Dipyridamole is an oral coronary vasodilator and antiplatelet drug used in combination with other anti-coagulant drugs to prevent thrombosis in patients with valvular and vascular disorders. Dipyridamole works through many mechanisms including inhibition of phosphodiesterase-5, inhibition of adenosine deaminase and adenosine transporter, decreased thromboxane synthesis and increased prostacyclin synthesis. Platelets have adenosine A2A and A2B receptors on their cell membrane. When these receptors are activated by adenosine, the Gs signaling cascade is triggered, adenylate cyclase is activated and cAMP is produced. Through a number of mechanisms, cAMP leads to an inhibition of platelet activation and aggregation. cAMP may prevent release of arachidonic acid from membrane phospholipids. Arachidonic acid produces prostaglandin H2 via prostaglandin G/H synthase 1 & 2. Thromboxane A2 is then formed from prostaglandin H2 via thromboxane A synthase. Thromboxane causes platelet activation and aggregation, therefore, inhibition of arachidonic release by cAMP leads to reduced thromboxane production and thus, less platelet activation and aggregation. Phosphodiesterase-5 can breakdown cAMP into AMP, preventing this inhibitory effect. Dipyridamole enters platelets through the multidrug resistance associated protein 4. It inhibits phosphodiesterase-5, preventing the breakdown of cAMP and causing a high intracellular concentration of cAMP. This causes increased inhibition of platelet activation and aggregation. Dipyridamole may also inhibit the adenosine transporter, preventing adenosine reuptake and causing an accumulation of adenosine in the extracellular space. This increases the amount adenosine surrounding the platelets, resulting in increased activation of the adenosine receptors. Dipyridamole also potentiates this effect by inhibiting adenosine deaminase, the enzyme responsible for breaking down adenosine. Dipyridamole may also directly stimulate prostacyclin I2 production endothelial cells. Prostacyclin I2 is transported out of the endothelial cells and activates prostacyclin receptors on the platelet. These prostacyclin receptors, when activated, activates adenylate cyclase and increases cytosolic cAMP which leads to further inhbition of platelet activation and agreggation. Dipyridamole may involve side effects such as gastrointestinal upset, headache, facial flushing, dizziness, hypotension, chest pain, nausea, diarrhea, rash and itchiness.

Dipyridamole Pathway References