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Antiplatelet Drugs

Antiplatelet drugs affect the fluidity of blood in thromboembolic conditions.

Platelet Plug

Normally when endothelial injury occurs, it exposes tissues to platelets, leading to activation and aggregation.

During this activation, different substances are synthesized and released, leading to:

a. platelet aggregation

b. vasoconstriction

The important ones are:

–        Thromboxane A2

–        ADP

–        Serotonin

Conformational change occurs in IIb/IIIa receptors present on platelet surface to which fibrinogen binds, leading to anchoring with other platelets and endothelial lining.

Antiplatelet drugs either:

1. act on these receptors or

2. inhibit the release of these substances

 Classification

1. Thromboxane-A2 inhibitor

–        Aspirin

2. ADP receptor inhibitors

–        Clopidogrel

–        Ticlopidine

3. Glycoprotein IIb/IIIa receptor blockers

–        Abciximab

–        Eptifibatide

–        Tirofiban

4. Phosphodiesterase inhibitors

–        Dipyridamole

–        Cilostazol

 Thromboxane-A2 Inhibitor Aspirin (details with NSAIDS)

Aspirin is normally present in platelets

Arachidonic acid is converted into thromboxane A2 by cyclooxygenase I (COX-I) enzyme.

This enzyme is inhibited by aspirin, acetylating it irreversibly.  

Thus, no thromboxane A2 is produced responsible for platelet activation and aggregation.

Vasoconstrictor as well as vasoconstriction is decreased.

Dose

75 – 300 mg/day, but in certain patients for prophylaxis of MI, 325 mg are given.

Advantages of low dose

1. Toxic effects (GIT) are less

2. Antiplatelet effects but production of prostacyclines are not affected (vasodilator substances beneficial in cardiac patients).

 ADP Receptor Inhibitors
  • Thienopyridine derivatives
  • 2 drugs acting on purinergic receptors – P2Y1 & P2Y12
  • Irreversible binding –staying for life of platelets (7-10 days)
  • When ADP binds, it leads to platelet aggregation, so these drugs prevent ADP binding.
  • Both drugs are prodrugs, activated after oral administration
Ticlopidine
  • Ticlopidine is used along with aspirin producing synergistic effects, as both have different sites of action.
  • It produces more side effects including:

a. GIT disturbance

b. Leukopenia

c. Thrombotic thrombocytopenic pupura-hemolytic uremic syndrome (TTP-HUS)

Side effects involving while blood cells are visible during the first three months, so repeated counts are taken during this time.

Dose 250 mg twice daily

 Clopidogrel  

Once daily dose of 75 mg OD. It has fewer side effects.

 Glycoprotein IIb/IIIa Receptor Blockers

Receptors are present on platelet surface to which fibrinogen, fibronectin, vitronectin, von Willebrand factor bind, leading to platelet activation and aggregation with one another and endothelium, leading to clot formation. These drugs inhibit this binding and prevent platelet aggregation.

Individuals lacking these receptors suffer from Glanzmann’s thrombasthenia, leading to bleeding tendency.

 Abciximab

Chimeric (part animal part human source). It not only effects IIb/IIIa receptors only but also Vitronectin receptors on other tissues, leading to side effects like:

a. Bleeding

b. thrombocytopenia

It is mostly used with heparin, aspirin (anticoagulants) in patients of angioplasty.

 Eptifibatide

Peptide analog having same structure as the terminal part of fibrinogen, so instead of fibrinogen, it binds receptors, blocking them to which fibrinogen cannot bind.

 Tirofiban

Nonpeptide small molecule having same action as eptifibatide.

 Phosphodiesterase Inhibitors
Dipyridamole

It has two main functions:

  1. Blocks adenosine uptake – adenosine acts on A2 receptors, increasing cAMP.
  2. Inhibits phosphodiestrase which degrades AMP and GMP to cAMP / cGMP, their levels rise, producing antiplatelet effect
  3. Has vasodilator effect in addition

It is not a powerful drug, so combined with other drugs.

a. Aspirin (25mg) + Dip. (200mg) –in patients having cerebrovascular ischemia because of stroke or transient ischemic attack (TIA)

b. with warfarin in patients having prosthetic valves

 Cilostazol

Phosphodiesterase inhibitor used for intermittent claudication

 Uses of Antiplatelet drugs

1. Cerebrovascular diseases – TIA / stroke

2. Coronary artery diseases – unstable angina / MI

3. Peripheral arterial diseases

4. Coronary bypass implants / stents

5. Prosthetic heart valves

6. Arterial graft

7. Arterio-venous shunts

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