Rationale for the combination of anti-aggregating drugs.
Different pathways of platelet activation lead to the exposure of the glycoprotein (GP) IIb/IIIa receptor resulting in binding with fibrinogen and platelet aggregation. The impact of these pathways depends on the types of agonist present. Most agonists release arachidonic acid (AA), which is metabolised to thromboxane A2 (TXA2). This increases intracellular calcium, which is crucial for exposure of the GP IIb/IIIa receptor and the release of the dense and/or alpha granule contents. Anti-aggregating drugs act via different mechanisms. Some antagonise pro-aggregating stimuli while others inhibit the metabolism of AA to TXA2, blocking only one pathway of aggregation and not affecting granule content release. Agents that increase cAMP and/or cGMP interfere with all known pathways of aggregation and with the release mechanism. Inhibitors of cAMP and/or cGMP specific phosphodiesterases also increase intracellular nucleotide concentrations and a stimulatory agent together with a phosphodiesterase inhibitor is a very effective combination. Finally, GP IIb/IIIa antagonists abolish the binding of fibrinogen to the platelets, which inhibits platelet aggregation but leaves the release reaction intact. Different mediators cause aggregation via different pathways. Thus a broader spectrum of anti-aggregating activity can be expected by combining drugs accordingly. Drug combination might also increase the chances of interfering more efficiently with the release reaction, thereby preventing the release of pro-coagulant and growth factors. Synergism might also lead to a reduction in dosage and a decreased risk of side-effects.
University of Antwerp (UIA), Wilrijk, Belgium. aherman@uia.ua.ac.be
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D016718:Arachidonic Acid / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D004338:Drug Combinations; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D013928:Thromboxane A2 / Q000097:blood
D004338:Drug Combinations; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016718:Arachidonic Acid; D013928:Thromboxane A2; D000242:Cyclic AMP; D006152:Cyclic GMP