A29. Drugs used in coagulation disorders I: Antiplatelet agents

Question 1

What happens during the adhesion phase of primary hemostasis?

Answer 1

1. Collagen-contact → adhesion of platelets to surface
2. GP-Ib/IX connects to vWF which connects to collagen, fibronectin, vitronectin, thrombospondin.

Question 2

What are the side effects of Vorapaxar?

Answer 2

Can cause more severe bleeding.

Question 3

How is Vorapaxar metabolized?

Answer 3

1. Metabolized in liver.
2. Interacts with CYP3A.

Question 4

What happens in the tertiary phase of hemostasis?

Answer 4

Dissolution of the fibrin clot. (Fibrinolysis)

Question 5

What is the mechanism of antiplatelet drugs?

Answer 5

Referring to arterial thrombi disorders (not venous! platelets less important there)

1. Inhibit TXA2: Aspirin.
2. Antagonize P2Y12 receptors: Clopidogrel, Prasugrel, Ticagrelor.
3. Antagonize PAR-1 receptors: New oral option!
4. Antagonize surface GP IIb/IIIa receptors: Abciximab, Eptifibatide, Tirofiban. None of these are oral, only administered at the hospital, special situations.
5. PDE inhibitors: Dipyridamole. Belongs to this category but not really important.

Question 6

List the PDE inhibitors.

Answer 6

1. Dipyridamole: again, not really important - blocks both PDE and also adenosine uptake. By itself, almost doesn’t cause effect. Only in combo with warfarin does it work. Can be used for 1° prophylaxis of thrombi in prosthetic heart valve pts. High IV dose can cause coronary steal effect.
2. Cilostazole: Newer. used for intermittent claudication.

Question 7

What is the MOA of Abciximab?

Answer 7

Abciximab is a monoclonal Ab against GP IIb/IIIa.

Question 8

What is the MOA of Vorapaxar?

Answer 8

Vorapaxar has been taken off market recently, maybe will return. It is independent from ADP, it antagonizes the thrombin receptor (PAR-1 R).

Question 9

What is the MOA of Aspirin?

Answer 9

Aspirin is extracterd from willow tree bark → salicylic acid → acetylsalicylic acid. Aspirin is an irreversible inhibitor of COX. Its irreversibleness seems to be important for it to work well to reduce platelet function. Low dose ASA blocks COX1 more than COX2 → blocks TXA2 more than prostacyclin…shifts balance against platelet aggregation.

Question 10

What happens during secondary hemostasis?

Answer 10

1. Coagulation cascade activation
2. Fibrin deposition + cross-linking.

Question 11

List the P2Y12 (ADP) receptor antagonists.

Answer 11

1. Ticlopidine
2. Clopidogrel
3. Prasugrel

(Last 2 are better, Ticlopidine is worse)

Question 12

What are the side effects of using P2Y12 (ADP) receptor antagonists?

Answer 12

1. Similar adverse effects of bleeding, peptic ulcer.
2. Also rarely leukopenia and thrombocytopenia, especially with ticlopidine but not really the other two. Regular blood tests needed in 1st 3 months.

Question 13

What are the indications of P2Y12 (ADP) receptor antagonists use?

Answer 13

Same indications: cardio and cerebrovascular circulatory problems (TIA -transient ischemic attack, stroke)

Question 14

What are the adverse effects of using aspirin?

Answer 14

1. Bleeding
2. Peptic ulcer
3. Reye’s syndrome (only children)
4. many more in NSAID section.

Question 15

What are the steps in primary hemostasis?

Answer 15

With vascular injury: platelet adhesion, activation, and aggregation occurs.

Question 16

What happens in the activation phase of primary hemostasis?

Answer 16

1. Platelets release ADP, serotonin.
2. Synthesis of TXA2
3. P2Y12 receptor = most important ADP receptor. P2Y1 also exists.
4. Serotonin → 5HT2A receptor
5. Epinephrine → α2 receptor
6. Prostacyclin inhibits, thromboxane A2 promotes aggregation.

Question 17

What happens in the aggregation phase of primary hemostasis?

Answer 17

GP-IIb/IIIa binds and connects cross-linked fibrinogen between platelets. Also other RGD proteins (Arg-Gly-Asp, e.g. vWF, vitronectin) bridges btwn thrombocytes.

Question 18

What are the adverse effects of using GP IIb/IIIa receptor antagonists?

Answer 18

1. Bleeding
2. Thrombocytopenia
3. Hypotension
4. Bradycardia
5. GI symptoms: Nausea and Vomiting (N/V)

Question 19

What are the contraindications of PAR-1 antagonists?

Answer 19

1. TIA (Transient Ischemic Attack) / Stroke
2. Bleeding

Question 20

What happens in secondary hemostasis?

Answer 20

1. Coagulation cascade activation.
2. Fibrin deposition + cross-linking.

Question 21

What happens in the teritary phase of hemostasis?

Answer 21

Dissolution of fibrin clot.

Question 22

What are the indications for PAR-1 antagonists?

Answer 22

1. MI (sec prophylaxis)
2. Peripheral artery thrombi (combo with aspirin)

Question 23

What is the route of administration and DOA Abciximab?

Answer 23

They are only active in IV form and therefore not given at home. They technically has a short half life (30 min), but it’s irreversible and so the effect lasts for a day. They are used in PCI. The synthetic compounds are also only active IV. They have a shorter duration of action (2-4 hrs), more selective action on thrombocytes.

Question 24

What are the recommended doses of Aspirin?

Answer 24

1. Much better for anticoagulant to take low dose ASA (100mg) than the higher doses (500mg) for headache or fever.
2. In acute cases (e.g. MI, UA- Unstable Angina, coronary angioplasty) give 250-500mg loading dose then ~100mg daily. Blockade lasts for a few days.

Question 25

Pharmacokinetics of P2Y12 (ADP) receptor antagonists use?

Answer 25

kinetics: good absorption, high protein binding - additive/synergistic effects with other antiplatelet drugs o interactions: CYP2C19 inhibitors (omeprazole, fluoxetine, fluconazole) inhibit activation of clopidogrel • omeprazole used for peptic ulcer, and clopidogrel also used when ASA contraindicated due to peptic ulcer. not so common clinically but likely asked on the exam • Ticagrelor, cangrelor: 2 new drugs o reversible blockers, not pro-drugs - act quicker! o becoming more commonly used o typically given with ASA too

Question 26

How are the pharmacokinetics of P2Y12 (ADP) R antagoinists?

Answer 26

1. Part of thienopyridines group
2. Orally given
3. Synergistic with ASA
4. Prodrugs, must be activated in the liver.

Question 27

What is the MOA of Eptifibatide?

Answer 27

Eptifibatide is a synthetic cyclic hexapeptide, analogue of fibrinogen carboxy terminal peptide, that binds to platelet receptor glycoprotein and inhibits platelet aggregation. It’s derived from venom of the Southeastern pygmy rattlesnake (Sistrurus miliarus barbouri) and belongs to the class of arginin-glycin-aspartat-mimetics.

Question 28

What is the MOA of Tirofiban?

Answer 28

Tirofiban prevents the blood from clotting during episodes of chest pain or a heart attack, or while the patient is undergoing a procedure to treat a blocked coronary artery. It is a smaller molecule of the non-peptide reversible antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, and inhibits platelet aggregation.

Question 29

How is aspirin metabolized?

Answer 29

Aspirin has good oral absorption. It is metabolized in the liver. The liver de-acetylates, makes it into salicylic acid again.

Question 30

How strong of a plasma binding capacity does Aspirin have?

Answer 30

It has high plasma protein binding.