2008B07 List the agents used therapeutically to reduce platelet function. Outline their mechanisms of action,
adverse effects, mode of elimination and duration of action.

 

*Note increased bleeding risk is a potential side effect of all*

 

Pharmacodynamics:

Mechanism of action (MoA)

Side effects (SE)

Pharmacokinetics:

Metabolism (M)

Excretion (E)

Duration (D)

Aspirin (irreversible)

· MoA: Irreversible COX1&2 acetylation

· ↓TXA2 production in platelet

· Minimal effect on endothelial PGI2 at low dose

· SE: bleeding peptic ulcer, nausea, Reye’s syndrome, toxicity -> metabolic acidosis

· M: 80% (liver)

· E: 20% (kidney)

· D: 7 days (new platelets)

Dipyridamole

· MoA: PDE inhibition -> ↑cAMP

· MoA: potentiate PGI2

· SEs: bleeding headache, hypotension

· M: live

· E: bile

· D: t1/2β 10 hours -> BD dose

Clopidogrel

· Prodrug with active thiol metabolite

· MoA: irreversible P2Y12 ADP receptor antagonist (ADPRA)

· SE: bleeding, risk of failure (2C19 polymorphism)

· M: 50% (2C19)

· E: 50% (renal)

· D: 7 days

Ticlopidine

· Prodrug

· MoA: irreversible P2Y12 ADPRA

· SE: bleeding, TTP

· M: liver

· E: urine > bile

· D: 7 days

Ticagrelor

· MoA: Reversible P2Y12 ADPRA

· Has an equipotent metabolite

· SE: bleeding, dyspnoea (esp if asthma)

· M: hepatic CYP3A4, 3A5

· E: bile > urine

· D: 2 days

Abciximab

· MoA: GPIIbIIIa mAb antagonist

· SE: bleeding, ↓plt

· M&E: reticulo-endothelial system

· D: 2 days (prolonged binding)

Tirofiban

· MoA: GPIIbIIIa inhibitor

· SE: bleeding, ↓plt

· M: nil

· E: 66% urine, 33% bile

· D: 8 hours

Prostacyclin

· MoA: Gs GPCR -> ↑cAMP -> inhibit activation

· M: liver, kidney, lung

· D: very short (t1/2β 6 minutes)

Dextrans

· MoA: ↓von Willebrand factor

· SE: anaphylaxis, impair blood cross matching

· M: nil?

· E: renal

· Duration: 6-8 hours for volume expansion, ? antiplatelet duration