That Inhibit Platelet Activation

Platelets the ways that drugs that inhibit platelet activity are used to treat arterial disease... 

DRUGS THAT INHIBIT PLATELET ACTIVITY (ANTIPLATELET DRUGS)... 

Detwiler and co-workers were the first to demonstrate a role for csPDI in platelet physiology (Chen et al, 1995 Essex et al, 1995). Essex and co-workers (1999, 2001) and Hogg and co-workers (Burgess et al., 2000) showed that the inactivation of csPDI with anti-PDI antibodies and thiol alkylating agents inhibited platelet activation and aggregation. Recent studies have identified two distinct activities for csPDI. 

As shown in double-blind, placebo-controlled, randomized studies with healthy subjects, both infused [145] and oral [146] L-arg significantly inhibited (by =40%) ADP-induced platelet aggregation in vitro and potentiated platelet cGMP content. The effect, though, was weak the plasma concentration of L-arg required to produce an anti-platelet effect was some 2-fold above normal, steady-state levels, and the oral anti-aggregatory L-arg dose was 4-fold greater than the usual daily L-arg intake in humans. The infused L-arg dose that effectively inhibited platelet activity (30 g total) was hypotensive and increased heart rate, whereas the oral anti-platelet dose (7 g per day over 3 days) did not affect blood pressure, suggestive of oral L-arg platelet selectivity. 

Reminiscent of the trend with laboratory studies, most (33 out of 43 cited above) uncontrolled clinical trials with either healthy volunteers or cardiovascular patients suggest that oral and intravenous NO donors at therapeutic doses acutely inhibit platelet activation in vivo (vide supra). Aside from their lack of long-term dosing and a placebo control group, several considerations restrict the predictive clinical value of these uncontrolled clinical studies limited numbers of subjects nonuniform criteria for subject entry and treatment outside of the trial induction of adrenaline or... 

Ginkgo leaf extract appears to act primarily as a mild cerebral vasodilator that increases cerebral blood flow and reduces blood viscosity. Ginkgolides inhibit platelet activating factor, and this may improve microcircula-tory blood flow in atherosclerotic disease with slightly increased risk of bleeding. There appears to be an antioxidant effect that may be neuroprotective. Although some studies suggested a monoamine oxidase inhibitor (MAOI) effect, this is considered to have questionable clinical relevance. 

Mechanism of Action A blood modifier and platelet aggregation inhibitor that inhibits the activity of adenosine deaminase and phosphodiesterase, enzymes causing accumulation of adenosine and cyclic adenosine monophosphate. Therapeutic Effect Inhibits platelet aggregation may cause coronary vasodilation. 

The drug has a short half-life with clearance that is 20% renal and the remainder metabolic. Bivalirudin also inhibits platelet activation and has been FDA-approved for use in percutaneous coronary angioplasty. 

Dipyridamole is a vasodilator that inhibits platelet function by inhibiting adenosine uptake and cGMP phosphodiesterase activity. Dipyridamole by itself has little or no beneficial effect. Therefore, therapeutic use of this agent is primarily in combination with aspirin to prevent cerebrovascular ischemia. It may also be used in combination with warfarin for primary prophylaxis of thromboemboli in patients with prosthetic heart valves. A combination of dipyridamole complexed with 25 mg of aspirin is now available for secondary prophylaxis of cerebrovascular disease. 

This hemostatic/prothrombotic process is counterbalanced by vascular prostacyclin (PGl2) derived predominantly from COX-2 activity and nitric oxide (NO) released from endothelial cells. In vascular endothelial cells, COX-2 produces primarily PGI2 that inhibits platelet aggregation, induces vasodilation, inhibits the proliferation of vascular smooth-muscle cells, and is less susceptible to inhibition by low doses of aspirin. PGI2 and NO induce an intracellular increase of second messengers. NO inhibits platelet function by stimulation of a soluble guanylyl cyclase to produce cGMR... 

Each eicosanoid is associated with specific types of biological activity (Table 29.4). In some cases, the effects oppose one another. For example, thromboxanes are vasoconstrictors that trigger blood platelet aggregation, whereas prostacyclins are vasodilators that inhibit platelet aggregation. The levels of these two eicosanoids must be in the right balance for cells to function properly. 

NO reacts with PUFAs to yield their respective nitroalkene derivatives that can be detected in plasma. These nitroalkene derivatives of various EFAs induce vascular relaxation, inhibit neutrophil degranulation and superoxide formation, inhibit platelet activation, and have endogenous PPAR-y ligand activity... 

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