Platelet-Active Drugs: Effectiveness and Side Effects

Moreover, the direct stimulation of PGI2 synthesis and protection against its degradation have been reported, although the dipyridamole concentrations required to produce these effects far exceed the low micromolar plasma levels achieved after the oral administration of conventional doses (ie, 100 to 400 mg daily). Thienopyridines

The absorption of dipyridamole from conventional formulations is quite variable and may result in low systemic bioavailability of the drug. A modified-release formulation of dipyridamole with improved bioavailability has been developed in association with low-dose aspirin. Dipyridamole is eliminated primarily by biliary excretion as a glucuronide conjugate and is subject to enterohepatic recirculation. A terminal half-life of 10 h has been reported. This is consistent with the twice-a-day regimen used in recent clinical studies.

Although the clinical efficacy of dipyridamole, alone or in combination with aspirin, has been questioned on the basis of the results of earlier randomized trials, the whole issue has been reopened by the reformulation of the drug to improve bioavailability and the results of the ESPS-2 study of the new preparation in 6,602 patients with prior stroke or TIA (see elsewhere in this Supplement). Headache was the most common adverse effect of dipyridamole therapy. Bleeding at any site was almost doubled in the two aspirin arms of the study but was surprisingly indistinguishable from the results of treatment with placebo in the dipyridamole-treated patients. In a post hoc analysis of cardiac events in patients with coronary heart disease or MI at study entry, therapy with dipyridamole did not result in a higher number of fatal and nonfatal cardiac events.

The ESPS-2 study has been criticized for the continued inclusion of a placebo arm after the place of aspirin in the secondary prevention of stroke had been established to the satisfaction of most authorities. Whether the favorable results obtained in ESPS-2 reflect the higher dose (400 vs 225 mg daily) and improved systemic bioavailability of modified-release dipyridamole compared with conventional formulations, or the substantially larger sample size and statistical power of the study as compared with previous trials, remains to be established. The combination of modified-release dipyridamole and low-dose aspirin has been approved by the US Food and Drug Administration (FDA).

Thienopyridines

Ticlopidine and clopidogrel are structurally related thienopyridines with platelet-inhibitory properties. Both drugs selectively inhibit ADP-induced platelet aggregation with no direct effects on arachidonic acid metabolism. Although ticlopidine and clopidogrel also can inhibit platelet aggregation induced by collagen and thrombin, these inhibitory effects are abolished by increasing the agonist concentration and, therefore, are likely to reflect the blockade of ADP-mediated amplification of the platelet response to other agonists.

Neither ticlopidine nor clopidogrel affect ADP-induced platelet aggregation when added in vitro, up to 500 M, thus suggesting that in vivo hepatic transformation to an active metabolite is necessary for their antiplatelet effects. A short-lived metabolite of clopidogrel has been charac-terized. Some evidence suggests that clopidogrel and, probably, ticlopidine induce irreversible alterations of the platelet receptor P2Y12 that mediates the inhibition of stimulated adenylyl cyclase activity by ADP. Interestingly, mutations in the P2Y12 gene are associated with a congenital bleeding disorder and an abnormality in the platelet response to ADP resembling that induced by thienopyridines. The inhibition of platelet function by clopidogrel is associated with a selective reduction in the number of ADP-binding sites, with no consistent change in the binding affinity. The irreversible modification of this ADP receptor site could be explained by the formation of a disulfide bridge between the reactive thiol group of the active metabolite of clopidogrel and one or more cysteine residues of the platelet P2Y12 receptor. The permanent modification of a platelet ADP receptor by thienopy-ridines is consistent with the time-dependent, cumulative inhibition of ADP-induced platelet aggregation on repeated daily dosing with ticlopidine or clopidogrel and with the slow recovery of platelet function after drug withdrawal.

Ticlopidine Ticlopidine

Up to 90% of a single oral dose of ticlopidine is rapidly absorbed in humans. Peak plasma concentrations occur 1 to 3 h after a single oral dose of 250 mg is administered. Plasma levels of ticlopidine increase by approximately threefold on repeated twice-daily dosing over 2 to 3 weeks because of drug accumulation. Greater than 98% of ticlopidine is reversibly bound to plasma proteins, primarily albumin. Ticlopidine is metabolized rapidly and extensively. A total of 13 metabolites have been identified in humans. Of these, only the 2-keto derivative of ticlopidine is more potent than the parent compound in inhibiting ADP-induced platelet aggregation.

The apparent elimination half-life of ticlopidine is 24 to 36 h after a single oral dose and up to 96 h after 14 days of repeated dosing. The recommended regimen of ticlopidine is 250 mg bid, although it is unclear how a twice-daily regimen is related to the pharmacokinetic and pharmacodynamic features noted above. A delayed antithrombotic effect was noted in at least one clinical trial of ticlopidine, in patients with unstable angina, with no apparent protection during the first 2 weeks of drug administration. Therefore, ticlopidine therapy is not useful when a rapid antiplatelet effect is required.

Ticlopidine as a single agent has been evaluated in patients with stroke, transient cerebral ischemia, unstable angina, MI, intermittent claudication, and in patients undergoing aortocoronary bypass sur-gery. Therapy with ticlopidine was significantly (but marginally, in absolute terms.

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