Wendt's Antiplatelet Lectures

Question 1

Explain the role that platelets play in hemostasis.

Answer 1

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.

Question 2

What are the three steps of platelet activation?

Answer 2

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

Question 3

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

Answer 3

ADP

Question 4

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

Answer 4

Because they are just pieces of larger cells (megakaryocytes)

Question 5

Platelet adhesion is mediated by what three processes?

Answer 5

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

Question 6

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

Answer 6

PGI2 (prostacyclin), thrombogenesis

Question 7

What molecules do platelet granules release during secretion?

Answer 7

• ADP
• TXA2
• Serotonin (5-HT)

Question 8

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

Answer 8

• Released by platelet granules
• Activate and recruit other platelets

Question 9

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

Answer 9

They are potent vasoconstrictors

Question 10

Explain the process of platelet aggregation, step by step.

Answer 10

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

Question 11

List the 5 classes of antiplatelet drugs.

Answer 11

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

Question 12

What drug class does aspirin belong to?

Answer 12

COX-1 inhibitor

Question 13

Does aspirin inhibit COX-1 reversibly or irreversibly?

Answer 13

Irreversibly

Question 14

How does aspirin inhibit COX-1?

Answer 14

By acetylation

Question 15

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

Answer 15

Inhibition of TXA2 synthesis

Question 16

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

Answer 16

50 - 320 mg per day

Question 17

Higher doses of aspirin inhibit the production of what molecule?

Answer 17

Prostacyclin

Question 18

When is aspirin strongly indicated?

Answer 18

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

Question 19

How does aspirin affect PT time?

Answer 19

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

Question 20

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

Answer 20

36 hours

Question 21

When is aspirin modestly indicated?

Answer 21

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

Question 22

In what 3 situations is aspirin not generally indicated?

Answer 22

• Cancer prevention
• Pain
• Fever

Question 23

What is the most prominant adverse effect associated with aspirin?

Answer 23

Upper GI bleeding

Question 24

Why is upper GI bleeding an adverse effect of aspirin?

Answer 24

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

Question 25

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

Answer 25

* Older age * Concurrent use of NSAIDs * Alcohol

Question 26

At what dose can acute aspirin overdose be induced?

Answer 26

Anything above 150 mg/kg

Question 27

What doses of aspirin can be fatal?

Answer 27

\>500 mg/kg

Question 28

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

Answer 28

* Nausea * Vomiting * Diarrhea * Fever * Coma

Question 29

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

Answer 29

Vasodilation and inhibition of platelet aggregation

Question 30

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

Answer 30

Vasoconstriction and platelet aggregation

Question 31

Why are selective COX-2 inhibitors not necessarily preferred?

Answer 31

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

Question 32

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

Answer 32

Celecoxib

Question 33

What are the 2 ADP receptors involved in activating platelets?

Answer 33

* P2Y₁ * P2Y₁₂

Question 34

What pathway is P2Y₁ coupled to?

Answer 34

G_q - PLC - IP₃ - Ca²⁺ pathway

Question 35

What pathway is P2Y₁₂ paired to?

Answer 35

G_i (and inhibition of adenylyl cyclase)

Question 36

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

Answer 36

* Clopidogrel (Plavix) * Prasugrel (Effient) * Ticlopidine (Ticlid)

Question 37

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

Answer 37

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)

Question 38

Evaluate the toxicity of clopidogrel and prasugrel.

Answer 38

Lower toxicity profiles

Question 39

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

Answer 39

Ticlopidine (Ticlid)

Question 40

What are the indications for thienopyridine pro-drugs?

Answer 40

* Acute Coronary Syndrome * Recent MI * Stroke * Established peripheral vascular disease * Coronary stent procedures

Question 41

What is ADAMTS13?

Answer 41

A protease that cleaves circulating vWF

Question 42

Explain how ticlopidine induces thrombocytopenic purpura (TTP).

Answer 42

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

Question 43

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

Answer 43

* Prasugrel (Effient) * Ticagrelor (Brilinta)

Question 44

Which ADP receptor inhibitors bind reversibly?

Answer 44

* Ticagrelor (Brilinta) * Cangrelor (Kengreal)

Question 45

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

Answer 45

Ticagrelor has a faster onset of action than clopidogrel.

Question 46

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

Answer 46

Cangrelor (Kengreal)

Question 47

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

Answer 47

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

Question 48

What CYP is clopidogrel metabolized by?

Answer 48

CYP2C19

Question 49

What CYPs is prasugrel metabolized by?

Answer 49

CYP3A4/2B6

Question 50

What drugs are considered PDE inhibitors?

Answer 50

Dipyridamole and cilostazol

Question 51

What is the mechanism of action of PDE inhibitors?

Answer 51

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

Question 52

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

Answer 52

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

Question 53

What are the two uses of dipyridamole (Persantine)?

Answer 53

* Combined with warfarin to prevent embolization from prosthetic heart valves * With aspirin to prevent cerebrovascular ischemia

Question 54

What is cilostazol (Pletal) indicated for?

Answer 54

Intermittent claudication

Question 55

What are the functions of GPIIb/IIIa receptors?

Answer 55

* Receptor for fibrinogen * Anchors platelets to eachother

Question 56

What molecules activate GPIIb/IIIa receptors?

Answer 56

* TXA2 * Thrombin * Collagen

Question 57

What drugs are considered GPIIb/IIIa receptor inhibitors?

Answer 57

* Abciximab (ReoPro) * Eptifibitide (Integrilin) * Tirofiban (Aggrastat)

Question 58

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

Answer 58

Fibrinogen

Question 59

Identify this structure.

Answer 59

Eptifibatide (Integrilin): a cyclic heptapeptide

Question 60

Identify this structure.

Answer 60

Tirofiban (Aggrastat)

Question 61

When would you use tirofiban over abciximab and eptifibatide?

Answer 61

When using heparin to treat Acute Coronary Syndrome

Question 62

What is eptifibatide (Integrilin) indicated for?

Answer 62

Preventing thromboembolism in unstable angina and angioplastic coronary procedures

Question 63

What is abciximab (ReoPro) indicated for?

Answer 63

* Prevent thromboembolism in coronary angioplasty * Combined with t-PA for early treatment of acute MI

Question 64

What drug class does vorapaxar (Zontivity) fall into?

Answer 64

PAR inhibitors

Question 65

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

Answer 65

Reversible

Question 66

What is vorapaxar (Zontivity) indicated for?

Answer 66

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

Question 67

What medications can vorapaxar be used concomitantly with?

Answer 67

* Aspirin * Clopidogrel

Question 68

When is vorapaxar (Zontivity) contraindicated?

Answer 68

History of stroke, TIAs, or intracranial hemorrhage

Question 69

Explain vorapaxar's metabolism.

Answer 69

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

Question 70

Which PDE does dipyridamole inhibit?

Answer 70

PDE5

Question 71

Which PDE does cilostazol inhibit?

Answer 71

PDE3