ANTIPLATELETES AGENTS

BY :DR. ISRAA OMAR

The role of platelets • Platelets play a critical role in thromboembolic disease

like ischemic heart disease and stroke • Platelets adhere to the diseased or damaged areas and

become activated, exposing phospholipids and GPIIb/IIIa receptors.

• Platelet change their shape to stellate form• Activate platelets also synthesize and release mediators

like TXA2 and ADP, which stimulate other platelets to aggregate and eventually fibrin formation and thrombosis.

• Platelet aggregation is inhibited by prostaglandin I2

• TXA2 production is reduced by cAMP

1. Aspirin( Acetylsalicylic acid )

Mechanism of action: • Aspirin inhibits COX-1 irreversibly, this will lead to

inhibition of synthesis of thromboxane A2 which in turn lead to inhibition of platelet activation and aggregation.

Aspirin (Acetylsalicylic acid) – mechanism of action

Acetylsalicylic acid – (Aspirin)mechanism of action

Acetylsalicylic acid – (Aspirin)mechanism of action

Acetylsalicylic acid –(Aspirin ) mechanism of action

Acetylsalicylic acid – (Aspirin) mechanism of action

Pharmacokinetics

• Rapid absorption of aspirin occurs in the stomach and upper intestine, with the peak plasma concentration being achieved 15-20 minutes after administration

• The peak inhibitory effect on platelet aggregation is apparent approximately one hour post-administration

• Aspirin produces the irreversible inhibition of the enzyme cyclooxygenase and therefore causes irreversible inhibition of platelets for the rest of their lifespan (7 days)

Clinical uses:

• Secondary prevention of transient ischaemic attack (TIA), ischaemic stroke and myocardial infarction

• Prevention of ischaemic events in patients with angina pectoris

• Prevention of coronary artery bypass graft (CABG) occlusion

Adverse effects:

• Risk of gastrointestinal adverse events (ulceration and bleeding)

• Allergic reactions

• Is not a very effective antithrombotic drug but is widely used because of its ease of use

• Lack of response in some patients (aspirin resistance)

• The irreversible platelet inhibition

2. Clopidogrel and Ticlodipine (Thienopyridines )

Mechanism of action: • It inhibits platelets aggregation by irreversibly

binding for ADP receptors on the surface of platelets.• This will lead to reduce mobilization of calcium from

intracellular stores and reduces the expression of glycoprotein receptors on the platelets surface

ADP-receptor antagonists – mechanism of action

ADP-receptor antagonists – mechanism of action

ADP-receptor antagonists – mechanism of action

ADP-receptor antagonists – mechanism of action

Pharmacokinetics

• Both currently available ADP-receptor antagonists are thienopyridines that can be administered orally, and absorption is approximately 80-90%

• Thienopyridines are pro-drugs that must be activated in the liver

Clinical uses:

• Secondary prevention of ischaemic complications after myocardial infarction, ischaemic stroke and established peripheral arterial disease

• Secondary prevention of ischaemic complications in patients with acute coronary syndrome (ACS) without ST-segment elevation

Drawbacks

• Clopidogrel is only slightly more effective than aspirin

• As with aspirin, clopidogrel binds irreversibly to platelets

• In some patients there is resistance to clopidogrel treatment

3. GPIIb/IIIa-receptor antagonists

Mechanism of action: • Abciximab is a monoclonal

antibody with Fc region removed to prevent immunogenicity .

• It bind irreversibly to GPIIb/IIIa receptors and prevent its binding to fibrinogen .

• It can reduce the platelets aggregation by more than 90% .

GPIIb/IIIa-receptor antagonists – mechanism of action

GPIIb/IIIa-receptor antagonists – mechanism of action

GPIIb/IIIa-receptor antagonists – mechanism of action

GPIIb/IIIa-receptor antagonists – mechanism of action

GPIIb/IIIa-receptor antagonists – mechanism of action

Clinical uses:

• Prevention of ischaemic cardiac complications in patients with acute coronary syndrome (ACS) without ST-elevation and during percutaneous coronary interventions (PCI), in combination with aspirin and heparin

4. Dipyramole• It is a phosphodiaestrase inhibitor .• It increases intracellular cyclic AMP, thus reducing

TXA2 synthesizes and also potentiate the prostacyclin effect on platelets making them less sticky and therefore making them less adhesive to thrombogenic surface .

• It is ineffective when used alone; should be used with aspirin

• It reduces the risk of stroke .• Unlike aspirin it does not increase the risk of

bleeding

Good luck

Referrences:

• Lippincottes pharmacology• Rang and dale pharmacology