Overall cardiovascular profile of sildenafil citrate

Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), is th e first in a new class of orally effective treatments for erectile dysfunct ion. During sexual stimulation,; the cavernous nerves release nitric oxide (NO), which induces cyclic guanosine monophosphate (cGMP) formation and smo oth muscle relaxation in the corpus cavernosum. Sildenafil facilitates the erectile process during sexual stimulation by inhibiting PDE5 and thus bloc king the breakdown of cGMP. Sildenafil alone can cause mean peak reductions in systolic/diastolic blood pressure of 10/7 mm Hg that are not dose relat ed, whereas the heart rate is unchanged. Sildenafil and nitrates both incre ase cGMP levels in the systemic circulation but at different points along t he NO-cGMP pathway. The combination is contraindicated because they synergi stically potentiate vasodilation and may cause excessive reductions in bloo d pressure. Erectile dysfunction is a significant medical condition that sh ares numerous risk factors with ischemic heart disease, and hence a substan tial overlap exists between these patient groups. From extensive clinical t rials, the most commonly reported cardiovascular adverse events in patients treated with sildenafil were headache (16%), flushing (10%), and dizziness (2%). The incidences of hypotension, orthostatic hypotension, and syncope and the rate of discontinuation of treatment due to adverse events were < 2 % and were the same in patients taking sildenafil and those taking placebo. Retrospective analysis of the concomitant use of antihypertensive medicati ons (beta blockers, alpha blockers, diuretics, angiotensin-converting enzym e inhibitors, and calcium antagonists) in patients taking sildenafil did no t indicate an increase in the reports of adverse events or significant epis odes of hypotension compared with patients treated with sildenafil alone. I n clinical trials, the incidence of serious cardiovascular adverse events, including stroke and myocardial infarction, was the same for patients treat ed with sildenafil or placebo. Concurrent disease states, such as renal or hepatic impairment, or concomitant use of inhibitors of the cytochrome P450 isozyme CYP3A4 could increase systemic exposure to sildenafil. Since the U S market launch in April 1998, monitoring of spontaneous adverse event repo rts in association with sildenafil has demonstrated a pattern that is gener ally consistent with the experience observed during clinical development, w ith the exception of infrequent reports of priapism. In conclusion, extensi ve clinical testing has shown that overall treatment with sildenafil for up to 1 year is well tolerated and is associated with a low incidence of adve rse events that result in discontinuation of treatment in < 3% of patients. (C) 1999 by Excerpta Medica, Inc.