How does dipyridamole prevent adenosine reuptake in platelets?

From the Guidelines

Dipyridamole prevents adenosine reuptake in platelets by blocking the uptake of adenosine, which binds to A2 receptors, stimulates platelet adenyl cyclase, and increases cyclic AMP, an inhibitor of platelet aggregation, as suggested by the American College of Chest Physicians evidence-based clinical practice guidelines 1. The mechanism of action of dipyridamole as an antiplatelet agent is complex and involves multiple pathways. Some of the key mechanisms include:

• Inhibition of cyclic nucleotide phosphodiesterase, resulting in the intraplatelet accumulation of cyclic AMP
• Blockade of the uptake of adenosine, which stimulates platelet adenyl cyclase and increases cyclic AMP
• Direct stimulation of PGI2 synthesis and protection against its degradation, although this effect may not be significant at conventional doses
• Differential inhibition of the expression of critical inflammatory genes by platelet-leukocyte aggregates The blockade of adenosine uptake by dipyridamole leads to an increase in extracellular adenosine concentration, which then binds to adenosine A2 receptors on platelets, activating adenylyl cyclase and increasing intracellular cyclic AMP levels. Elevated cyclic AMP inhibits platelet activation and aggregation by reducing calcium mobilization within platelets. Additionally, dipyridamole also inhibits phosphodiesterase enzymes, which normally break down cyclic AMP, further enhancing the antiplatelet effect, as seen in studies such as the European Stroke Prevention Study (ESPS-2) 1. The combination of dipyridamole and aspirin has been shown to be effective in secondary stroke prevention, with a reduced risk of stroke and death compared to aspirin alone, although it may be less well tolerated by patients 1.

From the FDA Drug Label

Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in vivo; the inhibition occurs in a dose-dependent manner at therapeutic concentrations (0.5-1. 9 mg/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A2-receptor thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3',5'-adenosine monophosphate (cAMP) levels Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP).

Dipyridamole prevents adenosine reuptake in platelets by inhibiting the uptake of adenosine into platelets. This inhibition occurs in a dose-dependent manner at therapeutic concentrations, resulting in an increase in local concentrations of adenosine. The increased adenosine then acts on the platelet A2-receptor, stimulating platelet adenylate cyclase and increasing platelet cyclic-3',5'-adenosine monophosphate (cAMP) levels, ultimately inhibiting platelet aggregation 2.

From the Research

Mechanism of Dipyridamole in Preventing Adenosine Reuptake

• Dipyridamole inhibits platelet aggregation in whole blood by blocking the reuptake of adenosine formed from precursors released by red blood cells following microtrauma 3.
• The inhibitory effect of dipyridamole on platelet aggregation is potentiated by its slight phosphodiesterase inhibitory action, which enhances the effects of adenosine on platelets 3.
• Adenosine deaminase, an enzyme that breaks down adenosine, reverses the inhibitory action of dipyridamole, suggesting that adenosine plays a key role in the antiplatelet effect of dipyridamole 3.
• Adenosine receptor antagonists, such as 5'-deoxy-5'-methylthioadenosine and theophylline, partially neutralize the activity of dipyridamole in blood, further supporting the role of adenosine in its mechanism of action 3.

Role of Dipyridamole in Antiplatelet Therapy

• Dipyridamole is used in combination with aspirin for the secondary prevention of ischemic stroke, and this combination has been shown to be more effective than aspirin alone 4.
• The combination of dipyridamole and aspirin has been recommended by joint guidelines from the American Heart Association and American Stroke Association as a first-line option for secondary prevention of ischemic events in patients with a history of ischemic stroke or transient ischemic attack (TIA) 4.
• Dipyridamole has also been shown to have vaso-protective effects, including inhibition of platelet aggregation and vasodilatation, mainly in the coronary tree 5.