Pharmacology: Pharmacodynamics: Sildenafil, is a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phosphodiesterase type 5 (PDE5). In vitro studies have shown that Sildenafil is >80-fold selective for PDE1, >700-fold for PDE2, PDE3 (involved in the control of cardiac contractility), PDE4, including PDE7 to PDE11, 4000-fold for PDE5 and 10-fold selective for PDE6 (responsible for blue/green visual discrimination).
The physiologic mechanism of erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum upon sexual stimulation. Nitric oxide (NO) then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP). This cGMP stimulates smooth muscle relaxation in the corpus cavernosum, allowing the inflow of blood and thus leading to an erection. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but inhibits phophodiesterase type 5 (PDE5), which degrades cGMP in the corpus cavernosum. Increased levels of cGMP results in further smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil has no effect whatsoever in the absence of sexual stimulation.
Sildenafil is dose-proportional over the recommended dose range. It is eliminated predominantly by the liver (mainly cytochrome P-450 3A4) and is converted to an active metabolite with properties similar to the parent drug.
Pharmacokinetics: Absorption: Sildenafil is rapidly absorbed after oral administration, with absolute bioavailability of about 40% (range 25-63%). Sildenafil inhibits the PDE5 enzyme in vitro by 50% at a concentration of 3.5 nM. The mean maximum free plasma concentration of Sildenafil following a single oral dose of 100 mg is approximately 18 ng/mL or 38 nM.
Maximum plasma concentrations are reached within 30-120 minutes (median 60 min) after oral administration during fasting. When Sildenafil is taken with high-fat meat, the rate of absorption is reduced, with a mean delay in Tmax of 1 hour and a mean reduction in Cmax of 29-30%.
Distribution: The mean steady-state volume of distribution (Vss) for Sildenafil is 105 L, indicating wide distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein-binding is independent of total drug concentrations. <0.0002% (average of 188 ng) of the administered dose may appear in the semen of healthy patients 90 minutes after oral administration.
Metabolism: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from the N-desmethylation of Sildenafil which in itself is further metabolized. 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. This N-desmethyl metabolite is further metabolized, with a terminal half-life of approximately 4 hours.
Elimination: The total body clearance of Sildenafil is 41L/hr with a terminal phase half-life of 3-5 hours. After an oral administration, Sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to lesser extent in the urine (approximately 13% of administered oral dose).
Renal Insufficiency: In volunteers with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of Sildenafil (50 mg) was not altered. In volunteers with severe (creatinine clearance <30 mL/min) renal impairment, Sildenafil clearance was reduced, resulting in approximately doubling of the AUC (100%) and Cmax (88%) compared to age-matched volunteers with no renal impairment.
Hepatic Insufficiency: 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.
Safety and Efficacy Studies: Safety: (Cardiac) Single oral doses of Sildenafil up to 100 mg produced no clinically significant changes in the ECGs of normal male volunteers. The mean maximum decrease in supine systolic blood pressure following a 100-mg oral dosing was 8.4 mm Hg. The corresponding change in supine diastolic blood pressure was 5.5 mm Hg. In a study of the hemodynamic effects of a single oral 100-mg dose of Sildenafil in 14 patients suffering from severe coronary artery disease (CAD) (>70% stenosis of at least 1 coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7% and 6%, respectively, compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil had no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries resulting in an improvement (approximately 13%) in adenosine-induced coronary flow reserve (in both stenosed and reference arteries).
In a double-blind, placebo-controlled trial, 144 patents with ED and stable angina, who were taking their regular anti-anginal medications (with the exception of nitrates) were subjected to exercise until a limiting angina occurred. The duration of the treadmill exercise was significantly longer (19.9 sec; 95% confidence interval: 0.9-38.9 sec) in the evaluated patients who had taken a single dose of Sildenafil 100 mg compared to patients who had taken a single dose of placebo. The mean exercise times (adjusted for baseline) to the onset of limiting angina were 423.6 and 403.7 sec for Sildenafil and placebo, respectively. A randomized, double-blind, placebo-controlled, flexible-dose study (Sildenafil of up to 100 mg) in males (N=568) with ED and arterial hypertension taking ≥2 antihypertensive agents was conducted.
Sildenafil improved the erections in 71% of men compared to 18% in the placebo group, and 62% of attempts of sexual intercourse were successful with Sildenafil compared to 26% on placebo. The incidence of adverse effects was consistent with observations in other patient populations, as well as in the subjects taking ≥3 antihypertensive agents.
Efficacy: The efficacy and safety of Sildenafil was evaluated in 21 randomized, double-blind, placebo-controlled trials of up to 6 months duration. Sildenafil was administered to >3000 patients aged 19-87 years, with ED of various etiologies. The efficacy was evaluated by global assessment questions, diary of erections, the International Index of Erectile Function (IIEF - a validated sexual function questionnaire) and a partner questionnaire. Sildenafil efficacy was determined as the ability to achieve and maintain an erection sufficient for sexual intercourse. This was demonstrated in all 21 studies and was maintained in long-term extension studies of 1 year. In fixed-dose studies, the proportions of patients reporting that the treatment improved their erections were 62% (25 mg), 74% (50 mg) and 82% (100 mg) compared to 25% on placebo. In addition to improvements in ED, analysis of IIEF showed that Sildenafil treatment also improved domains of orgasm satisfaction with intercourse and overall/general satisfaction.
Across all trials, the proportions of patients reporting improvement on Sildenafil were 59% of diabetic patients, 43% of radical prostatectomy patients and 83% of patients with spinal cord injury versus 16%, 15% and 12% on placebo, respectively.