Antiplatelet Agents Frederick Villamena, PhD Associate Professor of Pharmacology College of Medicine The Ohio State University.

Antiplatelet Agents

Frederick Villamena, PhD

Associate Professor of Pharmacology

College of Medicine

The Ohio State University

Block Objective

Describe

• the mechanisms of action• indications• and major side effects of

drugs affecting platelet activation and aggregation.

Objectives

Identify

the main molecules responsible in platelet

activation and aggregation.

Classify and name

antiplatelet agents according to their

mechanisms of actions.

Identify

the properties, applications,

pharmacokinetics, toxicity, and contraindications of

various antiplatelet drugs.

References

Lilly, L. Pathophysiology of Heart Disease, 5th ed. 2010. Chapter 17, pp. 423-427.

Harvey, R.A. and Champe, P. C. Pharmacology, 5th ed. Lippincott Illustrated Reviews.

Mechanism of Platelet Activation and Aggregation

Lippincott Williams and Wilkins

Platelet Aggregation Inhibitors

To decrease the formation or signaling action that promote aggregation.

Regulation of platelet activating agents that promote binding of GP IIb/IIIa receptor to fibrinogen.

COX-1 Inhibitor

Aspirin is the most commonly used one and is orally administered. Used to prevent thrombosis in atherosclerotic disease of coronary

and peripheral vessels. Used in treatment of transient cerebral ischemia, reduce

recurrence of MI and decrease mortality in MI patients. Side effects are GI-related, allergy and bleeding.

ADPTXA2

GP IIb/IIIa receptors activation

fibrinogenCa2+

thrombin

ADP, TXA2 synthesis

prostaglandin H2

arachidonic acid

COX-1

TXA2

ADP inhibitors

Antiplatelet substitutes in patients allergic to aspirin.

Orally administered.

Thienopyridine-based drugs: ticlopidine, clopidogrel, and prasugrel

Ticlopidine is rarely used now. Clopidogrel is an approved pro-drug for prevention of

atherosclerotic events from MI, stroke, and peripheral arterial disease. Prevents thrombotic events during and after percutaneous coronary intervention (PCI) with or without stent.

Prasugrel is a newer ADP inhibitor. More effective than clopidogrel in reducing cardiovascular disease death, nonfatal heart attack and stroke.

Ticagrelor (not a thienopyridine) is used to prevent thrombosis during PCI with stent replacement. Co-administered with aspirin (75-150 mg). Reduced efficacy at higher ASA doses.

Side effects of thienopyridines: bleeding,

indigestion, and diarrhea.

Potentially life-threatening hematologic effects in small number of patients with the

use of ticlopidine.

Fibrinogen (GP IIb/IIIa) receptor inhibitors

Administered by IV injection. Abciximab is a monoclonal antibody

injected with either heparin or aspirin as an adjunct to percutaneous coronary intervention (angioplasty).

Tirofiban (synthetic nonpeptide) and eptifibatide (synthetic peptide) decrease incidence of thrombotic complications from acute coronary syndromes.

All can cause bleeding and thrombocytopenia as adverse side affects.

Phosphodiesterase inhibitor

Cilostazol is an oral antiplatelet agent with vasodilating activity. FDA approved to reduce claudication in peripheral artery disease (PAD). Highly metabolized. Contraindicated in patients with congestive heart failure.

ATP cAMP degradationphosphodiesterase

elevated level cAMP

Ca2+ platelet aggregation

NO and prostacylcin from endothelium

Comparison of Major Antiplatelet Drugs

Drugs

Mechanism of action

Indications

Route of administration

Adverse/Side effect

COX-1 inhibitors

TXA2 synthesis via COX-1 inhibition

Prevent thrombosis in atherosclerotic

disease

Oral

Allergy/Bleeding

ADP Inhibitors

ADP receptors inhibition

Prevent thrombosis in CAD, PAD

Prevent stent thrombosis-PCI

Oral

Bleeding (contraindicated in hepatic diseases)

IIb/IIIa Receptor inhibitors

GP IIb/IIIa receptor blockage

Acute coronary syndromes where

angioplasty is planned

IV

Bleeding

Phosphodiesterase inhibitors

Inhibition of cAMP degradation via PDE inhibition

Used in peripheral arterial disease

Oral

Contraindicated in patients with heart

failure

Antiplatelets Quiz

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