What is the mechanism of action of cilostazol?

Mechanism of Action of Cilostazol

Cilostazol is a phosphodiesterase type III (PDE III) inhibitor that increases intracellular cyclic adenosine monophosphate (cAMP) levels, resulting in vasodilation and platelet inhibition. 1, 2

Primary Mechanism

• PDE III inhibition leads to suppression of cAMP degradation, causing accumulation of cAMP in platelets and blood vessels 2
• The increased cAMP produces two main effects:
  • Vasodilation through effects on vascular smooth muscle 1, 2
  • Platelet inhibition through reversible inhibition of platelet aggregation 2

Antiplatelet Effects

• Cilostazol reversibly inhibits platelet aggregation induced by multiple stimuli including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress 2
• The antiplatelet effect is mediated through cAMP-dependent mechanisms in platelets 3, 4

Vascular Effects

• Produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid, or superior mesenteric arteries 2
• Increases coronary blood flow and myocardial contractile force 2
• Exhibits antiproliferative effects on vascular smooth muscle cells, which may contribute to prevention of restenosis 1, 3

Additional Mechanisms

• Inhibits expression of vascular cell adhesion molecule-1 (VCAM-1), reducing inflammatory vascular responses 1
• May involve adenosine reuptake inhibition and other cAMP-independent pathways 4
• Activates cAMP-dependent protein kinase (PKA)-coupled maxi-K channels, which may contribute to neuroprotective effects 5

Metabolic Effects

• Increases plasma HDL cholesterol by approximately 10% 1, 2
• Decreases triglyceride concentrations by approximately 15% (29.3 mg/dL reduction) 1, 2

Cardiovascular Effects

• Increases heart rate in a dose-proportional manner (mean increase of 5.1 beats/min with 50 mg twice daily and 7.4 beats/min with 100 mg twice daily) 2
• Increases left ventricular contractility and accelerates A-V conduction 2
• These cardiovascular effects explain why cilostazol is absolutely contraindicated in heart failure of any severity, as other PDE III inhibitors have demonstrated increased mortality in heart failure patients 1, 6

Clinical Relevance

• The precise mechanism by which cilostazol improves intermittent claudication symptoms is not fully understood, as the modest hemodynamic improvements (increased ankle-brachial index) cannot fully account for the 40-60% improvement in walking distance observed in clinical trials 1, 2
• The therapeutic benefit likely results from the combination of vasodilation, platelet inhibition, antiproliferative effects, and metabolic improvements rather than any single mechanism 3, 7