Inhibition of Platelet Functions by Aspirin Aspirin selectively inhibits prostaglandin production in human platelets [241]. This effect is now more precisely referred to as the inhibition ofthrombox-ane A2 formation and the generally accepted mode of antiplatelet action of aspirin (Section 2.2.1). Aspirin does not modify ADP-induced platelet aggregation, that is, the contraction of the platelet cytoskeleton, granule secretion, and thromboxane formation, in native blood [242]. Nor does it change the number of thromboxane receptors [243]. Inhibition of (stimulated) thromboxane formation, for example, in Ca2+-depleted media, such as citrated plasma, will provide more substrates for biosynthesis of 12-hydro(pero)xyarachidonic acid (12-H(P) ETE) that can also modify platelet function by interaction with cyclooxygenases (Section 2.2.1). In addition to thromboxane inhibition, aspirin inhibits thrombin generation at least at analgesic doses (0.5-1 g) [239, 240, 244]. However, since thie-nopyridines also inhibit platelet-dependent thrombin formation [245, 246], it is likely that antiplatelet effects of these compounds are more important for their antithrombotic efficacy than their specific actions on clotting factors (Section 3.1.2). Aspirin might increase platelet-dependent NO production at high intravenous doses (800 mg) [247]. Whether this effect is clinically significant, considering also the activation of endothelial NO formation by aspirin (Section 2.2.2), is unknown.

Time-Dependent Inhibition of Platelet Function by Aspirin The antiplatelet action of aspirin is maximum in vitro after about 15 min [248] and irreversible because of the absence of sufficient synthesis of new enzyme proteins in platelets. In vivo, significant inhibition of thromboxane formation and platelet aggregation in the absence of an aspirin loading-dose requires about 1 h of continuous i.v. infusion of aspirin at effective plasma levels of 2 or 4mM [249]. After oral administration, at least two daily doses (e.g., 75 mg) of standard aspirin are necessary to obtain sufficient inhibition of serum thromboxane. Oral single doses of325,162 (plain), and 75 mg (slow-release) aspirin result in peak plasma aspirin levels of 10.7, 6.8, and 0.3 mM [23]. Intravenous low-dose aspirin (50 mg) requires about 1 h for maximum inhibition ofthromboxane formation [250] whereas nearly complete inhibition of thromboxane formation and arachidonic acid-induced platelet aggregation was seen within 5 min after 250 and 500 mg i.v. soluble aspirin (Figure 2.25). For oral dosing of 500 mg, 20 min were required for a maximum effect [251]. This is the reason for a "loading" dose if immediate inhibition ofplatelet function is required, for example, as an emergency first-line treatment in acute coronary syndromes (Section 4.1.1). Once sufficient acetylation is obtained, only a maintenance dose of aspirin per day is necessary.

Pretreatment with (nonselective) reversible COX-1 inhibitors, such as ibuprofen or indometh-acin, will antagonize the antiplatelet effects of aspirin because of interference with aspirin (salicylate) binding within the substrate channel of COX-1 (Section 2.2.1). Theoretically and under certain experimental conditions with a high salicylate/as-pirin ratio (>20 : 1), this type of interaction can also be shown for salicylate [252, 253]. However, there is no evidence for a clinically relevant antagonistic antiplatelet interaction of aspirin and salicylate at

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