Original Articles
Overall cardiovascular profile of sildenafil citrate

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Abstract

Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), is the first in a new class of orally effective treatments for erectile dysfunction. During sexual stimulation, the cavernous nerves release nitric oxide (NO), which induces cyclic guanosine monophosphate (cGMP) formation and smooth muscle relaxation in the corpus cavernosum. Sildenafil facilitates the erectile process during sexual stimulation by inhibiting PDE5 and thus blocking 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 related, whereas the heart rate is unchanged. Sildenafil and nitrates both increase cGMP levels in the systemic circulation but at different points along the NO–cGMP pathway. The combination is contraindicated because they synergistically potentiate vasodilation and may cause excessive reductions in blood pressure. Erectile dysfunction is a significant medical condition that shares numerous risk factors with ischemic heart disease, and hence a substantial overlap exists between these patient groups. From extensive clinical trials, 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 medications (β blockers, α blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists) in patients taking sildenafil did not indicate an increase in the reports of adverse events or significant episodes of hypotension compared with patients treated with sildenafil alone. In clinical trials, the incidence of serious cardiovascular adverse events, including stroke and myocardial infarction, was the same for patients treated 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 US market launch in April 1998, monitoring of spontaneous adverse event reports in association with sildenafil has demonstrated a pattern that is generally consistent with the experience observed during clinical development, with the exception of infrequent reports of priapism. In conclusion, extensive 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 adverse events that result in discontinuation of treatment in <3% of patients.

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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