Pharmacology Of Antithrombotic Agents I

Front 1

3 steps of primary hemostasis?

Back 1

1. vascular injury exposes matrix proteins

2. Platelet adhesion & activation

3. Platelet granule release

Front 2

What two steps happen in the platelet adhesion & activation phase

Back 2

1. Thromboxane A2 (TXA2), synthesized from arachadonic acid by COX-1, is a potent vasoconstrictor and platelet activator

2. Conformational change in the integrin (IIb/ IIIa) receptor, resulting in fibrinogen binding

Front 3

What three things are released from platelets in the "platelet granule release" phase? Effect of each?

Back 3

a. ADP = activates integrin receptor (IIb/IIIa)
b. TXA2 = vasocontrictor + platelet activator
c. Calcium release = important for clotting factors

Front 4

Process of secondary hemostasis

Back 4

Sequential proteolytic cascade culminating in thrombin activation and formation of fibrin fibers to stabilize hemostatic plug

Thrombin is the final active protease

Front 5

What are the four major activities of thrombin?

Back 5

1. Activates factor XIII, to cross-link the fibrin polymer

2. Cleaves fibrinogen, allowing fibrin to polymerize and form a fibrin clot.

3. Activates multiple clotting factors

4. Potent platelet activator

Front 6

What are the 5 factors that contribute to anticoagulation and fibrinolysis

Back 6

1. tPA

2. Thrombomodulin

3. Prostacyclin

4. Antithrombin III

5. Tissue factor pathway inhibitor

Front 7

Effect of t-PA

Back 7

tissue plasminogen activator:

activates plasminogen to plasmin; plasmin degrades fibrin

Front 8

Effect of thrombomodulin

Back 8

Binds thrombin leading to inactivation of Factors V and VIII

Front 9

Effect of prostacyclin

Back 9

Inhibits platelet degranulation, aggregation and vasoconstriction

Front 10

Effect of antithrombin III

Back 10

serine protease inhibitor, binds to and inactivates Factors IIa, IXa, Xa, XIa, and XIIa

Front 11

Effect of tissue factor pathway inhibitor

Back 11

Inhibits extrinsic coagulation pathway

Front 12

What are the 3 classes of antiplatelet agents?

What is the prototype for each class?

Back 12

1. COX inhibitors = ASA

2. ADP receptor antagonists = Clopidogrel

3. Glycoprotein IIb/IIIa inhibitors = Abciximab

Front 13

ASA mechanism of action? At what dose does it have this effect?

Back 13

Low dose ASA (325 mg/day) following MI - selectively inhibits the synthesis of thromboxane A2 (which causes platelet aggregation and granule release) by irreversible acetylation of the enzyme cyclooxygenase (COX-1)

Front 14

1. Absorption time of ASA?

2. Duration of effect?

3. Result of high-dose ASA?

Back 14

1. Rapid – peak [plasma] 15-20 min post administration

2. The effect of ASA persists for platelet lifespan (7-10 d)

3. Higher dose ASA leads to inhibition of prostacyclin production and reduced clinical efficacy of ASA therapy

(protacyclin prevents formation of platelet plug so you dont want to block it)

Front 15

Clinical uses of ASA (5)?

Back 15

1. Chronic angina

2. Unstable angina/NSTEMI

3. STEMI

4. Mechanical Heart valve (in combo with warfarin)

5. PCI

Front 16

What antiplatelet drug is more effective than ASA?

Back 16

none

Front 17

Adverse effects of ASA?

Back 17

increased incidence of hemorrhagic stroke; GI bleeding, gout exacerbation

excreted by kidneys > competes with uric acid transporter > may exacerbate gout

Front 18

Benefit of ASA in prevention of stroke in pts with Afib?

Back 18

No benefit. Warfarin is superior

Front 19

Mechanism of action of Clopidogrel

Back 19

Irreversibly inhibits the P2Y12 ADP receptor

ADP receptor blockade inhibits activation of the glycoprotein IIb/IIIa pathway.

Front 20

What effect does inhiting the glycoprotein IIb/IIIa pathway have

Back 20

Activation of the IIb/IIIa receptor complex is the "final common pathway" for platelet aggregation and is important in the cross-linking of platelets by fibrin

Front 21

Clopidogrel is a ______ metabolized by _______.

Duration of action?

Back 21

Clopidogrel is a prodrug metabolized by CYP2C19.

Duration of the antiplatelet effect is 7–10 days

Front 22

Therapeutic uses of clopidogrel

Back 22

• Reduction of the rate of stroke, MI, heart attack, unstable angina and death in patients with recent MI or stroke, peripheral arterial disease, or acute coronary syndrome

• Clopidogrel equivalent to ASA in stroke prevention

Front 23

Adverse effects of clopidogrel

Back 23

• Prolonged bleeding
• Thrombotic thrombocytopenic purpura
• FDA black box warning 2010 highlighting CYP2C19 poor metabolizers (up to 14% of patients) are at high risk of treatment failure (cause they cant metabolize the prodrug)

Front 24

Are there tests available to screen for poor metabolizers of plavix? aka genetic differences in CYP2c19?

Back 24

Yes

Front 25

Mechanism of action of Abciximab

Back 25

antibody fragment that reversibly inhibits the GP IIb/IIIa receptor = inhibits final common pathway

GP IIb/IIIa on platelets cant bind fibrinogen and von Willebrand

Front 26

1. Therapeutic use?

2. Route of administration of Abciximab?

3. length and implication of half life

Back 26

1. used with ASA and heparin to treat coronary thromboses or during coronary angioplasty, reduces restenosis, recurrent MI

2. IV

3. Short half-life (30 min) can be reversed

Front 27

Major side effect of abciximab

Back 27

Major hemorrhagic event 1% to 10% patients