Platelet aggregation inhibitors

Definition and Clinical Scope
Platelet aggregation inhibitors—also known as antiplatelet agents—constitute a pharmacological class of agents that impede platelet activation and aggregation, essential processes in thrombus (clot) formation. By targeting specific molecular pathways in the platelet activation cascade, these drugs reduce the risk of arterial thrombotic events, such as myocardial infarction (MI), ischemic stroke, and peripheral arterial thrombosis.

Antiplatelet agents are central to the prevention and treatment of atherothrombotic diseases, particularly in patients with acute coronary syndromes (ACS), percutaneous coronary intervention (PCI), and cerebrovascular disease.

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1. Classification of Platelet Aggregation Inhibitors

Platelet aggregation inhibitors are categorized by mechanism of action and molecular target:

A. Cyclooxygenase (COX) Inhibitors

• Aspirin (acetylsalicylic acid)

B. Adenosine Diphosphate (ADP) Receptor Inhibitors

• Thienopyridines: Irreversible P2Y₁₂ receptor inhibitors

  • Clopidogrel, Prasugrel, Ticlopidine

• Cyclopentyl-triazolo-pyrimidines: Reversible P2Y₁₂ receptor inhibitors

  • Ticagrelor, Cangrelor

C. Glycoprotein IIb/IIIa (GpIIb/IIIa) Inhibitors

• Abciximab, Eptifibatide, Tirofiban

D. Phosphodiesterase (PDE) Inhibitors

• Dipyridamole, Cilostazol

E. Protease-Activated Receptor-1 (PAR-1) Antagonist

• Vorapaxar

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2. Mechanism of Action

Each class disrupts a critical pathway in platelet activation or aggregation:

A. Aspirin

• Irreversibly acetylates COX-1 enzyme in platelets

• Inhibits synthesis of thromboxane A₂ (TXA₂), a potent vasoconstrictor and platelet aggregator

• Platelets cannot synthesize new COX-1 → inhibition lasts for platelet lifespan (~7–10 days)

B. P2Y₁₂ Inhibitors

• Block ADP-mediated activation of GpIIb/IIIa receptors

• Prevent platelet aggregation and activation

Irreversible Inhibitors:

• Clopidogrel, prasugrel: prodrugs requiring hepatic activation

• Ticlopidine: older drug with more side effects (rarely used)

Reversible Inhibitors:

• Ticagrelor: binds directly without hepatic conversion

• Cangrelor: IV agent with rapid onset and offset

C. GpIIb/IIIa Inhibitors

• Block final common pathway of platelet aggregation: fibrinogen binding to GpIIb/IIIa complex

• Used intravenously during PCI or ACS

D. PDE Inhibitors

• Inhibit breakdown of cAMP in platelets → increased intracellular cAMP → reduced activation

• Dipyridamole also inhibits adenosine uptake

E. PAR-1 Antagonists

• Inhibit thrombin-induced platelet aggregation by blocking PAR-1

• Vorapaxar is a long-acting oral inhibitor

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3. Therapeutic Indications

Platelet aggregation inhibitors are used for prevention and treatment of thrombotic events.

A. Cardiovascular Disease

• Acute coronary syndromes (ACS)

• Post-myocardial infarction

• Percutaneous coronary intervention (PCI)

• Chronic coronary artery disease

B. Cerebrovascular Disease

• Ischemic stroke prevention

• Transient ischemic attack (TIA)

• Secondary stroke prophylaxis

C. Peripheral Artery Disease (PAD)

• Symptomatic PAD (e.g., claudication)

• Limb ischemia prevention

D. Atrial Fibrillation (AF)

• In patients unsuitable for anticoagulants (aspirin + clopidogrel as alternative)

E. Other Uses

• Stent thrombosis prevention (dual antiplatelet therapy)

• Thromboprophylaxis in mechanical heart valves (aspirin adjunct)

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4. Generic Drug Names and Brand Examples

Generic Name	Brand Name(s)	Class	Route
Aspirin	Ecotrin, Bayer	COX-1 inhibitor	Oral
Clopidogrel	Plavix	P2Y₁₂ inhibitor	Oral
Prasugrel	Effient	P2Y₁₂ inhibitor	Oral
Ticagrelor	Brilinta	Reversible P2Y₁₂	Oral
Cangrelor	Kengreal	Reversible P2Y₁₂	IV
Dipyridamole	Persantine	PDE inhibitor	Oral, IV
Dipyridamole + ASA	Aggrenox	Dual-action	Oral
Cilostazol	Pletal	PDE-3 inhibitor	Oral
Vorapaxar	Zontivity	PAR-1 antagonist	Oral
Abciximab	ReoPro	GpIIb/IIIa antagonist	IV
Eptifibatide	Integrilin	GpIIb/IIIa antagonist	IV
Tirofiban	Aggrastat	GpIIb/IIIa antagonist	IV

5. Pharmacokinetics Overview

Agent	Onset	Half-life	Duration
Aspirin	30–60 min	~20 min	7–10 days (irreversible)
Clopidogrel	2–4 hours	Active metabolite: ~8 h	3–5 days (irreversible)
Prasugrel	~30 min	~7 hours	7–10 days
Ticagrelor	~1–2 hours	~7–9 hours	Reversible (~24 h)
Cangrelor	Immediate (IV)	~3–6 min	Rapidly reversible
Dipyridamole	1–2 hours	~10–12 hours	Short (reversible)
Cilostazol	2–4 hours	~11–13 hours	Reversible
Vorapaxar	1–2 hours	~8 days	Prolonged activity

6. Adverse Effects

A. Bleeding (most common across all agents):

• Gastrointestinal bleeding

• Intracranial hemorrhage

• Easy bruising

B. Drug-specific side effects:

Agent	Adverse Effects
Aspirin	GI upset, ulcers, tinnitus, Reye’s syndrome in children
Clopidogrel	Rash, diarrhea, TTP (rare)
Prasugrel	Higher bleeding risk, contraindicated in stroke/TIA
Ticagrelor	Dyspnea, bradycardia, increased uric acid
Dipyridamole	Headache, hypotension, flushing
Cilostazol	Palpitations, diarrhea, contraindicated in heart failure
Vorapaxar	Bleeding, not recommended in stroke or ICH history
GpIIb/IIIa inhibitors	Thrombocytopenia, bleeding, allergic reactions

7. Contraindications

• Active bleeding (e.g., GI, intracranial)

• Severe liver disease

• Recent hemorrhagic stroke

• Hypersensitivity to agent

• Thrombocytopenia

• History of TIA/stroke (for prasugrel and vorapaxar)

Special cases:

• Ticagrelor contraindicated with strong CYP3A4 inhibitors

• Aspirin contraindicated in children with viral illness (Reye’s syndrome)

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8. Drug Interactions

Interaction Class	Effect
NSAIDs (e.g., ibuprofen)	Additive bleeding; may blunt aspirin action
Anticoagulants (e.g., warfarin, DOACs)	Increased bleeding risk
Proton pump inhibitors (e.g., omeprazole)	Reduce clopidogrel activation
CYP3A4 inhibitors	Increase levels of ticagrelor and vorapaxar
SSRIs/SNRIs	Additive antiplatelet effect; bleeding risk

9. Monitoring Parameters

• CBC with platelet count (baseline and periodically)

• Signs of bleeding (GI, bruising, hematuria)

• Renal and hepatic function (for agents like ticagrelor, cilostazol)

• Cardiac biomarkers and ECG (in ACS patients)

• Adherence monitoring, especially in dual therapy

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10. Clinical Considerations

Dual Antiplatelet Therapy (DAPT):

• Aspirin + P2Y₁₂ inhibitor (e.g., clopidogrel, ticagrelor)

• Standard in:

  • Acute coronary syndromes (ACS)

  • Post-PCI with stent placement

• Duration: 6–12 months typically, then aspirin monotherapy

Choice of Agent:

• Clopidogrel: widely used, but variable efficacy due to CYP2C19 metabolism

• Ticagrelor/Prasugrel: preferred in ACS for more potent inhibition

• Cangrelor: rapid onset/offset; useful in PCI when oral agents unsuitable

• Vorapaxar: limited to specific patients; high bleeding risk

In Stroke Prevention:

• Aspirin, clopidogrel, or Aggrenox (aspirin + dipyridamole)

• Cilostazol in Asian populations with small-vessel disease