Protein + Phosphate -> Chelator of Calcium

Free Calcium (Ca2+)-> Bound Calcium necessary for inhibits aggregation platelet aggregation

Figure 19.22 • Role of adenosine 3',5'-cydic monophosphate (cAMP) in inhibition of platelet aggregation.

released from a--granules in the platelets and ADP, ATP, serotonin, and calcium are released from dense bodies in the platelets. The dense bodies are likened to the storage granules associated with adrenergic neurons. Increased levels of cAMP inhibit platelet aggregation. cAMP activates specific dependent kinases, which form protein-phosphate complexes that chelate calcium ions. The reduced levels of calcium inhibit aggregation (Fig. 19.22). Inhibitors of platelet aggregation can increase cAMP levels by either stimulating adenylate cyclase or inhibiting phosphodiesterase.74 Substances such as glucagon, adenosine, and isoproterenol increase cAMP levels and inhibit platelet aggregation. Drugs such as theophylline, aminophylline, dipyramidole, papaverine, and adenosine inhibit phosphodiesterase and aggregation of platelets. Epinephrine, collagen, and serotonin inhibit adenylate cyclase and stimulate platelet aggregation.75 The role of platelets in arterial thrombosis is similar to that in he-mostasis. The factors contributing to venous thrombosis are circulatory stasis, excessive generation of thrombin formation of fibrin, and, to a lesser extent than in the artery, platelet aggregation.

Aspirin, sulfinpyrazone, and indomethacin have an inhibitory effect on platelet aggregation. They inhibit COX, the enzyme that controls the formation of prostaglandin endoperoxides and increases the tendency for platelets to aggregate.76 Aspirin also inhibits the platelet-release reaction. Dipyridamole inhibits adenosine deaminase and adenosine uptake by platelets. As a result, the increased plasma concentrations of adenosine inhibit ADP-induced aggregation of platelets.

Among the many pharmacological actions of prostaglan-dins is the ability of some to stimulate or inhibit the aggregation of platelets and alter the clotting time of blood. Prostaglandins are synthesized from 20-carbon polyunsaturated fatty acids containing from three to five double bonds. These fatty acids are present in the phospholipids of cell membranes of all mammalian tissues. The main precursor of prostaglandins is arachidonic acid. Arachidonic acid is released from membrane phospholipids by the enzyme phospholipase A2. Once released, arachidonic acid is metabolized by COX synthetase to form unstable cyclic endoperoxides, PGG2 and PGH2, which subsequently are transformed into PGI2 and TXA2. The conversion to TXA2 is aided by the enzyme thromboxane synthetase. The formation of PGI2 can occur nonenzymatically. Blood platelets convert arachidonic acid to TXA2, whereas PGI2 is formed mainly by the vascular endothelium. Both PGI2 and TXA2

are unstable at physiological pH and temperatures. Their half-lives are 2 to 3 minutes.

PGI2 inhibits platelet aggregation by stimulating adenylate cyclase to increase cAMP levels in the platelets. PGI2 is also a vasodilator and, as a result, has potent hypotensive properties when given intravenously or by intra-arterial administration. TXA2 induces platelet aggregation. Together with PGI2, TXA2 plays a role in the maintenance of vascular homeostasis. In addition to being a platelet aggregator, TXA2 is a potent vasoconstrictor.

Retardation of clotting is important in blood transfusions, to avoid thrombosis after surgery or from other causes, to prevent recurrent thrombosis in phlebitis and pulmonary embolism, and to lessen the propagation of clots in the coronary arteries. This retardation may be accomplished by agents that inactivate thrombin (heparin) or substances that prevent the formation of prothrombin in the liver (the coumarin derivatives and the phenylindanedione derivatives).

Although heparin is a useful anticoagulant, it has limited applications. Many of the anticoagulants in use today were developed following the discovery of dicumarol, an anticoagulant present in spoiled sweet clover. These compounds are orally effective, but there is a lag period of 18 to 36 hours before they increase the clotting time significantly. Heparin, in contrast, produces an immediate anticoagulant effect after intravenous injection. A major disadvantage of heparin is that the only effective therapeutic route is parenteral.

Dicumarol and related compounds are not vitamin K antagonists in the classic sense. They appear to act by interfering with the function of vitamin K in the liver cells, which are the sites of synthesis of the clotting factors, including prothrombin. This lengthens the clotting time by decreasing the amount of biologically active prothrombin in the blood.

The discovery that dicumarol and related compounds were potent reversible competitors of vitamin K coagulant-promoting properties (although at high levels, dicumarol is not reversed by vitamin K) led to the development of antivitamin K compounds such as phenindione, which was designed in part according to metabolite-antimetabolite concepts. The active compounds of the phenylindanedione series are characterized by a phenyl, a substituted phenyl, or a diphenylacetyl group in the 2-position. Another requirement for activity is a keto group in the 1- and 3-position, one of which may form the enol tautomer. A second substituent, other than hydrogen, at the 2-position prevents this keto-enol tautomerism, and the resulting compounds are ineffective as anticoagulants.

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