Pharmacodynamic Properties of Antiplatelet Agents

Current Knowledge and Future Perspectives

Kallirroi I Kalantzi; Maria E Tsoumani; Ioannis A Goudevenos; Alexandros D Tselepis

Disclosures

Expert Rev Clin Pharmacol. 2012;5(3):319-336. 

In This Article

Phosphodiesterase Inhibitors

Platelet activation can be inhibited either by specific antagonists of membrane receptors coupled with intracellular signaling pathways or by selective inhibitors of enzymes that are involved in critical steps of the intracellular signaling pathways. Such enzymes are COX-1 (discussed above) and PDEs. PDEs catalyze hydrolysis of the cyclic nucleotides cAMP and cGMP, which are important intracellular second messengers for platelet function (Figure 2).[79,80] These nucleotides are formed through the action of the membrane-bound enzyme adenylcyclase and the increase in their intracellular levels is associated with inhibition of platelet activation. Thus, PDEs limit the intracellular levels of cAMP and cGMP, inducing platelet activation. Therefore, inhibition of PDEs may confer a strong inhibitory effect on platelets.[81] Two PDE inhibitors are currently in use in clinical practice, namely dipyridamole and cilostazol.

Dipyridamole

Dipyridamole is a pyrimidopyrimidine with vasodilator and antiplatelet properties. Several mechanisms of action have been proposed for dipyridamole.[82] It has been suggested that it inhibits types 3 and 5 PDEs, leading to the intraplatelet accumulation of cAMP. Dipyridamole is also an inhibitor of platelet adenosine uptake. Direct stimulation of PGI2 synthesis and protection against its degradation have been reported, although the dipyridamole concentrations required to produce these effects far exceed the low micromolar plasma levels achieved after oral administration of conventional doses (100–400 mg/day). Dipyridamole also differentially inhibits the expression of critical inflammatory genes in platelet–leukocyte conjugates.[83]

The absorption of dipyridamole from conventional formulations is quite variable and may result in low systemic drug bioavailability. A modified release formulation of dipyridamole with improved bioavailability has been developed in association with low aspirin dose.[84] Dipyridamole is eliminated primarily by biliary excretion as a glucuronide conjugate and is subject to enterohepatic recirculation. It has a half-life of 10 h, consistent with the twice-daily regimen used in recent clinical studies.[85,86]

The combination of dipyridamole with aspirin has greater efficacy than aspirin monotherapy for the secondary prevention of stroke.[87] By contrast, this combination does not provide any further benefit compared with clopidogrel for the secondary prevention of stroke.[88]

Cilostazol

Cilostazol, a 2-oxo-quinoline, is a potent, reversible type 3 phosphodiesterase inhibitor, targeting both platelets and vascular smooth muscle cells. Cilostazol also reduces cellular adenosine uptake.[89] It is metabolized in the liver through the CYP isoenzymes. Thus, its plasma levels and antiplatelet efficacy may be influenced by other CYP-metabolized drugs, such as erythromycin and omeprazole. Cilostazol is excreted by the kidney. The plasma half-life of cilostazol is approximately 10 h, resulting in approximately twofold accumulation of the drug during repeated administration.[90] Adding to a standard aspirin–clopidogrel combination, cilostazol (100 mg twice daily) potentiates inhibition of ADP-induced platelet aggregation.[91] The ACCEL-RESISTANCE study showed that adding cilostazol to clopidogrel monotherapy increases platelet inhibition, even compared with a high maintenance clopidogrel dose of 150 mg/day.[92] Thus, cilostazol may be a helpful tool in overcoming clopidogrel resistance.

Cilostazol exhibits greater efficacy than aspirin in the secondary prevention of stroke.[93] A meta-analysis showed that adding cilostazol to traditional dual-antiplatelet therapy reduces angiographic restenosis but it does not affect ST in patients undergoing PCI.[94] However, a recent randomized trial assessing the efficacy of cilostazol in patients undergoing PCI with drug-eluting stents did not demonstrate any significant reduction in composite adverse CV events, despite a greater reduction in platelet reactivity.[95] Consequently, further clinical studies are necessary to validate the potential benefits of cilostazol in patients with CV disease.

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