ADP receptor

Ticlopidine inhibits the P2Yj2 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP Ilb/IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33% for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke. Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. 

Clopidogrel also inhibits the P2Yj2 ADP receptor following hepatic activation in... 

Gachet C. ADP receptors of platelets and their inhibition. Thromb Haemost 2001 86 222-232. 

Conley, P. B., Jantzen, H. M., Vincent, D., et al. (2000) Molecular identification of the platelet ADP receptor targeted by antithrombotic drugs. Blood. 96, 222A. 

Pharmacology Clopidogrel is a thienopyridine derivative, chemically related to ticlopidine, that inhibits platelet aggregation. It acts by irreversibly modifying the platelet ADP receptor. Conseguently, platelets exposed to clopidogrel are affected for the remainder of their lifespan. 

Which of the following is a drug that blocks the ADP receptor on the antiplatelet membrane ... 

Hollopeter G, Jantzen HM, Vincent D et al (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409 202-7 Holton FA, Holton P (1953) The possibility that ATP is a transmitter at sensory nerve endings. J Physiol 119 50P—51P... 

Zhang FL, Luo L, Gustafson E et al (2002) P2Y13 identification and characterization of a novel Gaj-coupled ADP receptor from human and mouse. J Pharmacol Exp Ther 301 705-13 Zhang JM, Wang HK, Ye CH et al (2003) ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron 40 971-82 Zimmermann H (1992) 5 -Nucleotidase molecular structure and functional aspects. Biochem J 285 345-65... 

There are three important ADP receptors on the platelet surface (16). The P2X, inotrophic receptor is responsible for rapid influx of calcium into the cytosol. The P2Y, receptor mediates mobilization of calcium through activation of PLC and shape change. The P2Y,2 receptor is coupled to adenyl cyclase inhibition mediated by a G-protein with subsequent decrease in the cAMP The decrease in cAMP stimulates dephosphorylation of VASP that is closely correlated with the GPIIb/llla activation. 

Geiger J, Brich J, Honing-Liedl M, et al. Specific impairment of human platelet P2YAC ADP receptor-mediated signalling by the antiplatelet drug Clopidogrel. Arterioscler Thromb Vase Biol 1999 19 2007-201 I. 

ADP receptor inhibitors might be used in patients with coronary artery disease, in neurology, and in angiology. This chapter will mainly consider indications of ticlopidine and clopidogrel since these are the only two drugs currently available in the market. 

ADP receptor inhibitors play a major role in the management of ACS in interventional cardiology before and after stent... 

A number of questions are still to be resolved, particularly the matter of long-term treatment. This topic is not only a major issue for the clinical outcome of patients with atherosclerotic disease but also from the economic standpoint. Finally, in the future, new ADP receptor blockers will have to be considered and compared to currently available thienopyridines. 

Foster CJ, Prosser DM, Agans JM, et al. Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs. J Clin Invest 2001 107 1591-1598. 

Savi P Labouret C, Delesque N, Guette p LupkerJ, HerbertJM. P2y( 12), a new platelet ADP receptor, target of clopidogrel. Biochem Biophys Res Commun 2001 283 379-383. 

The pharmacological treatment options for ACS include agents that either reduce oxygen demand (beta blockers) or increase oxygen supply (nitrates, potassium channel activators, calcium channel blockers) to the heart and antiplatelet (aspirin, ADP-receptor antagonists, GPIIb/llla receptor blockers) and antithrombin therapy (unfractionated heparin, low molecular weight heparin, direct thrombin inhibitors) (10). 

There are a number of additional targets that may lead to effective antithrombotic therapy in ACS. In terms of anticoagulants, the concepts of agents that have dual inhibitor sites such as the one we find in heparin but that lack in some of its undesirable qualities could be very useful. The same concept may apply to drugs that have both anticoagulant and antiplatelet properties, It is quite probable that inhibitors of tissue factor as well as of the platelet ADP receptor when combined with aspirin might be very effective. An ability to block the feedback action of the polyphosphates released from platelets upon activation is also an attractive aim (Fig. 3),... 

Dorsam RT Tuluc M, Kunapuli SR Role of protease-activated and ADP receptor subtypes in thrombin generation on human platelets. J Thromb FHaemost 2004 2 804-812. 

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