ANTIPLATELETES AGENTS

BY :DR. ISRAA OMAR

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

The role of platelets

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 )

Aspirin (Acetylsalicylic acid) – mechanism of action

Acetylsalicylic acid – (Aspirin)mechanism of action

(Acetylsalicylic acid – (Aspirinmechanism of action

(Aspirin )Acetylsalicylic acid – mechanism of action

(Aspirin) Acetylsalicylic acid – mechanism of action

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)

Aspirin– pharmacokinetics

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

Acetylsalicylic acid – major use

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

(Aspirin )– major drawbacks

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

2. Clopidogrel and Ticlodipine (Thienopyridines )

ADP-receptor antagonists – mechanism of action

ADP-receptor antagonists – mechanism of action

ADP-receptor antagonists – mechanism of action

ADP-receptor antagonists – mechanism of action

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

ADP-receptor antagonists – pharmacokinetics

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

ADP-receptor antagonists – major use

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

ADP-receptor antagonists – major drawbacks

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

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

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

GPIIb/IIIa-receptor antagonists – major use

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

Dipyramole

Thank you

Lippincottes pharmacology Rang and dale pharmacology

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