Cheapest online sildenafil

Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood 5,12,13,16,8 . Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP 5,12,13,16,8 .

Sildenafil has a peripheral site of action on erections 5,12,13,16,8 .

Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue 5,12,13,16,8 .

When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP 5,12,13,16,8 .

Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects 5,12,13,16,8 . Moreover, apart from the presence of PDE5 in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature 4,11,14,15,9 . Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation 4,11,14,15,cheapest online sildenafil 9 . In patients with pulmonary arterial hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation 4,11,14,15,9 .

Sildenafil is known to be quickly absorbed, with maximum plasma concentrations being observed within 30-120 minutes (with a median of 60 minutes) of oral administration in a fasting patient 11,12,13,14,15,16,8,9 .

Moreover, the mean absolute bioavailability observed for sildenafil is about topical sildenafil cream 41% (from a range of 25-63%) 11,12,13,14,15,16,8,9 .

In particular, after oral three times a day dosing of sildenafil, the AUC and Cmax increase in proportion with dose over the recommended dosage range of 25-100 mg 11,12,13,14,15,16,8,9 . When used in pulmonary arterial hypertension patients, however, the oral bioavailability of sildenafil after a dosing regimen of 80 mg three times a day, was on average 43% greater than compared to the lower doses 11,12,13,14,15,16,8,9 . Finally, if sildenafil is administered orally with food, the rate of absorption is observed to be decreased with a mean delay in Tmax of about 60 minutes and a mean decrease in Cmax of approximately 29% 11,12,13,14,15,16,8,9 . Regardless, the extent of absorption is not observed to be significantly affected as the recorded AUC decreased by only about 11 % 11,12,13,14,15,16,8,9 . The mean steady-state volume of distribution documented for sildenafil is approximately 105 L - a value which suggests the medication undergoes distribution into the tissues 11,12,13,14,15,cheapest online sildenafil 16,8,9 . It is generally observed viagra tablets 50 mg online that sildenafil and its main cheapest online sildenafil circulating N-desmethyl metabolite are both estimated to be about 96% bound to plasma proteins 11,12,13,14,15,16,8,9 .

Nevertheless, it has been determined that protein binding for sildenafil is independent of total drug concentrations 11,12,13,14,15,16,8,9 .

The metabolism of sildenafil is facilitated primarily by the CYP3A4 hepatic microsomal isoenzymes and to a minor extent, via the CYP2C9 hepatic isoenzymes 6,11,12,13,14,15,16,8,9 .

The predominant circulating metabolite results from the N-demethylation of sildenafil 6,11,12,13,14,15,16,8,9 . This particular resultant metabolite possesses a phosphodiesterase selectivity that is similar to the parent sildenafil molecule and a corresponding in vitro potency for PDE5 that is approximately 50% that of the parent drug 6,11,12,13,14,15,16,8,9 .

Moreover, plasma concentrations of the metabolite are about 40% of those recorded for sildenafil, a percentage that accounts for about 20% of sildenafil’s pharmacologic effects 6,11,12,13,14,15,16,8,9 . This primary N-desmethyl metabolite of sildenafil also undergoes further metabolism, with a terminal half-life of about 4 hours 6,11,12,13,14,15,16,8,9 . In patients with pulmonary arterial hypertension, plasma concentrations of the primary N-desmethyl metabolite are about 72% those of the original parent sildenafil molecule after a regimen of 20 mg three times a day - which is consequently responsible for about a 36% contribution to sildenafil’s overall pharmacological effects 6,11,12,13,14,15,16,8,9 .

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After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose) 11,12,13,14,15,16,8,9 . The terminal phase half-life observed for sildenafil is approximately 3 to 5 hours 11,12,13,14,15,16,8,9 .

The total body clearance documented for sildenafil is 41 L/h 11,12,13,14,15,16,8,9 . In single-dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased 11,12,13,14,15,16,8,9 .

Doses of 200 mg did not result in increased efficacy but the incidence of adverse reaction (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased 11,12,13,14,15,16,8,9 .

Due to the lack of data on the effect of sildenafil indicated for the treatment of pulmonary arterial hypertension (PAH) in pregnant women, sildenafil is not recommended for women of childbearing potential unless also using appropriate contraceptive measures 11,14,15,9 .

The safety and efficacy of sildenafil indicated for treating PAH in a woman during labor and delivery have not been studied 11,14,15,9 . Caution should ultimately be exercised when sildenafil is administered to nursing women as it is not known if sildenafil or its metabolites are excreted in human breast milk 11,14,15,9 .

The safety and efficacy of sildenafil for the treatment of PAH in children below 1 year of age has not been established as no data is available 15 .

Clinical experience with the elderly population in the use of sildenafil for the treatment of PAH has been varied. Some reports suggest that there are no identified differences in responses between elderly and younger patients 11 while others have documented that clinical efficacy as measured manforce sildenafil tablets online by 6-minute walk distance could be less in elderly patients 9 .

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy 11 . Conversely, when sildenafil was used to treat erectile dysfunction in healthy elderly volunteers (65 years or over), a reduced clearance of sildenafil was observed 12,8 . This reduction resulted in about 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years) 12,8 . Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40% 12,8 .