Patency of the fetal ductus arteriosus depends on COX-2-derived PGE2 acting on the EP4 receptor. At birth, reduced PGE2 levels, a consequence of increased PGE2 metabolism, allow ductus arteriosus closure. In certain types of congenital heart disease (eg, transposition of the great arteries, pulmonary atresia, pulmonary artery stenosis), it is important to maintain the patency of the neonate’s ductus arteriosus until corrective surgery can be carried out. This can be achieved with alprostadil (PGE1). Like PGE2, PGE1 is a vasodilator and an inhibitor of platelet aggregation, and it contracts uterine and intestinal smooth muscle. Adverse effects include apnea, bradycardia, hypotension, and hyperpyrexia. Because of rapid pulmonary clearance (the half-life is about 5–10 minutes in healthy adults and neonates), the drug must be continuously infused at an initial rate of 0.05–0.1 mcg/kg/min, which may be increased to 0.4 mcg/kg/min. Prolonged treatment has been associated with ductal fragility and rupture.
In delayed closure of the ductus arteriosus, COX inhibitors are often used to inhibit synthesis of PGE2 and so close the ductus. Premature infants in whom respiratory distress develops due to failure of ductus closure can be treated with a high degree of success with indomethacin. This treatment often precludes the need for surgical closure of the ductus.
As noted above, TXA2 promotes platelet aggregation while PGI2, and perhaps also PGE2 and PGD2, inhibit aggregation. Chronic administration of low-dose aspirin (81 mg/d) selectively and irreversibly inhibits platelet COX-1, and its dominant product TXA2, without modifying the activity of nonplatelet COX-1 or COX-2 (see Chapter 34). TXA2, in addition to activating platelets, amplifies the response to other platelet agonists; hence, inhibition of its synthesis inhibits secondary aggregation of platelets induced by adenosine diphosphate, by low concentrations of thrombin and collagen, and by epinephrine. Because their effects are reversible within the typical dosing interval, nonselective NSAIDs (eg, ibuprofen) do not reproduce this effect, although naproxen, because of its variably prolonged half-life, may provide antiplatelet benefit in some individuals. Not surprisingly, given the absence of COX-2 in platelets, selective COX-2 inhibitors do not alter platelet TXA2 biosynthesis and are not platelet inhibitors. However, COX-2-derived PGI2 generation is substantially suppressed during selective COX-2 inhibition, removing a restraint on the cardiovascular action of TXA2, and other platelet agonists. It is highly likely that selective depression of PGI2 generation explains the increase in vascular events, particularly major coronary events, in humans treated with a coxib or nonselective NSAID. High-dose ibuprofen may confer a similar risk, whereas high-dose naproxen appears to be neutral with respect to thrombotic risk. All NSAIDs appear to increase the risk of heart failure.
Large clinical studies have now clearly demonstrated secondary prevention of adverse cardiovascular events (ie, preventing a second event after an initial event) by low-dose aspirin. There is also some evidence that low-dose aspirin can confer primary cardiovascular protection (protection from an initial cardiovascular event), particularly in high cardiovascular risk populations. However, low-dose aspirin also elevates the low risk of serious gastrointestinal bleeding about twofold over placebo. The effects of aspirin on platelet function are discussed in greater detail in Chapter 34.