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It is believed that platelet reactivity and interaction with prosthetic cardiac valve surfaces, resulting in abnormally shortened platelet survival time, is a significant factor in thromboembolic complications occurring in connection with prosthetic heart valve replacement.
Persantine (dipyridamole USP) tablets have been found to lengthen abnormally shortened platelet survival time in a dose-dependent manner.
In three randomized controlled clinical trials involving 854 patients who had undergone surgical placement of a prosthetic heart valve, Persantine (dipyridamole) tablets, in combination with warfarin, decreased the incidence of postoperative thromboembolic events by 62 to 91% compared to warfarin treatment alone. The incidence of thromboembolic events in patients receiving the combination of Persantine (dipyridamole) tablets and warfarin ranged from 1.2 to 1.8%. In three additional studies involving 392 patients taking Persantine (dipyridamole) tablets and coumarin-like anticoagulants, the incidence of thromboembolic events ranged from 2.3 to 6.9%.
In these trials, the coumarin anticoagulant was begun between 24 hours and 4 days postoperatively, and the Persantine (dipyridamole) tablets were begun between 24 hours and 10 days postoperatively. The length of follow-up in these trials varied from 1 to 2 years.
Persantine (dipyridamole) tablets do not influence prothrombin time or activity measurements when administered with warfarin.
Mechanism of Action
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 µg/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 inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic-3',5'-guanosine monophosphate-PDE (cGMP-PDE), thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, now identified as nitric oxide).
In dogs intraduodenal doses of dipyridamole of 0.5 to 4.0 mg/kg produced dose-related decreases in systemic and coronary vascular resistance leading to decreases in systemic blood pressure and increases in coronary blood flow. Onset of action was in about 24 minutes and effects persisted for about 3 hours.
Similar effects were observed following IV Persantine (dipyridamole) in doses ranging from 0.025 to 2.0 mg/kg.
In man the same qualitative hemodynamic effects have been observed. However, acute intravenous administration of Persantine (dipyridamole) may worsen regional myocardial perfusion distal to partial occlusion of coronary arteries.
Pharmacokinetics and Metabolism
Following an oral dose of Persantine (dipyridamole) tablets, the average time to peak concentration is about 75 minutes. The decline in plasma concentration following a dose of Persantine (dipyridamole) tablets fits a two-compartment model. The alpha half-life (the initial decline following peak concentration) is approximately 40 minutes. The beta half-life (the terminal decline in plasma concentration) is approximately 10 hours. Dipyridamole is highly bound to plasma proteins. It is metabolized in the liver where it is conjugated as a glucuronide and excreted with the bile.
Last reviewed on RxList: 4/18/2008
This monograph has been modified to include the generic and brand name in many instances.
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