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Pharmacology: Pharmacodynamics: Sildenafil, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
Mechanism of Action: The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation.
NO 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.
Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting of phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum.
When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum.
Sildenafil at recommended doses has no effect in the absence of sexual stimulation.
Studies in vitro have shown that sildenafil is selective for PDE5.
Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, and PDE4, PDE7 - PDE11).
The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in the control of cardiac contractility.
Clinical studies: Cardiac: Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers.
The mean maximum decreases in supine systolic blood pressure following 100 mg oral dosing was 8.3 mmHg. The corresponding change in supine diastolic blood pressure was 5.3 mmHg.
Larger but similarly transient effects on blood pressure were recorded among patients receiving concomitant nitrates (see Contraindications and Interactions).
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. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed coronary arteries, and resulted in improvement (approximately 13%) in adenosine-induced coronary flow reserve (in both stenosed and reference arteries).
In a double-blind, placebo-controlled trial, 144 patients with erectile dysfunction and stable angina, who were taking their regular antianginal medications (except nitrates) were exercised until limiting angina occurred. The duration of treadmill exercise was statistically significantly longer (19.9 seconds; 95% confidence interval: 0.9-38.9 seconds) in the evaluable 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 seconds for sildenafil and placebo, respectively.
A randomized, double-blind, placebo-controlled, flexible-dose study (sildenafil up to 100 mg) in males (N=568) with erectile dysfunction and arterial hypertension taking two or more antihypertensive agents was conducted. Sildenafil improved the erections in 71% of men compared to 18% in the placebo group, and 62% of attempts at sexual intercourse were successful with sildenafil compared to 26% on placebo. The incidence of adverse events was consistent with observations in other patient populations, as well as in the subjects taking three or more antihypertensive agents.
Visual: Mild and transient differences in colour discrimination (blue/green) were detected in some subjects using the Farnsworth-Munsell 100 hue test at 60 minutes following a 100 mg dose, with no effects evident after 120 minutes post-dose. The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. In vitro studies show that sildenafil is 10-fold less potent against PDE6 than PDE5. Sildenafil has no effect on visual acuity, contrast sensitivity, electroretinograms, intraocular pressure, or pupillometry.
In a placebo-controlled, crossover study of patients with documented early age-related macular degeneration (n=9), sildenafil (single dose, 100 mg) was well-tolerated and demonstrated no clinically significant changes in the visual tests conducted (visual acuity, Amsler grid, color discrimination, simulated traffic light, Humphrey perimeter and photostress).
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 more than 3000 patients aged 19-87, with ED of various etiologies (organic, psychogenic, mixed). The efficacy was evaluated by global assessment question, diary of erections, the International Index of Erectile Function (IIEF, a validated sexual function questionnaire) and a partner questionnaire.
Sildenafil efficacy, determined as the ability to achieve and maintain an erection sufficient for sexual intercourse, was demonstrated in all 21 studies and was maintained in long-term extension studies (one year). In fixed-dose studies, the proportions of patients reporting that 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 erectile dysfunction, analysis of the IIEF showed that sildenafil treatment also improved the domains of orgasm, satisfaction with intercourse and overall 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).
Pharmacokinetics: Sildenafil pharmacokinetics are dose-proportional over the recommended dose range.
It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil.
Absorption: Sildenafil is rapidly absorbed after oral administration, with mean absolute bioavailability of 41% (range 25%-63%).
Sildenafil inhibits the human PDE5 enzyme in vitro by 50% at a concentration of 3.5 nM. In man, 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 observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state.
When sildenafil film-coated tablets are taken with a high fat meal, the rate of absorption of sildenafil is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%, however, the extent of absorption was not significantly affected (AUC decreased by 11%).
Distribution: The mean steady-state volume of distribution (Vss) for sildenafil is 105 L, indicating 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.
Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.0002% (average 188 ng) of the administered dose may appear in the semen of patients.
Metabolism: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes.
The major circulating metabolite results from N-desmethylation of sildenafil, and is itself 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.
In healthy volunteers, plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil.
The N-desmethyl metabolite is further metabolized, with a terminal half-life of approximately 4 hours.
Elimination: The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half-life of 3-5 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
Pharmacokinetics in special patient groups: Elderly: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.
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) were not altered.
In volunteers with severe (creatinine clearance = <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC (100%) and Cmax (88%) compared to age-matched volunteers with no renal impairment (see Dosage & Administration).
In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased by 200% and 79% respectively in subjects with severe renal impairment compared to subjects with normal renal function.
Hepatic Insufficiency: In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment (see Dosage & Administration). The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh class C) have not been studied.
Toxicology: Preclinical safety data: No evidence of drug related carcinogenicity was revealed in a 24-month study in rats at doses up to 42 times the Maximum Recommended Human Dose (MRHD) on a mg/kg basis and approximately five times the MRHD on a mg/m2 bases) and in an 18-21 month study in mice at doses up to 21 times the MRHD on a mg/kg basis (approximately two times the MRHD on a mg/m2 basis).
Bacterial and in vivo mutagenicity tests were negative.
There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers.
