Antiplatelet Drugs - List-MOA-Use-Classes-Side-effects

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Today, we are going to see all About Antiplatelet drugs, like- List, MOA, Use, Classes, Side-effects.

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At first, the Table of contents is given below.

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Table of contents

• What is a platelet?
• What are Antiplatelet drugs?
• What do antiplatelet drugs do?
• How the platelets clotted blood flow or created plug formation?
• List of the Anti-platelet drugs or antiplatelet medications?
• Classification of Anti-platelet drugs?
• Mechanism of action of Antiplatelet drugs?
• Used & Side-effect of Antiplatelet drugs?

What is a Platelet?

The thrombocytes or platelets are small blood cells that help your body to form clots and stop bleeding.

Platelets physiology

• These are produced in the bone marrow
• Life Span is approximately 7 days

What are Antiplatelet Drugs?

Antiplatelet drugs are those agents, that inhibit platelet aggregation and prevent blood clots and formation of the primary platelet plug.

Example: Aspirin(low dose), Ticlopidine, Tirofiban.

What do antiplatelet drugs do?

In the previous section, we have already discussed the platelet the which helps to form clots and stop bleeding.

After some time, the clots flow through the blood vessels and aggregate and form embolus in some places.

Or, the lot of plug blocks the blood vesicles or artery, which triggers Myocardium Infarction, vascular disease,

It increases the risk of heart failure and triggers heart diseases like a heart attack or stroke. or in the future, you may atrial fibrillation or coronary artery bypass.

 The Antiplatelet drugs help to inhibit the aggregation and form embolus formation.

How the platelets clotted blood flow or created plug formation?

Now, we are going to see platelet plug formation. We know that platelet plug formation is one of the mechanisms of hemostasis.

Let’s say, about the structure of a blood vessel of your hand. Here, on the upper portion of the blood vessel, the endothelium layer, and below the endothelium, the collagen layer is present.

According to our physiological condition, platelet plug formation is prevented by endothelial cells.

Let’s think, unfortunately, your hand is injured by some accident.

It is broken or damaged by the endothelial cells of your blood vessel. And exposed the collagen underneath it.

This will now trigger platelet plug formation which helps to blood clots forming.

So let’s see how it is formed.

The broken or damaged endothelial cells, release von Willebrand factor (vWF). It binds with collagen that is exposed to the blood.

Now in blood, we have platelets that are flowing closer to the vessel wall.

The platelets have glycoprotein Ib, glycoprotein Ia/IIa, and glycoprotein VI on their surface.

Through these receptors, platelet attaches to the exposed collagen.

Glycoprotein Ib binds via von Willebrand factor (vWF).

And glycoprotein Ia/IIa and glycoprotein VI bind directly with collagen.

Likewise, a lot of platelets come and cover the broken or damaged area.

This is called platelet adhesion.

Now the next step.

The binding activates those receptors which are present in the platelet.

Platelets have storage vesicles like alpha (α) and dense granules.

After the activation, the content of those granules is released into the surroundings.

Content of α granules include various growth factors which will carry out wound healing,

Von Willebrand factor (vWF) that, contributes to platelet aggregation,

Fibrinogen that, contributes to aggregation as well as coagulation,

And Factor V (which is the clotting factor) that, contributes to coagulation.

The content of dense granules are ADP, which helps in platelet aggregation,

serotonin, which causes vasoconstriction

And calcium contributes to coagulation.

Among these, fibrinogen and ADP play important role in platelet aggregation.

We will come back to them later.

First, let’s complete what else is going on inactivated platelet.

From the membrane phospholipid of activated platelet, Cyclooxygenase (COX-1, COX-2) and thromboxane synthase start producing thromboxane A2.

           The thromboxane A2 is synthesized from the phospholipid of the platelet by some steps.

Step 1: The Arachidonic acid is synthesized from the phospholipid of the platelet with the help of phospholipase A2.

Step 2: The PGG2  is synthesized from the Arachidonic acid with the help of Cyclooxygenase (COX-1, COX-2).

Step 3: The PGH2  is synthesized from the PGG2 with the help of Prooxidase.

Step 4: The PGI2, PGE2, PGF2, PGD2, TXA2 are synthesized from the PGH2 with the help of several enzymes.

• Pathway 1: The Prostacyclin (PGI2) is synthesized from the PGH2 with the help of Prostacyclin Synthesase.
• Pathway 2: Many types of Prostaglandin (PGE2, PGF2, PGD2) are synthesized from the PGH2 with the help of Prostaglandin Synthesase.
• Pathway 3: The Thromboxane A2  (TXA2 ) is synthesized from the PGH2 with the help of Thromboxane Synthesase.

It is also released into the blood.

Parallel to any or all these, thrombin is generated on the surface of the platelet.

As a result of activation of the coagulation cascade.

It also joins ADP and thromboxane A2.

Next, activated platelets change shape. And They increase the surface area of platelets.

Lastly, activation of platelets causes conformational changes in its surface receptor GP IIb/IIIa,

which is now capable of binding with fibrinogen.

So these were the things happening inactivated platelet.

Now let’s move to these molecules – thrombin, ADP, and thromboxane A2.

They help in recruiting a lot of platelets from circulation.

Circulating platelets have receptors like P2Y12 for ADP,

thromboxane A2 receptors for TxA2 and protease-activated receptors-1 (PAR-1) for thrombin.

When attached by their several ligands, these receptors cause activation of the platelet.

This activated platelet undergoes almost all the processes that we all know within the previous.

Like, conformational changes in GP IIb/IIIa, which binds with the fibrinogen, bound to the already activated platelet.

See fibrinogen is working as a bridge between two platelets here.

Similarly von Willebrand factor (vWF). also serves as a bridge to connect platelets.

The activated platelet change shape and also release a lot of ADP, TXA2, and thrombin to aggregate a lot of platelets.

Again, the ligands bind with their several receptors, causing platelet activation

followed by activation of GP IIb/IIIa, binding with another activated platelet, and change in the shape.

In this way, platelets are recruited till the wound is plugged.

This is called platelet aggregation.

Plug thus formed is called a primary hemostatic plug or primary platelet plug.

It quickly seals the break-in vasculature but it is comparatively weak.

Fibrin, synthesized at the end of the coagulation cascade strengthens this plug.

And now it’s called the secondary plug.

So that was about platelet plug formation.

List of the Anti-platelet drugs?

• Aspirin (Low-Dose)
• Dipyridamole
• Ticlopidine
• Clopidogrel
• Prasugrel
• Cangrelor
• Ticagrelor
• Abciximab
• Eptifibatide
• Tirofiban

Classification of Anti-platelet drugs?

There are four types of Antiplatelet drugs are present.

a)    Thromboxane (TX A2) Synthesis inhibitor

b)    Phosphodiesterase Inhibitor.

c)     Purinergic receptor blocker(p2y12)

d)    Glycoprotein(GP) IIb / IIIa

Mechanism of action of Anti-platelet drugs?

Aspirin (TXA2 Synthesis Inhibitor):– Low-dose aspirin (50-325 mg/day) irreversibly acetylates platelet cyclooxygenase-1 (COX-1) and reduces the production of TXA2.

Since platelets cannot synthesize new enzymes, the antiplatelet effect lasts for the lifetime of the platelets, i.e. 7-10 days.

In higher doses, aspirin inhibits both TXA2 and PGI2, hence antiplatelet efficacy is reduced.

Common adverse or side effects are gastrointestinal irritation and bleeding.

Dipyridamole (Phosphodiesterase Inhibitor):-

It is a vasodilator. It inhibits phosphodiesterase and increases the concentration of cyclic adenosine monophosphate (cAMP) levels and its triggers platelet aggregation.

 It is occasionally used in combination with warfarin during the postoperative period in patients with prosthetic heart valves.

 Purinergic receptor blocker(p2y12):- Adenosine diphosphate (ADP) released from platelets promotes their aggregation.

Ticlopidine, Clopidogrel, and Prasugrel (Thienopyridine Derivatives) are prodrugs and structurally related. They inhibit adenosine diphosphate (ADP)-mediated platelet aggregation by irreversibly blocking purinergic (P2Y12) receptors on the platelets.

The antiplatelet effect persists discontinuation of the drugs. They produce a synergistic effect when combined with aspirin or GP Il, /II, antagonists. They are administered orally.

Prasugrel has a faster onset of action and better antiplatelet effect than ticlopidine and clopidogrel. Bleeding is an important adverse effect; the risk is more with prasugrel.

The other adverse effect of ticlopidine and clopidogrel is diarrhea. Neutropenia and thrombocytopenia are serious adverse effects of ticlopidine but rare with clopidogrel.

Ticlopidine inhibits ADP-mediated platelet aggregation by reversibly inhibiting platelet P2Y12 receptors.

 Cangrelor is administered as i.v. infusion whereas ticagrelor is effective orally. Abciximab, Eptifibatide, and Tirofiban (GP II, Receptor Antagonists).

The GP I,/l1, receptors:-

These receptors are present on the platelet surface which blocks the fibrinogen, and von Willebrand’s factor.

IT inhibits the final step in the process of platelet aggregation produced.

Abciximab is a monoclonal antibody that binds to GP I1,/11I, receptor.

Eptifibatide is a synthetic drug, which is more specific for GP I1,/1I, receptor. Tirofiban is a non-peptide GP II/1ll, receptor antagonist. These drugs are administered intravenously and are used in percutaneous coronary intervention, unstable angina, and acute MI.

 The main side effects of these drugs are bleeding and thrombocytopenia.

Used & Side-effect of Antiplatelet drugs?

1. Acute coronary syndrome: Antiplatelet Agents include myocardial infarction (MI) and unstable angina.

Dual antiplatelet therapy is the used-reduces incidence of myocardial infarction, stroke, and mortality.

Aspirin in combination with clopidogrel/prasugrel is used. The combination has enhanced the antiplatelet effect.

ST-elevation myocardial infarction (STEMI): Early initiation of therapy with aspirin + P2Y12 blocker (clopidogrel/prasugrel) is recommended.

It helps to maintain patency of recanalized coronary vessels, decreases the occurrence of occlusion, and reduces the risk of stent thrombosis.

The first dose of aspirin (loading dose of 162-325 mg chewed or crushed) is given as soon as possible after the diagnosis is made.

P2Y12 blocker is selected after deciding the reperfusion strategy-percutaneous coronary intervention (PCI) or thrombolytics. Aspirin + clopidogrel is used for patients who are planned for treatment with fibrinolytic. Aspirin + prasugrel is preferred in patients undergoing PCI.

In unstable angina, A combination of aspirin with clopidogrel has been reducing cardiovascular death, myocardial infarction,.

The stroke as compared to aspirin alone.

2. Coronary artery disease: The low-dose aspirin reduces the occurrence of myocardial infarction, stroke, and death in post-MI patients. Clopidogrel can be used as an alternative if aspirin cannot be used.

3. Prosthetic heart valves: Valve thrombosis and thromboembolism are problems occlusion area unit issues related to prosthetic valves. Aspirin with warfarin reduces these risks. Dipyridamole may be used with warfarin to prevent thromboembolism in patients with prosthetic heart valves.

4. Transient ischaemic attack (TIA): Early initiation of aspirin in patients with TIA reduces the risk of recurrent attacks. For secondary prevention of stroke, aspirin/clopidogrel/aspirin + dipyridamole is used.

5. Peripheral artery disease: Aspirin/clopidogrel may prevent thromboembolism.

Side effects

These is the following side effects:

• Bruising more easily 
• Risk of bleeding
• Heavy periods
• Nose bleeds.
• Upset stomachs
• Bleeding for longer if you cut yourself
• Blood in your urine
• Blood in your stools
• Coughing up blood
• Vomiting blood
• Ringing in your ears

Conclusion

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