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

Aspirin( Acetylsalicylic acid ) 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 Antithrombotic drugs Aspirin (Acetylsalicylic acid) – mechanism of action September 2007

Acetylsalicylic acid – (Aspirin) mechanism of action Antithrombotic drugs Acetylsalicylic acid – (Aspirin) mechanism of action September 2007

(Acetylsalicylic acid – (Aspirin mechanism of action Antithrombotic drugs (Acetylsalicylic acid – (Aspirin mechanism of action September 2007

(Aspirin )Acetylsalicylic acid – mechanism of action Antithrombotic drugs (Aspirin )Acetylsalicylic acid – mechanism of action September 2007

(Aspirin) Acetylsalicylic acid – mechanism of action Antithrombotic drugs (Aspirin) Acetylsalicylic acid – mechanism of action September 2007

Aspirin– pharmacokinetics Antithrombotic drugs Aspirin– 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) Reference: Patron C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287–94. September 2007

Acetylsalicylic acid – major use Antithrombotic drugs Acetylsalicylic acid – major use 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 September 2007

(Aspirin )– major drawbacks Antithrombotic drugs (Aspirin )– major drawbacks 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 September 2007

2. Clopidogrel and Ticlodipine (Thienopyridines ) 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 Antithrombotic drugs ADP-receptor antagonists – mechanism of action September 2007

ADP-receptor antagonists – mechanism of action Antithrombotic drugs ADP-receptor antagonists – mechanism of action … September 2007

ADP-receptor antagonists – mechanism of action Antithrombotic drugs ADP-receptor antagonists – mechanism of action September 2007

ADP-receptor antagonists – mechanism of action Antithrombotic drugs ADP-receptor antagonists – mechanism of action . September 2007

ADP-receptor antagonists – pharmacokinetics Antithrombotic drugs ADP-receptor antagonists – 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 September 2007

ADP-receptor antagonists – major use Antithrombotic drugs ADP-receptor antagonists – major use 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 September 2007

ADP-receptor antagonists – major drawbacks Antithrombotic drugs ADP-receptor antagonists – major 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 September 2007

GPIIb/IIIa-receptor antagonists 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 Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action September 2007

GPIIb/IIIa-receptor antagonists – mechanism of action Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action . September 2007

GPIIb/IIIa-receptor antagonists – mechanism of action Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action September 2007

GPIIb/IIIa-receptor antagonists – mechanism of action Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action September 2007

GPIIb/IIIa-receptor antagonists – mechanism of action Antithrombotic drugs GPIIb/IIIa-receptor antagonists – mechanism of action September 2007

GPIIb/IIIa-receptor antagonists – major use Antithrombotic drugs GPIIb/IIIa-receptor antagonists – major use 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 September 2007

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

Thank you

Referrences: Lippincottes pharmacology Rang and dale pharmacology