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In addition, improvement in exercise ability and delay in clinical worsening was demonstrated in adult patients who were already stabilized on background epoprostenol therapy 14 ; and. c) the EMA product information specifically indicates sildenafil for the treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity 15 .

Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease 15 .

The EMA label also indicates sildenafil for the treatment of pediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension 15 .

Efficacy in terms of improvement of exercise capacity or pulmonary hemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease 15 boner pills online .

Erectile Dysfunction NYHA Functional Class II-III Pulmonary arterial hypertension Pulmonary Arterial Hypertension (PAH) Contraindications & Blackbox Warnings. Learn about our commercial Contraindications & Blackbox Warnings data. In vitro studies have shown that sildenafil is selective for phosphodiesterase-5 (PDE5) 11,12,13,14,15,16,8,9 . Its effect is more potent on PDE5 than on other known phosphodiesterases 11,12,13,14,15,16,8,9 . In particular, there is a 10-times selectivity over PDE6 which is involved in the phototransduction pathway in the retina 11,12,13,14,15,16,8,9 . There is an 80-times selectivity over PDE1, and over 700-times over PDE 2, 3, 4, 7, 8, 9, 10 and 11 11,12,13,14,15,16,8,9 .

And finally, sildenafil has greater than 4,000-times selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility 11,12,13,14,15,16,8,9 .

In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (via the use of RigiScan®), after sildenafil administration compared with placebo 11,12,13,14,15,16,8,9 .

Most studies assessed the efficacy of sildenafil approximately 60 minutes post-dose 11,12,13,14,15,16,8,9 . The erectile response, as assessed by RigiScan®, generally increased with increasing sildenafil dose and plasma concentration 11,12,13,14,15,16,8,9 .

The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours 11,12,13,14,15,16,8,9 .

Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects 11,12,13,14,15,16,8,9 .

After chronic dosing of 80 mg, three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mmHg respectively 11,12,13,14,15,16,8,9 .

After chronic dosing of 80 mg, three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg) 11,12,13,14,15,16,8,9 .

At the recommended dose of 20 mg three times a day no reductions in systolic or diastolic pressure were seen 11,12,13,14,15,16,8,9 . Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG 11,12,13,14,15,16,8,9 .

After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported either 11,12,13,14,15,16,8,9 .

In a study of the hemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (> 70 % stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7 % and 6 % respectively compared to baseline 11,12,13,14,15,16,8,9 .

Mean pulmonary systolic blood pressure decreased by 9% 11,12,13,14,15,16,8,9 . Sildenafil showed no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries 11,12,13,14,15,16,8,9 . Mild and transient differences in color discrimination (blue/green)

were

The postulated mechanism for this change in color discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina 11,12,13,14,15,16,8,9 . Sildenafil has no effect on visual acuity or contrast sensitivity. In a small size placebo-controlled study of patients with documented early age-related macular degeneration (n = 9), suhagra 50 mg online sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (which included visual acuity, Amsler grid, color discrimination simulated traffic light, and the Humphrey perimeter and photostress test) 11,12,13,14,15,16,8,9 .

Sildenafil is an oral therapy for erectile dysfunction 5,12,13,16,8 .

with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis 5,12,13,16,8 .

The physiological mechanism responsible for the erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation 5,12,13,16,8 . 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 4,11,14,15,9 .

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 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 11,12,13,14,15,16,8,9 . It is generally observed that sildenafil and its main 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 viagra shop online 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 suhagra 50 mg online 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 suhagra 50 mg online 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,suhagra 50 mg online 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 .