Original ArticlesOverall cardiovascular profile of sildenafil citrate
Section snippets
Physiology of erection
Penile erection involves increased blood flow into and engorgement of cavernous spaces of the corpora cavernosa and relaxation of smooth muscle, expansion of arterial inflow, and reduction of venous outflow.4, 5 Penile erection is controlled by nitric oxide (NO), derived from the endothelium and nitrergic neurons, which activates guanylate cyclase resulting in an increase in cyclic guanosine monophosphate (cGMP) levels.6, 7 Elevated cGMP levels initiate further biochemical pathways involving
Risk factors
The risk factors associated with erectile dysfunction increase with age and overlap extensively with risk factors associated with cardiovascular disease. In addition to age, these risk factors include diabetes, hypertension, smoking, and hypercholesterolemia.2 With the development of new and effective treatments for erectile dysfunction,8 awareness and consideration needs to be given to these overlapping risk factors.
Cardiovascular exertion associated with sexual activity can trigger myocardial
Mechanism of action and profile of sildenafil
Sildenafil, the first of a new class of orally active agents effective for the treatment of erectile dysfunction, is a selective inhibitor of phosphodiesterase type 5 (PDE5) and was originally investigated as an antianginal medication. It became apparent in early studies that although sildenafil had only minor clinical effects on the cardiovascular system, it had considerable effects on the biochemical pathway mediating erection. PDE5, found in high concentrations in the penile corpus
Effects of sildenafil on cardiovascular hemodynamic parameters
An important component in the maintenance of resting arterial blood pressure is the regulation of tonic vasodilation by NO mediated by cGMP.18, 19 Both sildenafil and organic nitrates or NO-donating drugs act to increase cGMP levels and produce smooth muscle relaxation. Therefore, initial studies investigated the ability of sildenafil alone to lower blood pressure. Results from these pilot studies showed that the cardiovascular effects of sildenafil administered alone and at therapeutic dose
Pharmacodynamic interactions–nitrates
NO, generated by NO synthase, can be released by nitrergic neurons or produced in endothelium.23, 24 NO release can be stimulated by pulsatile blood flow and mechanical stress. The formation of NO stimulates guanylate cyclase to produce cGMP, which by a series of further actions results in reduction of intracellular calcium levels and vascular smooth muscle relaxation.18, 19, 25 Since sildenafil and nitrates or NO-donor drugs work at different points along the pathway leading to elevated levels
Pharmacokinetics in special populations
The pharmacokinetic parameters of sildenafil can be modified in certain populations.
Cardiovascular adverse events in phase II/III clinical trials
The incidence of cardiovascular adverse events in extensive Phase II/III clinical trials investigating the efficacy of sildenafil in patients with erectile dysfunction has been assessed.27 The studies included in the sildenafil safety database incorporate 18 Phase II/III, placebo-controlled, double-blind studies (2,722 patients) and 10 Phase II/III, open-label extension studies (2,199 patients). The primary inclusion criteria for these studies were that patients had to be ≥18 years of age and
Epidemiologic data and spontaneous reporting of deaths
Erectile dysfunction and adverse cardiovascular events are more common in older men and are associated with multiple risk factors, such as smoking, hypertension, diabetes, and hyperlipidemia.2 Consequently, strokes, heart attacks, and deaths are more likely to occur among the population of men most at risk for erectile dysfunction. The distribution of these risk factors in the patients taking sildenafil since the drug was launched is broadly consistent with that in the clinical studies.
The most
Conclusions
Erectile dysfunction is a common medical condition that shares a number of risk factors with cardiovascular diseases. Sildenafil is the first of a new class of orally active drugs designed to treat erectile dysfunction.3 Sildenafil is rapidly absorbed, has a short plasma half-life, and is selective at inhibiting PDE5. This inhibition results in increased levels of cGMP, which induces smooth muscle relaxation, vasodilation, and restores effective erectile function in men with erectile
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