes and anchors aggregated platelets
  6. Surface forms for clot formation
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11
Q

List the 5 classes of antiplatelet drugs.

A
  • COX-1 inhibitors
  • ADP receptor inhibitors
  • GPIIb/IIIa receptor blockers
  • Phosphodiesterase-3 inhibitors
  • Protease-activated receptor inhibitors
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12
Q

What drug class does aspirin belong to?

A

COX-1 inhibitor

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13
Q

Does aspirin inhibit COX-1 reversibly or irreversibly?

A

Irreversibly

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14
Q

How does aspirin inhibit COX-1?

A

By acetylation

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15
Q

What is the main consequence of permanent loss of platelet COX-1 activity?

A

Inhibition of TXA2 synthesis

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16
Q

At what dosing ranges is aspirin most effect as an antiplatelet therapy?

A

50 - 320 mg per day

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17
Q

Higher doses of aspirin inhibit the production of what molecule?

A

Prostacyclin

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18
Q

When is aspirin strongly indicated?

A
  • Acute coronary syndrome
  • Acute stroke
  • Secondary prevention of cardiovascular disease
  • Non-valvular atrial fibrillation (when CHA2DS2 - VASc = 0-1 or anticoagulation is contraindicated)
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19
Q

How does aspirin affect PT time?

A

It doesn’t; no increase in PT time even though bleeding time is prolonged

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20
Q

How long will it take for a patient to return to hemostasis after taking their last aspirin dose?

A

36 hours

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21
Q

When is aspirin modestly indicated?

A

Primary prevention of cardiovascular disease (in patients with higher-than-average 10-year risk)

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22
Q

In what 3 situations is aspirin not generally indicated?

A
  • Cancer prevention
  • Pain
  • Fever
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23
Q

What is the most prominant adverse effect associated with aspirin?

A

Upper GI bleeding

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24
Q

Why is upper GI bleeding an adverse effect of aspirin?

A

Because the COX-1 mediated prostaglandins needed for gastric mucosa production are inhibited

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25
Q

What three risk factors can increase the probability of developing an upper GI bleed while taking aspirin?

A
  • Older age
  • Concurrent use of NSAIDs
  • Alcohol
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26
Q

At what dose can acute aspirin overdose be induced?

A

Anything above 150 mg/kg

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27
Q

What doses of aspirin can be fatal?

A

>500 mg/kg

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28
Q

What are the five prominent symptoms associated with acute aspirin overdose?

A
  • Nausea
  • Vomiting
  • Diarrhea
  • Fever
  • Coma
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29
Q

What is the result of COX-2 producing prostacyclin in endothelial cells?

A

Vasodilation and inhibition of platelet aggregation

30
Q

What is the result of COX-1 producing thromboxanes in platelets?

A

Vasoconstriction and platelet aggregation

31
Q

Why are selective COX-2 inhibitors not necessarily preferred?

A

They block prostacyclin synthesis while not prevening TXA sythesis = increased cardiovascular risk

32
Q

What COX inhibitor reamins on the market with a black box warning for serious CV risk?

33
Q

What are the 2 ADP receptors involved in activating platelets?

A
  • P2Y1
  • P2Y12
34
Q

What pathway is P2Y1 coupled to?

A

Gq - PLC - IP3 - Ca2+ pathway

35
Q

What pathway is P2Y12 paired to?

A

Gi (and inhibition of adenylyl cyclase)

36
Q

What drugs belong to the thienopyridine class of ADP receptor inhibitors (pro-drugs)?

A
  • Clopidogrel (Plavix)
  • Prasugrel (Effient)
  • Ticlopidine (Ticlid)
37
Q

What is the mechanism of action of thienopyridine pro-drugs?

A

Irreversibly block the P2Y12 ADP receptor on platelet and subsequent activation of GPIIb/IIIa complex (making them long-lasting for several days after last dose)

38
Q

Evaluate the toxicity of clopidogrel and prasugrel.

A

Lower toxicity profiles

39
Q

Which thienopyridine pro-drug may induce thrombotic thrombocytopenia purpura (TTP)?

A

Ticlopidine (Ticlid)

40
Q

What are the indications for thienopyridine pro-drugs?

A
  • Acute Coronary Syndrome
  • Recent MI
  • Stroke
  • Established peripheral vascular disease
  • Coronary stent procedures
41
Q

What is ADAMTS13?

A

A protease that cleaves circulating vWF

42
Q

Explain how ticlopidine induces thrombocytopenic purpura (TTP).

A

Ticlopidine induces antibodies against ADAMTS13, which decreases proteolytic activity (spurious and excessive platelet aggregation)

43
Q

Which ADP receptor inhibitors are approved for both Acute Coronary Syndrome and percutaneous coronary intervention (PCI)?

A
  • Prasugrel (Effient)
  • Ticagrelor (Brilinta)
44
Q

Which ADP receptor inhibitors bind reversibly?

A
  • Ticagrelor (Brilinta)
  • Cangrelor (Kengreal)
45
Q

Compare ticagrelor’s speed of onset of action compared to clopidogrel.

A

Ticagrelor has a faster onset of action than clopidogrel.

46
Q

Which ADP receptor inhibitor is only used as an adjunct to PCI?

A

Cangrelor (Kengreal)

47
Q

What is the only ADP receptor inhibitor administered intravenously? How does it’s R.O.A. affect its onset and half-life?

A

Cangrelor (Kengreal); fast onset of action and short half-life (3-5 minutes)

48
Q

What CYP is clopidogrel metabolized by?

49
Q

What CYPs is prasugrel metabolized by?

A

CYP3A4/2B6

50
Q

What drugs are considered PDE inhibitors?

A

Dipyridamole and cilostazol

51
Q

What is the mechanism of action of PDE inhibitors?

A

General vasodilation and inhibition of PDE in order to prevent the degradation of cAMP into AMP (increases cAMP levels in platelets), opposing P2Y12 signaling and decreasing platelet aggregation; inhibits adenosine reuptake by RBCs and increases PGI2 synthesis

52
Q

What happens when there is an increased concentration of intracellular cAMP in platelets?

A

A decrease in intracellular calcium and subsequent decreases in platelet activation and aggregation

53
Q

What are the two uses of dipyridamole (Persantine)?

A
  • Combined with warfarin to prevent embolization from prosthetic heart valves
  • With aspirin to prevent cerebrovascular ischemia
54
Q

What is cilostazol (Pletal) indicated for?

A

Intermittent claudication

55
Q

What are the functions of GPIIb/IIIa receptors?

A
  • Receptor for fibrinogen
  • Anchors platelets to eachother
56
Q

What molecules activate GPIIb/IIIa receptors?

A
  • TXA2
  • Thrombin
  • Collagen
57
Q

What drugs are considered GPIIb/IIIa receptor inhibitors?

A
  • Abciximab (ReoPro)
  • Eptifibitide (Integrilin)
  • Tirofiban (Aggrastat)
58
Q

Fill in the blank: abciximab and eptifibitide act by inhibiting _________ crosslinking of platelets.

A

Fibrinogen

59
Q

Identify this structure.

A

Eptifibatide (Integrilin): a cyclic heptapeptide

60
Q

Identify this structure.

A

Tirofiban (Aggrastat)

61
Q

When would you use tirofiban over abciximab and eptifibatide?

A

When using heparin to treat Acute Coronary Syndrome

62
Q

What is eptifibatide (Integrilin) indicated for?

A

Preventing thromboembolism in unstable angina and angioplastic coronary procedures

63
Q

What is abciximab (ReoPro) indicated for?

A
  • Prevent thromboembolism in coronary angioplasty
  • Combined with t-PA for early treatment of acute MI
64
Q

What drug class does vorapaxar (Zontivity) fall into?

A

PAR inhibitors

65
Q

Is vorapaxar’s inhibition of PAR-1 reversible or irreversible?

A

Reversible

66
Q

What is vorapaxar (Zontivity) indicated for?

A

Prophylaxis for thrombosis in patients with previous MI or peripheral artery disease (PAD)

67
Q

What medications can vorapaxar be used concomitantly with?

A
  • Aspirin
  • Clopidogrel
68
Q

When is vorapaxar (Zontivity) contraindicated?

A

History of stroke, TIAs, or intracranial hemorrhage

69
Q

Explain vorapaxar’s metabolism.

A

Metabolized by CYP3A4; avoid concomitant use with strong 3A4 inhibitors or inducers

70
Q

Which PDE does dipyridamole inhibit?

71
Q

Which PDE does cilostazol inhibit?

Fall 2020: Therapeutics 2 (11 decks)

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