Aggrenox Mechanism Of Action

Please let me know the rational for the use of aspirin and dipyridamole.
I am intersested in MOA (mechanism of action for aggrenox) OF AGGRENOX.
* * Edited by Site Admin 6/9/2005 11:23:12 AM PDT * *

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Mechanism of Action
The antithrombotic action of AGGRENOX (aspirin/extended-release dipyridamole) is the result of the additive antiplatelet effects of dipyridamole and aspirin.

Dipyridamole
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).

Aspirin
Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of thromboxane A2, a powerful inducer of platelet aggregation and vasoconstriction.

Pharmacokinetics
There are no significant interactions between aspirin and dipyridamole. The kinetics of the components are unchanged by their coadministration as AGGRENOX.

Dipyridamole
Absorption: Peak plasma levels of dipyridamole are achieved 2 hours (range 1-6 hours) after administration of a daily dose of 400 mg AGGRENOX (given as 200 mg b.i.d.). The peak plasma concentration at steady-state is 1.98 µg/mL (1.01-3.99 µg/mL) and the steady-state trough concentration is 0.53 µg/mL (0.18-1.01µg/mL).

Effect of Food: When AGGRENOX capsules were taken with a high fat meal, dipyridamole peak plasma levels (Cmax) and total absorption (AUC) were decreased at steady-state by 20-30% compared to fasting. Due to the similar degree of inhibition of adenosine uptake at these plasma concentrations, this food effect is not considered clinically relevant.

Distribution: Dipyridamole is highly lipophilic (log P=3.71, pH=7); however, it has been shown that the drug does not cross the blood-brain barrier to any significant extent in animals. The steady-state volume of distribution of dipyridamole is about 92 L. Approximately 99% of dipyridamole is bound to plasma proteins, predominantly to alpha 1-acid glycoprotein and albumin.

Metabolism and Elimination: Dipyridamole is metabolized in the liver, primarily by conjugation with glucuronic acid, of which monoglucuronide which has low pharmacodynamic activity is the primary metabolite. In plasma, about 80% of the total amount is present as parent compound and 20% as monoglucuronide. Most of the glucuronide metabolite (about 95%) is excreted via bile into the feces, with some evidence of enterohepatic circulation. Renal excretion of parent compound is negligible and urinary excretion of the glucuronide metabolite is low (about 5%). With intravenous (i.v.) treatment of dipyridamole, a triphasic profile is obtained: a rapid alpha phase, with a half-life of about 3.4 minutes, a beta phase, with a half-life of about 39 minutes, (which, together with the alpha phase accounts for about 70% of the total area under the curve, AUC) and a prolonged elimination phase ëz with a half-life of about 15.5 hours. Due to the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with AGGRENOX which, in trial 9.123 was 13.6 hours.

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i found a moa under this link:

http:/­/­www.animares.com/­de/­medical/­161/­161.html

anima res - 3d computeranimation

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