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VIAGRA (sildenafil citrate) Action And Clinical Pharmacology

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Action And Clinical Pharmacology

Mechanism of Action

VIAGRA (sildenafil citrate) is a cGMP-specific phosphodiesterase type 5 (PDE5) inhibitor, used for the treatment of male erectile dysfunction.

The physiological mechanism responsible for erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum in response to sexual stimulation. 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.

Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of NO by inhibiting PDE5, which is responsible for the biodegradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil produces increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and increased 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 has between 10 and 10,000-fold greater selectivity for PDE5 than for other phosphodiesterase isoforms namely PDEs 1, 2, 3, 4, and 6 and greater than 700-fold effect on PDE7-PDE11. In particular, sildenafil has greater than 4,000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility. Sildenafil is about 10-fold as potent for PDE5 compared to PDE6, an isoenzyme found in the retina; this lower selectivity is thought to be the basis for colour vision abnormalities observed with higher doses or plasma levels of sildenafil (see WARNINGS AND PRECAUTIONS, DETAILED PHARMACOLOGY).

PDE5 is also found in lower concentrations in platelets, vascular and visceral smooth muscles, and skeletal muscle. The sildenafil-induced inhibition of PDE5 in these tissues appears to be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, and inhibition of platelet thrombus formation in vivo, and peripheral arterial-venous dilation in vivo (see WARNINGS AND PRECAUTIONS).

Pharmacodynamics

Effects of VIAGRA on Blood Pressure (BP):

Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease of 8.3/5.3 mm Hg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing. The effects are not related to dose or plasma levels. Larger effects were recorded among patients receiving concomitant nitrates (see CONTRAINDICATIONS).

Effects of VIAGRA on Cardiac Parameters:

Single oral doses of VIAGRA up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG.

Effects of VIAGRA on Erectile Response:

VIAGRA was studied in clinical trials of various designs. In fixed-dose clinical trials, 62%, 74%, and 82% of patients on 25 mg, 50 mg and 100 mg of VIAGRA, respectively, reported an improvement in their erections, compared to 25% on placebo (p <0.0001, see CLINICAL TRIALS).

In eight double-blind, placebo-controlled, cross-over studies using RigiScan® (a device used to objectively measure penile rigidity and duration of erections), erections during sexual stimulation improved significantly on VIAGRA compared to placebo. These studies included patients with organic etiologies (such as spinal cord injury and diabetes mellitus), and patients without an established organic cause. Most studies assessed the efficacy of VIAGRA approximately 60 minutes post-dose.

All eight studies investigating the effects of sildenafil on penile plethysmography (RigiScan®) after visual sexual stimulation (VSS) under laboratory conditions, consistently showed that doses of up to 100 mg resulted in statistically significant improvements in duration of erections of 60% rigidity (considered hard enough for penetrative sexual intercourse), compared with placebo. In patients who respond, the median time to onset of erections (60% rigidity) in response to VSS, was 25 minutes after an oral dose of 50 mg sildenafil. The mean total duration of erections 60% rigidity at the base of the penis was 3, 24 and 32 minutes for subjects receiving placebo, 25 mg and 50 mg doses, respectively, when exposed to VSS for 2 hours.

VIAGRA increases couples’ ability to have sexual intercourse (see CLINICAL TRIALS).

Pharmacokinetics

Absorption: Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute bioavailability is 41% (range 25%-63%). The oral pharmacokinetics of VIAGRA is proportional over the recommended dose range studied (25 mg to 100 mg).

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.

When VIAGRA was administered with a high-fat meal, the rate of absorption was significantly decreased, with a 29% reduction in Cmax and a 60-minute delay in Tmax. The patient may find that it takes longer to work if taken with a high-fat meal. However, although it was statistically significant (AUC decreased by 11%), the decrease in the extent of absorption was not clinically relevant. The relative bioavailability fed/fasted was 89% (90% CI; 84-94%) (see DRUG INTERACTIONS).

Distribution: The mean steady state volume of distribution (Vss) for sildenafil is 105 litres, 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 the semen of healthy volunteers, less than 0.001% of the ingested dose may appear in the semen of patients 90 minutes after drug intake.

Metabolism: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil at the N-methyl piperazine moiety. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency against PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 hours.

Excretion: 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 dose) and to a lesser extent in the urine (approximately 13% of the administered dose).

Special Populations and Conditions

Geriatrics: Healthy elderly subjects (65 years or older) 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 %.

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. The pharmacokinetics of sildenafil in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Since sildenafil clearance is reduced in geriatric patients (65 years or older), patients with renal impairment or patients with hepatic impairment, a starting dose of 25 mg should be considered. Based on efficacy and toleration, the dose may be increased to 50 mg or 100 mg (see WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION).

Renal Insufficiency: In volunteers with mild (CLcr = 50-80 mL/min) and moderate (CLcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in increases in AUC (100%) and Cmax (88%) compared to age-matched volunteers with no renal impairment.

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.