Sildenafil (Viagra)
Revatio™, Viagra®
Classification:
Cardiovascular Agents
Genitourinary Agents
- Impotence Agents
- Phosphodiesterase inhibitors
Description: Sildenafil is a phosphodiesterase inhibitor. It is administered orally for the treatment of male erectile dysfunction (ED) and pulmonary arterial hypertension (PAH). Sildenafil was originally developed as an antianginal agent but was found to be more effective in treating ED and subsequently PAH. In regards to ED, sildenafil (Viagra®) was the first drug with this mechanism of action to be marketed; it is not a prostaglandin inhibitor. As opposed to other therapies for impotence which require direct injection into the penis or insertion of a urethral suppository, sildenafil is given orally. The drug was tested in more than 4000 men in 21 clinical trials. The average age of these men was 55 years and they had erectile dysfunction for an average of 5 years before entering the study. Sildenafil was effective in roughly 70% of subjects. Response rates of 90% have been achieved in trials of male patients with psychogenic impotence. Sildenafil may also be effective in male patients with impotence related to diabetes mellitus or due to pelvic fracture urethral disruption. In a study comparing oral sildenafil to sublingual apomorphine, an investigational ED drug, sildenafil was significantly more effective than apomorphine. Sildenafil has been shown to be effective and well tolerated in patients on multidrug antihypertensive regimens and not associated with additional safety risks in these patients. Sildenafil continues to be studied clinically to assess its utility in treating sexual dysfunction in females, but initial studies have found sildenafil to provide results similar to placebo in women. Shortly after approval for ED, studies showed sildenafil was effective in treating patients with PAH. Sildenafil improved exercise capacity as well as mean pulmonary artery pressure and other measures of cardiac function in patients with PAH. Sildenafil is the first oral therapy approved for treating early stages of PAH. Sildenafil has also shown efficacy in treating altitude sickness. Due to a risk of cardiovascular adverse events, this drug should not be used in patients taking nitrate therapy. Final FDA approval for sildenafil (Viagra®) for the treatment of erectile dysfunction (ED) in men was granted on March 27, 1998. Final FDA approval for sildenafil (Revatio™) for treatment of pulmonary arterial hypertension (PAH) was granted June 3, 2005.
Mechanism of Action: Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. In vitro studies show that sildenafil is selective for PDE5 and its effect is more potent on PDE5 than on other known phosphodiesterases (>80-fold for PDE1, >1,000-fold for PDE2, PDE3, and PDE4). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is one-tenth as potent for PDE6, an enzyme found in the retina, as it is for PDE5; this lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of the drug.
As reported by the manufacturer, the pharmacodynamic response to sildenafil was assessed in eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction. In these studies sexual stimulation resulted in improved erections, as assessed by penile plethysmography, after sildenafil administration compared with placebo. Most studies evaluated the efficacy of sildenafil approximately 60 minutes post dose. The erectile response, as determined by penile plethysmography, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study. The effects of sildenafil were evident for up to 4 hours but the response was diminished compared to 2 hours.
Viagra Tablets(Tab 25 mg)
Sildenafil can inhibit PDE5 present in esophageal smooth muscle, lung tissue, and brain tissue. Inhibition of PDE5 in lung tissue results in relaxation of pulmonary vascular smooth muscle and subsequently pulmonary vasodilation, thereby making sildenafil an effective agent in treating pulmonary hypertension. Inhibition of PDE5 present in esophageal smooth muscle can cause a marked inhibition of esophageal motility as well as a reduction in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Sildenafil has been shown to cross the blood-brain barrier and inhibit PDE5 in cerebral blood vessels. The areas of the brain that have the highest activity of PDE5 are the hippocampus, cerebral cortex, and basal ganglia. Although clinical studies have not proven this effect, inhibition of PDE5 by sildenafil in the brain may result in emotional, neurological, and psychological effects (see Adverse Reactions).
Pharmacokinetics: Sildenafil is administered orally. The drug is rapidly absorbed after oral administration, with absolute bioavailability of about 40%. Its pharmacokinetics are dose-proportional over the recommended dose range. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating widespread tissue distribution. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.
Sildenafil is predominantly metabolized by hepatic cytochrome P450 (CYP) enzymes. CYP3A4 is the major metabolizing enzyme and CYP2C9 the minor one. One active metabolite with properties similar to the parent drug has been identified and is formed by N-desmethylation of sildenafil. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil and accounts for about 20% of the pharmacologic effects of sildenafil. The metabolite is further metabolized to inactive compounds.
Sildenafil is excreted as metabolites primarily in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Both sildenafil and its active metabolite have terminal half-lives of about 4 hours. Sildenafil levels at 24 hours post a single 100 mg oral dose average 2 ng/ml (compared to peak plasma levels of approximately 440 ng/ml). Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, with free plasma concentrations approximately 40% greater than those seen in healthy younger volunteers (18 - 45 years). In volunteers with mild (CrCl = 50 - 80 mL/min) and moderate (CrCl = 30 - 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) were not altered. In volunteers with severe (CrCl <= 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment.
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References
. Bortolotti M, Mari C, Giovannini M, et al. Effects of sildenafil on esophageal motility of normal subjects. Dig Dis Sci 2001;46:2301 - 6.
. Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart 2000;84:E4.
. Hossein AG, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136:515 - 22.
. Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension. Circulation 2002;105:2398 - 2403.
. Richalet JP, Gratadour P, Robach P, et al. Sildenafil Inhibits the altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med. Published ahead of print on October 29, 2004 as doi:10.1164/rccm.200406-804OC on the Word Wide Web at http://ajrccm.atsjournals.org.
. Pickering TG, Shepherd AM, Puddey I, et al. Sildenafil citrate for erectile dysfunction in men receiving multiple antihypertensive agents: A randomized controlled trial. Am J Hypertens 2004;17:1135 - 42.
. Basu A, Ryder REJ. New treatment options for erectile dysfunction in patients with diabetes mellitus. Drugs 2004;64:2667 - 88.
. Shenfeld OZ, Gofrit ON, Gdor Y, et al. The role of sildenafil in the treatment of erectile dysfunction in patients with pelvic fracture urethral disruption. J Urol 2004;172:2350 - 2.
. Pavone C, Curto F, Anello G, et al. Prospective, randomized, crossover comparison of sublingual apomorphine (3 mg) with oral sildenafil (50 mg) for male erectile dysfunction. J Urol 2004;172:2347 - 9.
[ Revised 2/28/2006 10:18:00 PM ]
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