Effects in the Cardiovascular System

Because smooth muscle cells of both the arterial and venous system contain significant amounts of PDE-5, blood pressure-lowering effects of the three agents are especially important. In a study by Zusman et al. oral administration of sildenafil resulted in a non-dose-dependent reduction of arterial systolic and diastolic blood pressure of 7 to 10 mmHg. These mild blood pressure-lowering effects were similar in patients with hypertension; small reductions in blood pressure were also observed with vardenafil and tadalafil. Most importantly, combination with a broad spectrum of antihypertensive agents was well-tolerated, as investigated in several studies in normotensive and hypertensive patients. However, there are two important exemptions: Nitrates or any drug serving as a nitric oxide donor must not be combined with PDE-5 inhibitors, because this combination can result in life-threatening hypotension.

Looking at the mechanism by which PDE-5 inhibitors enhance smooth muscle relaxa-tion, it is obvious that pre-activation of the NO system followed by increasing concentra-tions of intracellular cGMP can result in uncontrolled accumulation of cyclic guanosine phosphate when its breakdown is inhibited by PDE-5 inhibitors. Therefore, a 24-h time interval is necessary between the use of sildenafil and nitrates and vice versa (37). This safety period is similar for vardenafil, which has a similar half-life (approx 4 h) as sildenafil. However, a much longer interval is necessary for tadalafil. After administering 20 mg of tadalafil, 48 h should elapse before any NO donor is administered.