Cheap viagra with prescription

The risk of ED has been shown to markedly increase with age, with a high prevalence of ED found in patients with cardiovascular disease (3).

Greenstein and colleagues (5) have shown that there is a significant correlation between the severity of ED and the number of vessels involved in patients with coronary artery disease (CAD). The age-adjusted prevalence of complete ED has been reported to be 1.5 times higher in men with hypertension than in the entire population studied (3).

Epidemiologic studies have reported that ED is commonly found in smokers, cheap viagra with prescription diabetics and patients with hypercholesterolemia; thus, ED shares important risk factors with CAD (6). A report by Khan and colleagues (7) also found that patients with CAD and peripheral vascular disease have an increased prevalence of ED.

ED is considered to be a significant medical condition because it can lead to a loss of self-esteem, frustration, depression, and difficulty with disruption of sexual relationships (8). Increasing attention has recently been focused on ED due to cheap viagra with prescription the advent of effective oral treatments.

Although ED was once diagnosed and treated primarily by urologists, primary care physicians and other specialists such as cardiologists now write. 80% of the prescriptions for sildenafil citrate, the most popular drug used to treat this condition (9).

Sildenafil citrate is a useful tool for the treatment of ED because it selectively inhibits phosphodiesterase type 5 (PDE-5) (10), which inactivates cyclic guanine monophosphate (cGMP), the mediator of smooth muscle relaxation in the corpus cavernosum. By selectively inhibiting cGMP catabolism in cavernosal smooth-muscle cells (10), sildenafil citrate can restore the natural erectile response to sexual stimulation without causing erections in the absence of such stimulation.

Sildenafil citrate is rapidly absorbed, with maximal plasma concentrations occurring within 1 h after oral administration and a mean terminal half-life of 3 to 5 h (10). Sildenafil citrate has been shown to be an effective treatment for ED.

However, after sildenafil citrate was approved by the US Food and Drug Administration (FDA) in 1998, several deaths were reported in patients taking sildenafil citrate. It was generally assumed that they were related to an underlying disease (e.g., ischemia) and not to a specific drug effect (11).

Nevertheless, these reports raised concerns that sildenafil citrate may increase the risk of cardiovascular events in men with ED and cardiovascular disease (12), which led to many basic and clinical investigations of the adverse cardiovascular effects of this drug (12).

Use of sildenafil citrate in patients with cardiovascular disease.

Sildenafil citrate is a cGMP-specific PDE-5 inhibitor (10). PDE-5, which is located primarily in the cavernous body, thrombocytes and vascular smooth muscle cells, degrades cGMP (13). Thus, by inhibiting PDE-5, sildenafil citrate selectively increases cGMP levels (10). It shows far less affinity for other phosphodiesterase isozymes, including PDE-1, which is abundant in ventricular myocytes (14). However, concern about adverse cardiovascular effects remains (15) since PDE-5 inhibitors promote vasodilation, and thus have the potential to cause hypotension.

This concern has been greatest for elderly patients with pre-existing cardiovascular disease. Mittleman and colleagues (16) reviewed the clinical database for this drug, which supports its cardiovascular safety in a wide range of patients. During placebo-controlled trials, the rate of myocardial infarction (MI) or cardiovascular death was 0.91 (95% CI: 0.52-1.48) per 100 person-years (PY) of follow-up among sildenafil citrate-treated patients compared with 0.84 (95% CI: 0.39-1.60) per 100 PY of follow-up among placebo-treated patients.

The relative risk of MI or cardiovascular death was 1.08 (95% CI: 0.45-2.77) for sildenafil citrate compared with placebo (P = 0.88).

During open-label studies, the rate of MI or cardiovascular death was 0.56 (95% CI: 0.44-0.72) per 100 PY of follow-up.

This analysis

demonstrated

A single oral dose of sildenafil citrate had no significant hemodynamic effects in supine patients with stable angina and, thus, the authors concluded that isolated administration of sildenafil citrate does not appear to be associated with adverse cardiovascular effects (17). The ACC/AHA consensus statement recommended that patients taking sildenafil citrate with combinations of antihypertensive drugs (such as calcium-channel blockers, ?-blockers, diuretics, and angiotensin-converting enzyme inhibitors) be alerted to the possibility of hypotension, particularly patients with congestive heart failure (18). The Princeton Consensus Panel concluded that patients with well-controlled hypertension can be safely managed with approved medical treatments for ED (12).

However, concomitant use of nitrates is considered to be an absolute contraindication for the use of sildenafil citrate (19). Nitrates are prescribed in several different forms, including sublingual nitroglycerin, oral isosorbide mononitrate or dinitrate, cheap viagra with prescription nitropatch, and nitropaste, all of which have been associated with a prolonged decrease in blood pressure when used concomitantly with sildenafil citrate (19). Nitrates are metabolized in vessel walls, where they release nitric oxide. Sildenafil citrate prolongs the vasodilatory effects of nitrates by decreasing the breakdown of nitric oxide's main effector, cGMP. It is not known cheap viagra with prescription how much time must elapse between administration of sildenafil citrate and administration of nitrates to avoid significant hypotensive effects (19), but it has been suggested to assume an interval of at least 24 h (19). Nitroprusside also causes vasodilatation by nonenzymatic release of nitric oxide, and thus is predicted to have a synergistic hypotensive effect

with

Effects of sildenafil citrate on cardiac contractility, blood pressure and heart rate.

Sildenafil citrate belongs to a class of compounds called PDE inhibitors.

PDEs comprise a diverse family of enzymes that hydrolyze cyclic nucleotides (cAMP and cGMP) and therefore play a critical role in the modulation of second messenger signaling pathways (13).

Sildenafil citrate is a highly selective ( 4,000-fold) inhibitor of human PDE-5 over human PDE-3 (19).

This is important because inhibitors of PDE-3 (the isozyme involved in the regulation of cardiac contractility), such as milrinone, vesnarinone and enoximone, which have been used in patients with heart failure, are generally associated with an increased incidence of cardiac arrhythmias and other serious side effects (20).

The cardiotoxic effects of

PDE-3

Corbin and colleagues (23) demonstrated in both dog and human hearts that sildenafil citrate was unlikely to directly produce an inotropic effect on cardiac muscle.

Systemic and pulmonary arterial and venous smooth muscle cells contain PDE-5.

However, sildenafil citrate causes only a mild and transient decrease in blood pressure (8-10 mmHg for systolic blood pressure and 5-6 mmHg for diastolic blood pressure) (19). The peak effects are evident 1 h after the dose is given and last for approximately 4 h (19).

Heart rate and cardiac output are not significantly affected.

Along with a mild decrease in systemic vascular resistance and afterload, there is also a mild decrease in preload and stroke volume due to venous vasodilatation. These effects are not dependent upon age or dose (within the range of 25 to 800 mg) (19). In a study of patients with severe coronary artery disease, Herrmann and colleagues (24) confirmed that the hemodynamic effects of sildenafil citrate (when taken alone) are not associated with clinically significant hypotension.

Effects of sildenafil citrate on central hemodynamics and peripheral vasculature.

In normal volunteers, no significant changes in cardiac index

were

Significant decreases in the systemic vascular resistance index were reported at the end of intravenous sildenafil citrate infusion (20 to 80 mg), when plasma concentrations were highest (19).

Sildenafil citrate has both vasodilator and venodilator effects on the peripheral vasculature (19).

In 8 patients with stable angina, intravenous sildenafil citrate reduced systemic and pulmonary arterial pressures, as well as cardiac output, by 8, 25, and 7%, respectively, consistent with its mixed arterial (systemic and pulmonary hypotension) and venous (drop in stroke volume secondary to decreased preload) vasodilator effects (25). Although the therapeutic efficacy of sildenafil citrate in the treatment of ED has been proven, little is known about the potential beneficial effects of sildenafil citrate in other diseases. Studies in rats demonstrated that PDE-5 inhibition with sildenafil attenuates the rise in pulmonary artery pressure and vascular remodeling when given before chronic exposure to hypoxia-induced pulmonary hypertension (26). Likewise, clinical investigations in patients with pulmonary arterial hypertension have shown that sildenafil citrate therapy may be beneficial to patients receiving long-term infusion of epoprostenol (27,28).

A recent meta-analysis study has buy generic viagra online no prescription suggested that the validity of the observed effect of sildenafil on pulmonary hypertension is not conclusive due to small participant numbers and inadequate investigation of different disease etiologies. In addition, further studies are needed to investigate the long-term outcome (29). Sudden cardiac death is a major cause of death in many industrialized countries including Thailand (27,30). It is most often caused by a lethal cardiac arrhythmia known as ventricular fibrillation (VF) (27,30-35).

VF has been characterized as a rapid, disorganized, and asynchronous contraction of ventricular muscle, which causes the failure of the pumping function of the heart, leading to vital organ failure and causing death within minutes (36-39). According to a report by the World Health Organization, the annual incidence of sudden cardiac death in industrialized countries ranges from 10 to 32% of natural deaths, depending upon the time that elapses from the onset of symptoms to death, making it the most common form of fatal cardiac disease (40).

In the past few years, a growing number of studies have reported that this lethal arrhythmia led to sudden cardiac death in many middle-aged men treated with sildenafil citrate (41). Post-marketing surveillance data after the approval of sildenafil citrate by the US FDA revealed significant cardiovascular problems, including sudden cardiac death, related to the use of sildenafil citrate (4). As of February 1999, the US FDA had received 401 reports of death among men who had received a prescription for sildenafil citrate over the prior 10 to 11 months.

These included 219 cardiovascular events (MI,

arrhythmia

However, it was determined from an analysis of adverse events reported to the FDA between March 1998 and August 1999 that important data were missing from these reports, such as medical histories, cause of death and sildenafil citrate dosing (42).

As of September 30, 2001, Pfizer's clinical safety database contained information on the extent of exposure to sildenafil citrate from 124 completed and ongoing double-blind and open-label clinical trials involving 5054 placebo-treated and 6896 sildenafil citrate-treated patients, representing 2593 PY of observation (43).