Antithrombotic Drugs

Question 1

Aspirin

1. Class
2. Mechanism of Action

Answer 1

1. Antiplatelet Drug
2. Irreversibly inhibits COX-1 in platelets, and also decreases TXA₂ production (which normally activates platelets and induces vasoconstriction)

Question 2

Dipyridamole

1. Class
2. Mechanism of Action

Answer 2

1. Antiplatelet Drug
2. Increases cAMP (which increases intracellular Ca²⁺ –> decreased platelet activity) and blocks Adenosine reuptake (which increases A₂ receptor –> increases cAMP)

***Rarely given alone; commonly given as Aggrenox (Dipyridamole + aspirin)

Question 3

Clopidogrel**

1. Class
2. Mechanism of Action

Answer 3

1. Antiplatelet Drug
2. Prodrug that is activated in the liver - Irreversibly (long half-life) inhibits P2Y12 receptor, which leads to inhibition of GpIIa/IIIb receptor

Question 4

Prasugrel**

1. Class
2. Mechanism of Action
3. Contraindications

Answer 4

1. Antiplatelet Drug
2. Prodrug that is activated in the liver - Irreversibly (long half-life) inhibits P2Y12 receptor, which leads to inhibition of GpIIa/IIIb receptor
3. Hx of Intracranial Bleeding (due to greater rates of fatal/life-threatening bleeding)

Question 5

Ticagrelor

1. Class
2. Mechanism of Action
3. Contraindications

Answer 5

1. Antiplatelet Drug
2. Administered in Active Form - Reversibly (short half-life –> rapid recovery upon discontinuation) inhibits P2Y12 receptor, which leads to inhibition of GpIIa/IIIb receptor
3. Hx of Intracranial Bleeding (due to greater rates of fatal/life-threatening bleeding)

Question 6

Cangrelor

1. Class
2. Mechanism of Action

Answer 6

1. Antiplatelet Drug
2. Administered in Active Form - Reversibly (short half-life –> rapid recovery upon discontinuation) inhibits P2Y12 receptor, which leads to inhibition of GpIIa/IIIb receptor

Question 7

What enzyme activates Clopidogrel? What inhibits this enzyme? (2 things)

Answer 7

CYP2C19 (Liver cytochrome)

Inhibited by Omeprazole (PPI)

Polymorphisms reduce activity

Question 8

Abciximab**

1. Class
2. Mechanism of Action
3. Treatment
4. Toxicity

Answer 8

1. Antiplatelet Drug
2. Fragment of Antigen-Binding (Fab) segment of a mab (monoclonal antibody) directed against GpIIb/IIIa ; also binds GpIIb/IIIa on leukocytes leading to anti-inflammatory/-proliferative effects
3. PCI (sometimes w/ heparin and ASA)
4. Thrombocytopenia (higher risk) and Bleeding

Question 9

Eptifibatide

1. Class
2. Mechanism of Action
3. Treatment
4. Toxicity

Answer 9

1. Antiplatelet Drug
2. Peptide that inhibits GpIIb/IIIa
3. PCI (sometimes w/ heparin and ASA), Unstable Angina
4. Thrombocytopenia (lower risk) and Bleeding

Question 10

Tirofiban

1. Class
2. Mechanism of Action
3. Treatment
4. Toxicity

Answer 10

1. Antiplatelet Drug
2. Non-peptide small molecule that inhibits GpIIb/IIIa
3. Unstable Angina
4. Thrombocytopenia (lower risk) and Bleeding

Question 11

Vorapaxar

1. Class
2. Mechanism of Action
3. Treatment
4. Toxicity

Answer 11

1. Antiplatelet Drug
2. PAR (Protease-activated Receptor) antagonist
3. Prevention of thrombotic cardiovascular events in pts with a hx of MI or PAD (peripheral artery disease)
4. Intracranial Bleeding (contrindicated in pts with hx of Stroke or IC bleeding)

Question 12

Dual Antiplatelet Therapy (DAPT)

1. What is it?
2. When is it used?
3. What does it prevent?

Answer 12

1. P2Y12 antagonist + ASA (aspirin)
2. Post-Coronary Angioplasty
3. Prevents MI and Cardiac Death

Question 13

Triple Antiplatelet Therapy (TAPT)

1. What is it?
2. When is it used?

Answer 13

1. Warfarin + ASA + Clopidogrel
2. Used in patients with A-Fib and CAD

Question 14

Heparin

1. Mechanism of Action

Answer 14

• Pentasaccharide (5) sequence in heparin binds Antithrombin
• Conformation change facilitates binding of factor Xa (10a)
• Long-chain heparin forms a molecular bridge that brings Thrombin in close contact with Antithrombin

Question 15

Heparin

(Pharmacokinetics)

1. Route
2. 1/2 Life
3. Binds what?

Answer 15

1. IV (can be given SubQ, but loses bioavailability by >50%)
2. ~90 mins (requires frequent dosing)
3. Binds to Antithrombin, as well other plasma proteins (e.g. Acute phase proteins and platelet factor 4 (PF4))and endothelium of vessel walls
   - These other protein interactions reduce Heparin’s effects and make dosing variable and hard to predict

Question 16

Heparin

(Pharmacokinetics)

1. Clearance Mechanisms (2)
2. Effects on 1/2 life

Answer 16

Two Clearance Mechanisms:

1. Non-saturable involving the kidneys and liver
2. A rapid process of binding to and being taken up by endothelial cells
3. Clearance decreases as dose increases (as there are limited binding sites on endothelial cells –> saturable process)

***Half-life INCREASES as dose INCREASES***

Question 17

Partial Thromboplastin Time (PTT)

(i. e. Activated Partial Thromboplastin Time (aPTT))
1. Describe the Process

Answer 17

Place patients’ anticoagulated (citrate), platelet-poor plasma in a tube and mix with phospholipids and a negatively-charged surface like glass beads, which initiates the intrinsic pathway

Add Ca²⁺ to initiate clotting reaction and measure the time it takes the blood to clot

Question 18

Heparin

1. Adverse Effects (2)

Answer 18

Bleeding

• Discontinuation is often used to stop mild bleeding (due to short half-life)
• If bleeding is severe –> Protamine sulfate (basic polypeptide that inactivates longer heparin molecules) can be used to inhibit heparin

Osteoporosis (long-term heparin use, > 1-6 months)

Question 19

What drug is used as an antidote to heparin?

Answer 19

Protamine (basic polypeptide that binds to and inactivates longer heparin molecules)